Clinical Features of Infants With Primary Human ......Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga,...

1994;93;104PediatricsTakehiko Yazaki, Yuji Kajita and Takao Ozaki

Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga, Ikuko Kobayashi, Toshihiko Nakashima,Subitum, Roseola Infantum)

Clinical Features of Infants With Primary Human Herpesvirus 6 Infection (Exanthem

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104 PEDIATRICS Vol. 93 No. I January 1994

Clinical Features of Infants With Primary Human Herpesvirus 6 Infection(Exanthem Subitum, Roseola Infantum)

Yoshizo Asano, MD*; Tetsushi Yoshikawa, MD*; Sadao Suga, MD*; Ikuko Kobayashi, MD*;

Toshihiko Nakashima, MD*; Takehiko Yazaki, MD*; Yuji Kajita, MD*; and Takao Ozaki, MD�

ABSTRACT. Objective. To clarify clinical features ofpatients with primary human herpesvirus 6 (HHV-6) in-fection (roseola infantum, exanthem subitum) in a large-scale study.

Subjects and methods. Clinical signs and symptomswere analyzed in 176 infants in whom exanthem subitumwas initially suspected and primary HHV-6 infection waslater confirmed. The infection was proved by isolation ofthe virus from blood, a significant increase in the neu-tralizing antibody titers to the virus, or both.

Results. The primary HHV-6 infection, which oc-curred throughout the year, was observed in 94 boys and82 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 thefever, and lasted for 3.8 days. Other clinical manifesta-tions occurred as follows: mild diarrhea in 68%, edema-tous eyelids in 30%, erythematous papules in the pharynxin 65%, cough in 50%, and mild cervical lymph nodeswelling in 31%. Twenty-six percent had bulging of theanterior fontanelle and 8% had convulsions.

Conclusions. Clinical features of patients with viro-logically confirmed exanthem subitum were comparablewith those described before discovery of HHV-6.Pediatrics 1994;93:104-108; exanthem subitum, roseola in-f antum, human herpesvirus 6.

ods can differentiate ES from many febrile illnesseswith rashes caused by other agents such as the en-teroviruses and adenoviruses. There is so far limited

information about the precise clinical manifestationsand the courses of patients with virologicalty con-firmed ES.’�17 In the present study, we analyzed clini-

cat 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 Hospi-

tal, Kariya Sogo Hospital, and Showa Hospital. All infants seen at

these hospitals with fever or skin rash or both and clinical mani-

festations suggestive of ES were enrolled. Informed consent was

obtained from parents of the subjects after the project was thor-

oughly explained. A medical history and clinical signs and symp-

toms 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 con-

valescent 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 de-

scribed,2 and antibody activity to HHV-6 was measured by the

neutralization test as described elsewhere.’819

ABBREVIATIONS. ES, exanthem subitum; HHV-6, human herpes-

virus 6.

Exanthem subitum (ES) or roseota infantum, a com-mon benign infectious disease of infancy, is charac-terized by a fever persisting for 3 to 5 days and theappearance of skin rash after subsidence of the fever.Recently, the causative agent of ES was identified ashuman herpesvirus 6 (HHV-6),”2 originally isolated

from peripheral blood lymphocytes of immunocom-promised patients in 1986.� Serological and virologi-cal methods have shown that the virus is ubiquitous

in the human population,� seroconversion occursearly in life,� and primary infection with the viruscauses a wide spectrum of clinical manifestations,9’1#{176}including fatal outcome.1 114 Moreover, specific meth-

From the *Department of Pediatrics, Fujita Health University School of

Medicine, Toyoake; �Department of Pediatrics, Kariya Sogo Hospital,

Kariya; and §Department of Pediatrics, Showa Hospital, Kohnan, Aichi,

Japan.

Received for publication Mar 22, 1993; accepted Jun 10, 1993.

Reprint 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 Acad-

emy of Pediatrics.

RESULTS

Blood samples for isolation of HHV-6 were ob-tamed from 688 patients during the acute stage of the

disease, and 265 paired blood samples were obtainedfrom them for determination of the antibody. Therewere 176 patients in whom HHV-6 infection was con-firmed and clinical manifestations could be evalu-ated; 82 patients were confirmed to have primaryHHV-6 infection by isolation of the virus from blood,18 patients by a significant increase in the antibodytiters to the virus, and 76 patients by both. The firstday of an elevation of body temperature �37.5#{176}C was

defined as day 0, except when we evaluated the de-velopment of skin rashes. Because only complete de-scriptions in I 76 records from the patients were evalu-

ated, the number in each category of clinical featuresis different.

There were 94 boys and 82 girls, aged 7.3 ± 2.7 (SD)months (range, 3 weeks to 18 months) (Fig 1). The ageat onset peaked at 6 and 7 months. HHV-6 infectionwas observed throughout the year (Fig 2), but themonthly incidence was somewhat higher betweenMarch and June. Among 61 whose birth history wasdescribed, 56 (92%) were born via birth canal and 5(8%) by cesarean section. Feeding method until onset



U)

U)(0

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a).0

E

z

40

90

33

14

36

72

32

13

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2

37

12

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2

3

U)

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0.6

24.4

54.920.1

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20.9

41.9

18.6

7.6

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64.9

21.1

5.3

3.5

5.3

* Complete description for each category was analyzed.

%

ARTICLES 105

0 1 2 3 4 5 6 8 9 10 11 12 13 14 15 16 17 18

Age in Months

Fig 1. Age distribution of patients with exanthem subitum who

have primary human herpesvirus 6 infection.

1 2 3 4 5 6 7 8 9 10 11 12

Month

Fig 2. Monthly distribution of patients with exanthem subitum

who have primary human herpesvirus 6 infection. Between De-

cember 1987 and June 1992, 176 infants and children were ana-

lyzed in four hospitals in Aichi, Japan.

of the disease was evaluated in 62; 21 (34%) receivedbreast-feeding, 17 (27%) bottle-feeding, and 24 (39%)a mixture of breast- and bottle-feedings.

Clinical features are summarized in Table I . Pro-dromal symptoms such as listlessness or irritabilitywere observed in 9 (14%) of 63 evaluated. Fever wasreported in 173 (98%) of 176 with primary HHV-6infection (Table 2), with a maximum body tempera-

hire of 39.4 ± 0.7#{176}C(n = 164), which persisted for 4.1

± 1.2 days (n = 172). In the majority this was the first

TABLE 1. Frequency of Signs and Symptoms in Infants

With Virologically Confirmed Exanthem Subitum

Category of

Findings

No. of Patients

Evaluated

No. (%)With

Positive Findings

Prodromal symptoms* 63 9 (14)

Fevert 176 173 (98)

Rash 176 172 (98)

Diarrhea 171 116 (68)

Edematous eyelids 60 18 (30)

Nagayama’s spots� 49 32 (65)

Cough 173 90(50)Cervical lymph node 61 19 (31)

swelling

Bulging fontanelle 152 39 (26)

Convulsion 173 13 ( 8)

* Nonspecific symptoms such as listlessness or irritability.

t Equal to or more than 37.5#{176}C.

:�: Erythematous papules on the mucosa of the soft palate and the

base of uvula.

TABLE 2. Characteristics of Fever in Infants With Primary

Human Herpesvirus 6 Infection*

Categories of Fever No. of Patients %

Maximum body

temperature (n = 164)

37.5-37.9#{176}C

38.0-38.9#{176}C

39.0-39.9#{176}C

�40.0#{176}CDuration of fever (n = 172)

2 days

3 days

4 days

5 days

6 days

7 days

8 days

History of febrile episodes

(n = 57)

1st

2nd

3rd

4th

�Sth

episode of fever since delivery (n = 57). Skin rasheswere observed in 172 (98%) of 176 with primaryHHV-6 infection (Table 3). If the day on which thefever returned to normal was defined as day 0, therash appeared on day 0 ± 1.0 (n = 162) and persistedfor 3.8 ± 1.5 days (n = 131). The nature of rashes wasevaluated in 147. Papule (rubella-like) was observedin 80 (54.4%), macule (measles-like) in 58 (39.5%), andmaculopapule in 9 (6.1%). The rashes initially ap-

peared on face, or trunk, or both, then spread to otherplaces (n = 161) (Table 4). Mild pigmentation wasobserved in 11 of 155 evaluated, but desquamationwas 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 for5.2 ± 2.5 days (range, I day to more than 10 daysEn = 961). Edematous eyelids, which were observed in

TABLE 3. Time of Onset and Duration of Skin Rashes*

Categories of Skin Rashes No. of Patients

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

3 1.9

7 4.330 18.5

73 45.1

41 25.3

7 4.3I 0.6

4 3.1

21 16.0

38 29.0

33 25.2

19 14.5

9 6.9

3 2.3

4 3.1


t The day on which body temperature returned to less than 37.5#{176}C

was defined as day 0.



TABLE 4. Initial Sites of the Skin Rashes and Their Progression (n = 162)

106 EXANTHEM SUBITUM

Face

Initial Sites

Face and trunk

Face and extremities

Trunk

Trunk and extremities

Extremities

Whole body area

Progress No. of %

Patients

Face only I 0.6

Totrunk 11 6.8

To trunk and extremities 13 8.0

Face and trunk only 28 17.3

To extremities 8 4.9

Face and extremities only 4 2.5

To trunk 1 0.6

Trunk only 32 19.8

To face 10 6.2

To face and extremities 16 9.9

To extremities I 0.6

Trunk and extremities only 3 1.9

To face I 0.6

Extremities only 2 1.2

To trunk I 0.6

To face and trunk 1 0.6

Whole body area 29 17.9

18 (30%) of 60 evaluated, developed on day 1.7 ± 1.4

(n = 18) and persisted for 4.5 ± 1.6 days (n = 12)(Table 5). Erythematous papules on the mucosa of thesoft palate and the base of uvula (called Nagayama’s

spots in Japan), which were observed in 32 (65%) of49 evaluated, appeared on day 2.3 ± I .4 (n = 32) and

persisted for 4.4 ± 2.4 days (n = 11) (Table 6).During the course of ES, mild cough, noted in 90

(50%) of 172 evaluated, developed on day 0.9 ± 1.6(n = 71) and persisted for 5.2 ± 2.9 days. Mild cervicallymph node swelling, observed in 19 (31%) of 61evaluated, developed on day 2.6 ± 1.4 (n = 19). Bulg-ing of the anterior fontanelle, observed in 39 (26%) of152 evaluated, was initially noted on day 1.5 ± 0.9 (n

= 38) and persisted for 2.6 ± 1.2 days (n = 21) (Table7). The age of infants with bulging of the anterior fon-tanelle ranged from 4 months to I I months (mean, 6.3months). During the course of ES, convulsive seizureswere observed in 13 (8%) of 173 evaluated; all seizuresdeveloped during the febrile stage, and in most cases

they were of short duration (Table 8). The age of thosewith seizures ranged from 5 months to 17 months(mean, 10.9 months). A convulsive seizure developedin I patient of the 39 with bulging of the anterior fon-tanelle.

DISCUSSION

The epidemiology and clinical features of ES ob-

served in the present study were comparable withthose described in many excellent studies20’� reportedsince the first description by Zahorsky22 in 1910. ESoccurred throughout the year, with a concentration of

TABLE 5. Char actenstics of Edematous Eyelids*

Time of onsett No. of Patients %

(n = 18)

DayO 3 16.7

Day 1 7 38.9

Day2 4 22.2

Day3 I 5.6

Day4 2 11.1

Day5 1 5.6


t The first day of elevation of fever was defined as day 0.

TABLE 6. Characteristics of Papules on the Mucosa of the SoftPalate and the Base of Uvula (Called Nagayama’s Spots in Japan)*

Time of onsett No. of Patients %

(n - 32)

Day I 12 37.5

Day2 7 21.9

Day3 6 18.8

Day4 5 15.6

Day5 I 3.1

Day6 I 3.1


1� The first day of elevation of fever was defined as day 0.

TABLE 7. Time of Onset and Duration of Bulging Fontanelle*

Categories N o. of Patients %

Time of onsett(n = 38)

Day 0 4 10.5

Day I 17 44.7

Day2 11 28.9

Day 3 6 15.8

Duration(n = 21)

lday 2 9.5

2 days 12 57.1

3 days 3 14.3

4 days 2 9.5

5 days I 4.8

6 days I 4.8



cases between March and June, as pointed byJuretic.�Of interest is the age incidence of patients with ESobserved in this study. The peak age-range preva-lence was observed at 6 and 7 months of age; 64% ofthe cases occurred within the first 7 months of life and94% within the first year of life. The majority of casesof ES in Japan may occur earlier than those in Europeand the United States.20’21’24 This speculation is sup-ported by our seroepidemiological observafions,5’7’�’19in which the seroprevalence increased rapidly from 5and 6 months of age to between 90% and 100% by Ito 2 years of age,5’7’8 and the increased prevalence ofneutralizing 1gM antibodies was observed in infants6 months to I year of age.19 Moreover, this patternmay be further supported by recent reports in which



ARTICLES 107

TABLE 8. Time of Onset and Duration of Convulsive

Seizures*

Categories of Seizure No. of Patients %

Time of onsett(n = 13)

Day -1 1 7.7DayO 6 46.2

Day 1 4 30.8

Day 2 2 15.4

Duration(n = II)

0-15 mm 5 45.5

6-10 mm 3 27.3�11 mm 3 27.3



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

in Malaysia?-� 20% in Morocco, and 92% in Ecuador.26The early acquisition of HHV-6 infection in infants

may suggest that the virus is more ubiquitous inJapan than in other countries, which may be relatedto a higher population density. However, there are nocomparative data to clarify this point.

Since the frequency of cesarean section and breast-feeding was similar in the study population and theoverall maternal population, there is nothing to sug-gest either pennatal or breast milk transmission.Horizontal transmission from oral secretions is likely,since the virus has been frequently detected in salivaof healthy adults2728 and the virus-specific DNA andantigen have been identified in salivary and bronchialglands.29’�#{176} However, this route is still controversial.We could not isolate the virus from more than 100saliva specimens of healthy adults including womenof childbearing age (unpublished data). Recent re-ports did not support previous findings of the highfrequency of HHV-6 excretion from saliva.31’32 Thepossibility of perinatal or breast milk transmission ofthe virus remains.

Most of the clinical manifestations of ES with pri-mary HHV-6 infection were the same as those de-scribed in the standard textbooks.21’24 The frequencyof the apparent infection in this study was almostcomparable with that reported from Sweden,’6 buthigher than that found in the United States,17 whereonly 9% of the patients with primary HHV-6 infection

had a rash typical of ES. Although the reason for thisdiscrepancy is unknown, it is likely that the differencebetween experimental designs conducted in both lo-cations might influence the apparent frequency of theinfection. In addition, the biological characteristics ofthe virus strains isolated from different countries

should be studied because it has been reported thattwo groups of HHV-6 isolates have variations withregard to their replication and antigenic proper-ties.�”” It is reasonable to believe that the rash in ESis related to viral localization in the skin, because vi-remia is a common occurrence in HHV-6 infection.2”5

If each virus strain has different cellular tropisms, thefrequency of skin infection may be different in eachcountry where the virus is isolated. Of interest is thatmild pigmentation was observed in I I patients afterdisappearance of the skin rash; this finding has not

been reported previously. It is possible that some typeof HHV-6 strain having a tropism to melanocytesstimulated the cells in the skin. However, it is likelythat simultaneous infection with other viruses doesoccur in some patients with ES,35 since the most ma-ternal antibodies are lost by I year of age. The char-

acteristics of other clinical features such as diarrhea,cough, edematous eyelids, and cervical lymphad-enopathy, which were rather nonspecific and mild,were comparable with those described in the text-books.21’24 Among them, erythematous papules on themucosa of soft palate and the base of uvula (calledNagayama’s spots� in Japan) were observed in 65%of the patients by day 4 of ES. Although many pe-diatricians in Japan use the spots as the marker for theearly diagnosis of ES, their predictive value and speci-

ficity are still controversial.In the present series, 26% of the patients had bulg-

ing of the anterior fontanelle which persisted for 2.6days and 8% of the patients had convulsive seizures.All of these episodes occurred before skin rashes de-veloped. Invasion of the central nervous system withHI-IV-6 was proved in some of these patients.’4’-�7”#{176} Ifthese features are due to acute encephalitis caused byinfection with HHV-6, specific therapeutic interven-

tions must be considered, because some patients havea fatal outcome while others recover with a variety ofsequelae.’4”#{176}� HHV-6 is sensitive to ganciclovir invitro,45’� although clinical efficacy trials have not yetbeen published.

ACKNOWLEDGMENT

This work was supported, in part, by a grant from Fujita Health

University. Recombinant human interleukin-2 was kindly sup-

plied by Takeda Chemical Industries, Ltd. Osaka, Japan.

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POWER STRUGGLES IN MEDICAL PRACTICE

[There isi a central ethical tension in medicine which has rarely been discussed

explicitly in the medical literature but which demands consideration as soon as one

looks at the patient-physician encounter in terms of relative power. That tension is

between care and work-between the individualized demands of compassion and

sympathy and the impersonalized demands of the efficient workplace.

Brody H. The Healer’s Power. New Haven: Yale University Press; 1992.

Submitted by Student



1994;93;104PediatricsTakehiko Yazaki, Yuji Kajita and Takao Ozaki

Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga, Ikuko Kobayashi, Toshihiko Nakashima,Subitum, Roseola Infantum)

Clinical Features of Infants With Primary Human Herpesvirus 6 Infection (Exanthem

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Clinical Features of Infants With Primary Human ......Yoshizo Asano, Tetsushi Yoshikawa, Sadao Suga,...

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