Exanthem_Subitum

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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 PED IA TR IC S V ol. 93N o. I January 1994

C linical Features of Infants W ith Prim ary H um an H erpesvirus 6 Infection

(E xanthem Subitum , R oseola Infantum )

Y oshizo A sano, M D *; Tetsushi Y oshikaw a, M D *; Sadao Suga, M D *; Ikuko K obayashi, M D*;

Toshihiko N akashim a, M D*; Takehiko Y azaki, M D *; Y uji K ajita , M D *; and Takao O zaki, M D

A B S T R A C T. bjective T o clarify clin ical featu res of

patien ts w ith prim ary hum an herpesvirus 6 (H H V -6) in-

fection (roseola in fan tum , exan them subitum ) in a large-

scale study .

Subjects and m ethods. C linical signs and sym ptom s

w ere analyzed in 176 infan ts in w hom exanthem subitum

w as in itia lly suspected and prim ary H H V -6 infection w as

la ter confirm ed. The infection w as proved by isolation of

the virus from blood, a sign ifican t increase in the neu-

tra liz ing antibody titers to the virus, or both.Results T he prim ary H H V -6 infection , w hich oc-

curred throughout the year,w as observed in 94 boys and

girls (m ean age, 7.3 m onths). Fever developed in 98(m ean m axim um fever, 39 .4 { 176}C ) and lasted for 4.1 days.

M acular or papula r rashes appeared in 98 , on face,

trunk, or both , m ostly a t the tim e of subsidence of the

fever, and lasted for 3.8 days. O ther clinical m anifesta -

tions occurred as follow s: m ild d iarrhea in 68 , edem a-

tous eyelids in 30 , erythem atous papules in the pharynx

in 65 , cough in 50 , and m ild cervica l lym ph node

sw elling in 31 . Tw enty-six percent had bulging of the

an terior fontanelle and 8 had convulsions.

Conclusions C lin ica l featu res of pa tien ts w ith viro-

logica lly confirm ed exanthem subitum w ere com parab le

w ith those described before discovery of H H V -6 .

Pediatrics 1994;93:104-108; exan them subitum roseo la in

f antum hum an herpesv irus 6

ods can differentia te ES from m any febrile illnesses

w ith rashes caused by other agents such as the en-teroviruses and adenoviruses . There is so far lim ited

inform ation about the precise clinical m anifestationsand the courses of patients w ith virologicalty con-firm ed ES.’17 In the present study, w e analyzed clini-

cat signs and sym ptom s in 176 patients w ith prim ary

H H V -6 infection to clarify these points.

M A TER IA L S A N D M ET H O D S

The study w as conducted between Decem ber 1987 and June

1992 at Fujita H ealth U niversity H ospital, Toyokaw a City Hospi-tal, K ariya Sogo H ospital, and Showa Hospital. A ll infants seen a

these hospitals w ith fever or skin rash or both and clinical m ani-

fe sta tio ns su gg estiv e of ES were enrolled. Inform ed consent w as

obtained from parents of the subjects after the project w as thor-

oughly explained. A m edical history and clinical signs and sym p-

toms w ere recorded every day by parents on a special form for thisproject, and the record was checked every 2 to 3 days by the

authors. The first blood sam ple w as collected within 5 days of the

initia l visit to our hospital, and we attempted to collect the con-

valescent sam ple I to 2 weeks later. Infants w ith a history of

im mune deficiency, those taking cytotoxic or imm unosuppressivedrugs, and those who had received im mune globulin w ithin the

past 4 weeks w ere excluded from participation.

The m ethod for isolation of HH V-6 w as as previously de-

scribed,2 and antibody activity to H H V-6 w as measured by theneutralization test as described elsew here.’819

ABBREV IA TION S. ES, exanthem subitum; H H V-6, hum an herpes-

virus

Exanthem subitum (ES) or roseota infantum , a com -

m on benign infectious disease of infancy, is charac-terized by a fever persisting for 3 to 5 days and theappearance of sk in rash after subsidence of the fever.Recently , the causative agent of ES w as identified ashum an herpesvirus 6 (H H V-6),”2 originally isolated

from peripheral b lood lym phocytes of im m unocom -prom ised patients in 1986. Serological and virologi-

cal m ethods have show n that the virus is ubiquitous

in the hum an population, seroconversion occurs

early in life, and prim ary infection w ith the viruscauses a wide spectrum of clinical m anifestations,9’1#{176}including fatal outcom e.1 11 4 M oreover, specific m eth-

From the *D epartm ent of Pediatrics, Fujita H ealth U niversitySchool of

M edicine , Toyoake; Departm ent of Pediatrics, K ariya Sogo H ospita l,Kariya; and §D epartm ent of Pediatrics, Show a H ospita l, K ohnan, A ichi,

Japan.

Received for publication M ar 22,1993; accepted Jun 10,1993.

Reprint requests to (Y .A .) D ept of Pediatrics, Fujita Health University

School of M edicine, Toyoake, A ichi 470-1 1 Japan.

PEDIATRICS (ISSN 0031 4005). Copyright ©1994 by the Am erican A cad-

em y o f P ed iatrics.

R S U T S

B lood sam ples for isolation of HH V -6 w ere ob-

tam ed from 688 patients during the acute stage of the

disease, and 265 paired blood sam ples w ere obtainedfrom them for determ ination of the antibody. Therew ere 176 patien ts in w hom H H V -6 infection w as confirm ed and clinical m anifestations could be evalu-

ated; 82 patients w ere confirm ed to have prim aryH HV -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 tem perature 37 .5#{176}C was

defined as day 0, except w hen w e evaluated the de-velopm ent of skin rashes. Because only com plete de-

scriptions in I 7 6 records from the patients w ere evalu-

ated, the num ber in each category of clinical featuresi s d if fe re nt .

There w ere 94 boys and 82 girls, aged 7.3± 2.7 (SD)m onths (range, 3 weeks to 18 m onths) (Fig 1). The age

at onset peaked at 6 and 7 m onths. HH V -6 infection

w as observed throughout the year (Fig 2), but them onthly incidence w as som ew hat higher between

M arch and June. A m ong 61 w hose birth his tory w as

described, 56 (92% ) w ere born via birth canal and 5

(8% ) by cesarean section. Feeding m ethod until onset








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* Com plete descrip tion for each category w as analy z ed.

%

A R T I C L E S 105

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

Ag e in Mo nth s

F ig 1 A ge distribution of patients w ith exanthem subitum w ho

hav e prim ary hum an herpesv irus 6 infection.

1 2 3 4 5 6 7 8 9 1 0 1 1 1 2

Mon th

F ig 2 M onthly distribution of patients w ith exanthem subitum

w ho hav e prim ary hum an herpesv irus 6 infection. B etw een D e-

cem ber 1987 and June 1992, 176 infants and children w ere ana-

ly z ed in four hospitals in A ichi, Japan.

of the disease w as ev aluated in 62; 21 (34% ) receiv ed

breast-feeding, 17 (27% ) bottle-feeding, and 24 (39% )

a mixture of breast- and bottle-feedings.C linical features are sum m arized in T able I. Pro-

drom al sy m ptom s such as listlessness or irritab ilityw ere observ ed in 9 (14% ) of 63 ev aluated. Fev er w asreported in 173 (98% ) of 176 w ith prim ary HHV -6infection (Table 2), w ith a m axim um body tem pera-

hire of 39.4 ± 0.7#{ 176} Cn= 164), w hich persisted for 4.1

± 1.2 day s (n = 172). In the m ajority this w as the first

T A B L E 1 Frequency of S igns and Sy m ptom s in Infants

W ith V irologically Confirm ed Exanthem Subitum

C ategory of

Findings

N o. of Patients

Evaluated

N o. (% )W ith

Positiv e Findings

Prodrom al sy m ptom s* 63 9 (14)Fe v e r t 1 7 6 1 7 3 ( 9 8 )

Rash 176 172 (98)

Diarrhea 171 116 ( 68)

Edem atous ey elids 60 18 (30)

N agay am a’s spots 49 32 (65)

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

swelling

Bulging fontanelle 152 39 (26)

Conv ulsion 173 13 8)

* N onspecific sy m ptom s such as listlessness or irritability .

Equal to or m ore than 37.5#{ 176} C.

: Ery them atous papules on the m ucosa of the soft palate and the

base of uv ula.

TA B L E 2. C haracteristics of Fev er in Infants W ith Prim ary

Hum an Herpesv irus 6 Infection*

C ategories of Fev er N o. of Patients %

M axim um body

tem perature (n = 164)

37.5-37.9#{176}C

38.0-38.9#{176}C

3 9 . 0 - 3 9 . 9 { 1 7 6} C

40 .0#{176}C

D uration of fev er (n= 172)

2 d a y s

3 d a y s

4 day s

5 d a y s

6 day s

7 days

8 d a y s

His tory of febrile episodes

(n = 57 )

1s t

2n d

3rd

4t h

S t h

episode of fev er since deliv ery (n= 57). Skin rashes

w ere observ ed in 172 (98% ) of 176 w ith prim ary

HHV -6 infection (T ab le 3). If the day on w hich the

fev er returned to norm al w as defined as day 0, therash appeared on day 0 ± 1.0 (n= 162) and persisted

for 3.8 ± 1.5 day s (n = 131). The nature of rashes w as

ev aluated in 147. Papule (rubella-like) w as observ ed

in 80 (54.4% ), m acule (m easles-like) in 58 (39.5% ), and

m aculopapule in 9 (6.1% ). The rashes initially ap-

peared on face, or trunk, o r both, then spread to o therplaces (n = 161) (Table 4). M ild pigm entation w as

observ ed in 11 of 155 ev aluated, but desquam ation

w as not observ ed. M ild diarrhea w as reported in I 16

(68% ) of 171 ev aluated; it dev eloped on day I .5± 1. 6

(range, day -2 to day 6 En= 1051) and pers isted for

5. 2 ± 2.5 day s (range, I day to m ore than 10 day s

En = 961). Edem atous ey elids, w hich w ere observ ed in

T A B L E 3 Tim e of O nset and D uration of Skin Rashes*

Categories of Skin R ashes N o. of Patients

Tim e of onsett

(n = 162)

D ay -3

D ay -2

D ay -1

D ay 0

D ay I

D ay 2D ay 3

D uration of the

rash (n = 131)

I day

2 d a y s

3 d a y s

4 day s

5 d a y s

6 day s

7 days

8 d a y s

3 1 . 9

7 4 330 18.5

7 3 4 5 . 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

* Com plete descrip tion for each category w as analy z ed.

t The day on w hich body tem perature returned to less than 37.5#{ 17

w as defined as day 0.







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

106 E X A N TH EM SU BITU M

Face

Initia l Sites

Face and trunk

Face and extremities

Trunk

Trunk a nd e xtre mit ie s

Extremities

W hole body area

Progress N o. of %

Patients

Face only I 0.6

Totrunk 11 6. 8

To trunk and extrem ities 13 8.0

Face and trunk only 28 17.3

To extrem ities 8 4.9

Face and extrem ities only 4 2.5

To trunk 1 0.6

Trunk only 32 19.8

To face 10 6.2To face and extremities 16 9.9

To extrem ities I 0.6

Trunk and extrem ities only 3 1.9

To face I 0.6

Extrem ities only 2 1.2

To trunk I 0.6

To face and trunk 1 0.6

W hole 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). Erythem atous papules on the m ucosa of thesoft palate and the base of uvula (called N agayam a’s

spots in Japan), w hich w ere 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, m ild 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. M ild cervical

lym ph node swelling, observed in 19 (31% ) of 61

evaluated , developed on day 2.6± 1.4 (n = 19). B ulg-ing of the anterior fontanelle, observed in 39 (26% ) of152 evaluated, was initially noted on day 1.5± 0.9 (n

= 38) and persis ted for 2.6± 1.2 days (n = 21) (T able7). The age of infants w ith bulging of the anterior fon-tanelle ranged from 4 m onths to I I m onths (m ean, 6.3months). During the course of ES, convulsive seizures

w ere observed in13 (8% ) of 173 evaluated; all seizuresdeveloped during the febrile stage, and in m ost cases

they were of short duration (Table 8). The age of those

w ith seizures ranged from 5 m onths to 17 m onths(m ean, 10 .9 m onths). A convulsive seizure developedin I patien t of the 39 w ith bulg ing of the anterior fon-tanelle.

D I S US S I ON

The epidem iology and clinical features of ES ob-

served in the present study w ere com parable w iththose described in m any excellent studies20’ reportedsince the first description by Zahorsky22 in 1910. ESoccurred throughout the year, with a concentration of

T A B LE 5. Char actenstics of Edem atous Eyelids*

T ime of onsett N o. 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

Com plete description for each category w as analyzed.

t T he first day of elevation of fever was defined as day 0.

T A B LE 6. Characteristics of Papules on the M ucosa of theSoftPalate and the Base of Uvula (Called N agayam a’s Spots in Japan)*

T ime of onsett No. of Patients %

(n 32 )

D ay I 12 37.5D ay2 7 21.9

D ay3 6 18.8

D ay4 5 15.6

D ay5 I 3.1

D ay6 I 3.1

Com plete description for each category was analyzed.

1 The first day of elevation of fever w as defined as day 0.

TA B L E 7. Tim e of Onset and D uration of Bulging Fontanelle*

Categories No. o f Patients %

Time of onsett(n = 38 )

D ay 0 4 10.5

D ay I 17 44.7

Day2 11 28.9

D ay 3 6 15.8

Duration(n = 21 )

lday 2 9.5

2 days 12 57.1

3 days 3 14.34 days 2 9.5

5 days I 4.8

6 days I 4.8

Com plete description for each category was analyzed.

t Th e first day of elevation of fever w as defined as day 0.

cases betw een M arch and June, as pointed byJuretic.O f interest is the age incidence of patien ts w ithobserved in this study. The peak age-range prevalence w as observed at 6 and 7 m onths of age; 64%the cases occurred within the first 7 m onths of life an94% w ithin the first year of life. The m ajority of casof E S in Japan m ay occur earlier than those in Europeand the U nited States.20’21’24 This speculation is suported by our seroepidem iological observafions,5’7’ 19in w hich the seroprevalence increased rapidly from5and 6 m onths of age to betw een 90% and 100% byto 2 years of age,5’7’8 and the increased prevalenceneutralizing 1gM antibodies w as observed in infant6 m onths to I year of age.19 M oreover, this pattern

m ay be further supported by recent reports in w hich






http://slidepdf.com/reader/full/exanthemsubitum 5/7A R T IC LE S 107

TA BLE 8. Time of Onset and D uration of Convulsive

Seizures*

Categories of Seizure No. of Patients %

Tim e of onsett(n = 13 )

D ay -1 1 7.7DayO 6 46.2

D ay 1 4 30.8

D ay 2 2 15.4

Duration(n = II)

0-15 m m 5 45.5

6-10 m m 3 27.3 11 m m 3 27.3

Complete description for each category was analyzed.

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

there appeared to be som e relationship betw eenprevalence and ethnicity or geographic location; theprevalence is 49% to 76% depending on ethnicorigin

in M alaysia?- 20% in M orocco, and 92% in Ecuador.26

The early acquisition of HH V -6 infection in infants

m ay suggest that the virus is m ore ubiquitous in

Japan than in other countries, w hich m ay be relatedto a higher population density. H ow ever, there are no

com parative data to clarify th is point.Since the frequency of cesarean section and breast-feeding w as sim ilar in the study population and theoverall m aternal population, there is noth ing to sug-gest either pennatal or breast m ilk transm ission.Horizontal transm ission from oral secretions is likely,

since the virus has been frequently detected in salivaof healthy adults2728 and the virus-specific D N A andantigen have been identified in salivary and bronchialglands.29’#{176} H ow ever, this route is still controversial.W e could not iso late the virus from m ore than 100saliva specim ens of healthy adults including w om en

of childbearing age (unpublished data). R ecent re-ports did not support previous findings of the high

frequency of H H V -6 excretion from saliva.31’32 Thepossib ility of perinatal or breast m ilk transm ission ofthe virus rem ains.

M ost of the clinical m anifestations of ES w ith pri-mary H H V -6 infection w ere the sam e as those de-scribed in the standard textbooks.21’24 The frequency

of the apparent infection in this study w as alm ostcom parable w ith that reported from Sw eden,’6 buthigher than that found in the U nited States,17 w hereonly 9% of the patients w ith prim ary H HV -6 infection

had a rash typical of ES. A lthough the reason for thisdiscrepancy is unknow n, it is likely that the differencebetw een experim ental designs conducted in both lo-cations m ight influence the apparent frequency of the

infection. In addition, the biological characteristics ofth e virus strains isolated from different countries

should be studied because it has been reported thattw o groups of H H V -6 iso lates have variations w ithregard to their rep lication 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 com m on occurrence in H H V-6 infection.2”5

If each virus strain has different cellu lar tropism s, thefrequency of skin infection m ay be different in eachcountry w here the virus is isolated. O f interest is thatm ild pigm entation w as observed in I I patien ts afterdisappearance of the skin rash; this finding has not

been reported previously . It is possible that som e tyof H HV -6 strain having a tropism to m elanocytes

stim ulated the cells in the skin. H ow ever, it is likethat sim ultaneous infection w ith other v iruses dooccur in som e patients with ES,35 since the m ost m aternal antibodies are lost by I year of age. The char-

acteristics of other clinical features such as diarrhea,cough, edem atous eyelids, and cerv ical lym phad-enopathy, w hich w ere rather nonspecific and m ild,

w ere com parable w ith those described in the texbooks.21’24 A m ong them , erythem atous papules onm ucosa of soft palate and the base of uvula (called

N agayam a’s spots in Japan) w ere observed in 65%

of the patients by day 4 of ES. A lthough m any pediatric ians in Japan use the spots as the m arker for th

early diagnosis of ES, their predictive value and speci

ficity are still controversial.In the present series, 26% of the patien ts had bulg

ing of the anterior fontanelle w hich persisted fordays and 8% of the patients had convulsive seizures.

A ll of these episodes occurred before skin rashes dveloped. Invasion of the central nervous system w iH I-IV -6 w as proved in som e of these patien ts.’4’-7”#{176} Ifthese features are due to acute encephalitis caused b

infection w ith H H V-6, specific therapeutic interven-

tions m ust be considered, because som e patients hav

a fatal outcom e w hile others recover w ith a varietysequelae.’4”#{176} H H V -6 is sensitive to ganciclovirv itro ,45’ although clinical efficacy trials have not ybeen p ub lished.

KNOWLE DGMENT

This work was supported, in part, by a grant from Fujita HealthU niversity . Recom binant human interleukin-2 w as kindly sup

plied by Takeda Chem ical Industries, L td. O saka, Japan.

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P O W E R STR U G G L ES IN M ED IC A L PR A C TIC E

[There isi a central ethical tension in m edicine w hich has rarely been discussed

explicitly in the m edical literature but w hich dem ands consideration as soon as one

looks at the patient-physician encounter in term s of relative pow er. That tension is

between care and w ork-betw een the individualized dem ands of com passion and

sym pathy and the im personalized dem ands of the effic ient workplace.

B rody H .The H ea ler ’s P ow er New Haven: Yale U niversity P ress; 1992.

Subm itted by Student







1994;93;104Pediatrics

Takehiko Yazaki, Yuji Kajita and Takao OzakiYoshizo 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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