eMedicine Specialties > Dermatology > Viral Infections

Human Herpesvirus 6

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Cris Jagar, MD, Staff Physician, Department of Psychiatry, Saint Vincent Catholic Medical Centers; Ewa Koziorynska, MD, Staff Physician, Department of Neurosciences, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Jun 18, 2009

Introduction

Background

Human herpesvirus 6 (HHV-6) is the virus that most commonly causes the childhood disease roseola. It was first isolated in 1986. Two genetically distinct variants have been discovered: human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B). HHV-6B has been associated with a variety of viral illnesses, including exanthem subitum (roseola infantum), mononucleosis syndromes, focal encephalitis, and pneumonitis.1 The virus is spread through saliva and possibly by genital secretions. This virus shows the closest homology with cytomegalovirus and human herpesvirus 7 (HHV-7).

HHV-6 infection in infants is the most common cause of fever-induced seizures. Infection in adults is seen primarily in immunocompromised hosts who have undergone solid organ transplants or in those with HIV infection.2,3 Reactivation of latent HIV infection attributable to HHV-6 infection has been reported.4 No prophylaxis or treatment for infection with HHV-6 presently exists. The great majority of HHV-6 infections are silent or appear as a general mild febrile illness.

The child with HHV-6 usually does not appear seriously ill during this disease. HHV-6 infection is much more serious in adults and can lead to organ involvement (usually presenting as gastrointestinal symptoms or hepatitis), encephalitis, or death.

To elucidate the role of HHV-6 and HHV-7 in pityriasis rosea (PR), their DNA load in plasma, peripheral blood mononuclear cells (PBMCs), and tissues was evaluated using a calibrated quantitative real-time polymerase chain reaction assay.5 In addition, HHV-6– and HHV-7–specific antigens in skin were evaluated by immunohistochemistry and anti–HHV-7 neutralizing activity using a syncytia-inhibition test. HHV-6 and HHV-7 DNA were found in 17% and in 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 patients analyzed, 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.

Related eMedicine articles include Human Herpesvirus Type 6 (from Infectious Diseases section), Roseola Infantum, Encephalitis, and Pityriasis Rosea.

Pathophysiology

Human herpesvirus 6 (HHV-6) infection in children most commonly leads to roseola infantum, also known as exanthem subitum. Children aged 6 months to 3 years are most at risk and contract the virus from saliva. It replicates in leukocytes and in salivary glands and then spreads throughout the body. The virus is predominantly T lymphotropic and is believed to invade the CNS, which may lead to such CNS complications as seizures and encephalitis. The incubation period is thought to be between 5-15 days.

Serologic studies demonstrate that HHV-6 infects approximately 90% of children by age 2 years.6 A cohort was prospectively studied. HHV-6 was found to be acquired in infancy, to usually be symptomatic, and to often result in a medical evaluation. However, only a minority of these patients developed roseola or febrile seizures with primary HHV-6 infection. Older siblings appeared to be a source of HHV-6 transmission.

Time course characteristics of HHV-6–specific cellular immune response and natural killer cell activity in patients with exanthema subitum were studied.7 Natural killer cells seem to play a major role in resolving acute-phase HHV-6 infection, while specific lymphocyte activity develops later. The lymphoproliferative response to phytohemagglutinin ratios was interpreted as implying that HHV-6 infection has some impact on host T-cell immunity during the course of exanthema subitum.

HHV-6 chromosomal integration in immunocompetent patients was found to result in high levels of viral DNA in blood, sera, and hair follicles.8 These characteristically high HHV-6 DNA levels in chromosomal integration should be considered in establishing laboratory diagnosis methods.

Frequency

United States

Evidence of past human herpesvirus 6 (HHV-6) infection is found in most people, but initial infection usually occurs within the first 2 years of life. Roseola is estimated to affect as many as 30% of all children and is most common in spring and fall.

International

Human herpesvirus 6 (HHV-6) has a worldwide distribution. The predominant form of HHV-6 was found to be variant A in infant infections in an HIV-1 endemic region of sub-Saharan Africa.9 HHV-6B is the predominant infant infection in the United States, Europe, and Japan, where HHV-6A appears to be rare.

Mortality/Morbidity

Human herpesvirus 6 (HHV-6) infection is 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. It is very rarely fatal.

  • In adults who are immunosuppressed (eg, those with AIDS), HHV-6 is a major source of morbidity and mortality, especially in those who do not take antiretroviral therapy. In these patients, 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.

Race

No increased incidence exists in any particular race. HHV-6 infection is nearly universal.

Sex

Both males and females are affected equally.

Age

The most common age group affected by roseola is children aged 6 months to 3 years. The average age is 9 months. This occurrence is thought to coincide with decreasing maternal antibodies, which leave the child more susceptible to infection. Most people are infected with HHV-6 by age 2 years.

Clinical

History

  • Classic history in healthy children developing roseola
    • A child aged 6 months to 3 years (9 mo is the most common) acquires a high fever, often as high as 103-106°F.
    • The fever lasts 3-5 days.
    • The fever then resolves but is followed by a maculopapular eruption. It begins on the trunk and spreads over the next few hours or days to the extremities before resolution.
    • The child may have febrile seizures.
    • The child may also exhibit irritability and anorexia but does not appear seriously ill.
  • Adults who are immunocompromised and become infected with human herpesvirus 6 (HHV-6) develop a high fever and may have a variety of organs affected.
  • Healthy adults can get a mononucleosislike illness and, more rarely, severe disease, including encephalitis.
  • A relationship between HHV-6 reactivation and graft versus host disease after allogeneic stem cell transplantation has been suggested.10 HHV-6 reactivation may be involved in the pathogenesis of the cutaneous and visceral manifestations of graft versus host disease after allogeneic stem cell transplantation.11
  • HHV-6 reactivation may also occur with drug-induced hypersensitivity syndromes, including toxic epidermal necrolysis,12 among others.13

Physical

  • Very few physical examination findings exist in children who are infected with human herpesvirus 6 (HHV-6) until skin findings become apparent.
    • The eruption begins on the trunk and is composed of blanchable, erythematous papules.
    • Children may also have febrile seizures and encephalitis.
  • Adults can have a wide variety of symptoms, which can be mild or severe.
    • Healthy adults can have fever and CNS problems, such as encephalitis, but patients who are immunocompromised can have organ failure and death.
    • Patients who have undergone transplantation can have accelerated rejection of the transplant.
  • Neurologic manifestations
    • Febrile seizures: HHV-6 is a major precipitant of seizures in infants, not merely because of the high fever that the infection provokes but also because HHV-6 replicates in the CNS.
    • Encephalitis
      • Reports of encephalitis as a complication of exanthem subitum and the appreciation that HHV-6 is highly neurotropic predicted that the virus might be associated with encephalitis in other settings as well.
      • Current controversy exists regarding reports of HHV-6 in the brain of patients with multiple sclerosis. Active HHV-6 infection in the CNS has been postulated to promote inflammatory injury and demyelination, but this is far from proven.

Causes

Human herpesvirus 6 (HHV-6) infection is responsible for roseola and is transmitted by saliva. Though rare, patients who are immunocompetent can have reactivation of HHV-6 and a recurrence of roseola.

More on Human Herpesvirus 6

Overview: Human Herpesvirus 6
Differential Diagnoses & Workup: Human Herpesvirus 6
Treatment & Medication: Human Herpesvirus 6
Follow-up: Human Herpesvirus 6
References
Further Reading
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References

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Keywords

HHV-6, human herpes virus 6, roseola, human herpes virus 6A, HHV-6A, human herpes virus 6B, HHV-6B, exanthem subitum, roseola infantum, mononucleosis syndromes, focal encephalitis, pneumonitis, common childhood illness

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Cris Jagar, MD, Staff Physician, Department of Psychiatry, Saint Vincent Catholic Medical Centers
Disclosure: Nothing to disclose.

Ewa Koziorynska, MD, Staff Physician, Department of Neurosciences, UMDNJ-New Jersey Medical School
Ewa Koziorynska, MD is a member of the following medical societies: Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Franklin Flowers, MD, Chief, Division of Dermatology, Professor, Department of Medicine and Otolaryngology, University of Florida College of Medicine
Franklin Flowers, MD is a member of the following medical societies: American College of Mohs Micrographic Surgery and Cutaneous Oncology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio
Jeffrey Meffert, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Association of Military Dermatologists, and Texas Dermatological Society
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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