eMedicine Specialties > Infectious Diseases > Viral Infections

Human Herpesvirus Type 6

Author: Michelle R Salvaggio, MD, Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, University of Oklahoma College of Medicine; Medical Director of Infectious Diseases Institute, University of Oklahoma Health Sciences Center
Coauthor(s): Peter S Miele, MD, Fellow, Department of Internal Medicine, Section of Infectious Diseases, Washington Hospital Center; Margo A Smith, MD, Associate Program Director, Department of Medicine, Washington Hospital Center; Assistant Professor, Department of Internal Medicine, Section of Infectious Diseases, George Washington University
Contributor Information and Disclosures

Updated: Oct 8, 2008

Introduction

Background

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 lymphotrophic virus with high affinity for CD4 lymphocytes.

A beta herpesvirus (like cytomegalovirus [CMV] and human herpesvirus type 7), HHV-6 has two variants, A and B. HHV-6B causes the childhood illness roseola infantum, while HHV-6A has been isolated mainly in immunocompromised hosts. Specific disease 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.

• Primary HHV-6 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 with 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. The virus remains latent in lymphocytes and monocytes and persists at low levels in cells and tissues. In the immunocompetent host, 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, these cases are not common and a causal relationship has not been established.¹
• In the immunosuppressed host, HHV-6 reactivation is associated with a worse outcome. HHV-6 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, and delayed engraftment. While reactivation of HHV-6 accounts for most infections, transmissions of HHV-6 with the donor allograft, solid organ, or hematopoietic stem cell have been reported.²
• 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:
  • Kikuchi lymphadenitis
  • Lymphoma
  • Lymphadenopathy
  • Drug-induced hypersensitivity syndrome³
  • Sjögren syndrome
  • Sarcoidosis
  • Systemic lupus erythematosus
  • Chronic fatigue syndrome
  • Guillain-Barré syndrome
  • Multiple sclerosis (MS)
• A causal relationship has not been yet been established between HHV-6 and these conditions.

Pathophysiology

• The exact mode of transmission of HHV-6 has yet to be proven. Studies indicate that primary HHV-6 infection is acquired during the first 6 months of life.
• Infants likely acquire infection through contact with adult caretaker saliva. DNA restriction enzyme profile studies have shown mothers' isolates were genetically similar to their infants'.
• In vivo, HHV-6 primarily infects and replicates in CD4 lymphocytes. The cellular receptor is CD46, a 52- to 57-kDa 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.
• 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 up-regulate CD4 lymphocytes and natural killer cells and down-regulate CD3 T cells. HHV-6 infection has been reported to induce down-regulation of CXC chemokine receptor 4 in CD4+ T lymphocytes.⁴
• HHV-6 is also a powerful inducer of cytokines and triggers the release of interferon-alpha, 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.
• HHV-6 antigen has been found in the nuclei of oligodendrocytes in the plaques of patients with MS.⁵ Researchers have also found a strong association between anti–HHV-6 immunoglobulin M (IgM) antibodies and early MS compared with healthy controls 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.⁶ Thus, the host response may be responsible rather than the viral infection. However, further investigation is needed to fully define the role of HHV-6 in MS.

Frequency

United States

HHV-6 infection is ubiquitous worldwide, with greater than 90% seropositivity reported in children older than 2 years.

Mortality/Morbidity

• HHV-6 infection is the most common cause of febrile seizures in childhood (age 6-24 mo).
• 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.
• HHV-6 infection induces bone marrow suppression, respiratory failure, graft versus host disease, and encephalitis in patients undergoing hematopoietic stem cell or solid-organ transplantation.

Race

HHV-6 infection is found in people of all races.

Sex

HHV-6 infection has no sexual predilection.

Age

• HHV-6 Infection most commonly occurs after maternal antibodies have waned, usually at age 6-24 months.
• Primary HHV-6 infection is rare in adults.
• Reactivation can occur at any age.

Clinical

History

Human herpesvirus 6 (HHV-6) infection is often asymptomatic. Symptomatic manifestations occur predominately after primary infection in infants and after either primary or reactivation disease in immunocompromised adults.

• Children: Approximately 20% of HHV-6 infections manifest as roseola, with an abrupt onset of high fever that lasts 3-5 days. This is followed by an erythematous maculopapular rash that appears when the temperature normalizes. The rash starts at the trunk and spreads centrifugally to the face and limbs. More commonly, the infection presents as an acute nonspecific febrile illness in a child younger than 2 years. HHV-6 infection may also manifest as a rash and no fever.
  • Irritability
  • Ear symptoms, otitis
  • Upper respiratory tract symptoms
  • Gastrointestinal symptoms, including liver dysfunction and hepatitis
  • Fever-induced seizures
  • Bulging fontanelles
  • Symptoms of meningoencephalitis
• Adults
  • Fever with lymphadenopathy, a mononucleosislike disease with negative test results for acute CMV and EBV infection
  • Symptoms consistent with hepatitis
  • Symptoms consistent with encephalitis
  • Possible role for HHV-6 in MS (HHV-6 antigen has been demonstrated in the oligodendrocytes of patients with MS. In addition, HHV-6 DNA and high rates of IgM antibody to HHV-6 have been detected in patients with relapsing-remitting type MS, but not chronic progressive MS disease or controls.)
• Immunocompromised hosts and transplant recipients (bone marrow and solid organ)
  • Fever, usually very high
  • Cytopenia, in particular leukopenia
  • Symptoms of graft versus host disease
  • Symptoms of graft rejection
  • Symptoms of interstitial pneumonitis
  • Symptoms of meningoencephalitis or myelitis⁷
  • Rash
• HIV infection
  • Fever
  • Rash
  • Symptoms of interstitial pneumonitis
  • Symptoms of meningoencephalitis
  • Rising HIV viral load
  • Falling CD4 count

Physical

Physical findings of HHV-6 infection are those expected with the symptoms listed above. Most cases of HHV-6 infection are asymptomatic. The following findings may suggest HHV-6 infection.

• Infants
  • High fever
  • Erythematous macular or maculopapular rash on trunk and face and, later, lower extremities
  • Inflamed tympanic membranes
  • Signs of upper and, occasionally, lower respiratory tract involvement
  • Hepatomegaly (common GI sign)
  • CNS symptoms - May include bulging fontanelles, irritability, stupor, meningismus, and/or seizures
• Adults
  • Fever
  • Lymphadenopathy
  • Hepatosplenomegaly
  • CNS symptoms - Meningismus and mental status changes
• Immunocompromised individuals
  • Fever
  • Rash
  • Signs of pneumonitis
  • Hepatosplenomegaly
  • Mental status changes or meningismus

• Search for CME/CE on This Topic »

• Pediatrics, Roseola Infantum (Emergency Medicine)
• Meningitis, Aseptic (Pediatrics: General Medicine)