Clinical Features of Infants With Primary Human

Clinical Features of Infants With Primary Human Herpesvirus 6 Infection (Exanthem
Subitum, Roseola Infantum)
Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga, Ikuko Kobayashi, Toshihiko Nakashima,
Takehiko Yazaki, Yuji Kajita and Takao Ozaki
Pediatrics 1994;93;104
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Clinical
Features
Yoshizo
of Infants
(Exanthem
Asano,
Toshihiko
MD*;
Nakashima,
With
Primary
Human
Herpesvirus
Subitum,
Roseola
Infantum)
Tetsushi
Yoshikawa,
MD*;
Takehiko
MD*;
Yazaki,
ABSTRACT.
Objective.
To clarify
clinical
features
of
patients
with
primary
human
herpesvirus
6 (HHV-6)
infection
(roseola
infantum,
exanthem
subitum)
in a largescale
study.
Subjects
and methods.
Clinical
signs
and symptoms
were analyzed
in 176 infants
in whom
exanthem
subitum
was initially
suspected
and primary
HHV-6
infection
was
later confirmed.
The infection
was proved
by isolation
of
the virus
from
blood,
a significant
increase
in the neu-
tralizing
antibody
titers
The
primary
Results.
to the virus,
throughout
the
ABBREVIATIONS.
virus
subitum
benign
terized
by
Recently,
human
(ES)
infectious
a fever
appearance
from
subitum;
HHV-6,
human
of skin
or roseota
disease
infantum,
of infancy,
persisting
for
rash
subsidence
after
a com-
is charac-
3 to 5 days
and
the
of the fever.
the causative
agent
of ES was identified
as
herpesvirus
6 (HHV-6),”2
originally
isolated
peripheral
blood
lymphocytes
of immunocom-
promised
patients
in 1986.
Serological
and virological methods
have
shown
that the virus
is ubiquitous
in the human
population,
seroconversion
occurs
early
in life,
and primary
infection
with
the virus
causes
a wide
spectrum
of clinical
manifestations,9’1#{176}
including
fatal outcome.1
114 Moreover,
specific
meth-
From
the
*Department
Medicine,
Kariya;
of Pediatrics,
Fujita Health
University
School
of
Department
of Pediatrics,
Kariya
Sogo
Hospital,
§Department
of Pediatrics,
Showa
Hospital,
Kohnan,
Aichi,
Toyoake;
and
Japan.
Received
Reprint
for publication
Mar 22, 1993; accepted
Jun 10, 1993.
requests
to (Y.A.) Dept of Pediatrics,
Fujita
Health
University
School
of Medicine,
Toyoake,
Aichi 470-1 1 Japan.
PEDIATRICS
(ISSN 0031 4005). Copyright
© 1994 by the American
Academy of Pediatrics.
104
PEDIATRICS
Kajita,
MD*;
MD*;
Ikuko
and
Kobayashi,
Takao
Ozaki,
MD*;
MD
ods can differentiate
ES from
many
febrile
illnesses
with
rashes
caused
by other
agents
such
as the enteroviruses
and adenoviruses.
There
is so far limited
information
about
the precise
clinical
manifestations
and
the courses
of patients
with
virologicalty
confirmed
ES.’17
In the present
study,
we analyzed
clinicat signs
and symptoms
in 176 patients
with primary
HHV-6
infection
to clarify
these
points.
MATERIALS
AND
METHODS
The study
was
conducted
between
December
1987 and
June
1992 at Fujita
Health
University
Hospital,
Toyokawa
City Hospital, Kariya
Sogo
Hospital,
and Showa
Hospital.
All infants
seen at
these
hospitals
with
fever
or skin rash
or both
and clinical
manifestations
suggestive
of ES were
enrolled.
Informed
consent
was
obtained
from
parents
of the subjects
after
the project
was thoroughly
explained.
A medical
history
and clinical
signs
and symptoms
were
recorded
every
day by parents
on a special
form for this
project,
and
the record
was
checked
every
2 to 3 days
by the
authors.
The first blood
sample
was collected
within
5 days
of the
initial
visit
to our hospital,
and
we attempted
to collect
the convalescent
sample
I to 2 weeks
later.
Infants
with
a history
of
immune
deficiency,
those
taking
cytotoxic
or immunosuppressive
drugs,
and those
who
had received
immune
globulin
within
the
past 4 weeks
were
excluded
from
participation.
The
method
for isolation
of HHV-6
was
as previously
described,2
and
antibody
activity
to HHV-6
was
measured
by the
neutralization
test as described
elsewhere.’819
herpes-
6.
Exanthem
mon
year,
ES, exanthem
Suga,
Yuji
or both.
HHV-6
infection,
which
ocwas observed
in 94 boys and
82 girls
(mean
age, 7.3 months).
Fever
developed
in 98%
(mean
maximum
fever,
39.4#{176}C)and lasted
for 4.1 days.
Macular
or papular
rashes
appeared
in 98%,
on face,
trunk,
or both,
mostly
at the time
of subsidence
of the
fever,
and lasted
for 3.8 days.
Other
clinical
manifestations
occurred
as follows:
mild
diarrhea
in 68%, edematous eyelids
in 30%, erythematous
papules
in the pharynx
in 65%, cough
in 50%, and mild
cervical
lymph
node
swelling
in 31%. Twenty-six
percent
had bulging
of the
anterior
fontanelle
and 8% had convulsions.
Conclusions.
Clinical
features
of patients
with
virologically
confirmed
exanthem
subitum
were
comparable
with
those
described
before
discovery
of
HHV-6.
Pediatrics
1994;93:104-108;
exanthem
subitum,
roseola
inf antum, human herpesvirus
6.
curred
Sadao
MD*;
6 Infection
RESULTS
Blood
samples
for
tamed
from 688 patients
disease,
and 265 paired
from
were
isolation
of HHV-6
were
obduring
the acute
stage
of the
blood
samples
were
obtained
them for determination
176 patients
in whom
of the antibody.
There
HHV-6
infection
was con-
firmed
and
clinical
manifestations
could
be evaluated;
82 patients
were
confirmed
to have
primary
HHV-6
infection
by isolation
of the virus
from blood,
18 patients
by a significant
increase
in the antibody
titers
to the virus,
and 76 patients
by both.
The first
day of an elevation
of body
temperature
37.5#{176}C was
defined
as day 0, except
when
we evaluated
the development
of skin rashes.
Because
only complete
descriptions
in I 76 records
from the patients
were evaluated,
the number
in each category
of clinical
features
is different.
There were 94 boys and 82 girls, aged 7.3 ± 2.7 (SD)
months
(range,
3 weeks
to 18 months)
(Fig 1). The age
at onset
peaked
at 6 and 7 months.
HHV-6
infection
was
observed
throughout
the year
(Fig 2), but the
monthly
incidence
was
somewhat
higher
between
March
and June.
Among
61 whose
birth
history
was
described,
56 (92%)
were
born
via birth
canal
and 5
(8%) by cesarean
section.
Feeding
method
until onset
Vol. 93 No.from
I January
1994
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pediatrics.aappublications.org
at UNIV OF CHICAGO on March 28, 2013
TABLE
2.
Characteristics
of
Herpesvirus
6 Infection*
Human
Categories
U)
U)
0
a)
in
of Fever
Maximum
body
temperature
(n
37.5-37.9#{176}C
(0
0
Fever
=
Infants
No.
E
z
1
0
2
3
4
5
6
8
1. Age
have
primary
distribution
human
15
16
days
days
days
days
days
7 days
8 days
History
of febrile
(n = 57)
1st
2nd
3rd
4th
Sth
of patients
herpesvirus
with
exanthem
6 infection.
subitum
who
U)
0)
U)
(0
0
*
Complete
0.6
24.4
40
(n
90
33
54.9
14
36
72
32
13
3
8.1
20.9
41.9
18.6
20.1
172)
=
2
3
4
5
6
17 18
in Months
Age
Fig
10 11 12 13 14
9
of fever
%
164)
40.0#{176}C
Duration
Primary
of Patients
38.0-38.9#{176}C
39.0-39.9#{176}C
.0
With
7.6
1.7
I .2
2
episodes
64.9
37
12
3
2
3
description
for
each
category
was
21.1
5.3
3.5
5.3
analyzed.
0
0)
.0
E
episode
of fever
were
observed
z
since
delivery
in 172 (98%)
HHV-6
infection
(Table
fever returned
to normal
2
1
3
4
5
6
7
8
9
10
11
12
Month
Fig
2. Monthly
distribution
of patients
who
have
primary
human
herpesvirus
cember
1987 and June
1992,
176 infants
lyzed
in four
hospitals
in Aichi,
Japan.
of the
disease
was
evaluated
with
exanthem
subitum
6 infection.
Between
Deand
children
were
ana-
in 62; 21 (34%)
received
.
infection
hire
(Table
2), with
a maximum
0.7#{176}C
(n = 164), which
(n = 172). In the majority
of 39.4
±
1.2 days
±
TABLE
With
1.
Frequency
Virologically
Confirmed
Category
Findings
Prodromal
Fevert
Rash
of Signs
and
Exanthem
of
No.
symptoms*
Cervical
eyelids
spots
lymph
node
swelling
Bulging
fontanelle
Convulsion
*
Nonspecific
t Equal
Symptoms
Subitum
of Patients
Evaluated
No.
Positive
9
173
172
116
18
32
symptoms
such
to or more
than
:: Erythematous
papules
base
of uvula.
Categories
(%)With
Findings
(14)
(98)
(98)
(68)
(30)
(65)
or irritability.
*
soft
palate
and
or both,
3.
Time
of Onset
of Skin
Rashes
and
the
then
Duration
No.
Day 0
Day I
Day 2
Day 3
Duration
of the
rash
(n = 131)
I day
2 days
3 days
4 days
5 days
6 days
7 days
8 days
39 (26)
13 ( 8)
of the
on face, or trunk,
Time
of onsett
(n = 162)
Day -3
Day -2
Day -1
19 (31)
as listlessness
37.5#{176}C.
on the mucosa
TABLE
90(50)
152
173
on which
the
as day 0, the
spread
to other
places
(n = 161) (Table
4). Mild
pigmentation
was
observed
in 11 of 155 evaluated,
but desquamation
was not observed.
Mild diarrhea
was reported
in I 16
(68%) of 171 evaluated;
it developed
on day I .5 ± 1.6
(range,
day -2 to day 6 En = 1051) and persisted
for
5.2 ± 2.5 days
(range,
I day to more
than
10 days
En = 961). Edematous
eyelids,
which
were observed
in
in Infants
63
176
176
171
60
49
173
61
Diarrhea
Edematous
Nagayama’s
Cough
body
temperapersisted
for 4.1
this was the first
3). If the day
was defined
rash appeared
on day 0 ± 1.0 (n = 162) and persisted
for 3.8 ± 1.5 days (n = 131). The nature
of rashes
was
evaluated
in 147. Papule
(rubella-like)
was observed
in 80 (54.4%),
macule
(measles-like)
in 58 (39.5%),
and
maculopapule
in 9 (6.1%).
The
rashes
initially
ap-
peared
breast-feeding,
17 (27%) bottle-feeding,
and 24 (39%)
a mixture
of breastand bottle-feedings.
Clinical
features
are summarized
in Table I Prodromal
symptoms
such as listlessness
or irritability
were observed
in 9 (14%) of 63 evaluated.
Fever was
reported
in 173 (98%) of 176 with primary
HHV-6
(n = 57). Skin rashes
of 176 with
primary
Complete
t The
was
description
day on which
defined
as day
for
body
0.
each
temperature
category
of Skin
Rashes*
%
of Patients
3
1.9
7
4.3
30
18.5
73
41
45.1
25.3
7
4.3
I
0.6
4
21
38
33
19
9
3
4
3.1
16.0
29.0
25.2
14.5
6.9
2.3
3.1
was
returned
analyzed.
to less
Downloaded from pediatrics.aappublications.org at UNIV OF CHICAGO on March 28, 2013 ARTICLES
than
37.5#{176}C
105
TABLE
4.
Initial
Initial
Sites
Sites
of the
Skin
Rashes
and
Their
Progression
(n
=
162)
Progress
Face
Face
No. of
Patients
only
Face
and
trunk
Face
and
extremities
trunk
and
Face
and
Trunk
6.8
8.0
only
28
8
17.3
4.9
4
1
32
10
16
0.6
19.8
6.2
9.9
I
3
I
2
I
1
29
0.6
1.9
0.6
1.2
0.6
0.6
17.9
extremities
only
extremities
To
Trunk
and
extremities
Trunk and extremities
To face
Extremities
only
To trunk
To face and trunk
Whole
body
area
extremities
Extremities
Whole
body
area
18 (30%) of 60 evaluated,
(n = 18) and persisted
developed
for 4.5
(Table
papules
soft
5). Erythematous
palate
and
the
base
on day
1.4
12)
±
1.6 days (n =
on the mucosa
of the
±
of uvula
spots in Japan),
which
49 evaluated,
appeared
1.7
(called
only
TABLE
Palate
6.
and
11) (Table
6).
cough,
noted
in 90
on day 0.9 ± 1.6
days.
Mild cervical
in 19 (31%)
of 61
2.6 ± 1.4 (n = 19). Bulg-
Day
Day2
Day3
Day4
Day5
Day6
=
152 evaluated,
was
=
38) and persisted
initially
for 2.6
observed
in 39 (26%)
noted
on day
± 1.2 days
(n
of
*
TABLE
they
during
were
of short
the
febrile
stage,
duration
(Table
and
in most
8). The
age
cases
served
in the
those described
since the first
occurred
5.
Time
(n
Char
the year,
actenstics
with
t
of onsett
=
18)
Complete
The first
No.
*
Complete
The first
106
for
of elevation
EXANTHEM
each
category
of fever
was
%
16.7
38.9
22.2
5.6
11.1
5.6
was
defined
analyzed.
as
day
0.
each
Time
category
of fever
of Onset
and
was
was
Duration
as
day
of Bulging
0.
Fontanelle*
N o. of Patients
%
38)
=
4
17
11
6
10.5
44.7
28.9
15.8
2
12
3
2
I
I
9.5
57.1
14.3
9.5
4.8
4.8
21)
=
description
day
analyzed.
defined
for
each
of elevation
category
of fever
was
was
analyzed.
defined
as day
0.
cases between
March and June, as pointed
byJuretic.
Of interest
is the age incidence
of patients
with ES
observed
in this study.
The peak age-range
prevalence was observed
at 6 and 7 months
of age; 64% of
the cases
Eyelids*
of Patients
for
of elevation
37.5
21.9
18.8
15.6
3.1
3.1
lday
2 days
3 days
4 days
5 days
6 days
t
%
ob-
of
3
7
4
I
2
1
description
day
of ES
a concentration
of Edematous
DayO
Day
1
Day2
Day3
Day4
Day5
*
features
present
study
were comparable
with
in many excellent
studies20’
reported
description
by Zahorsky22
in 1910. ES
throughout
TABLE
clinical
7.
Duration(n
of those
DISCUSSION
and
day
of the Soft
in Japan)*
Mucosa
Spots
12
7
6
5
I
I
Categories
tanelle.
epidemiology
I
Time
of onsett(n
Day 0
Day I
Day2
Day 3
with seizures
ranged
from 5 months
to 17 months
(mean,
10.9 months).
A convulsive
seizure
developed
in I patient
of the 39 with bulging
of the anterior
fon-
The
of Papules
on the
(Called
Nagayama’s
No. of Patients
description
first
1.5 ± 0.9 (n
=
21) (Table
7). The age of infants
with bulging
of the anterior
fontanelle
ranged
from 4 months
to I I months
(mean, 6.3
months).
During
the course
of ES, convulsive
seizures
were observed
in 13 (8%) of 173 evaluated;
all seizures
developed
Complete
1 The
Characteristics
Base of Uvula
2.5
of onsett
32)
(n
were observed
in 32 (65%) of
on day 2.3 ± I .4 (n = 32) and
evaluated,
developed
on day
ing of the anterior
fontanelle,
the
Time
Nagayama’s
persisted
for 4.4 ± 2.4 days
(n
During
the course
of ES, mild
(50%)
of 172 evaluated,
developed
(n = 71) and persisted
for 5.2 ± 2.9
lymph
node
swelling,
observed
0.6
13
Face and trunk
To extremities
To trunk
Trunk
only
To face
To face and
I
11
extremities
Totrunk
To
%
occurred
within
the first
7 months
of life and
94% within
the first year of life. The majority
of cases
of ES in Japan may occur earlier than those in Europe
and the United
States.20’21’24 This speculation
is supported
by our seroepidemiological
observafions,5’7’’19
in which the seroprevalence
increased
rapidly
from 5
and 6 months
of age to between
90% and 100% by I
to 2 years
neutralizing
of age,5’7’8
and
1gM antibodies
the
increased
was
observed
prevalence
in infants
6 months
to I year
of age.19 Moreover,
this pattern
may be further
supported
by recent
reports
in which
SUBITUM from pediatrics.aappublications.org at UNIV OF CHICAGO on March 28, 2013
Downloaded
of
TABLE
Seizures*
8.
Time
of Onset
and
Duration
of Convulsive
of
Categories
Time
of Seizure
of onsett(n
No.
of Patients
1
6
4
2
Day 1
Day 2
Duration(n
0-15
mm
11
Complete
description
first
day
7.7
46.2
30.8
15.4
II)
mm
mm
6-10
t The
=
for
of elevation
each
category
of fever
5
45.5
3
3
27.3
27.3
was
was
as day
0.
in Malaysia?20% in Morocco,
and 92% in Ecuador.26
The early
acquisition
of HHV-6
infection
in infants
may
suggest
that
the virus
is more
ubiquitous
in
Japan
than
in other
countries,
which
may be related
Since
population
density.
However,
data to clarify
this point.
the
feeding
overall
frequency
of cesarean
was similar
in the
maternal
population,
there
section
are no
and
breast-
study
population
there is nothing
and the
to sug-
gest
either
pennatal
or breast
milk
transmission.
Horizontal
transmission
from oral secretions
is likely,
since the virus
has been
frequently
detected
in saliva
We
could
saliva
not
isolate
specimens
did
frequency
possibility
the
age
not
support
scribed
in the
virus
from
adults
controversial.
more
than
including
data).
previous
of HHV-6
of perinatal
HHV-6
is still
(unpublished
virus
remains.
Most
of the clinical
mary
the
route
of healthy
of childbearing
ports
this
findings
excretion
or breast
100
women
Recent
of the
cough,
edematous
manifestations
infection
were
the
standard
textbooks.21’24
The
of
pri-
as those
de-
The
frequency
of the apparent
infection
in this study
was almost
comparable
with that reported
from Sweden,’6
but
higher
than that found
in the United
States,17 where
only
9% of the patients
with
primary
HHV-6
In addition,
the
biological
characteristics
of
the virus
strains
isolated
from
different
countries
should
be studied
because
it has been reported
that
two groups
of HHV-6
isolates
have variations
with
regard
to their
replication
and antigenic
properties.””
It is reasonable
to believe
that the rash in ES
is related
remia
If each
frequency
country
to viral
is a common
virus
localization
occurrence
strain
in the skin,
in HHV-6
has different
cellular
because
viinfection.2”5
tropisms,
of skin infection
may be different
where
the virus
is isolated.
Of interest
mild pigmentation
was observed
disappearance
of the skin rash;
type
melanocytes
and
cervical
lymphad-
rather
nonspecific
and
with
them,
those
described
in the texterythematous
papules
on the
mild,
mucosa
of soft palate
and the base
of uvula
(called
Nagayama’s
spots
in Japan)
were
observed
in 65%
of the patients
by day 4 of ES. Although
many
pediatricians
in Japan
use the spots
as the marker
for the
early diagnosis
of ES, their predictive
value
and specificity
are still controversial.
In the present
series, 26% of the patients
had bulging of the anterior
fontanelle
which
persisted
for 2.6
days
and 8% of the
All of these
episodes
veloped.
HI-IV-6
patients
occurred
had
convulsive
before
skin
seizures.
rashes
de-
Invasion
of the central
nervous
system
with
was proved
in some of these patients.’4’-7”#{176} If
these
features
are due
infection
with
HHV-6,
tions must be considered,
to acute
encephalitis
caused
by
specific
therapeutic
intervenbecause
some
patients
have
a fatal outcome
while others recover
with a variety
of
sequelae.’4”#{176} HHV-6
is sensitive
to ganciclovir
in
vitro,45’
although
clinical
efficacy
trials have not yet
been published.
ACKNOWLEDGMENT
This work
was supported,
University.
Recombinant
plied
by Takeda
Chemical
in part, by a grant
from
Fujita
Health
human
interleukin-2
was
kindly
supIndustries,
Ltd. Osaka,
Japan.
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SUBITUM from pediatrics.aappublications.org at UNIV OF CHICAGO on March 28, 2013
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Clinical Features of Infants With Primary Human Herpesvirus 6 Infection (Exanthem
Subitum, Roseola Infantum)
Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga, Ikuko Kobayashi, Toshihiko Nakashima,
Takehiko Yazaki, Yuji Kajita and Takao Ozaki
Pediatrics 1994;93;104
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