DOI: 10.1111/j.1610-0387.2008.06868.

x Review Article 309

Viral exanthems in childhood – infectious (direct)

exanthems. Part 1: Classic exanthems
Regina Fölster-Holst1, Hans Wolfgang Kreth2
(1) University Clinic Schleswig-Holstein – Campus Kiel, Clinic for Dermatology, Venerology and Allergology (Director:
Prof. Dr. T. Schwarz), Germany
(2) Pediatric Clinic and Polyclinic, University Clinic of Würzburg (Director: Prof. Dr. C. P. Speer), Germany

JDDG; 2009 • 7:309–316 Submitted: 16.7.2008 | Accepted: 20.7.2008

Keywords Summary
• infectious exanthems Exanthems during childhood occur quite often and are mostly harmless in
• immunization nature. Among different trigger factors, viruses are of prime importance. Viral
• classic childhood exanthems exanthems may manifest as a macular, maculopapular, papular, urticarial or
• enteroviruses vesicular rash. Exanthems with other causes (bacterial toxins, drugs, autoim-
• parvoviruses mune diseases) as well as those with unclear etiology such as unilateral lat-
erothoracic exanthem or Kawasaki disease must be differentiated from viral
exanthems. This review focuses on the classic viral exanthems.

Introduction
By definition, an exanthem appears
abruptly and affects several areas of the
skin simultaneously. In children, exan-
thems are usually related to an infection.
In one study, Goodyear and colleagues
[1] showed that 65 of 100 children with
an exanthem and fever had an underly-
ing infection. In 72 % of patients viral
infections were found to be the cause
(mainly enteroviruses).
Viral exanthems may be triggered directly
(infectious) or by an immune response
(indirect or parainfectious exanthem). In-
fectious exanthems are often triggered by
a specific pathogen (e.g., classic child-
hood diseases), while for many, even dis-
tinct parainfectious exanthems, several
viruses from entirely different groups can
cause an immune response leading to an
exanthematous skin eruption (e.g., Gian-
otti-Crosti syndrome).
Attribution of the exanthem to a specific
disease is based on the morphology and
dissemination of the rash as well as a
thorough patient history, including in-
formation on prodromal symptoms, pre-
vious illness (including infections and
mucosal disease), immunization status,
contact with infected persons, and use of
medication and assessment of overall
health and physical examination with
particular attention to lymph node status
as well as inspection of the nasopharynx.
If there is uncertainty, the diagnosis
should be verified by appropriate blood
tests (serology, BB, ESR, CRP), histol-
ogy, and skin and respiratory tract
smears (pathogen detection, inflamma-
tory cells, multinuclear giant cells).
Infectious (direct) exanthems – classic
viral exanthems (diseases of
childhood)
This group of diseases includes the clas-
sic infectious exanthematous diseases,
which more than 100 years ago were
numbered in the order of their appear-
ance as the six diseases of childhood. The
classic exanthems are: measles (1), scarlet
fever (2), rubella (3), erythema infectio-
sum (5), and exanthema subitum (6).
The exanthem identified as fourth dis-
ease in the late 19th century has not been
re-identified in modern times.
Measles
Epidemiology
Measles is a dangerous disease. It is noti-
fiable in Germany, where § 6 of the Pro-
tection against Infection Act (IfSG) from
2001 requires that any suspected disease,
illness, or deaths resulting from measles
be reported. Each year about 450 000
people die of measles [2], most of them
children in Third World countries.
While deaths related to measles are un-
common in industrialized nations (ac-
cording to the German Federal Office of
Statistics, there are 1–2 deaths annually),
regional outbreaks continue to occur.
One such recent outbreak was in the

© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704 JDDG | 4 ˙2009 (Band 7)
310 Review Article
spring of 2006 in the German state of
North Rhein Westphalia. This was the
largest outbreak since measles was de-
clared a notifiable disease, with 1750 in-
fected persons [3]. Infections continue to
occur because failure to receive vaccina-
tions, which underscores the need for
improved vaccination rates. Based on the
epidemiological data from the epidemic
in North Rhein Westphalia, it is clear
that the vaccinations were skipped more
than a decade ago, as the outbreak
mostly involved children and adolescents
between the ages of 12 and 19. Accord-
ing to recent figures provided by the
Robert Koch Institute, the immuniza-
tion rates collected during school entry
physical examinations were 94.0 % (first
measles vaccination) and 76.6 % (second
measles vaccination).
The goal set forth by the World Health
Organization (WHO) of eradicating
measles in Europe by the year 2000 was
not attained and has now been post-
poned to 2010. This would require,
however, that ≥ 95 % of children be im-
munized, an objective that cannot is un-
attainable by 2010. In 2006, the Assem-
bly of German Physicians in Magdeburg,
Germany, spoke for the first time in sup-
port of mandatory vaccination against
measles [4].
Etiology and pathogenesis
The measles virus is a single-stranded
RNA virus belonging to the Paramyx-
oviridae family of the genus Morbil-
livirus. There is only a single serotype,
but more than 20 genotypes which do
not differ in terms of virulence. Sequenc-
ing enables distinction between the wild-
type and vaccine virus.
Transmission is via direct contact with
respiratory droplets, or very rarely air-
borne transmission over larger distances.
The portals of entry for the virus are the
mucous membranes of the nose,
oropharynx, and conjunctiva. Initial
proliferation seems to occur not in ep-
ithelial cells, but rather in lymphocytes
(T and B cells), monocytes, and den-
dritic cells in the tissue. These cells are
the only ones that express the “signaling
lymphocyte activation molecule”
(SLAM, CD150), which is considered
one of the most important cellular recep-
tors for the measles virus [5]. In the first
viremia (2–4 days after infection) the
virus is carried by infected lymphocytes
and monocytes to the primary and sec-
JDDG | 4 ˙2009 (Band 7)
ondary lymphatic organs (thymus,
spleen, Peyer’s plaques, lymph nodes,
tonsils), where massive proliferation of
the virus occurs. During the second
viremia (about 7 days after infection) the
virus spreads to the skin, mucous mem-
branes, kidneys, lungs, gastrointestinal
tract, and liver. The typical cytopatho-
genic effect (CPE) observed in measles
result from the fusion of virus-infected
and non-infected cells to form multinu-
clear giant cells which then perish. The
exanthem is not caused directly by the
CPE but by the interaction of T cells
with virus-infected keratinocytes and en-
dothelial cells. The disease is contagious
3–5 days prior to eruption of the exan-
them and up to 4 days afterward. It is
most infectious during the prodrome
phase.
Clinical manifestations
Normal course: After an incubation pe-
riod of normally 8–10 days, the disease
begins with the prodrome phase. Clini-
cal presentation includes fever, conjunc-
tivitis (typically with hypersensitivity to
light) (Figure 1), runny nose, sore throat
and a dry cough which worsens at night.
Koplik spots (white dots on the buccal
mucosa) are pathognomonic and may
also be present at this time. Onset of ex-
anthem follows after another 3–4 days
(total incubation period of 11–14 days)
with a renewed increase in fever. The ex-
anthem begins behind the ears, near the
hairline, and spreads to the rest of the
skin over a period of three to four days. A
characteristic feature of disease is a con-
fluent maculopapular exanthem (Figure 2),
which begins to resolve after 4–7 days,
often with desquamation. Tiny spots
of capillary bleeding may persist for
another two weeks.
Complications: Transient immunosup-
pression occurs during the illness and
lasts for more than 6 weeks. Complica-
tions thus primarily involve opportunis-
tic bacterial infections (e.g., otitis me-
dia, pneumonia, or diarrhea) or renewed
activity of a chronic disease (e.g., tuber-
culosis). A particularly feared complica-
tion is acute post-infectious encephalitis
(1: 1000 patients) which can occur at
the end of the first week of the exan-
them. It is characterized by headache,
fever, and neurological symptoms such
as seizure. A much rarer complication
involving the central nervous system
(CNS) is subacute sclerosing panen-
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
Viral exanthems in childhood – Part 1
cephalitis (SSPE), which affects 7–11
patients out of 100 000 [6]. This is a
persistent infection of the CNS with a
(defect) wild-type measles virus. The
disease, which manifests clinically after a
latency period of 5–10 years, manifests
with neurologic disorders and a progres-
sive, fatal course. The risk of SSPE ap-
pears to be higher in early childhood
measles infections.
Unusual variants: Mitigated or modified
measles can affect infants with maternal
IgG antibodies and in patients on im-
munoglobulin therapy. Diagnosis is
more difficult owing to milder symp-
toms and often only minimal exanthem.
The disease is nevertheless still infectious
and affected persons are a potential
threat to others.
Measles is, in a sense, a test for the proper
functioning of the cellular (T cell-spe-
cific) immune system. The exanthem is a
reflection of the battle between the virus
and an intact immune system, and
patients with congenital or acquired
T-cell defects often exhibit only a mild
exanthem or none at all. Yet severe and
highly lethal organ complications, such
as progressive giant cell pneumonia or
measles inclusion body encephalitis
(MIBE) are dreaded complications.
Children with isolated humoral immune
defects (disorders affecting antibody for-
mation) can survive measles without any
complications.
Differential diagnosis
Morbilliform exanthems have also been
observed in other infections and use of
certain drugs (Table 1).
Infections: Enteroviruses, especially
echoviruses (no catarrhal symptoms),
rubella virus (with small plaques),
Epstein-Barr virus (severe disease affect-
ing the tonsils, liver, spleen and lymph
nodes, with morbilliform exanthem after
taking amoxicillin/ampicillin), herpes
viruses HHV-6 and HHV-7, Treponema
pallidum (for all forms of exanthem,
systemic syphilis must be ruled out).
Medications: Antibiotics (especially
beta-lactam antibiotics, macrolides,
cephalosporin), non-steroidal anti-in-
flammatory drugs, anticonvulsant drugs
(hypersensitivity syndrome, as well as
drug rash with eosinophilia and systemic
symptoms [DRESS] may begin with a
morbilliform exanthem which often
turns into erythrodermia with rapid
desquamation).
Viral exanthems in childhood – Part 1
Figure 1: 8-year-old boy with measles. Conjunctival injection (prodromal stage).
Figure 2: 8-year-old boy with measles. Maculopapular confluent exanthem.
Diagnosis
In an era of preventive vaccination, cor-
rectly diagnosing measles is increasingly
important. Epidemiological studies, in
particular those conducted in the
framework of the German Measles Sen-
tinel of the Working Group on Measles
and Varicella, show that in sporadic
cases of suspected measles, a diagnosis
of measles is confirmed in only 20 % –
compared with a confirmation rate of
80 % in endemic or epidemic disease.
This is especially apparent in countries
which are already very close to achiev-
ing the goal of eradication of measles
(e.g., Finland and England). Only one
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
in 10 suspected infections is confirmed
by laboratory tests.
Measles IgM can is usually detectable af-
ter the first three days of the exanthem
by an enzyme-linked immunosorbent as-
say (ELISA). If the patient is measles
IgM negative, as can occur in vaccinated
patients who experience measles reinfec-
tion, an additional blood test should be
taken 7–10 days later to identify any sig-
nificant increase in antibodies.
In rare circumstances, for instance in im-
munosuppressed patients or as part of an
epidemiological study, direct detection
of the virus may be necessary. Appropri-
ate tests include: RT-PCR (nasopharyn-
Review Article 311
geal sample), bronchial secretions, lym-
phocytes (EDTA blood smear), urine,
cerebrospinal fluid (CSF) or biopsy.
Therapy
There is currently no specific antiviral
therapy available. Treatment of measles is
symptomatic.
Prevention
The only effective means of preventing
measles is vaccination. In Germany, the
measles vaccine was introduced in 1967
in former East Germany and 6 years later
in West Germany. While vaccination
serves to protect the individual patient,
first and foremost is protection of the
population (herd immunity); hence by
receiving the vaccine, the individual con-
tributes to the health of the society as a
whole. Vaccination is recommended, but
not compulsory.
The measles vaccine is a live virus that is
grown in chicken fibroblasts. The vaccine
is available as a monovaccine; or in com-
bination with mumps and rubella
(MMR); or with mumps, rubella, and
varicella (MMRV). The German Immu-
nization Commission (STIKO) [7] rec-
ommends that the first vaccination be
given between the 11th and 14th months
of life and the second between the 15th
and 23rd months of life. The second vacci-
nation is designed to address primary or
secondary vaccine failure and to cover
children who have not yet been vacci-
nated. STIKO also advises all people who
have not been vaccinated and who have
not been exposed to the disease to be vac-
cinated. This applies especially to health
workers and employees of daycare centers,
orphanages, and the like. For patients
who have received only one vaccination or
none at all, and have had contact with an
infected person, disease may be prevented
by a post-exposure vaccination given
within three days after contact [8].
Prevention using human immunoglobu-
lins is recommended for patients who are
chronically ill or have an immune defi-
ciency. Passive post-exposure immuniza-
tion should be provided within 2–3 days
after contact.
Responding to measles outbreaks
In the event of a measles outbreak in a
community facility, an appropriate
response requires the cooperation of the
health authorities, the director of the
facility (e.g., school, kindergarten, or
JDDG | 4 ˙2009 (Band 7)

Disease
Drug-induced exanthems
Ampicillin/amoxicillin-exanthem
(in Epstein-Barr virus infection)
JDDG | 4 ˙2009 (Band 7)
Other drug-induced exanthems
Drug rash with eosinophilia and
systemic symptoms (DRESS);
synonym: anticonvulsant
hypersensitivity syndrome
Infectious exanthems (non-classic disease)
Epstein-Barr virus infection
Enterovirus infections (especially
ECHO and Coxsackie A viruses)
Syphilis (second stage)
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
Exanthem
1–2 days after beginning
antibiotics, pronounced
morbilliform exanthem,
lasting 7–10 days
After 1–2 weeks (if taken for the
first time) maculopapular (rarely
developing into blistering)
exanthem mainly on extensor
surfaces of the extremities, pruritus.
Facultative: enanthem
Facial edema, morbilliform exan-
them, later eczema. Develops into
erythema multiforme exudativum,
erythrodermia or toxic epidermal
necrolysis
Lid edema (30 % of infected
persons) maculopapular or urtica-
rial exanthem mainly on the trunk
(10 % of infected persons), palmar
erythema, persists 1–5 days
Maculopapular or morbilliform
exanthem
Commonest form: macular
exanthem (roseola, macular
syphilid, containing pathogen),
predominantly palmoplantar
regions and trunk, often
postinflammatory pigmentary
disorders (4–6 weeks after onset
of stage 2 syphilis)
Extracutaneous symptoms
Associated with Epstein-Barr virus
Rarely: fever, lymphadenopathy,
arthralgia, myalgia
Fever, lymphadenopathy, hepato-
megaly
Prodrome (3–5 days): fever,
headache
Illness: exudative pharyngotonsilli-
tis, lymphadenopathy, fever,
Facultative: hepatosplenomegaly
Fever, pharyngitis
Mucous membrane involvement
(plaques muqueuses), lymphadeno-
pathy, bone pain at night (dolores
osteocopi nocturni), night heada-
che (meningitis cerebrospinalis)
Diagnosis
Patient history, Epstein-Barr virus
serology
Patient history, allergy tests at
4 weeks or more after healing
(skin test, RAST, provocation)
Patient history, eosinophilia, eleva- Commonest triggers: antiepileptic
ted transaminases ↑
Lymphocytosis, atypical T
lymphocytes, serology
Virus isolation (oral rinse, stool)
Serology (TPHA test)
312
Notes/ Special features
Epstein-Barr virus infection and
amoxicillin/ampicillin: 80–100 %
Review Article
exanthem, most patients tolerate
the antibiotic again after infection
runs its course
Peak incidence: adults > 40 years
Commonest triggers: antibiotics,
non-steroidal anti-inflammatory
drugs
drugs, allopurinol, antibiotics
Primary age of manifestation: adole-
scence, association with lymphoma.
Complications: splenic rupture,
Table 1: Morbilliform exanthems – differential diagnostic considerations.
agranulocytosis, CNS involvement
Primary age of manifestation:
young children, seasonal increase
in summer
No pruritus! Begins 9th week after
infection; complication with florid
infection during pregnancy: conge-
nital syphilis
Viral exanthems in childhood – Part 1
 Disease Exanthem Extracutaneous symptoms Diagnosis Notes/ Special features

Classic exanthems
Rubella Maculopapular discrete exanthem, Lymphadenopathy affecting occi- Serology (rubella virus) Primary age of manifestation:
craniocaudal dissemination pital and postauricular nodes, fever adolescence, 3 % of women of
(< 38.5°C), mild course childbearing age have no
Table 1: Continued

antibodies → risk of rubella

embryopathy (Gregg syndrome)

Scarlet fever 1. Punctate papular exanthem, cra- High fever, pharyngotonsillitis, Leukocytosis, bacteriology, rapid More prevalent in winter
niocaudal spread, predominantly strawberry tongue strep test Primary age of manifestation:
Viral exanthems in childhood – Part 1

on joint flexures, perioral pallor 4–8-year-olds

2. Large flakes in acral regions, fine Complications: otitis media, myo-
scales on the trunk and face carditis, sepsis, acute glomerulo-
nephritis (delayed complication)

Erythema infectiosum 1. Slapped Cheek Complications: Serology (parvovirus B19), PCR More prevalent in the spring
2. Lacelike or reticulate macular arthralgia/arthritides, aplastic crises Primary age of manifestation:

© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
exanthem, predominantly affec- in chronic hemolytic anemia, school-age children, after
ting the extremities fetal hydrops exanthem eruption, disease is no
longer infectious

Exanthema subitum Maculopapular exanthem as the fe- 3–5 days of high fever preceding Serology (HHV-6), PCR (HHV-6, No seasonal preference
ver subsides exanthem HHV-7) Primary age of manifestation:
infants and young children
(< 2 years)

Exanthems of unknown origin

Kawasaki disease 1. Erythema and edema in acral regi- 1. High fever > 5 days, Leukocytosis and thrombocytosis, Most common systemic vasculitis
ons and about the lips, strawberry lymphadenopathy (70 %), acute-phase proteins ↑, ECG, in children
tongue, conjunctival injection arthralgia echocardiogram Primary age of manifestation:
2. Multiform (including morbilli- 2. Myocarditis, arrhythmia early childhood
form) exanthem, especially 3. Aneurysm or occlusion of coro- Most important differential diagno-
perineal nary arteries, heart attack sis: Streptococcus A infection
3. Acral desquamation

Abbreviations: RAST = radioallergosorbent test; TPHA = Treponema pallidum hemagglutination

JDDG | 4 ˙2009 (Band 7)

Review Article
313
314 Review Article
Figure 3: 12-year-old girl with rubella.
Maculopapular exanthem with small plaques.
other establishment), treating physi-
cians, and laboratory physicians. Para-
graph 34, sections 8 and 10 of the Ger-
man Protection Against Infection Act
(IfSG) require that all employees of the
facility and parents of the children at-
tending it be informed of the risk of in-
fection as well as how to protect against
infection. Reporting requirements (§ 34
section 6 of the IfSG) also stipulate that
the heads of community facilities inform
the local health authorities. Treating
physicians must notify the authorities of
any suspected disease, confirmed infec-
tions, or deaths. The same applies to lab-
oratory physicians at testing centers in
the event of positive test results showing
acute measles infection (§ 7 IfSG).
Rubella
Epidemiology
Similar to measles, rubella occurs across
the globe; it is also more prevalent in the
spring. In Germany, as many as 3 % of
18–30-year-old women have no anti-
bodies to rubella, so connatal rubella in-
fections continue to occur.
Etiology and pathogenesis
Rubella virus is an RNA virus (Togaviri-
dae family) which is found only in
human beings. Transmission is by
respiratory droplets or direct contact. The
portal of entry is the upper respiratory
tract. After initial proliferation in the mu-
cosa, there is lymphogenous [spread to
the cervical and occipital lymph nodes.
The infectious virus is detectable in the
blood and nasopharyngeal secretions at
the earliest 7–9 days after infection. Dur-
JDDG | 4 ˙2009 (Band 7)
ing viremia, the virus also spreads to the
skin and other organs (or joints). In
women who are pregnant, transplacental
spread to the fetus can also occur. In
rubella, the exanthem is an expression of
the immunological interaction.
Clinical manifestations
After an incubation period of 2–3 weeks,
manifest disease occurs in only 50 % of
infected persons. Characteristic for
rubella are subfebrile temperatures and
headache, already evident during pro-
drome and only disappearing at the end
of the illness, as well as a macular or mac-
ulopapular exanthem (Figure 3). The
rash spreads craniocaudally, similar to
measles, and disappears in 1–3 days. The
hallmark of disease is symmetrical lym-
phadenopathy, mainly affecting occipital
and postauricular nodes. Patients with
rubella are contagious for one week
before eruption of the rash and continue
to be infectious for at least a week after
the rash resolves.
Complications: The most serious compli-
cation is rubella embryopathy. The type
of complication (e.g., spontaneous abor-
tion, premature birth, deformity) is
determined by the point at which infec-
tion occurs during gestation.
Differential diagnosis
A rubella-like exanthem can also occur in
conjunction with other viral infections in-
cluding other classic childhood diseases,
adenovirus infections, Gianotti-Crosti
syndrome and unilateral laterothoracic
exanthem also present with papules, but
in these exanthems, the pathognomic pat-
tern of the rash is key to diagnosis.
Diagnosis
Diagnosis is especially important in preg-
nant women. It is advisable to conduct
serological tests prior to conception so
that the patient may be vaccinated be-
forehand. If rubella is suspected in a
woman who is already pregnant, infec-
tion should be confirmed by serology. If
specific IgM antibodies are detected dur-
ing pregnancy, rubella IgM should be
confirmed after 1–2 weeks using another
method (given the risk of false-positives).
Additional tests (e.g., immunoblot or
IgG avidity measurement) should be per-
formed if necessary to evaluate whether it
is a primary infection or a reinfection.
Positive identification of a primary
infection or reinfection is followed by de-
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
Viral exanthems in childhood – Part 1
termining the presence of prenatal
rubella: detection of rubella virus RNA
from the chorionic villi biopsy (weeks
11–18 of gestation), from amnionic fluid
or fetal blood (weeks 18–22 of gestation).
After the 22nd week of pregnancy, IgM
antibodies specific for rubella can also be
detected in the blood of the fetus.
The diagnosis of connatal rubella in
newborns and in early infancy is based
on the detection of IgM antibodies spe-
cific for rubella (positive in about 95 %)
and/or pathogen detection in nasal or
pharyngeal secretions, urine, or CSF.
Therapy
No specific antiviral therapy is available.
Associated symptoms usually do not re-
quire treatment.
Prevention
Vaccination (see “Prevention” under
measles) can protect against infection.
Erythema infectiosum (5th childhood
disease)
Epidemiology
Parvovirus B19 infections occur world-
wide, and are mainly seen among
children. The seroprevalence in children
and adolescents aged 10–15 years
is 40–50 %; in 20–30-year-olds it is
60–70 %; and in 60–70-year-olds it is
80 % [9]. Transmission is via respiratory
droplets, but can also occur by contact
with contaminated hands and, rarely,
with infected blood products. After on-
set of the exanthem, the patient is no
longer contagious.
Etiology and pathogenesis
Parvovirus B19 is a non-enveloped, sin-
gle-stranded DNA virus belonging to the
Parvoviridae family of the genus Ery-
throvirus. Because parvoviruses lack a
lipid coat, they are extremely resistant to
heat and detergents. Parvovirus B19 re-
produces only in mitotically highly ac-
tive cells, preferably in erythroblasts. In
the process, the erythroblasts perish,
briefly interrupting erythropoiesis. The
viral receptor, the blood group substance
P, which is found on erythroblasts, is also
found on endothelial cells, megakary-
ocytes, fetal liver cells, and placental and
cardiac muscle cells. Viremia begins 4–
5 days after infection, and peaks 2–3 days
later (up to 1014 virus particles/ml in the
blood), and then diminishes over the
following days. Even after the virus is
Viral exanthems in childhood – Part 1
Figure 4: 7-year-old girl with erythema infectiosum. Annular and gyrate urticarial plaques on the feet.
eliminated from the blood, viral DNA
may be found for the rest of the patient’s
life in various organs (e.g., skin, synovial
tissue, tonsils, liver, and bone marrow)
[10]. Exanthems caused by parvovirus
B19 are presumably triggered by anti-
gen-antibody complexes.
Clinical manifestations
The majority of parvovirus B19 infec-
tions is clinically silent or manifest as a
“flu-like“illness (without exanthem).
The typical exanthem is observed in only
15–20 % of patients infected with par-
vovirus B19 [11]. After an incubation pe-
riod of 1–2 weeks, there is a homogenous,
marked redness of the cheeks (“slapped
cheek“) and a lacy pattern or reticulate
maculo-urticarial exanthem, which is
mainly seen on the proximal extremities
and sometimes on the trunk or distal ex-
tremities (Figure 4). A common phenom-
enon is the repeated fading and recurrence
of the exanthem, triggered by local irrita-
tion, high temperatures (e.g., hot baths,
sunlight), and emotional stress [12].
Other certain clinical manifestations
caused by parvovirus B19 are the papu-
lar-purpuric “gloves and socks syn-
drome“, transient arthritis/arthralgia,
aplastic crises in patients with “stressed”
erythropoiesis and decreased erythrocyte
survival (e.g. spherocytosis), chronic
anemia in patients with congenital or
acquired immune deficiency, and anti-
body-formation disorders, spontaneous
abortion, fetal hydrops, and stillbirth as-
sociated with parvovirus B19 infection
during pregnancy.
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
Differential diagnosis
In patients with homogeneous redness
affecting the cheeks, differential diagno-
sis should include erythema migrans, a
common manifestation of cutaneous
borreliosis in children – although it is
often unilateral. Additional disorders are
macular exanthems such as measles,
scarlet fever, rubella, as well as exanthems
related to enterovirus, mycoplasma or
certain medications (e.g., drug rash with
eosinophilia and systemic symptoms
[DRESS]), and photodermatoses.
Diagnosis
The typical exanthem in erythema
infectiosum is usually not difficult to
diagnosis. If there is an atypical exanthem
and/or underlying disease (e.g., anemia
or immunosuppression) or, in pregnant
women reporting contact with a person
infected with parvovirus B19, acute B19
infection can be detected by serology.
Direct detection of the virus is also possi-
ble on PCR.
Therapy
The exanthem normally does not require
treatment. Associated joint complaints
usually respond to non-steroidal an-
tirheumatic drugs. In immunodeficient
patients with chronic anemia and
persistent parvovirus B19 infection,
immunoglobulins should be given. Isola-
tion is not necessary since the disease is
only contagious prior to the eruption of
the exanthem.
In pregnant women with recent par-
vovirus B19 infection, weekly (Doppler)
Review Article 315
ultrasound studies should be performed
to exclude fetal anemia and fetal hy-
drops. If the fetus is found to be anemic,
intrauterine erythrocyte transfusions are
made via the umbilical vein. Treatment is
successful in 80 % of serious cases of fe-
tal hydrops. The affected fetus is restored
to health and delivered at full term with-
out any associated effects.
Exanthema subitum (three-day fever,
6th childhood disease)
Epidemiology
Exanthema subitum is the most com-
mon exanthem in infants and young
children. It is primarily caused by human
herpes virus type 6 (HHV-6), but some-
times by human herpes virus type 7
(HHV-7). By the end of the second year
of life, almost 100 % of children are
seropositive for HHV-6. The primary in-
fection with HHV-7 is generally much
later. Not until the end of the sixth year
of life is the seroprevalence 80–90 %.
Both viruses are transmitted by contami-
nated saliva, and possibly by blood
products or organ and stem cell trans-
plants. Exanthema subitum occurs in
only 20 % of all children infected with
HHV-6 [13].
Etiology and pathogenesis
HHV-6 and HHV-7 are closely related,
and both belong to the Roseolovirus
genus in the subfamily of Betaherpesviri-
nae [14]. After the acute infection sub-
sides, both viruses remain in the body for
life (HHV-6 in salivary gland cells,
monocytes/macrophages, hematopoietic
stem cells and microglia cells; HHV-7 in
salivary gland cells and CD4-positive T
cells). A latent infection can be reacti-
vated at any time, e.g., by inflammatory
processes, other viral infections, or im-
munosuppression. After reactivation
only patients who are severely immuno-
compromised become symptomatic.
Clinical manifestation
Without a prodromal stage, after an incu-
bation period of 5–15 days the child devel-
ops a sudden high fever which persists on
average for 3–5 days. Typically, as the fever
subsides, there is abrupt eruption of dis-
crete macular or maculopapular exanthem
(Figure 5), which appears mainly on the
neck and trunk and begins to disappear
within a few hours. In older school-age
children, a primary infection with HHV-6
andHHV-7 occasionally may also cause
JDDG | 4 ˙2009 (Band 7)
316 Review Article
Figure 5: 1½-year-old boy with exanthema subitum. Small, partly confluent papules.
symptoms resembling mononucleosis and
accompanying hepatitis.
Complications: Exanthema subitum is
the exanthem which is most frequently
associated with febrile convulsions. The
risk is around 10 %.
Differential diagnosis
Other viral infections (e.g., adenovirus,
enterovirus, measles, parvovirus B19,
rubella, and parainfluenza viruses) and
drug-induced exanthems should be con-
sidered in the differential diagnosis.
Diagnosis
The early age of manifestation, patient
medical history, and clinical signs and
symptoms aid diagnosis. The primary
infection (HHV-6 or HHV-7) can also
be confirmed serologically by detection
of specific antibodies (IgM; 4-fold IgG
increase) on indirect immunofluores-
cence tests. It should be noted that the
antibodies to both viruses may cross
react. To distinguish between primary
and reactivated infection, additional
tests may be needed (IgG avidity test,
quantitative PCR).
Therapy
Treatment consists of antipyretic and, if
needed, anticonvulsant measures. <<<
JDDG | 4 ˙2009 (Band 7)
Conflict of interest
None.
Correspondence to
Prof. Dr. med. Regina Fölster-Holst
Universitätsklinikum Schleswig-
Holstein, Campus Kiel
Dermatologie, Venerologie und
Allergologie
Schittenhelmstraße 7
D-24105 Kiel
Tel.: +49-431-597-1596/1579/1501
Fax: +49-431-597-5349
E-mail:
rfoelsterholst@dermatology.uni-kiel.de
References
1 Goodyear HM, Laidler PW, Price EH,
Kenny PA, Harper JI. Acute infectious
erythemas in children: a clinico-micro-
biological study. Br J Dermatol. 1992;
126: 302.
2 Moss WJ. Measles Still Has a Devastat-
ing Impact in Unvaccinated Popula-
tions PLoS Medicine 2007; 4: e24.
3 Robert Koch-Institut: Masern: Erre-
ichen der Elimination in Deutschland
gefährdet. Bericht zur Molekularepi-
demiologie von 1999 bis 2007. Epi-
demiol. Bulletin 2007; 37: 341–344.
© The Authors • Journal compilation © Blackwell Verlag GmbH, Berlin • JDDG • 1610-0379/2009/0704
Viral exanthems in childhood – Part 1
4 Zylka-Menhorn V. Masern: Vermeintlich
harmlose Viruserkrankung. Dtsch
Arztebl 2006; 103: B-1356–1358.
5 Rima BK, Duprex WP. Morbilliviruses
and human disease. J Pathol 2006; 208:
199–214.
6 Bellini WJ, Rota JS, LE Lowe, Katz RS,
Dyken PR, Zaki SR, Shieh WJ, Rota
PA. Subacute sclerosing panencephali-
tis: more cases of this fatal disease are
prevented by measles immunization
than was previously recognized. J Infect
Dis 2005; 192: 1686–1693.
7 Robert Koch-Institut. Empfehlungen der
ständigen Impfkommission (STIKO).
Stand Juli 2007. Epidem Bull 2007; 30:
267–286.
8 Kreth HW. Masern. In: DGPI (Hrsg.)
DGPI (Deutsche Gesellschaft für pädi-
atrische Infektiologie) -Handbuch. In-
fektionen bei Kindern und Ju-
gendlichen. 4. Auflage, München:
Futuramed Verlag, 2003: 494–498.
9 Heegaard ED, Brown KE. Human par-
vovirus B19. Clin Microbiol Rev 2002;
15: 485–505.
10 Norja P, Hokynar K, Aaltonen LM,
Chen R, Ranki A, Partio EK, Kiviluoto
O, Davidkin I, Leivo T, Eis-Hübinger
AM, Schneider B, Fischer HP, Tolba R,
Vapalahti O, Vaheri A, Söderlund-Ven-
ermo M, Hedman K. Bioportfolio: life-
long persistence of variant and proto-
typic erythrovirus DNA genomes in
human tissue. Proc Nat Acad Sci 2006;
103: 7450–7453.
11 Gröbe H. Exantheme. In: Traupe,
Hamm (Hrsg.): Pädiatrische Derma-
tologie, Heidelberg: Springer Verlag,
2006: 343.
12 Bialecki C, Feder HM, Grant-Kels JM.
The six classic childhood exanthems: A
Review and update. J Am Acad Derma-
tol1998; 21: 891–903.
13 Zerr DM, Maier AS, Selke SS, Frenkel
LM, Huang ML, Wald A, Rhoads MP,
Nguy L, Bornemann R, Morrow RA,
Corey L. A population-based study of
primary human herpesvirus 6 infec-
tion. N Engl J Med 2005; 352:
768–776.
14 Caselli E, Di Luca D. Molecular biol-
ogy and clinical associations of Rose-
oloviruses human herpesvirus 6 and
human herpesvirus 7. New Microbio-
logica 2007; 30: 173–187.