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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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1994 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Clinical

Features

of Infants (Exanthem

With Primary Human Herpesvirus Subitum, Roseola Infantum)

6 Infection

Yoshizo Toshihiko

Asano, Nakashima,

MD*;

Tetsushi MD*;

Yoshikawa, Takehiko Yazaki,

MD*; MD*;

Sadao Yuji

Suga, Kajita,

MD*; MD*;

Ikuko and

Kobayashi, Takao Ozaki,

MD*; MD

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-

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
AND

points.

tralizing
Results.
curred

antibody
The
throughout

titers
primary
the

to the virus,
year,

or both.
MATERIALS 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

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.

ABBREVIATIONS.

ES, exanthem

subitum;

HHV-6,

human

herpes-

RESULTS

virus

6.

Exanthem

subitum

(ES) persisting

or roseota for

infantum, 3 to 5 days

a com-

Blood samples for tamed from 688 patients disease, and 265 paired

isolation of HHV-6 were obduring the acute stage of the blood samples were obtained

mon
terized

benign
by

infectious
a fever

disease rash after

of infancy, subsidence

is characand the

from were

them for determination 176 patients in whom

of the antibody. There HHV-6 infection was con-

appearance
Recently, human

of skin

of the fever.

the causative agent of ES was identified as herpesvirus 6 (HHV-6),2 originally isolated

from

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,91#{176} including fatal outcome.1 114 Moreover, specific meth-

From
Medicine, Kariya;

the and

*Department
Toyoake;

of Pediatrics, Fujita Health University School of Department of Pediatrics, Kariya Sogo Hospital, Department of Pediatrics, Showa Hospital, Kohnan, Aichi,

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.

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

104

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TABLE
Human
U)

2. Characteristics of Herpesvirus 6 Infection* Categories of Fever

Fever

in

Infants

With

Primary

No.

of Patients

(0 0
0

U)

Maximum body temperature (n 37.5-37.9#{176}C 38.0-38.9#{176}C 39.0-39.9#{176}C

164) 40 90 33 0.6 24.4

a)
.0

54.9
20.1 8.1 20.9 41.9 18.6
7.6

40.0#{176}C
Duration 2 3 4 5 6 of fever (n
=

172) 14 36 72 32 13 3
2

10 11 12 13 14

15

16

17 18

Age

in Months
with exanthem 6 infection. subitum who

Fig
have

1. Age
primary

distribution human

of patients herpesvirus

U)

0) U) (0
*

days days days days days 7 days 8 days History of febrile (n = 57) 1st 2nd 3rd 4th Sth Complete description

1.7 I .2

episodes 37 12 3 2 3 for each category was analyzed. 64.9

21.1

5.3 3.5 5.3

0 0) .0

episode of fever were observed

since delivery in 172 (98%)

(n = 57). Skin rashes of 176 with primary

HHV-6 infection (Table fever returned to normal

1

3). If the day was defined

on which the as day 0, the

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.
with exanthem subitum 6 infection. Between Deand children were ana-

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
received

on face, or trunk,

or both,

then

spread

to other

of the

disease

was

evaluated

in 62; 21 (34%)

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
.

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

infection

(Table

hire

of 39.4
1.2 days
1.
Virologically Category Findings Prodromal Fevert Rash

2), with a maximum 0.7#{176}C (n = 164), which (n = 172). In the majority

Frequency
Confirmed of of Signs and Exanthem No.

body temperapersisted for 4.1 this was the first

in Infants

TABLE
Categories

3.

Time of Skin

of Onset Rashes

and

Duration No.

of Skin of Patients

Rashes* %

TABLE
With

Symptoms Subitum

of Patients Evaluated 63 176 176 171 60 49 173 61 152 173

No. Positive 9 173 172 116 18 32

(%)With Findings (14) (98) (98) (68) (30) (65)

Time of onsett (n = 162) Day -3 Day -2 Day -1 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
*

1.9

7
30 73 41

4.3
18.5 45.1 25.3

symptoms*

7
I

4.3
0.6

Diarrhea
Edematous Nagayamas Cough
Cervical

eyelids spots

90(50)
19 (31) 39 (26) 13 ( 8) or irritability. of the soft palate and the

lymph

node

swelling Bulging fontanelle Convulsion

*

Nonspecific

symptoms

such

as listlessness

4 21 38 33 19 9 3 4 for body 0. each temperature category was returned analyzed. to less than

3.1 16.0 29.0 25.2 14.5 6.9 2.3 3.1

to or more than :: Erythematous papules base of uvula.

t Equal

37.5#{176}C. on the mucosa

Complete

description

t The

was

day on which defined as day

37.5#{176}C

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105

TABLE

4.
Initial

Initial Sites

Sites

of the

Skin

Rashes

and

Their

Progression

(n

162) No. of Patients I

11

Progress

Face

Face
Totrunk

only trunk and extremities only only

0.6 6.8 8.0 17.3 4.9 2.5 0.6 19.8 6.2 9.9 0.6 1.9 0.6 1.2 0.6 0.6 17.9

To Face Face and and trunk extremities

13 28 8 4 1 32 10 16 I 3 I 2 I 1 29

Face and trunk To extremities Face and extremities To trunk Trunk only To face To face and To

Trunk

extremities only

Trunk
Extremities

and

extremities

Whole

body

area

extremities Trunk and extremities To face Extremities only To trunk To face and trunk Whole body area

18 (30%) of 60 evaluated, (n = 18) and persisted

developed for 4.5

on day

1.7

(Table
soft

5). Erythematous
palate and the base

papules
of uvula

1.6 days (n = on the mucosa of the

(called Nagayamas

1.4 12)

TABLE
Palate

6.
and the

Characteristics Base of Uvula

of Papules on the (Called Nagayamas

Mucosa Spots

of the Soft in Japan)* %

Time (n

of onsett 32) Day Day2 Day3 Day4 Day5 Day6 I

No. of Patients

spots in Japan), which 49 evaluated, appeared

were observed in 32 (65%) of on day 2.3 I .4 (n = 32) 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=

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

12 7 6 5 I I for each category was was defined analyzed. as day

37.5 21.9 18.8 15.6 3.1 3.1

Complete

description day of elevation

1 The

first
7.

of fever

0.

evaluated, developed on day ing of the anterior fontanelle,

152 evaluated, was = 38) and persisted initially for 2.6

observed

in 39 (26%)

of

TABLE

Time Categories

of Onset

and

Duration

of Bulging

Fontanelle* %

noted on day 1.2 days (n

1.5 0.9 (n = 21) (Table

N o. of Patients
=

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 during the febrile stage, and in most cases

Time of onsett(n Day 0 Day I Day2 Day 3

Duration(n
=

38) 4 17 11 6 10.5 44.7 28.9 15.8 9.5 57.1 14.3 9.5 4.8 4.8 analyzed. as day 0.

21) 2 12 3 2 I I

they

were

of short

duration

(Table

8). The

age

of those

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 fontanelle.
*

lday 2 days 3 days 4 days 5 days 6 days Complete description day of elevation for each category was

was defined

DISCUSSION
t

The first

of fever

The

epidemiology

and

clinical

features

of ES

ob-

served in the those described since the first

occurred
TABLE
Time (n

present study were comparable with in many excellent studies20 reported description by Zahorsky22 in 1910. ES
the year, with a concentration of

throughout
5.
of onsett = 18)

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 occurred within the first 7 months of life and

Char

actenstics

of Edematous No. of Patients

Eyelids* %

DayO Day 1 Day2 Day3 Day4 Day5

*

3 7 4 I 2 1 for each category was was defined analyzed. as day 0.

16.7 38.9 22.2 5.6 11.1 5.6

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.202124 This speculation is supported by our seroepidemiological observafions,5719 in which the seroprevalence increased rapidly from 5 and 6 months of age to between 90% and 100% by I
to 2 years of age,578 and the increased prevalence of

neutralizing

1gM antibodies

was

observed

in infants

Complete

description day of elevation

The first

of fever

6 months to I year of age.19 Moreover, this pattern may be further supported by recent reports in which

106

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TABLE Seizures*

8.

Time

of Onset

and

Duration

of Convulsive

been
of
%

reported
HHV-6

previously.
strain having

It is possible
a tropism

that some
to melanocytes

type

Categories Time

of Seizure
=

No. 13)

of Patients

of onsett(n

stimulated the cells in the skin. However, it is likely that simultaneous infection with other viruses does
occur in some patients with ES,35 since the most maternal antibodies are lost by I year of age. The characteristics of other clinical features such as diarrhea,

Day -1 DayO Day 1 Day 2 Duration(n 0-15 mm

6-10

1 6 4 2
=

7.7 46.2 30.8 15.4 45.5 27.3 27.3 analyzed. as day 0.

cough,
enopathy,

edematous
which

eyelids,
were rather

and

cervical

lymphadand mild,

II) 5 3 3 for each category was was defined

nonspecific

11
*

mm mm description day of elevation

were comparable books.2124 Among

with them,

those described in the texterythematous papules on the

Complete first

t The

of fever

there appeared to be some relationship between prevalence and ethnicity or geographic location; the prevalence is 49% to 76% depending on ethnic origin
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

mucosa of soft palate and the base of uvula (called Nagayamas 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 patients occurred had convulsive before skin seizures. rashes de-

to a higher comparative
Since the

population density. However, data to clarify this point.

frequency of cesarean section

there
and

are no
breast-

veloped. HI-IV-6

Invasion of the central nervous system with was proved in some of these patients.4-7#{176} If
to acute encephalitis caused by specific therapeutic intervenbecause some patients have

feeding overall

was similar in the maternal population,

study population there is nothing

and the to sug-

these features are due infection with HHV-6, tions must be considered,

gest either pennatal or breast milk transmission. Horizontal transmission from oral secretions is likely, since the virus has been frequently detected in saliva

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.

of healthy adults2728 and the virus-specific DNA and antigen have been identified in salivary and bronchial
glands.29#{176} However, this route is still controversial.

We
saliva ports

could

not

isolate age
support

the

virus
adults

from

more data).

than
women

100 rehigh

specimens did not

of healthy previous

including findings

of childbearing frequency possibility

the
mary

(unpublished excretion or breast

manifestations

Recent
of the

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in the

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The frequency

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herpesvirus-6

POWER

STRUGGLES IN MEDICAL PRACTICE

been discussed as soon as one That tension is
and

[There isi a central ethical tension in medicine which has rarely explicitly in the medical literature but which demands consideration looks at the patient-physician encounter in terms of relative power.
between sympathy care and work-between and the impersonalized the individualized demands of the demands efficient

of compassion workplace.

Brody

H. The Healers

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New

Haven:

Yale

University

Press;

1992.

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by Student

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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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