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Human herpesvirus 6 (HHV-6) and herpesvirus 7 (HHV-7) are closely related members of the Roseolovirus genus of herpesviruses. Humans are the only known natural host for these two viruses. The cellular reservoir is believed to be peripheral blood mononuclear cells (PBMCs) and possibly epithelial cells of the salivary glands and the bronchial tree. The infection is believed to be transmitted primarily through saliva; sexual transmission may occur, and presumptive in utero infection has been described. Reactivation, with salivary shedding, occurs frequently among immunocompetent children and adults(758Caserta MT, McDermott MP, Dewhurst S, et al. Human herpesvirus 6 (HHV6) DNA persistence and reactivation in healthy children. J Pediatr 2004;145:478-84.).

HHV-6 has two subtypes, A and B. HHV-6B is the etiologic agent of most primary infections; HHV-6A has been linked to neurologic syndromes. The vast majority of children become infected with HHV-6 early in childhood, with 70%-90% of children HHV-6 seropositive by age 2 years, and virtually 100% by age 3 years (759Kositanont U, Wasi C, Wanprapar N, et al. Primary infection of human herpesvirus 6 in children with vertical infection of human immunodeficiency virus type 1. J Infect Dis 1999;180:50-5., 760Zerr D, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med 2005;352:768-76.). In a large prospective study of North American children, the peak age of acquisition of HHV-6 was 6-9 months (761Hall CB, Caserta MT, Schnabel KC, et al. Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr 2004;145:472-7.). Such infection is associated with varied clinical manifestations, viremia, and the frequent persistence of the viral genome in PBMCs (762Pruksananonda P, Hall CB, Insel RA, et al. Primary human herpesvirus 6 infection in young children. N Engl J Med 1992;326:1445-50.).

HHV-6 also can be transmitted from mother to child. In several recent studies, virtually 100% of pregnant women were HHV-6-seropositive. During pregnancy, 2%-9% of women shed virus in the genital tract(763Okuno T, Oishi H, Hayashi K, et al. Human herpesviruses 6 and 7 in cervixes of pregnant women. J Clin Microbiol 1995;33:1968-70., 764Bailllargeon J, Piper J, Leach CT. Epidemiology of human herpesvirus 6 (HHV-6) infection in pregnant and nonpregnant women. J Clin Virol 2000;16:149-57.). Congenital HHV-6 infection has been documented in ≤2% of newborns (760Zerr D, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med 2005;352:768-76., 761Hall CB, Caserta MT, Schnabel KC, et al. Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr 2004;145:472-7., 765Adams O, Krempe C, Kgler G, et al. Congenital infections with human herpesvirus 6. J Infect Dis 1998;178:544-6., 766Dahl H, Fjaertoft G, Norsted T, et al. Reactivation of human herpesvirus 6 during pregnancy. J Infect Dis 1999;180:2035-8.). In one large study of approximately 5000 births, 1% of cord blood samples were positive for HHV-6 DNA. None of the congenitally infected infants were symptomatic (761Hall CB, Caserta MT, Schnabel KC, et al. Congenital infections with human herpesvirus 6 (HHV6) and human herpesvirus 7 (HHV7). J Pediatr 2004;145:472-7.). The virus does not appear to be transmitted by breast-feeding.

HHV-6 infects the same target cells as HIV, and HHV-6 and HIV can simultaneously infect the same CD4 cells under experimental conditions. Some evidence exists for interactions between HHV-6 and HIV at the cellular or molecular levels. Some studies have suggested that HHV-6 upregulates HIV expression in coinfected cells in vitro (767Horvat RT, Wood C, Josephs SF, et al. Transactivation of the human immunodeficiency virus promoter by human herpesvirus 6 (HHV- 6) strains GS and Z-29 in primary human T lymphocytes and identification of transactivating HHV-6(GS) gene fragments. J Virol 1991;65:2895-902., 768Isegawa Y, Katahira J, Yamanishi K, et al. Reactivation of latent human immunodeficiency virus 1 by human herpesvirus 6 infection. Acta Virol 2007;51:13-20.).

In a study of HHV-6 infection in 227 children born to HIV-infected mothers, three (7%) of 41 HIV-uninfected infants were positive for HHV-6 DNA in the first month of life, suggesting possible intrauterine infection (759Kositanont U, Wasi C, Wanprapar N, et al. Primary infection of human herpesvirus 6 in children with vertical infection of human immunodeficiency virus type 1. J Infect Dis 1999;180:50-5.). The cumulative infection rates of HHV-6 at ages 6 and 12 months were significantly lower in HIV-infected children (11% and 33%, respectively) than in HIV-uninfected children (28% and 78%, respectively), and high CD4 percentage (>15%) in the child before HHV-6 infection was associated with high HHV-6 infection rate. However, HIV disease progressed longitudinally in all 10 infants with HIV/HHV-6 coinfection and in 58% of those without HHV-6 coinfection, suggesting that HHV-6 coinfection might increase risk for HIV disease progression.

HHV-7 is acquired later in life than HHV-6. In contrast to HHV-6, seropositivity to HHV-7 is approximately 50% at age 2 years. Reactivation and/or persistent shedding also can occur. Salivary shedding is common, noted in up to 90% of seropositive adults, and HHV-7 DNA has been found in breast milk (unlike HHV-6) (769Fujiwara N, Namba H, Ohuchi R, et al. Monitoring of human herpesvirus-6 and -7 genomes in saliva samples of healthy adults by competitive quantitative PCR. J Med Virol 2000;61:208-13.).

Many cases of primary infection with HHV-6, which usually occurs by age 2 years, are asymptomatic or accompanied by mild, nonspecific symptoms. The most common symptom is fever, which can be high and abrupt, associated with crankiness and rhinitis. In several studies, primary HHV-6 infection was associated with infants presenting for care of acute febrile illness. Among children aged <3 years presenting for evaluation of a febrile illness, 10% had primary HHV-6 infection; the incidence was 20% for febrile infants aged 6-8 months (770Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994;331:342-8.).

HHV-6 is the causative agent of most cases of exanthem subitum (also known as roseola infantum), a febrile illness of early childhood, associated with a distinctive exanthem. The incidence of HHV-6-related exanthem subitum peaks at age 6-9 months and is associated with fever of 4-5 days, with rash developing as the fever subsides (771Asano Y, Yoshikawa T, Suga S, et al. Clinical features of infants with primary human herpesvirus 6 infection (exanthem subitum, roseola infantum). Pediatrics 1994;93:104-8.). Ten percent to 20% of infants with primary HHV-6 infection will present with exanthem subitum. HHV-7 also has been associated with exanthem subitum.

Both primary infection with and reactivation of HHV-6 has been associated with several CNS syndromes in immunocompetent children and adults, including febrile and nonfebrile seizures, encephalitis/encephalopathy and acute necrotizing encephalopathy (770Hall CB, Long CE, Schnabel KC, et al. Human herpesvirus-6 infection in children. A prospective study of complications and reactivation. N Engl J Med 1994;331:342-8., 772Suga S, Yoshikawa T, Asano Y, et al. Clinical and virological analyses of 21 infants with exanthem subitum (roseola infantum) and central nervous system complications. Ann Neurol 1993;33:597-603., 773Isaacson E, Glaser CA, Forghani B, et al. Evidence of human herpesvirus 6 infection in 4 immunocompetent patients with encephalitis. Clin Infect Dis 2005;40:890-3.). Convulsions, a feature of severe HHV-6 infection, often can be prolonged and complicated (774Mannonen L, Herrgrd E, Valmari P, et al. Primary human herpesvirus-6 infection in the central nervous system can cause severe disease. Pediatr Neurol 2007;37:186-91.).

Reactivation of HHV-6 occurs in adults with immunodeficiency or in patients on immunosuppressive therapy after transplantation. Although the exact frequency of HHV-6 reactivation in transplant recipients (bone marrow and solid organ) is difficult to determine, it appears to be common and occurs within the first 12 weeks after transplantation (775Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis 2001;33:829-33.). Most reactivation involves HHV-6B. Many episodes of reactivation are asymptomatic, but when symptoms occur, they can include fever, skin rash, and leukopenia. Pneumonitis, encephalitis, bone marrow suppression, and graft versus host disease have been associated with reactivation of HHV-6 after bone marrow transplantation (775Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis 2001;33:829-33., 776Zerr DM, Frenkel LM, Huang ML, et al. Polymerase chain reaction diagnosis of primary human herpesvirus-6 infection in the acute care setting. J Pediatr 2006;149:480-5.).

HIV-infected persons exhibit frequent reactivation of HHV-6 (775Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis 2001;33:829-33.); whether this causes symptoms or progression of illness is controversial. Symptoms most likely to be associated with HHV-6 are pneumonitis and encephalitis.

Reactivation of HHV-7 also occurs in immunocompetent and immunodeficient persons. The relation of HHV-7 reactivation to disease states is still poorly understood.

Many primary infections result in a nonspecific febrile illness. The 10%-20% of primary infections that manifest as exanthem subitum can be clinically diagnosed on the basis of symptomatology and distinctive rash.

Diagnosing HHV-6-related illness can be difficult because of the frequent reactivation in immunocompetent healthy children and adults. Specific testing for HHV-6 or -7 infection may be performed using such laboratory methods as serology, culture, antigen detection, PCR, in situ hybridization, and immunohistochemistry. The latent nature of these herpesviruses must be considered, and the differing capability of these tests to distinguish nonreplicating latent virus from replicating active virus must be understood (777Leach CT. Human herpesvirus-6 and -7 infections in children: agents of roseola and other syndromes. Curr Opin Pediatr 2000;12:269-74.). Laboratory evaluations (e.g., serology and PCR) to diagnose HHV-7 infections are rarely used and typically limited to research.

Demonstration of an HHV-6-specific antibody seroconversion or significant change in antibody titer between acute and convalescent paired serum samples can diagnose infection with HHV-6; delay can occur between initial infection and seropositivity, especially in immunodeficient patients. The sensitivity of serology varies and does not distinguish between HHV-6A and HHV-6B. Some cross reactivity may occur with HHV-7.

Identification of HHV-6 or -7 in PBMCs by virus culture firmly establishes the presence of active infection in immunocompetent hosts, but association with specific disease is problematic in immunocompromised patients because of a low background rate of viremia. Virus culture requires cocultivation with PBMCs or cord blood and requires 1-3 weeks (777Leach CT. Human herpesvirus-6 and -7 infections in children: agents of roseola and other syndromes. Curr Opin Pediatr 2000;12:269-74.). Therefore, it is available only in specialized research laboratories.

PCR can be used to detect HHV-6 DNA or RNA. A positive serum, plasma, or PBMC viral DNA or RNA PCR assay, in the absence of measurable antibody, indicates a primary infection. HHV-6 is found in cellular material such as PBMCs and tissue even during latency; therefore, after primary infection a positive DNA PCR cannot be used to establish reactivation, whereas detection of cell-free viral DNA or RNA in plasma, serum, or CSF by PCR (776Zerr DM, Frenkel LM, Huang ML, et al. Polymerase chain reaction diagnosis of primary human herpesvirus-6 infection in the acute care setting. J Pediatr 2006;149:480-5.) is considered evidence of active viral replication - and thus reactivation - in a seropositive patient. Evidence of reactivation and clinical disease must be correlated cautiously because of the frequent asymptomatic reactivation in most adults and children (775Caserta MT, Mock DJ, Dewhurst S. Human herpesvirus 6. Clin Infect Dis 2001;33:829-33., 776Zerr DM, Frenkel LM, Huang ML, et al. Polymerase chain reaction diagnosis of primary human herpesvirus-6 infection in the acute care setting. J Pediatr 2006;149:480-5.).

Not applicable.

The major side effect of ganciclovir is myelosuppression (i.e., anemia, neutropenia, and thrombocytopenia). Dose reduction or interruption because of hematologic toxicity may be necessary in ≤40% of patients receiving IV ganciclovir; granulocyte colony-stimulating factor can be used to ameliorate marrow suppression. The main toxicities of foscarnet are decreased renal function and metabolic derangements. For patients receiving ganciclovir or foscarnet, complete blood counts, serum electrolytes, and renal function should be monitored twice weekly during induction therapy and once weekly thereafter. The major side effect of cidofovir is potentially irreversible nephrotoxicity; the drug produces proximal tubular dysfunction, including Fanconi syndrome and acute renal failure. When present, renal toxicity manifests as proteinuria and glycosuria. To minimize nephrotoxicity, probenicid should be administered before each infusion, and IV hydration with normal saline should be administered before and after each cidofovir infusion. For patients receiving IV cidofovir, blood urea nitrogen, creatinine, and urinalysis should be performed before each infusion; administration of the drug is contraindicated if renal dysfunction or proteinuria is detected. Other reported adverse events include anterior uveitis and ocular hypotony; serial ophthalmologic monitoring for anterior segment inflammation and intraocular pressure is needed while the drug is being received systemically. Cidofovir should not be administered concomitantly with other nephrotoxic agents. Cidofovir therapy must be discontinued if serum creatinine increases ≥0.5 mg/dL above baseline.

HHV-6 and HHV-7 have not been associated with IRIS with HAART treatment in HIV-infected children or adults.

Mutations conferring resistance of HHV-6 to ganciclovir, cidofovir, and foscarnet have been described (788De Bolle L, Manichanh C, Agut H, et al. Human herpesvirus 6 DNA polymerase: enzymatic parameters, sensitivity to ganciclovir and determination of the role of the A961V mutation in HHV-6 ganciclovir resistance. Antiviral Res 2004;64:17-25.). Whether a change from one drug to the other would be beneficial is unknown.

There are currently no recommendations for the management of treatment failure.

No data exist on preventing HHV-6 or HHV-7 reactivation from latency in HIV-infected patients.

Not applicable.