Human herpesvirus 6 (HHV-6) was the sixth herpesvirus discovered. Isolated in 1986 during attempts to find novel viruses in patients with lymphoproliferative diseases, HHV-6 is now recognized as a T-cell lymphotropic virus with high affinity for CD4 lymphocytes. [1, 2]
A beta herpesvirus (like cytomegalovirus [CMV] and human herpesvirus 7 [HHV-7]), HHV-6 comprises 2 forms, A and B; as of 2012, HHV-6A and HHV-6B are officially considered distinct species rather than variants of 1 species. HHV-6B causes the childhood illness roseola infantum, whereas HHV-6A has been isolated mainly in immunocompromised hosts. Specific manifestations of HHV-6A infection are still undefined. However, both HHV-6A and HHV-6B may be pathogenic in the settings of transplantation and AIDS. (See Pathophysiology and Etiology.)
Primary HHV-6B infection usually occurs in infants and is the most common cause of fever-induced seizures in children aged 6-24 months. Acute HHV-6 infection is rare in immunocompetent adults but may manifest as a mononucleosislike illness characterized by fever, lymphadenopathy, and hepatitis or encephalitis, with negative test results for CMV or Epstein-Barr virus (EBV). 
After primary infection, HHV-6 remains latent unless the immune system is compromised, at which time the virus may reactivate. HHV-6 remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. In immunocompetent hosts, this persistent infection is generally of no consequence. Isolated cases of pulmonary failure in immunocompetent patients have been attributed to HHV-6 when no other pathogens have been isolated; however, such cases are not common, and no causal relation has been established. 
In immunosuppressed hosts, HHV-6A reactivation is associated with a worse outcome. [5, 6] Such reactivation occurs in 33-48% of patients undergoing hematopoietic stem-cell transplantation. For example, in these patients, reactivation of HHV-6 has been associated with CMV reactivation and increased severity of CMV disease.
Other clinical conditions associated with HHV-6 reactivation in this population include hepatitis, idiopathic pneumonitis, bone-marrow suppression, encephalitis, fever and rash, graft versus host disease (GVHD), and delayed engraftment. Although reactivation of HHV-6 accounts for most infections, transmissions of HHV-6 with the donor allograft, solid organ, or hematopoietic stem cell have also been reported. [7, 8, 9]
In patients infected with HIV, HHV-6 infection may up-regulate HIV replication and hasten the progression toward AIDS. HHV-6 also has been implicated in the pathogenesis of white-matter demyelination in persons with AIDS dementia complex; however, causality has not been proven.
HHV-6 has been isolated from various tissues, cells, and fluid in association with the following conditions:
Drug-induced hypersensitivity syndrome (DIHS),  or drug reaction with eosinophilia and systemic symptoms (DRESS)
Chronic fatigue syndrome (CFS)
Multiple sclerosis (MS)
A causal relation has not been yet been established between HHV-6 and these conditions.
The great majority of HHV-6 infections are silent or appear as a general mild febrile illness (see Presentation). Laboratory diagnosis is rarely required in patients who are immunocompetent; most often, HHV-6 infection is diagnosed on the basis of its clinical features (see DDx and Workup).
No specific treatment for HHV-6 infection has been established. Treatment varies according to the presenting clinical situation and is usually unnecessary with primary infection in immunocompetent hosts. Supportive measures are the basis of care. Some infants may require hospitalization for atypical presentations. Antivirals such as ganciclovir and foscarnet have been suggested as possible therapies for acute disease, but they remain unproven. No vaccine exists. (See Treatment.)
HHV-6 belongs to the Betaherpesvirinae subfamily and to the Roseolovirus genus. The virion particle has the typical structure of a herpesvirus, with a central core containing the viral DNA, a capsid, and a tegument layer that, in turn, is surrounded by a membrane.
At the molecular level, HHV-6 encodes proteins similar to immune mediators in the chemokine family. The functional chemokine is encoded by an open reading frame U83; U12 and U51 encode the 7 transmembrane proteins analogous to the chemokine receptors. This molecular mimicry seems to help HHV-6 in immune invasion and to contribute to long latency in the host cells. 
The exact mode by which HHV-6 is transmitted has yet to be elucidated fully. Studies indicate that primary HHV-6B infection is acquired during the first 24months of life. Children likely acquire infection through contact with adult caretaker saliva or from older siblings. DNA restriction enzyme profile studies have shown mothers’ isolates to be genetically similar to their infants’. Vertical transmission of HHV 6 has been documented; however, this mode of transmission represents only 1-2% of all births. 
HHV-6 chromosomal integration in immunocompetent patients has been found to result in high levels of viral DNA in blood, sera, and hair follicles.  These characteristically high HHV-6 DNA levels in chromosomal integration should be considered in the effort to establish accurate laboratory diagnosis methods.
In vivo, HHV-6 primarily infects and replicates in CD4 lymphocytes. The cellular receptor is CD46, a 52- to 57-kd type 1 transmembrane glycoprotein expressed on the surface of all cells. The cell attachment protein of HHV-6 has not been identified. Entry occurs through receptor-mediated endocytosis. Subsequent stages of viral replication are similar to those of CMV.
During acute infection, replication occurs in lymphocytes, macrophages, histiocytes, endothelial cells, and epithelial cells. In vitro studies have demonstrated that HHV-6 also can replicate in glial cells. The virus is believed to invade the central nervous system (CNS), which may lead to such CNS complications as seizures and encephalitis.
HHV-6 causes direct cytolysis; this effect may be responsible for roseola, as well as the heterophile-negative mononucleosislike picture of acute infection.
HHV-6 has been shown to upregulate CD4 lymphocytes and natural killer (NK) cells and to downregulate CD3 T cells. HHV-6 infection has been reported to induce down-regulation of CXC chemokine receptor 4 in CD4+ T lymphocytes.  NK cells seem to play a major role in resolving acute-phase HHV-6 infection  ; specific lymphocyte activity develops later. The lymphoproliferative response to phytohemagglutinin ratios suggests that HHV-6 infection has some impact on host T-cell immunity during the course of exanthema subitum.
HHV-6 is also a powerful inducer of cytokines and triggers the release of interferon alfa, tumor necrosis factor, and interleukin-1b, thus potentially playing a role in the pathogenesis of HIV disease and other immunocompromised states. HHV-6 may also alter the natural history of other viral infections, such as those with CMV, EBV, and human papillomavirus (HPV).
HHV-6 antigen has been found in the nuclei of oligodendrocytes in the plaques of patients with MS.  Researchers have also found a strong association between anti–HHV-6 immunoglobulin M (IgM) antibodies and early MS in comparison with healthy control subjects and progressive MS.
Some theorize that viral infection plays a role in the pathogenesis of MS through potential molecular mimicry. Cross-reactivity between myelin basic protein and HHV-6 has been suggested.  Thus, the host response may be responsible, rather than the viral infection itself. However, further investigation is needed before the role of HHV-6 in MS can be fully defined. 
HHV-6 is the virus that most commonly causes the childhood disease roseola.  It includes 2 genetically distinct forms: HHV-6A and HHV-6B. These 2 forms were originally considered variants of a single species but are now considered separate species.  HHV-6B has been associated with a variety of viral illnesses, including exanthema subitum (roseola infantum), mononucleosis syndromes, focal encephalitis, and pneumonitis.  This virus shows the closest homology with CMV and HHV-7.
HHV-6B infection in infants is the most common cause of fever-induced seizures. In a prospective study involving children aged 1 month to 5 years, HHV-6B was found to be commonly associated with febrile status epilepticus (as was HHV-7, albeit to a lesser degree). 
To elucidate the roles of HHV-6 and HHV-7 in pityriasis rosea (PR), their DNA load in plasma, peripheral blood mononuclear cells (PBMCs), and tissues was evaluated by using a calibrated quantitative real-time polymerase chain reaction (PCR) assay.  In addition, HHV-6– and HHV-7–specific antigens in skin were evaluated by means of immunohistochemistry (IHC), and anti–HHV-7 neutralizing activity was assessed with a syncytia-inhibition test.
HHV-6 and HHV-7 DNA were found in 17% and 39% of PR plasmas, respectively, but in no controls.  HHV-6 levels in PBMCs were not higher in PR patients than in controls. HHV-6 and HHV-7 antigens were detected only in PR skin (17% and 67% of instances, respectively), presumably indicating a productive infection. These and other data strongly suggest a causal association between PR and active HHV-7 or, to a lesser extent, HHV-6 infection.
The reactivation of herpesviruses, including HHV-6 and EBV, is linked with a potentially serious drug eruption known as DRESS (drug reaction with eosinophilia and systemic symptoms; also referred to as DIHS).  A report of high-level HHV-6 viremia associated with the onset of Stevens-Johnson syndrome suggests an association. 
As noted (see Pathophysiology), the role of HHV-6 in MS remains controversial. 
An association between HHV-6 reactivation and CFS has been proposed. A high proportion of patients with CFS are infected with HHV-6 but have a low viral load. Study results to date have not supported HHV-6 reactivation in patients with CFS, though further investigation is required. 
Good prospective studies in patients with encephalitis, posttransplant pneumonia, and MS are needed.
It has been speculated that HHV-6 infection may act as an inducer of sporadic porphyria cutanea tarda, triggering it to become apparent clinically. 
United States statistics
HHV-6 infection is ubiquitous. HHV-6B is the cause of most symptomatic HHV-6 infections. Although evidence of past HHV-6 infection is found in most people, initial infection usually occurs within the first 2 years of life; greater than 90% seropositivity reported in children older than 2 years. Roseola is estimated to affect as many as 30% of all children and is most common in spring and fall.
HHV-6 has a worldwide distribution. In an HIV-1 endemic region of sub-Saharan Africa, the predominant form in infant infections was found to be HHV-6A.  In Europe and Japan, as in the United States, HHV-6B is the agent mainly responsible for infant infection; HHV-6A appears to be rare.
Seroprevalence is almost 100% in Europe and is close to 100% in the rest of the world—with certain exceptions, such as Morocco, which has 20% seroprevalence. Virus shedding evaluated by PCR in the saliva of healthy adults in Rio de Janeiro, Brazil, detected an HHV-6 prevalence of 9.8%, with HHV-6A detected in 7.1% of the samples and HHV-6B in 2.7%. 
Age-, sex, and race-related demographics
HHV-6 infection most commonly occurs after maternal antibodies have waned, usually between the ages of 6 months and 3 years (average, 9 months). The virus is shed in and probably spread through saliva of asymptomatic seropositive children.
Serologic studies demonstrate that HHV-6 infects approximately 90% of children by the age of 2 years.  A prospective study found that HHV-6 was acquired in infancy, was usually symptomatic, and often resulted in a medical evaluation. However, only a minority of these patients developed roseola or febrile seizures with primary HHV-6 infection. Older siblings and other care takers appeared to be a source of HHV-6 transmission. [12, 32]
Primary HHV-6 infection is rare in adults. However, reactivation can occur at any age.
HHV-6 infection has no sexual predilection and may occur in people of all races.
HHV-6 infections are mainly uncomplicated and have a self-limited course. They are usually asymptomatic. Even when HHV-6 leads to roseola, it is a mild illness in children who are immunocompetent. It usually resolves without any treatment; however, in some rare cases, patients who are immunocompetent may develop additional symptoms, including respiratory distress, seizures, and multiorgan involvement. One infection usually provides lifetime immunity, though HHV-6 may reactivate in patients who are immunocompromised.
Rarely, HHV-6 can be associated with fatal dissemination and death; 8 fatal cases have been reported. The causes of death were encephalitis, hepatitis,  sudden death in infancy, hemophagocytic lymphocytosis, and disseminated infections. In studies by Prezioso et al and Hoang et al, atypical monocyte infiltrate was found in multiple organs, including the brain, spleen, lungs, liver, heart, renal cortex, lymph nodes, and intestine. [34, 35]
In adults who are immunosuppressed (eg, those with AIDS), HHV-6A is a major source of morbidity and mortality, especially in those who do not take antiretroviral therapy; disseminated organ involvement and death can occur. In adults who are immunosuppressed because of undergoing a transplant, HHV-6 infection may cause multiorgan system involvement, accelerate organ rejection, and lead to death.
In adults who are immunocompetent, primary infection or reactivation with HHV-6 can produce a mononucleosislike illness and, more rarely, severe disease, including encephalitis.
HHV-6 may be associated with various complications, as follows:
HHV-6B infection is the most common cause of febrile seizures in childhood (age 6-24 months)
Encephalitis may develop in children with HHV-6 infection
HHV-6 has a possible role in CNS infections and demyelinating conditions
HHV-6 infection may increase the severity of CMV infection in immunocompromised and transplant populations
HHV-6 has a possible role in lymphoproliferative syndromes
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