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C H A P T E R 5 9

Roseola Infantum (Exanthem


Subitum)
James D. Cherry

Roseola infantum (i.e., exanthem subitum, pseudorubella, From 1920 through 1940, many excellent clinical
exanthem criticum, sixth disease, or 3-day fever) is a descriptions of the syndrome were published.* From
common, acute illness of young children characterized by 1940 through 1988, articles relating to roseola were con-
a fever of 3 to 5 days duration, rapid defervescence, and cerned with unusual manifestations and complications
then the appearance of an erythematous macular or mac- and attempts to recover an etiologic agent.26,30,40,45,64
ulopapular rash that persists for 1 to 2 days. In 1951 and 1954, Neva and associates50-52 noted the
association of a roseola-like illness and infection with
echovirus 16. This association was noted again in 1974.27
HISTORY In 1988, Yamanishi and associates79 identified human
herpesvirus6 (HHV-6) in the blood of infants with
Zahorsky81 generally is given credit for the original roseola, and since then the association between this virus
description of roseola infantum. However, in his writings, and the disease has been confirmed on many occasions.
he pointed out that the syndrome was described in earlier HHV-7 also has been found to be the cause of many cases
pediatric and dermatology texts.82-84 Altschuler1 observed of roseola.
that a British dermatologist, Willan, presented a descrip-
tion of the illness in his 1809 book On Cutaneous Diseases.
The descriptions in the older literature did not separate EPIDEMIOLOGY
the syndrome from the known exanthematous diseases
(i.e., measles, rubella, and scarlet fever), an omission that In his original article, Zahorsky81 reported that roseola
Zahorsky corrected. occurred most commonly in the fall. In his second article,
In 1921, Veeder and Hempelmann75 described the he observed a year-round incidence82; in 1925, he pointed
syndrome further and noted that leukopenia and relative out that most cases occurred in the spring, summer, and
lymphocytosis occurred. These investigators objected to fall.83 Breese10 noted that the greatest number of cases
the name roseola infantum, which in the past had been occurred in the summer and early fall. In contrast, 55
used to describe a large group of diseases with indefinite
causes. They suggested the term exanthem subitum because
it was descriptive of the most striking clinical symptom, *References 6, 7, 10, 17, 18, 20, 24, 25, 36, 83, 85.
References 8, 11-13, 22, 32, 46, 48, 49, 53, 56, 63.
namely, the sudden, unexpected appearance of the erup- References 2-5, 9, 19, 21, 27, 28, 33-35, 39, 41-44, 54, 58, 60, 66-69,
tion on the fourth day. Currently, the term roseola is used 77, 86.
most commonly to describe the syndrome. References 3, 14, 31, 68, 71, 72, 74.
59 Roseola Infantum (Exanthem Subitum) 769

percent of Clemens cases occurred in February, March, Since the advent of modern diagnostic virology in the
and April; 16 percent were seen in October.17 In a review early 1950s, numerous viral agents have been recovered
of 243 cases during a 10-year period, Juretic38 observed from children with roseola. In 1951, Neva and associ-
that the peak month was May. Juretic also reviewed the ates52 studied an epidemic exanthematous illness (i.e.,
seasonal incidence in 10 other studies and found only Boston exanthem) caused by echovirus 16, in which many
minor variations by month. Prevalence was greatest in of the illnesses were characteristic of roseola. In 1954,
March, April, and October and least in December. One Neva50 observed additional cases of roseola-like illness
epidemic of roseola in a maternity hospital occurred in associated with echovirus 16 infection. In 1974, Hall and
the summer,36 another epidemic in an infants home colleagues27 reported four additional echovirus 16 infec-
occurred in the fall,6 and a hospital outbreak occurred in tions with clinical manifestations of roseola. The report-
the winter.18 ing of roseola in Rochester, New York, nearly doubled
Roseola predominantly is an illness of young children. during the time of echovirus 16 activity in the area.
It occurs rarely in infants younger than 3 months old or Roseola-like illnesses that also have been associated with
children older than 4 years. In a review of 1462 cases, the enteroviruses are caused by coxsackievirus A6, A9, B1,
peak age range prevalence was 7 to 13 months of age; 55 B2, B4, and B5 and echovirus 9, 11, 25, 27, and
percent of the cases occurred within the first year of life, 30.15,16,27,66,78 Outbreaks of roseola that occur in the
and 90 percent occurred within the first 2 years of life.38 summer and fall probably are caused by enteroviral
Occasionally, cases have been seen in older children, ado- infections.
lescents, and young adults and in neonates and other In addition to enteroviruses, adenovirus types 1, 2, 3,
infants younger than 6 months.24,36 and 14 and parainfluenza type 1 virus have been recov-
Although Faber and Dickey20 found twice as many ered from children with roseola.23,37,51,78 Saitoh and asso-
girls as boys with the syndrome, the sex ratio in most ciates64 detected rotavirus capsomeres in fecal specimens
large studies has been equal.7,10,17,24,45 Although three of nine children with roseola. In contrast to these find-
epidemics have been reported, and cases frequently ings, Gurwith and colleagues26 studied fecal specimens
occur in groups by season, most cases occur sporadically from five children with roseola, and in none were viral
without known exposure. The syndrome, when seen spo- particles identified. One of 13 children in this study
radically, generally is considered to be noncontagious, did develop antibody to rotavirus around the time of
but secondary cases have been reported occasion- illness, however. In addition to the occurrence of roseola
ally.6,10,18,36 The incubation period range in epidemics is 5 associated with numerous natural viral infections, its
to 15 days.6,10,18 pattern (i.e., fever and then rash with defervescence) was
The attack rate of roseola has not been well studied. observed frequently in recipients of Edmonton B measles
Berenberg and associates7 stated that roseola is the exan- vaccine.15
them most commonly encountered in children younger In 1988, Yamanishi and associates79 isolated HHV-6
than 2 years old. Breese10 found that 16 percent of a from four infants with roseola and all four had significant
group of infants he followed for the first 12 months of titer increases for this virus. Shortly after this finding was
life had definite roseola. He estimated that 30 percent of reported, several other investigators noted similar find-
children would have clinical roseola. Juretic38 looked at ings.* The implication from these studies, as suggested
the frequency of roseola in 6735 children; the yearly by the various investigators, is that HHV-6 is the cause
attack rate during a 10-year period ranged from 1 to 10 of roseola. This viewpoint overlooks or ignores the past
percent, with a mean of 3.3 percent. experience in which other viral agents have been associ-
ated with the clinical syndrome. Subsequent studies indi-
cate that HHV-6 is a major cause of roseola and the
ETIOLOGY cause of acute febrile illness without exanthem in infants.
Since 1993, HHV-7 has been accepted as an additional
In 1941, Breese10 reported vigorous attempts to isolate a causative agent in roseola.
filterable virus from three children with pre-eruptive In a study of 1653 infants and young children with
roseola. These studies included extensive animal inocula- acute febrile illnesses, Hall and colleagues27 found that
tions, but no viral agents were uncovered. In 1950, 160 (9.7%) had primary HHV-6 infections; 27 (17%) of
Kempe and associates40 reported the passage of the illness the children who were infected with HHV-6 had roseola.
to a 6-month-old susceptible infant by the intravenous Zerr and associates86 identified 80 children with primary
injection of serum from an 18-month-old child with pre- HHV-6 infections, and of these, 30 percent had roseola.
eruptive roseola. Febrile illnesses without exanthem also In the same population-based study, 3/80 (4%) children
were produced in monkeys with serum and throat wash- without primary HHV-6 infection also had roseola. In a
ings from a child with the syndrome. In similar experi- study of clinical roseola, Okada and associates54 found
ments, Hellstrom and Vahlquist30 produced the syndrome that 81 percent had serologic evidence of HHV-6 infec-
in three children aged 6 to 9 days after the intramuscular tion, and that 8 percent had an echovirus-18 infection. In
administration of blood from typical roseola cases. a study of roseola in Italy, Braito and Uberti9 found
In electron microscopy studies, Reagan and associ-
ates61 observed uniform viruslike particles (100 to 110nm)
in the blood of an 18-month-old child with the syn- *References 2, 5, 19, 33, 41, 69, 73.
drome. Febrile illness was produced in two monkeys after References 4, 9, 27, 34, 42, 44, 54, 58, 60, 67, 77, 86.
concentrated virus-containing material was inoculated. References 3, 15, 31, 68, 71, 77.
770 SECTION X Skin Infections

serologic evidence of HHV-6 infection in only 30 percent in the summer and fall. Vomiting and diarrhea occur
of the cases. In 33 percent of the remaining cases, they infrequently.
attributed the illnesses to another infectious agent. In On initial physical examination during the febrile
1994, Hidaka and associates31 estimated that 73.5, 10.2, period, most children appear to be happy, alert, and
and 16.3 percent of their roseola cases were caused by playful. With high temperatures, some children are irri-
HHV-6, HHV-7, and other viruses, respectively. In a table; occasionally, a child appears to be sick, which sug-
study of HHV-6 infections in young Brazilian children gests more serious illness, such as meningitis or septicemia.
with rashes it was noted that only 21 percent had typical Examination within the oral cavity frequently reveals one
roseola.76 In summary, HHV-6 is an important cause of or more abnormalities. Mild inflammation of the pharynx
roseola, but not the only cause. and tonsils occurs most commonly. Occasionally, small
exudative follicular lesions are noted on the tonsils. In
other cases, small ulcerative lesions on the soft palate,
PATHOPHYSIOLOGY uvula, and tonsillar pillars are observed. Usually, the
lesions on the soft palate consist of only erythematous
The pathophysiology of roseola is unknown. Watson,78 macules and maculopapules, presumably because of lym-
in the preHHV-6 era, suggested that roseola is not an phoid hyperplasia.
infection caused by one particular pathogen, but is the Mild injection of the tympanic membranes occurs
result of an immunizing reaction against many different commonly. Enlargement of the suboccipital, posterior
viruses. He also suggested that the rash is caused by the cervical, and postauricular lymph nodes is a common
neutralization of virus in the skin at the end of the period finding, but the degree is not remarkable.
of viremia. Berliner8 noticed that children with roseola had pal-
Viremia is common in HHV-6, HHV-7, enteroviral, pebral edema. He suggested that the heavy eyelids or
and adenoviral infections; thus, a reasonable conclusion droopy or sleepy appearance resulting from this
(as originally suggested by Watson78) is that the rash edema was diagnostic of the syndrome before the appear-
in roseola is related to an immunologic event resulting ance of the rash. Bulging of the anterior fontanelle also
from the virus that is localized in the skin. Why the has been observed in roseola.56
pattern of fever and then rash with defervescence is Appearance of the rash in roseola usually coincides
so clearly age-dependent is unknown. Most of the with the subsidence of fever, but it may occur after
viruses that in the past have been associated with roseola an afebrile interlude of several hours to 2 days. When
cause other exanthematous manifestations in older defervescence occurs by lysis, onset of the exanthem
patients.15 can occur before the temperature has returned entirely
to normal. By definition, it is incorrect, however, to
call an illness roseola if the fever and rash are truly
CLINICAL PRESENTATION concomitant.
Zahorsky81,82 originally described the rash as morbil-
The basic clinical pattern of roseola is a febrile period of liform, but his use of morbilliform was not the same as is
3 to 5 days, defervescence, and the appearance of a rash used today (i.e., measles-like, erythematous, maculopap-
that persists for 1 to 2 days. Because the syndrome is ular with confluence). The rash is erythematous and
caused by many different viruses, the illness apparently macular or maculopapular, and the lesions are discrete.
may be associated with numerous other signs and symp- The lesions are 2 to 5mm in diameter and blanch on
toms. The major manifestations have been reviewed pressure. Frequently, individual lesions are surrounded
elsewhere.* by a whitish ring. The rash is most prominent on the neck
Illness usually occurs with the apparent abrupt onset and trunk, but the proximal extremities and the face also
of fever. Slight irritability and malaise occur frequently, may be affected. Although they have been reported,17,25
but more commonly, the childs temperature is taken pruritus and desquamation usually do not occur. The rash
because a parent notices that the child feels warm. The usually persists for 24 to 48 hours. In occasional cases,
temperature usually is in the range of 38.9 to 40.6C well-documented rashes have been observed to appear
(102.2 to 105F). Despite the high fever, the child and resolve within 2 to 4 hours. Yoshida and associates80
usually is active, alert, and generally unfazed. The fever described a 7-month-old boy with HHV-6 infection and
is constant or intermittent, with its greatest degree occur- typical roseola initially. On the ninth day of illness, vesic-
ring in the early evening. Restlessness and irritability ular lesions appeared on the face and limbs, however.
occur with higher temperatures. The usual duration of These lesions persisted for 12 days.
fever is 3 to 5 days, but it has persisted for 9 days. The Except for the white blood cell count, routine labora-
temperature most often returns to normal by crisis, but tory studies are of little use in roseola. The total white
in some cases, temperature lysis occurs over the course blood cell count usually is low. Early in the febrile period,
of 24 to 36 hours. high counts occasionally are found, however. The total
Mild cough and coryza are seen frequently in cases count reaches its nadir by the third to sixth day of illness
occurring in the winter and spring. Headache and and then gradually returns to normal over the ensuing 7
abdominal pain are reported in older children, mainly to 10 days. During the same time frame, the percentage
of lymphocytes increases from a normal value of about
50 percent to 60 to 80 percent on days 3 to 10 and then
*References 7, 10, 17, 24, 38, 82. returns to normal over the next 7 days. Frequently,
59 Roseola Infantum (Exanthem Subitum) 771

extreme counts in the range of 3000 cells/mm3 with 90 than immune-mediated peripheral consumption. A 14-
percent lymphocytes are found, which raises the consid- month-old girl developed a generalized eruptive histio-
eration of a granulocytic defect. cytoma with rapid progression and then resolution after
roseola.70

CLINICAL COMPLICATIONS
DIAGNOSIS
The most important complications of roseola are convul-
sions and other neurologic symptoms.* The incidence of Although detecting leukopenia with relative lymphocy-
convulsions has varied widely among reports. Juretic38 tosis is fortuitous, the only necessity in establishing the
did not find one instance of convulsions in the 243 cases diagnosis of roseola is to document the fever, deferves-
in his study. Breese10 did not report convulsions in any cence, and exanthem pattern. Frequently, the first exan-
of 100 roseola attacks that he studied. In contrast, Green- thematous illness that a child has is called roseola,
thal24 noted convulsions in 6 percent of his cases, and regardless of whether the exanthem and the fever are
Faber and Dickey20 found seizures in 8 of 26 cases of concomitant, or the child has no febrile period at all.
roseola. Mller48 observed that 8 percent of children The only problem in the differential diagnosis occurs
admitted to the hospital because of febrile convulsions when a febrile child is receiving antibiotics and a rash
eventually were diagnosed with roseola infantum. follows defervescence. This event occurs frequently, and
Mller48 also reported cerebrospinal fluid evaluations the child usually is labeled allergic to the antibiotic,
in 29 cases of roseola and febrile convulsions. In six rather than suspected of having roseola. In most instances
instances, the pressure was elevated; in two, there were of drug allergy, the exanthem lasts longer than roseola
5 white blood cells/mm3; and in another instance, there does, and in allergic cases, pruritus and fever may accom-
were 9 white blood cells/mm3. In most other cere pany the rash.
brospinal fluid examinations, the findings have been
normal, but mild pleocytosis with mononuclear cells has
been identified occasionally.7,32 A surprising number of
cases of encephalitis associated with roseola have been TREATMENT AND PROGNOSIS
reported,13,22,32,35 and residua have been common. Hemi-
plegia has occurred after illness,13,22,59,62 and permanent No specific treatment for roseola exists. When fever is a
paresis and mental retardation have occurred in some problem, it may be treated with acetaminophen. Acet-
affected patients. The syndrome of inappropriate secre- aminophen can alter the temperature curve, possibly
tion of antidiuretic hormone has been reported in roseola obscuring the correct diagnosis. Febrile seizures and
associated with HHV-6 infection.55,65 Facial nerve palsy other neurologic complications should be treated
and Guillain-Barr syndrome also have been noted after vigorously.
HHV-6 induced roseola.47,57 In most cases, the outlook is excellent. When encepha-
Thrombocytopenic purpura was noted in one report litis occurs, the prognosis must be guarded. Because
in five children with roseola; all of these patients recov- roseola is the result of infection with multiple different
ered.53 In a more recent study, Hashimoto and col- viruses, no practical way to prevent it exists.
leagues29 noted five children with thrombocytopenia
during the acute phase of roseola caused by HHV-6 NEW REFERENCES SINCE THE SIXTH EDITION
infection. Their data suggested that the thrombocy 76. Vianna RA, de Oliveira SA, Camacho LA, et al. Role of human
topenia was due to bone marrow suppression, rather herpesvirus 6 infection in young Brazilian children with rash ill-
nesses. Pediatr Infect Dis J 2008;27:5337.
The full reference list for this chapter is available at
*References 2, 7, 11-13, 20, 22, 25, 32, 35, 43, 48, 59, 62, 63. expertconsult.com.
59 Roseola Infantum (Exanthem Subitum) 771.e1

30. Hellstrom B, Vahlquist B. Experimental inoculation of roseola


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