Roseola Infantum

Roseola is a common childhood disease. The causative organism is human herpesvirus 6 (HHV-6). The classic presentation of roseola infantum 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 (see the image below).

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 (eg, liver transplantation[1, 2] ).

Pathophysiology

In the primary infection, replication of the virus occurs in the leukocytes and the salivary glands. HHV-6 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.

Epidemiology

Frequency

United States

Serologic tests indicate that human herpesvirus 6 (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.[3] 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.[4] 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.[5] 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.[3]

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 infantum, age ranges from 2 weeks to 3 years. In one study, almost one fourth of the patients were younger than 6 months. In a Brazilian study, 75% of HHV-6 infections occurred in children aged 6-17 months.[6]

History

The classic roseola infantum patient 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 roseola infantum 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 of roseola infantum. The lack of upper respiratory tract 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 infantum was discovered in 1986. The Roseolovirus genus of the beta herpes virus hominis subfamily contains human herpesvirus (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 infantum.

Recurrences of roseola infantum 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.

Differential Diagnoses

Meningococcemia

Laboratory 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.

Roseola infantum 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.

Medical Care

At present, no medical antiviral therapy is available for human herpesvirus 6 (HHV-6) infection that causes roseola. Thus, treatment of roseola infantum 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.[7] 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 roseola infantum who have febrile seizures.

Medication Summary

No effective pharmaceutical cure exists for roseola infantum.

Further Inpatient Care

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

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 infantum, complications are rare. Given that seroconversion is practically universal, finding any of the complications that have been reported in the gastrointestinal, central nervous, pulmonary, and hematopoietic systems is rare.

Children who have seizures with roseola are not expected to have further febrile or nonfebrile seizures.