Background
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.
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]
Vinnard C, Barton T, Jerud E, Blumberg E. A report of human herpesvirus 6-associated encephalitis in a solid organ transplant recipient and a review of previously published cases. Liver Transpl. Oct 2009;15(10):1242-6. [Medline].
Abdel Massih RC, Razonable RR. Human herpesvirus 6 infections after liver transplantation. World J Gastroenterol. Jun 7 2009;15(21):2561-9. [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].
Magalhães Ide M, Martins RV, Vianna RO, Moysés N, Afonso LA, Oliveira SA, et al. Detection of human herpesvirus 7 infection in young children presenting with exanthema subitum. Mem Inst Oswaldo Cruz. May 2011;106(3):371-3. [Medline].
Razonable RR, Lautenschlager I. Impact of human herpes virus 6 in liver transplantation. World J Hepatol. Sep 27 2010;2(9):345-53. [Medline]. [Full Text].
Vianna RA, de Oliveira SA, Camacho LA, et al. Role of human herpesvirus 6 infection in young Brazilian children with rash illnesses. Pediatr Infect Dis J. Jun 2008;27(6):533-7. [Medline].
Rapaport D, Engelhard D, Tagger G, Or R, Frenkel N. Antiviral prophylaxis may prevent human herpesvirus-6 reactivation in bone marrow transplant recipients. Transpl Infect Dis. Mar 2002;4(1):10-6. [Medline].
Ward KN. The natural history and laboratory diagnosis of human herpesviruses-6 and -7 infections in the immunocompetent. J Clin Virol. Mar 2005;32(3):183-93. [Medline].
Ward KN, Andrews NJ, Verity CM, Miller E, Ross EM. Human herpesviruses-6 and -7 each cause significant neurological morbidity in Britain and Ireland. Arch Dis Child. Jun 2005;90(6):619-23. [Medline].
Asano Y, Suga S, Yoshikawa T, Urisu A, Yazaki T. 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;5(3):353-66. [Medline].
Dockrell DH. Human herpesvirus 6: molecular biology and clinical features. J Med Microbiol. Jan 2003;52:5-18. [Medline].
Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med. Aug 18 1994;331(7):432-8. [Medline].
Nishiyama I et al. An epidemiological study of children with status epilepticus in Okayama,Japan:Incidence,etiologies,and outcomes. Epilepsy Res. Jul 2011;Epub ahead of print.
Wang FZ, Linde A, Hagglund H, Testa M, Locasciulli A, Ljungman P. 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].
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