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Roseola Infantum
Roseola Infantum
18th ed.
Copyright 2007 Saunders, An Imprint of Elsevier
ETIOLOGY.
Primary infection with HHV-6, and less frequently HHV-7, causes the majority of cases of
roseola. Other viruses (echovirus 16) probably account for the remainder. Nonetheless, most
primary infections with HHV-6 and HHV-7 do not result in roseola.
HHV-6 and HHV-7 belong to the -herpesvirus subfamily of herpesviruses, which includes
human cytomegalovirus (CMV). HHV-6 and HHV-7 share physical and biologic characteristics
with other herpesviruses, including a large double-stranded DNA genome, the presence of a
nucleocapsid, and the establishment of latency after primary infection. HHV-6 is essentially
colinear with HHV-7, and both viruses share much homology with CMV. HHV-6 and HHV-7
most efficiently replicate in CD4 T cells; HHV-6 can also infect other T cells, macrophages,
epithelial cells, endothelial cells, fibroblasts, hepatic cells, glial cells, fetal astrocytes, and bone
marrow progenitor cells. In the laboratory, HHV-6 and HHV-7 are typically cultivated in
mitogen-stimulated human mononuclear cells (isolated from cord blood or peripheral blood) and
can be identified by the development of large balloon-like cells accompanied by cell lysis. Two
distinct types of HHV-6 (types A and B) exist. Type B causes more than 99% of HHV-6-
associated roseola cases. Latent type A virus can be found in immunodeficient as well as healthy
patients and may reactivate in severely ill adult patients; however, it has not been consistently
linked with disease.
EPIDEMIOLOGY.
Primary HHV-6 infection occurs early in life. Most (>90%) of newborn infants are HHV-6
seropositive, reflecting transplacental transfer of maternal antibodies. Before 6 mo of age, there
is a low rate of primary HHV-6 infection (<10%). However, a rapid increase occurs
subsequently, and by 12 mo of age 40% of infants are HHV-6 infected, and 80% acquire
infection by 2 yr of age. Peak acquisition of primary HHV-6 infection, from 6 to 15 mo of age,
corresponds with peak incidence of roseola. The most common symptoms in infants with HHV-6
infection are fever and fussiness (90%). Only of infected children have clinically recognizable
roseola. Curiously, much higher rates of roseola symptoms occur in Japanese infants with
primary HHV-6 infection. Primary infection with HHV-7 generally occurs slightly later than
HHV-6 infection.
Roseola occurs throughout the year. Unlike some of the other childhood exanthems, children
with roseola rarely report contact with other affected children, and outbreaks are uncommon.
Sex, race, and geography do not play an important role in acquisition of roseola. The incubation
period averages 10 days, with a range of 515 days.
Most adults excrete HHV-6 and HHV-7 in saliva and may serve as primary sources for virus
transmission to children. Although women may uncommonly excrete HHV-6 and HHV-7 in the
genital tract, sexual transmissibility has not been demonstrated. HHV-6 can be transmitted in
utero at low rates (<2%), with approximately associated with type B; only 1 neonate with
symptomatic congenital infection has been described. Most congenitally infected patients are
asymptomatic, but reactivation may occur after birth. No congenital HHV-7 infections have been
identified. There are rare reports of HHV-6 transmission to susceptible infants via donor bone
marrow or solid organs. There is no evidence that infection is spread by breast milk, fecal-oral
contamination, or blood transfusion.
PATHOGENESIS.
Virus is probably acquired from the saliva of healthy persons and enters the host through the
oral, nasal, or conjunctival mucosa. Cellular receptors for both viruses have been identified:
HHV-6 uses the CD46 receptor (widespread among tissues), and HHV-7 uses the CD4 receptor,
which is also used by HIV-1. Following viral replication at an unknown site, a high level of
viremia develops in peripheral blood mononuclear cells (PBMCs). After acute infection, HHV-6
and HHV-7 establish latency in blood mononuclear cells and possibly in other sites, including
salivary glands, kidneys, lungs, and central nervous system. The basis for the unique pattern of
rash after resolution of fever in children with roseola is unknown.
HHV-6 can suppress all cellular lineages within the bone marrow; active HHV-6 infection is
associated with bone marrow suppression in bone marrow transplant patients. HHV-6 infection
also has significant effects on the immune system, including downregulation of the major
histocompatibility complex (MHC) type I response, enhancement of natural killer (NK) T-cell
activity, suppression of PBMC proliferation, and induction of a proinflammatory cytokine
response.
CLINICAL MANIFESTATIONS.
Roseola is the prototypical HHV-6 and HHV-7 infection, although nonspecific infections are
common.
Roseola is a mild febrile, exanthematous illness occurring almost exclusively during infancy.
More than 95% of roseola cases occur in children younger than 3 yr, with a peak at 615 mo of
age. Transplacental antibodies likely protect most infants until 6 mo of age.
Infants with classic roseola exhibit a unique constellation of findings displayed over a short
period of time. Consequently, classic roseola is infrequently confused with other childhood
exanthems.
The prodromal period of roseola is usually asymptomatic but may include mild upper respiratory
tract signs, among them minimal rhinorrhea, slight pharyngeal inflammation, and mild
conjunctival redness. Mild cervical or, less frequently, occipital lymphadenopathy may be noted.
Some children may have mild palpebral edema. Physical findings during the prodromal stage
have no clear relationship to roseola, and may simply reflect an accompanying respiratory viral
infection. Clinical illness is generally heralded by high temperature, usually ranging from 37.9 to
40C (101106F), with an average of 39C (103F). Some children may become irritable and
anorexic during the febrile stage, but most behave normally despite high temperatures. Seizures
may occur in 510% of children with roseola during this febrile period. Infrequent complaints
include rhinorrhea, sore throat, abdominal pain, vomiting, and diarrhea. In Asian countries,
ulcers at the uvulopalatoglossal junction (Nagayama spots) are common in infants with roseola.
Fever persists for 35 days, and then typically resolves rather abruptly (crisis). Occasionally,
the fever may gradually diminish over 2436 hours (lysis). A rash appears within 1224 hr of
fever resolution. In many cases, the rash develops during defervescence or within a few hours of
fever resolution. The rash of roseola is rose colored, as the name implies, and is fairly distinctive
( Fig. 253-1 ). However, it may be confused with exanthems resulting from rubella, measles, or
erythema infectiosum. The roseola rash begins as discrete, small (25 mm), slightly raised pink
lesions on the trunk and usually spreads to the neck, face, and proximal extremities. The rash is
not usually pruritic, and no vesicles or pustules develop. Lesions typically remain discrete but
occasionally may become almost confluent. After 13 days, the rash fades. Some children
experience evanescent rashes that resolve within a few hours. Subtle differences in clinical
presentation have been noted between roseola associated with HHV-7 compared with HHV-6.
These include a slightly older age, lower mean temperature, and shorter duration of fever in
HHV-7-associated cases. However, these differences are insufficient to clinically distinguish
HHV-6- from HHV-7-associated roseola. There are reports of children experiencing HHV-6-
associated roseola followed later by HHV-7-associated roseola.
Figure 253-1 Roseola infantum. Erythematous, blanchable macules and papules (A) in an infant who had a high fever for 3 days
preceding the skin eruption. On closer inspection (B), some lesions reveal a subtle peripheral halo of vasoconstriction. (From Paller
AS, Mancinin AJ [editors]: Hurwitz Clinical Pediatric Dermatology, 3rd ed. Philadelphia, Elsevier, 2006, p 434.)
HHV-6 and HHV-7 account for a significant proportion of nonspecific febrile illnesses, without
a focus of infection, in infants. Approximately 15% of febrile infants presenting to hospital
emergency room have primary HHV-6 or HHV-7 infection.
Because HHV-6 shares CD4 cell tropism with HIV, upregulates HIV, and stimulates in vitro
replication of HIV, there has been considerable interest in the role of HHV-6 as a cofactor for
clinical progression of AIDS. Epidemiologic studies in adults do not support a significant role
for HHV-6 as a cofactor. Only 1 small pediatric study suggests more rapid progression of
immune deficiency in HIV/HHV-6 co-infected infants. Further prospective studies are necessary
to assess the impact of HHV-6 on HIV-infected children.
Rash illness without fever has been described in a small number of infants with primary HHV-6
infection. Small studies or case reports have suggested that HHV-6 may be associated with a
wide range of other diseases, including some cases of hemophagocytic syndrome,
intussusception, idiopathic thrombocytopenic purpura, recurrent aphthous stomatitis,
myocarditis, drug hypersensitivity, Gianotti-Crosti syndrome, progressive multifocal
leukoencephalopathy, influenza encephalopathy, large vessel arteritis, Kikuchi's necrotizing
lymphadenitis, histiocytosis, and chronic fatigue syndrome. Controversy continues regarding a
relationship between HHV-6 and multiple sclerosis. There are conflicting data linking HHV-7
and pityriasis rosea. HHV-6 DNA has been detected in various malignancies, including non-
Hodgkin lymphoma, Hodgkin disease, cervical and oral carcinoma, and leukemia. No consistent
etiologic relationship has been established with any of these cancers.
DIAGNOSIS.
The most important reason for establishing the diagnosis of roseola is to differentiate this
generally mild illness from other potentially more serious childhood rash illnesses such as
measles. It is also important to identify other, more serious illnesses caused by HHV-6, such as
encephalitis and pneumonitis, especially in immunocompromised patients, for timely
consideration of antiviral therapy.
The diagnosis of roseola can be established primarily on the basis of age, history, and clinical
findings. HHV-6- and HHV-7-associated roseola cases cannot be distinguished solely on clinical
grounds. Specific testing for HHV-6 or HHV-7 infection may be performed using laboratory
methods, including serology, virus culture, and polymerase chain reaction (PCR).
HHV-6 serologic testing is available from many commercial laboratories; few offer HHV-7
serology. An HHV-6 immunoglobulin M (IgM) response typically develops by the 5th7th day
of illness, peaks at 23 wk, and resolves within 2 mo. Unfortunately, the accuracy of currently
available IgM tests varies widely, and none have been sufficiently evaluated to provide
unequivocal evidence of acute HHV-6 infection. Seroconversion of HHV-6 or -7 IgG antibodies
in serum samples collected 23 wk apart is a more reliable means of establishing primary
infection, but is not timely. Four-fold increases or decreases in HHV-6 or -7 IgG antibodies also
suggest active infection (primary or reactivated). Because of the high seroprevalence of these
viruses in the general population, a single positive HHV-6 or -7 IgG test is of no significance for
diagnosis of acute infection. CMV antibodies can cross react with HHV-6 and HHV-7; therefore,
diagnosis of HHV-6 and HHV-7 infections by serologic means requires exclusion of CMV
infection.
Identification of HHV-6 or HHV-7 in PBMCs by virus culture firmly establishes the presence of
active infection in immunocompetent hosts; association with specific disease is more
problematic in immunocompromised patients as a result of a low background rate of viremia.
Identification of HHV-6 and HHV-7 by culture requires incubation of PBMCs (with or without
co-cultivation with exogenous PBMCs) for days to several weeks, and is presently available only
in research laboratories. A commercial HHV-6 rapid (shell-vial) culture is available.
PCR amplification tests for HHV-6 are becoming available and may provide more timely
information for diagnosis. Active, replicating infection is indicated if HHV-6 DNA is detected in
acellular specimens such as serum or cerebrospinal fluid. It should be noted that detection at
other sites (PBMCs, saliva, tissues) does not necessarily indicate active infection, because HHV-
6 exists in latent form in many tissues after primary infection. Quantitative PCR and reverse
transcriptase PCR may be more useful for diagnosis of active infection using cellular blood
specimens, if suitable cutoff thresholds are established. Several commercial laboratories offer
quantitative as well as qualitative PCR testing on a variety of specimens. Although not widely
available, other diagnostic tests for consideration in selected circumstances include in situ
hybridization, immunohistochemistry, and antigen assays.
LABORATORY FINDINGS.
White blood cell (WBC) counts of 8,0009,000 WBCs/L may be found during the 1st few days
of fever in children with roseola, but by the time the exanthem appears, the WBC count falls to
4,0006,000 WBCs/L with a relative lymphocytosis (7090%). The cerebrospinal fluid in
children with HHV-6-associated febrile seizures typically is normal. The cerebrospinal fluid
from rare cases of HHV-6-associated meningoencephalitis and encephalitis is characterized by a
mild pleocytosis with predominance of mononuclear cells, normal glucose, and normal to
slightly elevated protein.
DIFFERENTIAL DIAGNOSIS.
Children with roseola typically present at 2 different stages of the illness: at the time of fever
before the rash (pre-eruptive) and after the rash has appeared. During the pre-eruptive stage,
many conditions may be confused with roseola. However, the pattern of fever in a generally well
child without significant physical findings, rather precipitous defervescence, and a subsequent
rash is unique for roseola.
Roseola historically has been most commonly confused with rubella and measles; with the
virtual elimination of these diseases in the United States, there should be little reason to confuse
roseola with these diseases, unless there is an exposure history. In contrast to the absence of a
distinct prodrome in children with roseola, children with rubella invariably have a mildly
symptomatic prodromal period, including prominent occipital and postauricular
lymphadenopathy (see Chapter 244 ). Lymphadenopathy is an inconsistent finding in roseola;
when present, the occipital lymph nodes are more frequently affected than those in the
postauricular region. Rubella usually causes only low-grade fever, which is coincident with the
exanthem. The rubella rash is typically more extensive than that seen with roseola, and
coalescence is more common. The development of an exanthem at the height of the fever as well
as the presence of cough, coryza, conjunctivitis, and Koplik spots on the buccal mucosa in the
early stages of measles should clearly differentiate measles from roseola (see Chapter 243 ).
Outbreaks of roseola-like illnesses have been associated with many different viruses, most
commonly enteroviruses. In summer and fall months, some cases of roseola-like illnesses may be
attributable to enteroviruses.
Scarlet fever may also resemble roseola. Important features of scarlet fever are its rarity in
infancy, the simultaneous presence of fever and rash, and the discrete, small, sandpaper-like rash
lesions.
It may be difficult to distinguish central nervous system disease caused by HHV-6 from other
causes. Development of a roseola-like illness in association with febrile seizures,
meningoencephalitis, or encephalitis makes HHV-6 infection more likely, yet this occurs
infrequently. Hepatitis and heterophile-negative mononucleosis are rarely associated with HHV-
6, and other causes for these infections should first be sought.
TREATMENT.
HHV-6 is inhibited by ganciclovir, cidofovir, and foscarnet (but not acyclovir) at levels that are
achievable in serum; HHV-7 is inhibited by cidofovir and foscarnet. Case reports have indicated
successes and failures with these drugs. Adequate prospective trials evaluating the clinical
efficacy of antiviral agents for HHV-6 or HHV-7 infections have not been performed. There is
not an approved treatment of these infections. The generally benign nature of roseola precludes
consideration of antiviral therapy in immunocompetent persons. Treatment is warranted for
immunocompromised children with severe disease confirmed to be associated with HHV-6 or
HHV-7. Ganciclovir and cidofovir are most commonly used, with duration of therapy typically
23 weeks.
Children in the febrile, pre-eruptive phase of roseola usually are quite comfortable and require
little supportive therapy. Those children who are uncomfortable and irritable, or in whom
histories of febrile convulsions exists, may benefit from treatment with acetaminophen or
ibuprofen. Adequate fluid balance should be maintained in all affected children. Referral should
be considered in those unusual circumstances in which serious disease develops, such as
encephalitis, hepatitis, or pneumonitis.
PROGNOSIS.
The prognosis for the great majority of children with roseola is excellent, with no obvious
sequelae. Before the discoveries of HHV-6 and HHV-7, rare complications of roseola
(hemiparesis, mental retardation) were attributable to brain anoxia during prolonged febrile
seizures, though damage resulting from direct viral invasion of the brain, liver, and other organs
has been demonstrated for HHV-6. Deaths directly attributable to HHV-6 have been reported in
normal as well as immunocompromised patients in whom encephalitis, hepatitis, pneumonitis,
disseminated disease, or hemophagocytosis syndrome developed.
PREVENTION.
Very little information is available on which to base guidelines for prevention of HHV-6 or
HHV-7 infection. Experimental evidence suggests that roseola may be transmitted via blood or
saliva, and both HHV-6 and HHV-7 are shed in the saliva. It is likely that healthy immune
carriers with latent viral infections transmit infection to susceptible infants and children via
saliva.
Viruses cause most pediatric infections. Mixed viral or viral-bacterial infections of the
respiratory and intestinal tracts are rather common, as is prolonged asymptomatic shedding of
some viruses in childhood. Thus the detection of a virus is not always proof that it is the cause of
a given illness. Viruses are often a predisposing factor for bacterial respiratory infections (eg,
otitis, sinusitis, and pneumonia).
Many respiratory and herpes viruses can now be detected within 2448 hours by combining
culture and monoclonal antibody techniques ("rapid culture technique"). Diagnosis of many viral
illnesses is also possible through antigen or nucleic acid detection techniques. These techniques
are more rapid than isolation of viruses in tissue culture and in most cases are equally sensitive
or more so. Polymerase chain reaction (PCR) amplification of viral genes has led to recognition
of previously undetected infections. New diagnostic tests have changed some basic concepts
about viral diseases and made diagnosis of viral infections both more certain and more complex.
Only laboratories with excellent quality-control procedures should be used, and the results of
new tests must be interpreted cautiously. The availability of specific antiviral agents increases
the value of early diagnosis for some serious viral infections. Table 381 lists viral agents
associated with common clinical signs, and Table 382 lists diagnostic tests. The viral diagnostic
laboratory should be contacted for details regarding specimen collection, handling, and shipping.
Table 383 lists common causes of red rashes in children that should be considered in the
differential diagnosis of certain viral illnesses.
Influenza Cytomegalovirus
Other respiratory viruses Varicellak
Parvovirus B19
a
Roseola agent.
b
Erythema infectiosum agent.
c
Conjunctivitis rare, only in primary infections; keratitis in older patients.
d
May cause isolated pharyngeal vesicles at any age.
e
May cause adenopathy without rash; especially post-auricular.
f
Over 70% of cases.
g
Immunosuppressed, pregnant, rarely other adults.
h
Usually only in young infants.
i
Severely immunosuppressed at risk.
j
Anicteric cases more common in children; these may resemble viral gastroenteritis.
k
Common, but only mild laboratory abnormalities.
l
Especially when the mother is HIV-positive.
Table 382. Diagnostic Tests for Viral Infections.
a
Useful only when performed on selected specimens by qualified laboratories.
Key:
Plus signs signify commercially or widely available; minus signs signify not commercially
available. Note: Results from some commercial laboratories are unreliable.
RL, CDC: Specific antibody titers or PCR available by arrangement with individual research
laboratories or the Centers for Disease Control and Prevention.
ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; RBC, red blood
cell.
Table 383. Red Rashes in Children.
CSF, cerebrospinal fluid; EIA, enzyme immunoassay; ESR, erythrocyte sedimentation rate; GI,
gastrointestinal; HHV-6, human herpesvirus 6; IFA, immunofluorescent assay; PCR, polymerase
chain reaction; URI, upper respiratory infection.