AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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-6A has not been shown to cause any disease; HHV-6B has been associated with a variety of viral illnesses, including exanthem subitum (roseola infantum), mononucleosis syndromes, focal encephalitis, and pneumonitis. 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. 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.¹ 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.

The following are related eMedicine articles:

• Human Herpesvirus Type 6 (from Infectious Diseases section)
• Roseola Infantum
• Encephalitis
• Pityriasis Rosea

Additionally, the Medscape CME course Beta-Herpesviruses in Febrile Children With Cancer may be of interest, as may the Medscape Emerging and Reemerging Infectious Diseases Resource Center.

Pathophysiology

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.² 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.³ 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.⁴ These characteristically high HHV-6 DNA levels in chromosomal integration should be considered in establishing laboratory diagnosis methods.

Frequency

United States

Evidence of past 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

HHV-6 has a worldwide distribution.

Mortality/Morbidity

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 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.⁵ 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.
• HHV-6 reactivation may also occur with drug-induced hypersensitivity syndromes, including toxic epidermal necrolysis.⁶

Physical

• Very few physical examination findings exist in children who are infected with 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

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Fever of unknown origin
Hepatitis
Otitis media
Pneumococcemia
Sepsis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• HHV-6 may be diagnosed by viral culture, serologic test, or polymerase chain reaction.⁷ Most often, it is diagnosed by its clinical features.
• A complete blood cell count with differential shows leukopenia with relative leukocytosis.
• HHV-6 and HHV-7 antigenemia was found to usually occur together with symptomatic cytomegalovirus (CMV) infection after liver transplantation.⁸ HHV-6 infection preceded CMV infection, but HHV-7 infection appeared together with CMV infection. However, further investigation of the clinical significance of HHV-6 and HHV-7 antigenemia in organ transplant patients is necessary.
• Rapid diagnosis of HHV-6 primary infections or reactivations can be facilitated by quantitative polymerase chain reaction assays.⁹ Detection of co-infections with multiple herpesviruses can also be accomplished, with quantitative results enabling monitoring of virus load during antiviral therapy.

Histologic Findings

Typical balloonlike cells (cells that show cytoplasmic swelling with a loss of intercellular bridges) may be seen in all affected organs.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

In roseola, symptomatic treatment of the fever is recommended, including baths, lightweight clothing, and rest. Fluids are encouraged. If the patient has a febrile seizure, no seizure medication is necessary.

• To evaluate the influence of ganciclovir (GCV) prophylaxis on HHV-6 replication in renal transplant recipients, Galarraga et al¹⁰ studied 3 groups, (1) patients not taking GCV, (2) patients taking short-term GCV prophylaxis (<30 d), and (3) patients taking long-term GCV prophylaxis (>60 d). The antiviral did not affect the prevalence of HHV-6 (67.2%), but HHV-6 viremia appeared after (42 ±31 d posttransplant) and was shorter (29 ±30 d) among patients on long-term GCV prophylaxis.
• Because HHV-6 and HHV-7 are possibly associated with pityriasis rosea, systemic drugs directed against HHV may hasten recovery of patients with pityriasis rosea. High-dose acyclovir may be effective in the treatment of pityriasis rosea, especially in patients treated in the first week from onset, when replicative viral activity of HHV is probably very high.¹¹

Consultations

Consult a pediatrician for evaluation of any atypical findings.

Activity

Advise rest for children with roseola until the fever breaks and the rash appears.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Although HHV-6 is inhibited by several antiviral drugs in the laboratory (eg, GCV, foscarnet), no clinical trials have assessed their benefit. No seizure medication is indicated for febrile seizures. Antipyretics (eg, acetaminophen) can be given for high fever. Avoid aspirin in children because of the risk of Reye syndrome.

The effectiveness of ganciclovir was evaluated against HHV-6 excreted in saliva in stem cell transplant recipients.¹² Ganciclovir can decrease the HHV-6 viral load in saliva.

Drug Category: Antipyretics

These agents are indicated for an excessively high fever.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Admit only patients who have atypical findings (eg, organ involvement, CNS complications).

Further Outpatient Care

• No further outpatient care for roseola is necessary once the eruption appears (if presentation is typical).

Deterrence/Prevention

• Infection with HHV-6 cannot be prevented. No vaccine exists.

Complications

• Febrile seizures
• Encephalitis
• Meningitis

Prognosis

• Patients usually recover fully without any problems.
• One infection usually provides lifetime immunity, though HHV-6 may reactivate in patients who are immunocompromised.

Patient Education

• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center and Children's Health Center. Also, see eMedicine's patient education articles Mononucleosis and Skin Rashes in Children.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Misdiagnosis of a condition more serious than roseola is a pitfall. Many differential diagnoses exist that can present with a rash and a fever.
• Failure to recognize roseola as a disease that can be treated on an outpatient basis so that children will not be subjected to unnecessary tests or hospital stays is a pitfall.

Special Concerns

• HHV-6 has also been associated with multiple sclerosis; it has been detected in oligodendrocytes, particularly in plaque regions. The role of HHV-6 in multiple sclerosis remains controversial. A more extensive understanding of its neurotropism and possible association with this disease is required.
• An association between HHV-6 reactivation and chronic fatigue syndrome (CFS) has been proposed. A high proportion of patients with CFS are infected with HHV-6 but with a low viral load. The results do not support HHV-6 reactivation in patients with CFS, though further investigation is required.¹³
• Good prospective studies in patients with encephalitis, posttransplant pneumonia, and multiple sclerosis are needed.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: May 16, 2008