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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.
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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
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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
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Clinical Manifestations
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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.
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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.
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Undifferentiated
Febrile Illness
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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.
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Central Nervous
System Complications
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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
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Immunocompromised
Patients
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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
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Other Human
Herpesvirus 6 Syndromes
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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.
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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.
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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.
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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.