Herpes Virus Type 6

Etiology

HHV-6A, HHV-6B, and HHV-7 all share some level of homology with human cytomegalovirus (CMV), the only other human beta-herpesvirus.[1] Both HHV-6A and HHV-6B replicate in T-cells. However, they differ in the receptors used for cellular entry.  Contrary to the human cluster differentiation 46 (CD46) used by the HHV-6A virus, studies show cluster differentiation 134 (CD134) is the primary receptor for HHV-6B.[2] CD134 only expresses on activated T cells.[3]  Similar to HHV-8 also known as the Kaposi sarcoma-associated herpesvirus (KSHV) and the Epstein Barr Virus (EBV),  studies of HHV-6 prove the virus to be oncogenic and destructive to autoimmune cells.  Once bound to its respective receptor, HHV-6 establishes latency in lymphocytes and possesses a robust immunomodulatory capacity that can trigger both immunosuppressive and chronic inflammatory pathways.[3]

By adulthood, more than 95% of the population is seropositive for HHV-6A, HHV-6B, or both variants. Present serologic methods are ineffective in isolating one variant from the other.[4] It is now well known that HHV-6 is the primary cause of roseola infantum in childhood. HHV-6B primarily infects infants and is the leading cause of virus reactivation in both, immunocompetent and immunocompromised hosts.[1] In the general population, the vast majority of adults with chronic HHV-6 remain asymptomatic. Research of HHV-6 and its role in the central nervous system is ongoing. In one study, more than 70% of children with primary HHV-6 infection had the virus DNA in their CSF. These children had neurologic sequelae concurrently with primary HHV-6 infection, including frequent febrile seizures.[5] Contrarily, other researchers identified only a 0% to 4% prevalence of HHV-6 DNA in the CSF of children with febrile seizures and AIDS patients with neurological symptoms.[5] These viruses have been linked to illnesses in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies.[4]  Additionally, successful investigations have identified HHV-6A and HHV-6B as the source of opportunistic infections in immunocompromised patients including those with encephalitis, hepatitis, colitis, and pneumonitis.[6]

Epidemiology

Researchers have identified HHV-6B as the etiologic pathogen responsible for most HHV-6 infections presenting with symptoms. While research supports that a majority of people have been infected with HHV-6 at some point in their life, primary infection with HHV-6 occurs within the first 2 years.  In this age group, it is usually associated with an undifferentiated febrile illness, albeit a subset of children will exhibit the classic manifestations of roseola infantum.[1] Several investigative reports have recorded a decline in seropositivity with an increase in age.[4]. Although primary HHV-6 infection is uncommon in adults, reactivation can occur at any age. HHV-6 infection has no sexual proclivity and may occur in people of all races.

HHV-6 is a ubiquitous virus found worldwide. In a large prospective study of North American children, the peak age of HHV-6 acquisition was between 6 and 9 months of age.[1] Similar to the United States, in the UK and Japan, 97 to 100 % of primary infections result from HHV-6B.  While epidemiology reports of HHV-6A are limited, research suggests that HHV-6A infection is acquired later in life and that primary infection with this particular variant often occurs without symptoms.[7]  However, several groups have recorded HHV-6A in symptomatic children from Africa and the USA. Furthermore, HHV-6A was identified as the predominant form of the virus isolated in HIV positive infants in an endemic region of sub-Saharan Africa.[7] Among different populations, seroprevalence varies drastically. There is a documented rate of 20% seroprevalence in pregnant Moroccan women and 100% in asymptomatic Chinese adults. Seroprevalence ranged roughly from 39 to 80% among ethnically diverse adult populations from Tanzania, Malaysia, Thailand, and Brazil.[4]

Pathophysiology

Overall, primary HHV-6 infection is among the most prevalent causes of acute febrile illness in young children. It is also a significant cause of visits to the emergency department, hospitalizations, and febrile seizures.[1]  HHV-6 belongs to the Betaherpesvirinae subfamily and the Roseolovirus genus. The virion particle has the characteristic structure of a herpesvirus, with a central core containing the viral DNA, a capsid, and a protein-rich tegument layer that is surrounded by a membrane.

The principal target cell for HHV-6 is the mature CD4+ T cell.[1] The virus has demonstrated pleiotropic effects on the immune system including modulating natural killer cell function. In vivo, HHV-6 primarily infects and replicates in CD4 lymphocytes after attachment to the CD46 cellular receptor. Via receptor-mediated endocytosis, HHV-6 gains entry into cells with subsequent viral replication (Ablashi). After primary infection, the virus DNA lives in peripheral blood mononuclear cells (PBMC).[1]

While the exact mechanism of HHV-6 transmission is still under investigation, several studies have elucidated the viral transmission via saliva. It appears that transfer via saliva from mother to infant is the most common route. Several early reports described infectious HHV-6 as being present in saliva from nearly every person tested.[4] Additionally, salivary samples from 90% of persons examined contained HHV-6 DNA, while in another PCR-based study only 3% of persons were positive, although 63% of salivary gland biopsy specimens were positive.[4] The HHV-6 genome has also appeared in the CSF of children during primary and latent infections as well as in the brain matter of normal adults on autopsy, suggesting both the CNS and salivary glands as a reservoir for viral latency and persistent infection.[1][4]

History and Physical

Though the various clinical features and diseases associated with HHV-6 are still under investigation, research already well documents that HHV-6 plays an extensive role in central nervous system diseases and immunocompromised individuals including transplant recipients.[8] Infection with HHV-6 is usually benign and self-limiting. Symptomatic individuals are generally infants or those immunocompromised adults who are experiencing reactivation of the disease.

HHV-6B is the causative agent in exanthema subitum (also known as roseola infantum), a childhood disease characterized by high fever and a mild skin rash, and accounts for up to 10 to 17% of acute febrile Emergency department visits in children up to 36 months of age.[9] Primary HHV-6 infection accounts for over 36% of all cases of acute fever in children between 12 and 15 months old and is almost exclusively caused by HHV-6B, not HHV-6A.[9][8][10]

The diagnosis of roseola infantum is clinical. It is often precipitated by abrupt onset of high fever with temperatures reaching 40°C (104 F) for three to five days. During the initial febrile phase, some children will have periorbital edema, conjunctivitis or inflammation of the tympanic membranes while many others will be active and well.[9] Other symptoms in children include lymphadenopathy, gastrointestinal (GI) symptoms, including liver dysfunction and hepatitis, and bulging fontanelles.[11] In adults, hepatitis and symptoms consistent with encephalitis are common.[9] In transplant recipients, symptoms often include fever, graft versus host disease (GVHD), symptoms of graft rejection, interstitial pneumonitis, myelitis, and rash.[12]

Physical examination findings are usually consistent with the symptoms previously described. In children, with defervescence of the fever, there is often an eruption of a blanching maculopapular rash that is rose-pink and approximately 2 to 5mm with a surrounding halo. The rash typically persists for one to two days and often spreads centrifugally. However, there are documented cases of fever without a rash.[13] Inflamed tympanic membranes and signs of upper or lower respiratory tract infections are common in children, while adults may have a fever, hepatosplenomegaly, and lymphadenopathy on physical exams.[12]

Evaluation

Human herpesvirus 6 (HHV-6) can be diagnosed by polymerase chain reaction (PCR), serology or viral cultures, with PCR being the predominant method used.[12] However, laboratory testing is unlikely to be obtained in immunocompetent individuals due to the self-limiting nature of the disease. Saliva is the primary reservoir for virus transmission, as it frequently isolated in salivary glands. While there have been no reports of virus transmission via blood transfusion and breastfeeding there has been documentation of HHV-6 after organ transplantation.[12] Most researchers strongly believe that infection with HHV-6B occurs early in life, while infection with HHV-6A develops later. Both variants of the virus have been simultaneously detected in adults suggesting the viruses chronically infect many people.

Laboratory studies in HHV-6 may show leukocytosis, leukopenia, and anemia.[13] In renal transplant patients and those with liver dysfunction, renal studies, and hepatic studies should be obtained respectively, to rule out electrolyte disturbance and hepatitis.

Indication for radiological imagining is dependent on the clinical presentation, especially in immunocompromised individuals. Chest radiography can be obtained to rule out other etiologies in adults including pneumonia and pneumonitis. The need for imaging is less frequently the case in children. Computed tomography (CT) of the head with and or without contrast can be obtained to search for other treatable diseases. In cases where the central nervous system is afflicted, a lumbar puncture can be performed. HHV-6 infection of the CNS often has a mild pleocytosis with elevated protein. CSF can be sent for HHV-6 PCR studies to confirm the diagnosis.[14]

Treatment / Management

Currently, there is no approved compound exclusively for the treatment of HHV-6, and there is no vaccine available.[8] It is generally not recommended to provide antiviral prophylaxis for HHV-6 infection. Instead, it is advised to implement early antiviral treatment, especially in cases of HHV-6 encephalitis. First-line therapy with intravenous ganciclovir and foscarnet are recommended, with treatment for 3 to 4 weeks.[15] In patients undergoing stem-cell transplantation, treatment with ganciclovir has documented benefits and is the suggested antiviral of choice.[15](B3)

HHV-6 infections in immunocompetent children are self-limiting and do not require treatment. Treatment of infants with roseola infantum is usually supportive.[12] Antipyretics like acetaminophen or ibuprofen are recommended therapy for high-grade fever and those at risk for febrile seizures. If a febrile seizure occurs, anti-epileptics are unnecessary. Individuals who present HHV-6 infection manifested by CNS involvement, including febrile seizures, should be admitted to the hospital.

Differential Diagnosis

The differential diagnosis includes:

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

In children with classic roseola infantum, HHV-6 is the etiologic pathogen. However, several other diseases can cause fever and rash. More severe, less benign, causes of such symptoms requires exclusion. In immunocompetent adults, infection with HHV-6 manifests similarly to mononucleosis. Thus EBV and CMV should be excluded. Immunocompromised patients, especially those receiving organ transplants and those with AIDS are generally symptomatic. This cohort of individuals with HHV-6 disease are often concomitantly infected with CMV, and antiviral treatment should commence promptly. HHV-6 correlates with several other diseases including hepatitis, herpes simplex, meningitis, rubella, viral pneumonia, and DRESS syndrome.[16] Additionally, documentation exists of HHV-6 in cases of multiple sclerosis encephalitis and interstitial pneumonitis.[17] It is worth noting that only HHV-6A has associations with Hashimoto thyroiditis.[12]

Prognosis

Generally, primary infection with HHV-6 is self-limiting, and those who are immunocompetent survive without sequelae. In immunosuppressed individuals, reports have described more severe illness. Documentation exists of pneumonitis, hepatitis, and organ rejection in transplant patients, with death reported in patients with encephalitis and meningoencephalitis.[18] Similarly, in Japan a 2003 to 2004 survey of patients with exanthema subitum-associated encephalitis had an unusually poor prognosis,[19] with reported fatalities in two children with encephalopathy secondary to HHV-6 infection. The children were discovered to have a genetic mitochondrial disorder.[20]

Complications

Universally, HHV-6 primary infection is benign with spontaneous resolution in 5 to 7 days. The most common complication of roseola infantum is febrile seizures. Additional complications are often due to HHV-6 neurotrophic effects, as highlighted in cases where the central nervous system becomes compromised, for example, in cases of meningoencephalitis and encephalopathy. In these cases, the virus occupies the brain during primary infection and can remain dormant in brain tissue.[21] Subsequently, there are records of cases of acute or subacute encephalitis sometimes associated with diffuse or multifocal demyelination.[4] HHV-6 infrequently causes opportunistic infection in immunocompromised individuals. HHV-6A and HHV-6B activity have been detected following renal, liver transplants and bone marrow transplants (BMT).[4]