PERSPECTIVE Sixth Disease and the Ubiquity of Human Herpesviruses
Sixth Disease and the Ubiquity of Human Herpesviruses
Charles Prober, M.D.
Human herpesvirus 6 (HHV-6) is the cause of the
sixth clinically distinct exanthematous disease of
childhood. Measles virus, erythrogenic group A
streptococci, and rubella virus are the causes of the
first three diseases, and parvovirus B19 is the cause
of the fifth disease. The origin of the fourth classic
childhood illness, formerly referred to as Dukes’
disease, is controversial. Some medical historians
believe that it probably represented misdiagnosed
cases of rubella or scarlet fever, rather than a distinct
illness.
HHV-6 is so named because it was the sixth hu-
man herpesvirus to be identified. This family of
large DNA viruses includes eight known human
pathogens. In addition to HHV-6, these include her-
pes simplex virus type 1 (HSV-1), herpes simplex vi-
rus type 2 (HSV-2), varicella–zoster virus (VZV),
Epstein–Barr virus (EBV), cytomegalovirus (CMV),
human herpesvirus 7 (HHV-7), and human herpes-
virus 8 (HHV-8) (see table). Herpesviruses have
several common features. Each roughly spherical
virion is 150 nm to 200 nm in diameter and con-
sists of a 100-nm icosahedral nucleocapsid con-
taining a core of linear, double-stranded DNA viral
genome, spooled around a nucleoprotein central
mass. The nucleocapsid is surrounded by a layer of
amorphous, asymmetrically distributed material
(tegument), which, in turn, is encased by a lipid-
containing envelope with multiple glycoprotein
protrusions.
The most important biologic property shared by
all herpesviruses is their ability to establish a per-
sistent state following primary infection. This ca-
pacity means that once a person has become infect-
ed with a herpesvirus, he or she is forever susceptible
to periodic viral reactivation. Reactivation results in
the emergence of transmissible virus. The site of vi-
ral latency varies. Even in the absence of signs or
symptoms of infection, common sites of periodic
Dr. Prober is a professor of pediatrics and of microbiolo-
gy and immunology at Stanford University School of
Medicine and scientific director of the Glaser Pediatric
Research Network — both in Stanford, Calif.
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Related article, page 768
appearance of herpesviruses include oral secretions
(for HSV-1, EBV, CMV, HHV-6, and HHV-7), genital
secretions (HSV-2, CMV, and HHV-6), urine (CMV),
mononuclear cells (CMV, HHV-6, and HHV-7), and
breast milk (CMV and HHV-7). Host immunity in-
fluences both the likelihood of reactivation and the
severity of clinical illness. In general, the greater the
degree of immune impairment, the more substan-
tial the consequences of herpesvirus reactivation.
Given the high incidence of all herpesvirus in-
fections (except HHV-8 infection) and the biologic
phenomenon of latency, the ubiquity of these virus-
es is readily apparent. In the United States, infec-
tions caused by HSV-1 begin in infancy, and at least
50 percent of young adults have been infected. In-
fections caused by HSV-2 begin with the onset of
sexual activity, and an estimated 25 percent of U.S.
adults have contracted infection. EBV infections in-
crease in frequency during adolescence, and most
of the population is infected by middle age. CMV is
the most common cause of congenital infection,
with 1 percent of all newborns infected; postnatal
infections begin to occur within the first few weeks
of life, and by early adulthood approximately 50 per-
cent of the population is seropositive. Before the
development of a vaccine for VZV, chickenpox (VZV
infection) occurred in virtually all people by late
childhood; the epidemiology of infection has been
changing since the introduction of universal vacci-
nation.
In this issue of the Journal, Zerr et al. (pages
768–776) note that approximately three quarters of
children have been infected with HHV-6 by two
years of age. Data from other studies suggest that
infection with HHV-7 has a similar epidemiologic
pattern. Clearly, herpesvirus infections are omni-
present, and at any given time, a substantial pro-
portion of the population is shedding one or more
of these infectious agents, maintaining the chain of
transmission and the high prevalence of infection.
Even though the majority of infections caused by
herpesviruses are asymptomatic or mild (see figure),
the morbidity attributable to these agents remains
substantial. Furthermore, death due to herpesvirus-
753
PERSPECTIVE Sixth Disease and the Ubiquity of Human Herpesviruses

Human Herpesviruses.

Approximate
Seroprevalence
among Young Common Site of Mode of
Virus U.S. Adults (%) Infections Persistence Transmission
Herpes simplex virus 50 Herpes labialis, herpes Neuronal cells, espe- Contact with secretions,
type 1 whitlow, herpetic ker- cially trigeminal especially oral
atitis, herpes simplex ganglia
encephalitis
Herpes simplex virus 25 Herpes genitalis, herpes Neuronal cells, espe- Contact with secretions,
type 2 proctitis, neonatal cially sacral gan- especially genital
herpes glia
Varicella–zoster virus 100 Chickenpox, herpes Neuronal cells, espe- Contact with infected skin
zoster (shingles) cially posterior lesions; respiratory
root ganglia route for chickenpox
Epstein–Barr virus 75 Infectious mononucleo- B lymphocytes Contact with oral secre-
sis, prolonged fever, tions, blood, or trans-
multiorgan manifes- planted organs
tations
Cytomegalovirus 50 Infectious mononucleo- Monocytes, macro- Contact with oral or genital
sis, prolonged fever phages secretions, urine,
breast milk, blood, or
transplanted organs
Human herpesvirus 6 100 Febrile illness, roseola T lymphocytes Contact with oral secre-
tions
Human herpesvirus 7 100 Febrile illness, roseola T lymphocytes Contact with oral secre-
tions or breast milk
Human herpesvirus 8 <10 Kaposi’s sarcoma Not established Contact with bodily secre-
tions

es is a major issue for the ever-increasing popula-
tion of immunocompromised persons. HSV-1 in-
fections cause herpes labialis, whose manifestations
range from periodic mild discomfort accompanied
by a few perioral vesicles to a severe infection neces-
sitating hospitalization. HSV-1 is also responsible
for most cases of herpetic whitlow and other cuta-
neous eruptions (e.g., herpes gladiatorum and ec-
zema herpeticum), herpetic keratitis, and a severe
form of nonseasonal, focal encephalitis. HSV-2 is
the predominant cause of genital herpes, herpes
proctitis, and neonatal herpes infections.
The most common manifestation of EBV infec-
tion is infectious mononucleosis, although EBV has
also been proposed as a cause of myriad diseases in-
volving virtually every organ in the body. The mani-
festations of CMV infection overlap substantially
with those of EBV infection, and both viruses are
important causes of prolonged febrile illnesses in
normal hosts. VZV causes chickenpox and, with re-
activation, herpes zoster.
The pathogenic role of herpesviruses in some
types of cancer is well established (e.g., EBV has a
role in Burkitt’s lymphoma in Africa, nasal pharyn-
geal carcinoma, and post-transplantation lympho-
proliferative disorder, and HHV-8 has a role in Ka-
posi’s sarcoma). In contrast, the role of these
viruses in several chronic diseases, such as multi-
ple sclerosis and the chronic fatigue syndrome,
continues to be debated.
Although HHV-6 was initially isolated in 1986
from the B lymphocytes of immunocompromised
adults, within two years it was described as the
cause of most cases of roseola (sixth disease). The
classic clinical picture of roseola, dating back to
1910, is three to five days of high fever in an infant,
followed by the acute onset of a rose-pink, nonpru-
ritic, macular rash, predominantly on the neck and
trunk. Because of the abrupt onset of the rash, the
disease was called exanthema subitum (“subitum”
meaning “sudden” in Latin).
Subsequent reports identified HHV-6 as a major
cause of illness in young children who were brought
to emergency departments for the evaluation of fe-

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 PERSPECTIVE
EBV HSV- 1
HSV- 2 VZV
HHV- 6 CMV
Clinical Characteristics of Herpesviruses.
The image of Epstein–Barr virus (EBV) infection shows a child with exudative
pharyngitis associated with infectious mononucleosis, the image of herpes
simplex virus type 1 (HSV-1) infection shows a paronychial infection (herpetic
whitlow), the image of herpes simplex virus type 2 (HSV-2) infection shows
ulcerative lesions on the vulva (genital herpes), the image of varicella–zoster
virus (VZV) infection shows vesicular lesions in a dermatomal distribution
(herpes zoster), the image of human herpesvirus 6 (HHV-6) infection shows
a child with the rash of roseola, and the image of cytomegalovirus (CMV) in-
fection shows chorioretinitis consistent with infection in an immunocompro-
mised host. EBV courtesy of Stanley Martin, M.D.
ver. Depending on the specific age range of the
population studied, 10 to 50 percent of febrile ill-
nesses leading to an emergency room visit have
been attributed to HHV-6 infection, the peak age of
infection being six to nine months. The conse-
quences of HHV-6 infection diagnosed in children
in emergency departments may be substantial;
among those younger than two years of age who
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Sixth Disease and the Ubiquity of Human Herpesviruses
have HHV-6 infection, more than 10 percent have
febrile seizures, and more than 10 percent are hos-
pitalized. HHV-6 appears to account for approxi-
mately one third of febrile seizures in children in
this age group.
The lack of a prospective, population-based study
of HHV-6 beyond the acute care setting had limited
our understanding of the full spectrum of illness
that is attributable to this virus. Zerr et al. have ad-
dressed this shortcoming. Using an intensive study
design that included the collection of weekly sam-
ples of saliva for the diagnosis of HHV-6 infection
on the basis of quantitative DNA testing, the Seattle
investigators prospectively followed a cohort of 277
infants from birth through two years of age. The fre-
quency and types of clinical illness associated with
HHV-6 infection were determined on the basis of
daily illness logs, and symptoms were compared
with those in age-matched controls who were not
acutely infected with HHV-6.
More than three quarters of the infants were in-
fected with HHV-6 by the second year of life, and
more than 90 percent of the infections were associ-
ated with symptoms. Fever and fussiness were the
most common manifestations of infection; roseola
was diagnosed in about one quarter of the study
population. Almost 40 percent of the children were
evaluated by a physician for symptoms coincident
with their HHV-6 infection. In contrast to studies
involving febrile young children recruited from
emergency departments, this study showed that
seizures were not a feature of HHV-6 infection.
Remarkably, HHV-6 DNA remained detectable
at moderately high levels in saliva for at least 12
months after the initial infection. Although the pre-
cise relationship between the quantity of viral DNA
and transmissible virus has not been established,
previous studies have indicated that saliva is the
principal source of infectious virus. Previous studies
also have demonstrated that persons who are sero-
positive for EBV, CMV, HSV-1, and HSV-2 shed reac-
tivated virus frequently throughout their lives. Taken
together, these studies underscore an inescapable
epidemiologic fact: herpesviruses are ubiquitous.
755