Roseola Infantum

Roseola is a common childhood disease, caused by primary infection with human herpesvirus 6 (HHV-6). ^[1] The classic presentation of roseola infantum is a 9- to 12-month-old infant who acutely develops a high fever and often experiences a febrile seizure. After 3 days, a rapid defervescence occurs, and a morbilliform rash appears (see the image below).

Roseola infantum. Image from Wikimedia Commons.

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Like other herpesviruses, HHV-6 then remains latent in most patients who are immunocompetent. Although clinical disease is uncommon (though not unknown ^[2] ) in patients who are immunocompetent, HHV-6 is a major cause of morbidity and mortality in patients who are immunosuppressed, particularly those with AIDS and those who are transplant recipients (eg, liver transplantation ^{[3, 4]} ).

In the primary infection, replication of the virus occurs in the leukocytes and the salivary glands. HHV-6 is present in saliva. A study monitoring HHV-6 and HHV-7 DNA in saliva samples during the acute and convalescent phases demonstrated a significantly higher rate of detection in children aged 3-9 years than in adults, suggesting that children in the convalescent phase of roseola infantum are the more probable source of infection. ^[5] Early invasion of the central nervous system (CNS) is believed to occur, thus accounting for seizures and other CNS complications.

Evidence has suggested that high serum levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinases (TIMP)-1 in infants infected with HHV-6 may lead to blood-brain barrier dysfunction, which may result in febrile seizures. ^[6] Study of cerebrospinal fluid (CSF) levels of interleukin (IL)-1β and basic fibroblast growth factor (bFGF) has suggested that they may play a role in contributing to HHV-6B growth and the onset of encephalitis. ^[7] Although rare in the primary disease of infancy, generalized organ involvement has been reported with gastrointestinal and hematopathic syndromes, hepatitis, and hepatosplenomegaly.

After 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 downregulates the host immune response through several mechanisms, including molecular mimicry by production of functional chemokine and chemokine receptors.

The two 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's broad tissue tropism. Both HHV-6A and HHV-6B integrate their genome into the chromosomes of infected cells and also of germ cells; thus, infected individuals have a copy of the viral genome in all of their nucleated cells. ^[8]

A possible association of HHV-6 with multiple sclerosis (MS) has been suggested, but study results have been conflicting. However, a large collaborative study that included 8742 patients with MS and 7215 health control subjects found that seropositivity for HHV‐6A was associated with an increased risk of future MS. ^[9]

HHV-6 has been isolated in Kaposi sarcoma (caused by HHV-8), where it may contribute to tumor progression. HHV-6 may facilitate oncogenic potential in lymphoma and has been associated with chronic fatigue syndrome.

The causative agent of roseola infantum, HHV-6, was discovered in 1986. The Roseolovirus genus of the Betaherpesvirinae subfamily contains HHV-6 and HHV-7. The major differences between the two HHV-6 variants, HHV-6A and HHV-6B, involve cellular tropism. There has been debate as to whether these two variants actually represent two species.

HHV-6A infection is rarely associated with roseola infantum. It is more commonly 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. Given that seropositivity is nearly 100% in older children, it follows that 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.

United States and international statistics

Serologic tests have indicated 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. ^[10] The peak age range for the acquisition of primary HHV-6 infection is 9-21 months.

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

Age, sex-, and race-related demographics

Antibody titers are high in newborns because of maternal antibody. Transplacental infection occurs in about 1% of cases. Titers decrease from 3 months of age to 9 months and then begin to rise because of primary infections. Titers for HHV-6B remain high 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 between the ages of 6 and 17 months. ^[11]

In a population-based study, HHV-6 acquisition was reported to be associated with female sex and with having older siblings. ^[10]

With rare geographic exceptions, race-related differences in HHV-6 infection have not been noted.

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

Primary infection with HHV-6 may be asymptomatic, or it may cause the exanthem subitum/roseola syndrome. ^[12] 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; however, cases of HHV-6 infection progressing to hepatitis, acute liver failure, and death have been reported. ^[13] Case reports of many organ systems being involved indicate potential morbidity, though 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. ^[14] Studies of these patients are complicated by frequent concomitant reactivation of 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 constitute 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.

In the case of an otherwise healthy infant with roseola infantum, educating the parents is important to alleviate anxiety about the hyperpyrexia and possible associated seizure.

In patients who are immunocompromised, educating the parents regarding the complexity of overlapping signs and symptoms with other viral syndromes and parasitic and fungal infections is crucial.