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

Roseola is a common childhood disease. The causative organism is human herpesvirus 6 (HHV-6). The classic presentation is a 9- to 12-month-old infant who acutely develops a high fever and often a febrile seizure. After 3 days, a rapid defervescence occurs, and a morbilliform rash appears.

Like other herpes viruses, HHV-6 then remains latent in most patients who are immunocompetent. Although it is uncommonly associated with clinical disease in patients who are immunocompetent, HHV-6 is a major cause of morbidity and mortality in patients who are immunosuppressed, particularly in patients with AIDS and in those who are transplant recipients.

Pathophysiology

In the primary infection, replication of the virus occurs in the leukocytes and the salivary glands. It is present in saliva. Early invasion of the CNS is believed to occur, thus accounting for seizures and other CNS complications. Although rare in the primary disease of infancy, generalized organ involvement has been reported with gastrointestinal, hematopathic syndromes; hepatitis; and hepatosplenomegaly.

Following the acute primary infection, HHV-6 remains latent in lymphocytes and monocytes and has been found in low levels in many tissues. Peripheral blood mononuclear cell cultures develop enlarged balloonlike cells. Cells supporting virus growth are CD4⁺ T lymphocytes. HHV-6 down-regulates the host immune response through several mechanisms, including molecular mimicry by production of functional chemokine and chemokine receptors.

The 2 variants of HHV-6 are A and B. The genomes of HHV-6A/B have been sequenced. HHV-6B, the main cause of roseola, consists of 97 unique genes. CD46 is the cell receptor for HHV-6, which imparts the virus' broad tissue tropism.

A possible association of HHV-6 and multiple sclerosis has been suggested but is still inconclusive. HHV-6 has been isolated in Kaposi sarcoma (caused by human herpesvirus 8), in which it may contribute to tumor progression. HHV-6 may facilitate oncogenic potential in lymphoma and has been associated with chronic fatigue syndrome.

Frequency

United States

Serologic tests indicate that HHV-6 infection is nearly universal. In emergency clinics, HHV-6 has been reported to be responsible for 10-45% of cases of febrile illness in infants. A 2005 population-based study revealed primary HHV-6 infection cumulative percentages of 40% by age 12 months and 77% by age 24 months. The peak age of acquisition of primary HHV-6 infection is 9-21 months.

International

International studies show some variation in worldwide seroprevalence. A strong association of HHV-6A in Zambian children with febrile illness suggests an endemic hot spot.

Mortality/Morbidity

• Primary infection with HHV-6 may be asymptomatic, or it may cause the exanthem subitum/roseola syndrome. Within that complex, otitis, gastroenteritis, respiratory distress, and seizures may occur. Primary infection in infants is rarely complicated by serious disease and is very rarely fatal. Case reports of many organ systems being involved indicate a potential morbidity, although this is rarely observed.
• The second stage of HHV-6 infection occurs in healthy children and adults. The virus replicates in the salivary glands and is latent in peripheral blood mononuclear cells. A form of latent infection is found in the integration of the virus in host chromosomes. In adults who are immunocompetent, infection or reactivation of HHV-6 is rare. These few patients have been reported to have lymphadenopathy, hepatitis, and a mononucleosislike syndrome.
• In patients who are immunocompromised, a more serious disease is seen. Transplant recipients (eg, marrow, kidney, liver) may have marrow suppression, pneumonitis, encephalitis, hepatitis, fever, and an eruption. Organ rejection and death may occur. Studies of these patients are complicated by frequent concomitant reactivation of human herpesvirus 7 (HHV-7) and cytomegalovirus. HHV-6 was implicated as the cause of 30% of cases of pneumonitis in patients who underwent bone marrow transplantation. Patients with AIDS comprise the second at-risk group; however, antiretroviral therapy has reduced morbidity. HHV-6 infection in patients with AIDS results in viremia, lymphadenopathy, disseminated organ involvement, active CNS infection, retinitis, and death. HHV-6A is more common in patients with AIDS than in other patients.

Race

With rare geographic exceptions, no racial differences seem to occur in HHV-6 infection.

Sex

Zerr et al reported HHV-6 acquisition is associated with female sex and having older siblings.

Age

Antibody titers are high in newborns because of maternal antibody. Transplacental infection occurs in about 1% of cases. Titers decrease from 3-9 months of age and then begin to rise because of primary infections. Titers remain high for HHV-6B until after age 60 years. Infection with HHV-6A appears later in life. In roseola, age ranges from 2 weeks to 3 years. In one study, almost one fourth of the patients were younger than 6 months.

CLINICAL

Section 3 of 10  

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

History

• The classic patient with roseola is a 9- to 12-month-old infant in previously good health and who has an abrupt onset of high fever (40°C), which lasts for 3 days with nonspecific complaints. A febrile seizure occurs in 15% of patients. Rapid defervescence is striking with the onset of a mild, pink, morbilliform exanthem.
• In patients who are immunocompromised, the onset of symptoms is usually abrupt, with fever, malaise, and CNS and other organ system involvement.

Physical

• Despite the high fever, few clinical findings are observed early in the course. The lack of upper respiratory infection is notable, and meningeal signs and encephalopathy are not present. Gastrointestinal symptoms, signs of electrolyte imbalance, or evidence of dehydration are rarely present.
• A febrile seizure, with no residual findings, may have occurred.
• After an abrupt loss of fever, the characteristic rash appears.
• • The eruption is generalized and subtle.
  • It is composed of either discrete, small, pale pink papules or a blanchable, maculopapular exanthem that is 1-5 mm in diameter. This rash may last 2 days.
• The characteristic enanthem (Nagayama spots) consists of erythematous papules on the mucosa of the soft palate and the base of the uvula. The enanthem may be present on the fourth day in two thirds of patients with roseola.

Causes

• The causative agent of roseola was discovered in 1986. The Roseolovirus genus of the beta herpes virus hominis subfamily contains HHV-6 and HHV-7. HHV-6 has 2 variants: HHV-6A and HHV-6B. Their major differences are cellular tropism. Debate has existed whether they represent 2 species.
• • HHV-6A infection is rarely associated with roseola infantum. HHV-6A is associated with infection in adults who are immunocompromised. HHV-6A infection occurs later in life, and details are lacking.
  • HHV-6B is the cause of roseola in infants. Because seropositivity is nearly 100% in older children, most primary infections with HHV-6B are asymptomatic.
  • HHV-7 has been identified in a few cases of roseola.
• Recurrences of roseola are not common. A well-documented case of a 13-month-old child who had a second episode of roseola exists. In the acute phase of the second episode, HHV-7 was identified and excreted in the saliva. This was followed by excretion of HHV-6.

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
Pneumococcemia
Viral syndromes with fever and exanthem
In patients who are immunocompromised, many differential diagnoses, including viral, bacterial, fungal, and immunologic conditions, exist.

WORKUP

Section 5 of 10  

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

Lab Studies

• In response to the early acute febrile presentation, laboratory studies may include a CBC count, urinalysis, blood cultures, and cerebrospinal fluid examination.
• If the patient presents with a febrile seizure, a seizure workup may be indicated.
• Diagnosis may be confirmed by virus isolation, seroconversion (immunoglobulin M), or detection of viral DNA sequences in peripheral blood mononuclear cells.

Histologic Findings

Typical ballooning cells may be seen in any organ system affected with HHV-6 infection.

TREATMENT

Section 6 of 10  

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

Medical Care

• At present, no medical antiviral therapy is available for HHV-6 infection that causes roseola. Thus, treatment is supportive. However, in 2002, Rapaport et al reported that antiviral prophylaxis with ganciclovir may prevent HHV-6 reactivation in high-risk bone marrow transplant patients. Further double-blinded randomized studies are needed.
• Acute or chronic antiseizure medications are not recommended for infants who have had a febrile seizure secondary to roseola.

Consultations

A pediatric consultation is recommended for infants with febrile seizures.

MEDICATION

Section 7 of 10  

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

No effective pharmaceutical cure exists.

FOLLOW-UP

Section 8 of 10  

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

Further Inpatient Care

• Inpatient care consists of support with antipyretics and treatment of gastroenterologic, respiratory, hematologic, or CNS complications.

In/Out Patient Meds

• Antipyretics and attention to hydration are important supportive measures in the care of a young child with high fever.

Deterrence/Prevention

• Because seroconversion in the United States is nearly 100%, isolation is not indicated. The infection is spread through saliva in both the acute phase and the chronic phase.

Complications

• In roseola, complications are rare. Given that seroconversion is practically universal, finding any of the complications that have been reported in the gastrointestinal, CNS, pulmonary, and hematopoietic systems is rare.
• Children who have seizures with roseola are not expected to have further febrile or nonfebrile seizures.

Prognosis

• Practically all patients who are immunocompetent survive roseola without sequelae.
• In patients who are immunosuppressed, multisystem complications are not unusual. Infection may be chronic, leading to viral progression and death.

Patient Education

• In the case of an otherwise healthy infant with roseola, educating the parents is important to alleviate anxiety about the hyperpyrexia and possible associated seizure.
• In patients who are immunocompromised, the complexity of overlapping signs and symptoms with other viral syndromes and parasitic and fungal infections must be explained.
• For excellent patient education resources, visit eMedicine's Children's Health Center. Also, see eMedicine's patient education article 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

• Failure to consider roseola in the differential diagnosis of a febrile child may lead to unnecessary tests, treatments, and admission to the hospital.
• In 2005, Ward suggested testing for HHV-6 and HHV-7 primary infection when serious neurological disease/encephalitis is temporally related to immunization, lest the condition be misdiagnosed as a vaccine reaction.

Special Concerns

• No risk appears to be present to pregnant women exposed to roseola. Care must be taken to distinguish this from rubella. No reports of infection or complications following exposure exist. This is probably because of the nearly universal seroconversion and latent infection. No sequelae of intrauterine infection are known. Isolation is not indicated.
• In patients who are immunosuppressed, infection may be from latent infection in most if not all cases. The many and severe complications are special concerns.

REFERENCES

Section 10 of 10

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

• Asano Y, Suga S, Yoshikawa T, et al. Human herpesvirus type 6 infection (exanthem subitum) without fever. J Pediatr. Aug 1989;115(2):264-5. [Medline].
• Asano Y, Yoshikawa T, Suga S, et al. Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum). Pediatrics. Jan 1994;93(1):104-8. [Medline].
• Campadelli-Fiume G, Mirandola P, Menotti L. Human herpesvirus 6: an emerging pathogen. Emerg Infect Dis. May-Jun 1999;(3):353-66. [Medline].
• Dockrell DH. Human herpesvirus 6: molecular biology and clinical features. J Med Microbiol. Jan 2003;52(Pt 1):5-18. [Medline].
• Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study ofcomplications and reactivation. N Engl J Med. Aug 18 1994;331(7):432-8. [Medline].
• Rapaport D, Engelhard D, Tagger G, et al. Antiviral prophylaxis may prevent human herpesvirus-6 reactivation in bone marrow transplant recipients. Transpl Infect Dis. Mar 2002;4(1):10-6. [Medline].
• Wang FZ, Linde A, Hagglund H, et al. Human herpesvirus 6 DNA in cerebrospinal fluid specimens from allogeneic bone marrow transplant patients: does it have clinical significance?. Clin Infect Dis. Mar 1999;28(3):562-8. [Medline].
• Ward K N, Andrews N J, Verity C M et al. Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland. Archives of Diseases in Childhood. 2005;90:619-623.
• Ward KN. The natural history and laboratory diagnosis of human herpesviruses-6 and -7infections in the immunocompetent. J Clin Virol. Mar 2005;32(3):183-93. [Medline].
• Ward KN, Andrews NJ, Verity CM, et al. Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland. Arch Dis Child. Jun 2005;90(6):619-23. [Medline].
• Zerr DM, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. Feb 24 2005;352(8):768-76. [Medline].

Article Last Updated: Jan 16, 2007