Chapter 312. Human Herpesviruses 6 and 7

Human herpesvirus 6 (HHV-6) was isolated in tissue culture in 1986 from peripheral blood leukocytes of patients with both lymphoproliferative disorders and HIV infection. It is the major etiologic agent of exanthem subitum and has also been implicated in other clinical syndromes. HHV-6 is a prototypical member of the betaherpesvirus family of herpesviruses, which also includes human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). The virus has a double- stranded DNA genome contained within an icosahedral capsid, surrounded by an outer envelope. HHV-6 is subclassified as either variant A or B, based on differences in nucleotide sequence, restriction enzyme profile, and reactivity with monoclonal antibodies. HHV-6B is the subtype associated with exanthem subitum.1 In contrast to the other human herpesviruses, which are maintained in a latent state in the host cell as circularized genomes.

Epidemiology

Infection with human herpesvirus 6 (HHV-6) is ubiquitous, and virtually all children are infected by 2 to 3 years of age. Infection is seldom seen before 6 months of age, presumably due to the protective effect of transplacental antibody. The incidence of infection peaks between 6 and 12 months of age. HHV-6 can be found in the salivary gland, and is shed in saliva of seropositive individuals, suggesting that saliva is the probable route of acquisition of infection. Primary infection in children most likely occurs via contact with HHV-6 shed in the secretions of older children or caregivers. HHV-6 can also be associated with congenital infections, which may occur through transmission of chromosomally integrated viral DNA in germ line cells: the clinical significance of such infections is not known.2,3

Pathophysiology

HHV-6 is a prototypical member of the betaherpesvirus family of herpesviruses, which also includes human herpesvirus 7 (HHV-7) and human cytomegalovirus (HCMV). It has tropism for T cells, and molecular studies reveal homology with HCMV, suggesting that the virus belongs to the family Herpesviridae. More recent evidence suggests that HHV-6 can be maintained in the host cell in a chromosomally integrated form, capable of producing viral mRNA and protein and, presumably, infectious virus.2

Clinical Manifestations

The spectrum of disease associated with primary human herpesvirus 6 (HHV-6) infection is broad, ranging from asymptomatic infection to fatal disseminated disease. Most commonly, however, primary infection occurs early in life and is manifest as either exanthem subitum or an undifferentiated febrile illness. Reports of HHV-6 infection linked to other clinical syndromes must be interpreted cautiously. Because infection is ubiquitous and persistent in nature, the finding of HHV-6 antibody, or even isolation of the virus, cannot with certainty always document HHV-6 as the cause of any given clinical syndrome in older patients.

Exanthem Subitum

Exanthem subitum (also known commonly as roseola infantum) is a common acute febrile illness of infants and young children characterized by 3 to 5 days of fever followed by rapid defervescence and the appearance of an erythematous macular or maculopapular rash (Fig. 312-1). This entity was first described by Zahorsky in 1910, and it was at one time classified as “sixth disease” among the exanthematous illnesses of childhood.4 The infection is characterized by viremia prior to the onset of the rash. Fever can be quite significant. Prior to development of the characteristic rash, there are few other clinical clues to reliably indicate that the febrile illness is due to human herpesvirus 6 (HHV-6), although posterior auricular adenopathy is common. Because of the high fever and lack of differentiating clinical findings, many young infants will be subjected to extensive laboratory evaluation and empiric antibiotic therapy prior to the onset of the exanthem. In children treated empirically with antimicrobials, the onset of the rash may often be misinterpreted as an antibiotic “allergy.” The rash is either papular, macular, or maculopapular and appears mainly on the trunk. The pathogenesis of the rash is unknown but is presumed to be immune mediated. The rash usually fades within 3 to 4 days following onset.

Undifferentiated Febrile Illness

Human herpesvirus 6 (HHV-6) infection can also be a common cause of undifferentiated febrile illness without rash in infants. In one study, evidence for acute HHV-6 infection was identified in approximately 10% of children presenting to an emergency department for evaluation of high fever. A peak fever higher than 40°C was found in 65% of the acutely HHV-6 infected children in this study.5 Inflammation of tympanic membranes and a modest depression in total leukocyte count were the only other features that differentiated these children from those without HHV-6 infection. Because very young infants with high fever due to HHV-6 infection are difficult to discriminate from those with occult bacteremia, many young infants with acute HHV-6 infection are treated with antibiotic therapy.

Central Nervous System Complications

Human herpesvirus 6 (HHV-6) infection can also be associated with central nervous system (CNS) complications in children both with and without rash. Febrile convulsions are the most common complication of HHV-6 infection. In a large study of emergency room visits, HHV-6 accounted for one third of all febrile seizures in children younger than 2 years. In some children, seizures may be prolonged or recurrent.6 However, in another, prospective population-based study of 81 children with a well-defined time of acquisition of HHV-6, although 93% had symptoms, none had seizures.7 The role of primary HHV-6 infection as a cause of neurologic disease in children requires further study. Other neurologic complications reported in acute HHV-6 infection have included encephalitis, meningoencephalitis, and aseptic meningitis. Provocative reports have hypothesized that latent CNS infection with HHV-6 may play a causative role in temporal lobe epilepsy, and controversial reports in adult patients have proposed a link to HHV-6 infection in the CNS and multiple sclerosis.8

Immunocompromised Patients

Immunocompromised patients are at increased risk for disease from human herpesvirus 6 (HHV-6). Presumably, the majority of such syndromes reflect reactivation of latent infection due to immunosuppression. Reactivation of HHV-6 has been linked to allograft rejection. HHV-6 reactivation may also contribute to an immunomodulatory and immunosuppressive milieu in the transplant patient that may, in turn, facilitate infection with other opportunistic pathogens, such as cytomegalovirus and fungi, contributing to an increased overall mortality.9 In hematopoietic stem cell transplant patients, HHV-6 has been implicated as a cause of encephalitis10 and graft failure.11

Other Human Herpesvirus 6 Syndromes

Some less common syndromes are postulated to be causally related to human herpesvirus 6 (HHV-6) infection.12 There is intriguing evidence to suggest a role for HHV-6 in the pathogenesis of multiple sclerosis (MS). These patients have a higher level of HHV-6 antibody compared to controls, and HHV-6 DNA has been detected by polymerase chain reaction in some MS patients, but not age-matched controls. HHV-6 has been implicated as causing some cases of heterophile-negative mononucleosis. Hepatitis, liver dysfunction, thrombocytopenia, thrombocytopenic purpura, hemophagocytic syndrome, chronic fatigue syndrome, and prolonged lymphadenopathy have also been described. A possible role for HHV-6 in malignancies has been suggested,12 possibly related to the virus’ ability to integrate into host cell chromosomal DNA. HHV-6 has also been implicated as a potential cofactor in the pathogenesis of AIDS. Both HIV and HHV-6 share a tropism for CD4+ cells, and there is evidence that dual infection may stimulate the replication of HIV. Progression of HIV disease appears to be more rapid in children vertically infected with HIV who are also infected with HHV-6.

Diagnosis

The diagnosis of primary human herpesvirus 6 (HHV-6) infection can often be made clinically in children with exanthem subitum. Primary HHV-6 infection may also be suspected in an irritable infant with high, unexplained fever and no other clinical findings. Leukopenia may suggest the diagnosis, but this laboratory abnormality is nonspecific. The differential diagnosis includes measles and rubella, but these are currently rare diseases in the United States. A more recent history of measles immunization should be sought because measles vaccine may produce fever and rash. The clinician should remember that enteroviral rashes may be indistinguishable from roseola, and can be associated with a prodrome of fever, but are more likely to be seen in the late summer or early fall. Erythema infectiosum (fifth disease) is usually seen in somewhat older children. Fever is usually not as high as in roseola, and the rash is most prominent on the cheeks (so-called “slapped cheek” appearance—Fig. 319-1). Epstein-Barr virus- and cytomegalovirus-associated infectious mononucleosis can also produce an exanthem that can be confused with exanthem subitum, particularly in those children who receive β-lactam antibiotics.

In those circumstances when specific etiologic diagnosis is necessary, the diagnosis of primary HHV-6 infection may be made by documenting a fourfold or greater rise in IgG titer. The virus can be cultured, but culture requires special techniques not available to most diagnostic virology laboratories. Polymerase chain reaction is available, but must be interpreted cautiously because viral nucleic acids can be detected in blood or saliva in a majority of older children and adults following acquisition of infection. The finding of HHV-6 DNA in the cerebrospinal fluid may be helpful in the diagnostic evaluation of a child with protracted seizures.

Treatment

Treatment of human herpesvirus 6 (HHV-6) infection is essentially supportive because virtually all infections are self-limited. Some use of empiric antimicrobials in highly febrile children with acute HHV-6 infection is probably unavoidable, but care should be taken to not confuse the classic rash of exanthem subitum, which occurs at the time of defervescence, with a drug allergy. For children with HHV-6-related seizures, anticonvulsants may be warranted. In immunocompromised patients with HHV-6 viremia or other disease syndromes, antiviral agents active against cytomegalovirus, in particular ganciclovir and foscarnet, are occasionally employed,13 but evidence of efficacy from controlled studies is lacking.

Human herpesvirus 7 (HHV-7) is highly related to HHV-6 and, like HHV-6, is responsible for the common childhood illness, exanthem subitum (roseola infantum).14 HHV-7 is also a beta herpesvirus, similar to human herpesvirus 6 (HHV-6). It was first isolated from CD4+ T cells of a healthy individual. The high degree of homology with HHV-6 creates difficulty in interpretation of serologic assays (which are largely investigational in nature and not generally useful for clinical practice) because there is considerable cross-reactivity of antibodies between HHV-6 and HHV-7 proteins. As with HHV-6, infection with HHV-7 appears to be ubiquitous, although infection appears to be acquired somewhat later in life than is HHV-6.15,16 By 2 years of age, approximately 40% to 45% of children have antibodies to HHV-7, and by 6 years of age, 70% of children are seropositive. Like other beta herpesviruses, HHV-7 can be found in the saliva, suggesting a route for person-to-person transmission.

Primary infection is clearly associated with exanthem subitum, and the rash is clinically indistinguishable from that caused by HHV-6. It has been estimated that HHV-7 may be responsible for up to 10% of episodes of exanthem subitum. Other manifestations of primary HHV-7 infection include fever of unknown origin, simple febrile seizures, lymphadenopathy, hepatitis, and heterophile-negative mononucleosis.17 Viremia can occur either as a consequence of primary infection or from reactivation of latent infection.18 As with HHV-6, congenital infections with HHV-7 have been reported,3 although their clinical significance remains unclear.