Roseola Infantum

Updated: Jun 02, 2016
  • Author: Christopher R Gorman, MD; Chief Editor: William D James, MD  more...
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Overview

Background

Roseola is a common childhood disease. The cause is primary infection with 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).

Roseola infantum. Image courtesy of Wikimedia Comm Roseola infantum. Image courtesy of Wikimedia Commons.

Like other herpes viruses, HHV-6 then remains latent in most patients who are immunocompetent. Although clinical disease is uncommon 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] ).

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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. Evidence suggests that high serum levels of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinases 1 in infants infected with HHV-6 may lead to blood-brain barrier dysfunction, which may result in febrile seizures. [3] 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.

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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. [4] 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.

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. [4]

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. [5]

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Prognosis

Practically all patients who are immunocompetent survive roseola infantum without sequelae. In patients who are immunosuppressed, 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. [6] 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. [7] 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.

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Patient Education

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, the complexity of overlapping signs and symptoms with other viral syndromes and parasitic and fungal infections must be explained.

For patient education resources, see the Children's Health Center, as well as Skin Rashes in Children.

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