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Viral exanthems: An update on laboratory testing of the adult patient

Article  in  Journal of the American Academy of Dermatology · October 2016

DOI: 10.1016/j.jaad.2016.08.034

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 Viral exanthems: An update on
laboratory testing of the adult patient
Abraham M. Korman, BS,a,b Ali Alikhan, MD,b and Benjamin H. Kaffenberger, MDa
Columbus and Cincinnati, Ohio

Although classic viral exanthems of childhood are well described, they are rarely differentiated in adults.
Laboratory techniques for viral identification have advanced without substantial literature to suggest how a
dermatologist ought to conduct a cost-effective and diagnostic viral panel. Certain clinical features such as
petechiae, vesicles, and dusky macular or morbilliform exanthems point strongly toward a viral exanthem.
Differentiation of drug and viral causes of morbilliform eruptions has proven difficult. It is possible that
with further diagnostic refinement that unnecessary and fruitless workups of an exanthem and unneeded
discontinuation of drugs can be avoided. We review viral exanthems based on clinical features and discuss
the available and optimal laboratory techniques to assist the dermatologist in a targeted workup. ( J Am
Acad Dermatol 2017;76:538-50.)

Key words: Cost-effectiveness; laboratory tests; morbilliform eruption; polymerase chain reaction;
serology; viral antigen tests; viruses.

INTRODUCTION
Abbreviations used:
Viral exanthems, both classic childhood exan-
thems and parainfectious exanthems provoked by CDC: Centers for Disease Control and
Prevention
viral infections, are well described in the pediatric CHIKV: chikungunya virus
population.1-3 Few data exist in adults regarding CMV: cytomegalovirus
these eruptions or how to differentiate between CV: Coxsackie virus
EBV: Epstein-Barr virus
different viruses or even between viruses and drugs, HFMD: hand-foot-and-mouth disease
which both may cause hypersensitivity reactions.4 HHV: human herpesvirus
Making this diagnosis is very important given the PCR: polymerase chain reaction
RT: reverse transcription
high frequency with which morbilliform eruptions
are seen in the hospital setting.5,6 We review features
suggestive of a viral origin for an exanthem (Table I),
differentiation of viral eruptions (Table II), and
combination of these is more consistent with a virus if
advances in laboratory testing (Table III).
drug reaction with eosinophilia and systemic symp-
toms is ruled out.8 Other distinguishing features are
Differentiating viral from nonviral
listed in Table I.
Although morbilliform eruptions often suggest
both viral and drug-related causes,7 minor features
including petechiae and vesicles are highly sugges- Differentiating among viral causes
tive of infection.8 The erythematovesicular pattern is We review viral exanthems based on 5 common
exclusive to viral infections whereas the erythemato- clinical features: (1) upper respiratory tract infection
pustular and papular patterns are found primarily in symptoms; (2) infectious mononucleosis (fatigue, fever,
drug-related causes.8 Presence of enanthem points lymphadenopathy, and pharyngitis); (3) arthralgia,
strongly toward an infectious cause.7-9 Location of arthritis, or myalgia; (4) underimmunized or unimmu-
the exanthem on the buttocks, hands/feet, face, or a nized status; and (5) acral/oral involvement. The

From the Division of Dermatology, Department of Internal Med- University Comprehensive Cancer Center, 2012 Kenny Rd, Room
icine, Ohio State University Comprehensive Cancer Center, 232, Columbus, OH 43212. E-mail: Benjamin.Kaffenberger@osumc.
Columbus,a and Department of Dermatology, University of edu.
Cincinnati College of Medicine.b Published online October 26, 2016.
Funding sources: None. 0190-9622/$36.00
Conflicts of interest: None declared. Ó 2016 by the American Academy of Dermatology, Inc.
Accepted for publication August 17, 2016. http://dx.doi.org/10.1016/j.jaad.2016.08.034
Reprint requests: Benjamin H. Kaffenberger, MD, Division of
Dermatology, Department of Internal Medicine, Ohio State

538
J AM ACAD DERMATOL Korman, Alikhan, and Kaffenberger 539
VOLUME 76, NUMBER 3

specific clinical features and laboratory diagnoses are petechial, or urticarial eruption can occur in the
summarized in Tables II and III. setting of infectious mononucleosis, occurring in
20% to 30% of cases, most commonly after the
UPPER RESPIRATORY TRACT INFECTION administration of a penicillin-derived antibiotic.22,23
SYMPTOMS Routine hematoxylin and eosinestained biopsy
Adenovirus specimens to screen for CMV are very insensitive.24
In immunocompetent adults, adenovirus causes up- CMV pp65 assay, a test that requires isolating pe-
per respiratory tract infections, ripheral blood mononuclear
and can uncommonly cause a cells from a blood sample,
diffuse morbilliform 6 vesicu- CAPSULE SUMMARY has been the gold standard
lar eruption,10 whereas in for diagnosis of CMV infec-
Viruses cause the majority of infectious
d

immunocompromised adults, tions with high sensitivity

morbilliform eruptions and can be
keratotic papules with a and specificity,25,26 but is
difficult to distinguish clinically.
vesicle-like appearance can very labor intensive and has
be seen beginning on the Subtle clinical features and new
d
substantial laboratory varia-
palms and soles and second- laboratory tests exist that allow for tion.27 Serologic diagnosis is
11 differentiation of viral causes of
arily disseminating. available with fair sensitivity
Viral culture has histori- morbilliform eruptions. and specificity but titers must
cally been the gold standard Recognition of clinical features and
d be repeated to differentiate
for diagnosis of adenovirus knowledge of optimal laboratory testing past from current reactiva-
infections but is time- allows for cost-effective workup. tion.28,29 PCR from periph-
consuming and has variable eral blood can diagnose
sensitivity12; viral antigen as- CMV infection with high
says are quick and have high specificity but are less sensitivity and specificity and represents the ideal
sensitive than viral culture13,14; and polymerase test in most circumstances.30,31
chain reaction (PCR) of a nasopharyngeal swab can
diagnose adenovirus infection with high sensitivity Epstein-Barr virus
and specificity.15 Thus, PCR should be performed for In immunocompetent adults, Epstein-Barr virus
suspected infection. (EBV) causes infectious mononucleosis and can
cause a morbilliform eruption, either as a primary
Influenza virus eruption in response to the infection itself or as a
Influenza virus infection causes cough, fever, secondary eruption, occurring 29.5% of the time after
headache, myalgia, and rhinitis. Infection can lead the administration of a penicillin-derived antibiotic
to a generalized morbilliform eruption,16 albeit rare such as amoxicillin.32 In the latter case, the eruption
17
and more often in children than adults. develops 7 to 10 days after use of the antibiotic,33
Serologic diagnosis of influenza virus is available appearing on the trunk and upper extremities and
with sensitivity lower than reverse transcription then extending to the face and forearms; the
(RT)-PCR.18 RT-PCR of specimens obtained via presence of GianottieCrosti syndrome, erythema
nasopharyngeal swab can diagnose influenza multiforme, and acute genital ulcers can bolster the
virus infection with high sensitivity and specificity, diagnosis.34
provide results within 2 hours of specimen submis- Serologic diagnosis of EBV (heterophile antibody
sion,19,20 and differentiate influenza types and testing) is available with high sensitivity and
subtypes. Rapid influenza antigen tests hold the specificity in individuals older than 13 years,35 but
advantage of providing results within 10 to the false-negative rate approaches 25% in the first
30 minutes with high specificity, but suffer from week of illness.36 In patients who test negative but
low sensitivity and are probably used too irregularly are clinically suspicious for disease, follow-up with
to be stocked in the dermatology office.21 Thus, an EBV-specific antibody test is warranted. These
RT-PCR should be performed for suspected tests detect EBV viral capsid antigen and are highly
infection. sensitive and specific.37 PCR can diagnose EBV
infection with high sensitivity and specificity.38,39
INFECTIOUS MONONUCLEOSIS For suspected cases of infectious mononucleosis,
Cytomegalovirus one should start with the heterophile antibody test
In immunocompetent adults, cytomegalovirus because of speed, sensitivity, and cost compared with
(CMV) infection is most commonly asymptomatic PCR. If the test result is negative and suspicion remains,
or causes infectious mononucleosis. A morbilliform, testing should be performed with EBV-specific
540 Korman, Alikhan, and Kaffenberger J AM ACAD DERMATOL
MARCH 2017

Table I. Distinguishing features of viral and drug causes of morbilliform eruptions

Viral Drug
Season Spring, summer Fall, winter
Location Buttocks, hands and feet, and face Proximal extremities and trunk
Pattern Bright macular or morbilliform rash 6 petechiae or vesicles Dusky macular or morbilliform
rash 6 petechiae
Symptoms Conjunctivitis, cough, diarrhea, fatigue, headache, insomnia, Diarrhea and sore throat
irritability, sore throat, and vomiting
Signs Fever, hepatomegaly, and lymphadenopathy Low-grade fever
Enanthem Yes No
Pruritus No Yes

antibodies. In cases where there is concern for Recommendations for HIV testing were updated
reactivation of latent EBV, false positivity of a test, or and published by the Centers for Disease Control
a transplant recipient with suspicion for EBV disease, and Prevention (CDC) in 2014 and consist of an
testing for EBV virus with PCR should be performed. initial immunoassay of the peripheral blood with
subsequent confirmatory testing for most patients.50
Human herpesvirus-6 and -7 The most recent immunoassays test for both HIV
In immunocompetent adults, human herpesvirus antibodies, and the HIV p24 antigen, to allow earlier
(HHV)-6/7 causes a mononucleosis-like syndrome detection of the virus. In addition, testing for
and can cause a macular or morbilliform syphilis in patients suspected to have HIV should
rash 6 petechiae. In immunocompromised adults, be performed.
HHV-6/7 can reactivate (occurs in 1% of solid organ
transplant recipients) to cause fever, morbilliform ARTHRALGIA, ARTHRITIS, OR MYALGIA
rash, and bone-marrow suppression.40,41 Thus, it Parvovirus B19
should be suspected in solid organ transplant In adults, parvovirus B19 infection commonly
recipients who develop a morbilliform eruption. In causes arthralgias with erythematous or purpuric
addition, pityriasis rosea is associated with systemic lesions in 4 patterns: reticular and annular (most
HHV-6/7 reactivation, but manifests as a papulosqu- common), gloves-and-socks, periflexural, and
amous rather than morbilliform eruption. palpable purpura.51 Parvovirus B19 infection is
Serologic diagnosis of HHV-6/7 is available but most common in young women in the spring or
most individuals over the age of 2 years are summer months,52 and adults may lack the
seropositive, making a single positive result unhelp- slapped-cheeks appearance seen in children.53 The
ful.42,43 A new immunoassay can detect HHV-6 IgM virus can also cause a transient aplastic crisis in
antibodies with high specificity, but is not widely individuals with underlying hematologic abnormal-
available.44 PCR for diagnosis of HHV-6/7 infection ities, such as sickle cell disease.54
should be performed because of its accessibility, and Serologic and PCR diagnoses of parvovirus B19
high sensitivity and specificity.45-47 are available with high sensitivity and specificity, but
the latter is not widely available.55,56 Thus, serologic
HIV diagnosis should be performed for suspected
Acute infection with HIV can cause a infection.
mononucleosis-like syndrome. In this setting it can
present with well-circumscribed, erythematous, small Chikungunya virus, dengue virus, and Zika
(5-10 mm), dull to bright-red macules 6 papules most virus
often on the face, neck, or upper aspect of the thorax, Arthralgias with fever and morbilliform rash along
although the extremities, palms and soles, and scalp with residence/travel to an endemic area should
can be involved.48 The rash typically follows 2 to raise suspicion for 3 mosquito-borne viruses:
3 days of fever, lasts 5 to 8 days, and gradually clears as chikungunya virus (CHIKV), dengue virus, and
the patient recovers from the acute infection.48 Zika virus. Each virus is presented separately but
Notably, the cutaneous manifestations of HIV testing for all 3 is summarized together below.
are extremely variable, and include sudden-onset Chikungunya virus. CHIKV was first reported
seborrheic dermatitis, folliculitis, and cutaneous in the continental United States in 2014,57 and in 2015
fungal infections.49 there were 679 cases from 44 states.58 CHIKV is the
Table II. Clinical features of viral causes of morbilliform eruptions

VOLUME 76, NUMBER 3

J AM ACAD DERMATOL
Incubation
Clinical syndrome Virus period Population Exanthem Other features
Upper respiratory Adenovirus 5-9 d Children Urticarial or unilateral Upper respiratory tract infections; future Kawasaki disease
tract infections laterothoracic exanthem
Immunocompetent Morbilliform or vesicular Upper respiratory tract infections
adults
Immunocompromised Keratotic papules with vesicular Cystitis, encephalitis, enterocolitis, hepatitis, pneumonia,
adults appearance and disseminated infection
Influenza virus 1-4 d Children Morbilliform or petechial Cough, fever, headache, myalgia, rhinitis
Associated: Gianotti-Crosti
syndrome
Adults Morbilliform
Infectious Cytomegalovirus 4-12 wk Children Gianotti-Crosti syndrome Asymptomatic
mononucleosis Immunocompetent Morbilliform (after Asymptomatic or infectious mononucleosis
adults administration of penicillin
antibiotic), petechial or urticarial
Immunocompromised Toxic epidermal necrolysis Viremia
adults
Epstein-Barr 4-8 wk Children Morbilliform Asymptomatic
virus Immunocompromised Acute infection: Morbilliform Asymptomatic or infectious mononucleosis 6 splenomegaly
adults (primary or after administration or splenic rupture
of penicillin antibiotic)
Associated: Gianotti-Crosti
syndrome, erythema multiforme,
and acute genital ulcers

Korman, Alikhan, and Kaffenberger 541

Immunocompromised Oral hairy leukoplakia Burkitt lymphoma, Hodgkin lymphoma, and T-cell
adults lymphomas
HHV-6 and -7 5-15 d Children Roseola infantum
Immunocompetent Morbilliform or morbilliform Mononucleosis-like syndrome; pityriasis rosea
adults with petechiae
Immunocompromised Morbilliform Fever and bone-marrow suppression
adults
HIV Variable Adults Acute infection Macular or morbilliform Mononucleosis-like
syndrome
Chronic infection Associated: pruritic papular dermatitis, -
molluscum contagiosum, and
eosinophilic folliculitis
Continued
Table II. Cont’d

542 Korman, Alikhan, and Kaffenberger

Incubation
Clinical syndrome Virus period Population Exanthem Other features
Arthralgias Parvovirus B19 4-14 d Children Erythema infectiosum (a syndrome characterized by fever and headache that precede by several
days a characteristic bright-red rash with a slapped-cheek appearance)
Adults Erythema or purpura in 4 patterns: Arthralgia, arthritis, and transient aplastic crisis
reticular and annular, gloves-and-
socks, periflexural, and palpable
purpura
CHIKV 2-4 d Adults Morbilliform, scaling and Chikungunya fever: severe arthralgias and myalgias,
macular erythema, headaches, oral ulcers, and photophobia
intertriginous aphthous-like
ulcers, and hypermelanosis
of face and hands
Dengue virus 4-7 d Adults Classic dengue fever Initial: transient flushing erythema of Arthralgias and
the face myalgias, headaches,
Second: macular or morbilliform high fever, and retro-
Less common: generalized confluent orbital eye pain
erythema with rounded areas of
white, unaffected skin
Dengue hemorrhagic fever Petechial, purpura, or ecchymosis Shock and circulatory
collapse
Zika virus Unknown All ages Morbilliform Acute infection: arthralgias and myalgias, conjunctivitis, fever,
headache, retro-orbital pain, and vomiting
Future development: Guillain-Barr e syndrome, fetal
microcephaly
Undervaccinated/ Measles virus 7-14 d All ages Immunocompetent: blanching Acute infection: cough, conjunctivitis, coryza, high fever, and
unvaccinated and morbilliform or purpura Koplik spots
Immunocompromised: Complications: hepatitis, hypocalcemia, pancreatitis, and
desquamation postinfectious encephalitis
Rubella virus 14 d All ages Morbilliform Forchheimer Acute infection: low-grade fever, lymphadenopathy, malaise,
spots and upper respiratory tract symptoms
Complications:
arthralgia and arthritis, encephalitis and hemorrhagic
manifestations (eg, purpura)

J AM ACAD DERMATOL
MARCH 2017
J AM ACAD DERMATOL Korman, Alikhan, and Kaffenberger 543
VOLUME 76, NUMBER 3

causal agent of chikungunya fever, a disease

primarily affecting adults characterized by high fever,
severe arthralgias and myalgias, headaches, and
photophobia.59 Rash is common in chikungunya
fever, occurring in about 50% of patients. The most
common manifestation is a morbilliform rash, occur-
ring primarily over the upper limbs, face, and trunk

Aseptic meningitis, encephalitis, pleurodynia

with less frequent involvement of legs.60 Other skin
manifestations include scaling, intertriginous
aphthous-like ulcers, and hyperpigmentation of
the face and hands.60,61 Exacerbation of existing
Coxsackie A6; pain or pruritus

dermatoses, including psoriasis and oral ulcers, can

occur.61
Dengue virus. In the continental United States,
Enterovirus 71: HFMD
Coxsackie A16; fever

dengue virus is usually present in returning travelers,

Aseptic meningitis

and the last continental epidemic was in 2005 in

Texas. Primary infections are seen in Puerto Rico, the
US Virgin Islands, Samoa, and Guam.62,63
Classic dengue fever consists of high fever,
headaches, retro-orbital eye pain, arthralgias and
myalgias, and morbilliform 6 petechial rash.64 Rash
the hands, feet, and oral mucosa

occurs in up to 82% of patients and is more common

vesiculobullous disease, eczema

in women,65,66 beginning as transient flushing

HFMD, morbilliform or vesicular

eruption classically limited to

coxsackium, onychomadesis,

erythema of the face within the first 24 to 48 hours

morbilliform or vesicular
Classic HFMD: nonspecific

Morbilliform, petechial, or

of symptom onset. The second rash usually occurs 3

Atypical HFMD: severe

to 6 days after the onset of fever and is morbilliform,

and perioral rash

involving the abdomen, face, extremities, and

thorax, and sparing the palms and soles.67 In some
Classic HFMD

cases the individual lesions may coalesce and form a

vesicular

generalized confluent erythema with petechiae and

CHIKV, Chikungunya virus; HFMD, hand-foot-and-mouth disease; HHV, human herpesvirus.

rounded areas of white, unaffected skin (‘‘white

islands in a sea of red’’). Pruritus and mucosal
involvement occur in 27.6% and 29.8% of patients,
respectively.68 The presence of petechiae, purpura,
or ecchymosis is ominous for the development of the
more severe dengue hemorrhagic fever, which may
be associated with circulatory collapse.67
Children

Children

Zika virus. Zika virus is an arbovirus with

Adults

Adults

Adults

maternal-fetal and sexual transmission cycles.69,70

The virus has been reported in more than 20
countries or territories in Central, North, and South
3-10 d

America and the Caribbean.

3-6 d

2-7 d

Acute infection with Zika virus is often asymp-

tomatic, with 20% to 25% of patients experiencing a
Coxsackie virus

rash, fever, arthralgias or myalgias, conjunctivitis,

headache, retro-orbital pain, edema, and vomiting.71
Enterovirus

Echovirus

The rash associated with Zika virus infection is

usually morbilliform, spares the palms and soles,
and begins on the face and spreads cephalocau-
dally.72 Zika virus can also cause hard palate
involvement

petechiae and scleral injection.

Testing for all 3 viruses should be performed
Acral/oral

whenever a particular virus is suspected. To test for

CHIKV, dengue virus, and Zika virus, the patient
should be given the specific CDC form (50.34) to
 544 Korman, Alikhan, and Kaffenberger
Table III. Laboratory tests for differentiating viral causes of morbilliform eruptions
Laboratory tests
Culture Serology Viral antigen tests PCR
Virus Specimens Features Specimens Features Specimens Features Specimens Features Ref
12-15
Adeno- Bronchoalveolar 2-7 d for Blood IgA, IgG, or IgM Respiratory S: 30%-55% Bronchoalveolar S: 93%
virus lavage fluid, CSF, Results S: 21%-77% (bronchoalveolar SP: 98.9%-100% lavage fluid, blood, SP: 100%
conjunctival swabs S: variable lavage fluid, eye, cerebrospinal fluid,
or scrapings, nasal swabs or nasopharyngeal
nasopharyngeal washes, swabs or aspirates,
swabs or aspirates, nasopharyngeal sputum, stool,
stool or rectal swabs, throat or throat swabs or
swabs, throat oral swabs, tracheal washes, tracheal
swabs or washes, aspirate and aspirates, or urine
sputum, tissue sputum) or
samples, tracheal nonrespiratory
aspirates, and (rectal swab, stool,
urine terminal ileum, and
urine) specimens
18-21
Influenza e e Nasopharyngeal S: 53.7%-92.6% Nasopharyngeal S: 53.9% Nasopharyngeal RT-PCR
virus swabs or swabs, nasal SP: [90% swabs, S: 100%
washes, washes or nasopharyngeal or SP: 97.7%
bronchial aspirates, throat bronchial washes,
washes, swabs nasal or
or nasal or endotracheal
endotracheal aspirates or
aspirates sputum, throat
swabs
CMV Bronchoalveolar 1-6 wk for Blood IgM or IgG CMV pp65 protein S: 89%-91% Blood or plasma S: 80%-94% 24-31
lavage fluid Results S: 6.4%-65.3% assay: PBMCs SP: 69%-93% (CMV DNA) SP: 90%-99%
or blood S: variable SP: 69.1%-100%
35-39
Epstein- e e Blood Heterophile Blood Anti-VCA Blood S: 100%
Barr antibodies IgM/IgG SP: 92%

J AM ACAD DERMATOL
virus S: 86% S: 97% Plasma S: 58%
SP: 100% SP: 100% SP: 100%
Anti-EBNA Serum S: 75%
IgG: SP: 98%

MARCH 2017
positive for life
 VOLUME 76, NUMBER 3
J AM ACAD DERMATOL
42-47
HHV-6* e e Blood IgM e e Blood, CSF, PBMCs, S: 95%
SP: 97.5% plasma, or serum SP: 98.8%
(HHV-6 DNA)
HHV-7* e e Blood IgG (children) e e Blood, CSF, PBMCs, SP: 100%
S: 95% plasma, or serum
SP: 76% (HHV-7 DNA)
50
HIV e e Blood 1. Antigen/antibody e e e e
combination
immunoassay
HIV-1: S: 99.76%-100%
HIV-2: S: 100%
2. HIV-1/HIV-2
antibody
differentiation
assay
S: 98.5%-100%
SP: 100%
3. HIV-1 NAAT
S: 97%-98%
SP: 99.6%-99.98%
55,56
Parvo- e e Blood IgM e e Amniotic fluid, bone S: 92.7%
virus S: 65.6%-91.4% marrow, plasma, SP: 100%
B19 SP: 93.6%-97.3% serum, or placental
IgG and fetal tissues
S: 95.7%-96.7% (parvovirus B19
SP: 49.3%-67.6% DNA)

Korman, Alikhan, and Kaffenberger 545

CHIKVy Serum S: 23% Blood IgM e e Blood RT-PCR 73

S: 96.9% S: 100%
SP: 98.3% SP: 100%
IgG
S: 95.4%
SP: 100%
Dengue e e Blood IgM Plasma: S: 64% Blood RT-PCR
virusy S: 96.9% nonstructural SP: 100% S: 91.4%
SP: 98.3% protein-1 SP: 95.4%
IgG
S: 99.2%
SP: 96.2%
Zika e e Blood IgM/IgG e e Blood, saliva, or RT-PCR
virusy S: 100% urine S: 100%
SP: 100% SP: 100%
Continued
Table III. Cont’d

546 Korman, Alikhan, and Kaffenberger

Laboratory tests
Culture Serology Viral antigen tests PCR
Virus Specimens Features Specimens Features Specimens Features Specimens Features Ref
78-80
Measles e e Blood IgM e e Nasal, PCR
virus S: 83%-89% nasopharyngeal, S: 48%
SP: 95%-100% or throat swabs SP: 100%
RT-PCR
S: 100%
SP: 100%
84
Rubella Blood, CSF, nasal, Labor intensive; Blood IgM e e Amniotic fluid RT-PCR
virus throat, and rarely S: 84.2%-96.5% S: 83%-95%
urine specimens performed SP: 96.8%-99.9% SP: 100%
96-102
Entero CSF, throat, rectal, 7-10 d for Results Blood S: 97.7% e e Blood, CSF, throat RT-PCR
virus and ulcer swabs, S: variable SP: 93.3% swabs, urine, or S: 77%-100%
vesicular fluid, and Under development vesicular fluid SP: 81%-88%
serum or urine
Coxsackie e e Blood IgM e e CSF, nasopharyngeal RT-PCR CSF
virus S: 84.6% secretions, throat S: 67%-98%
SP: 98.4% swabs, tracheal SP: 98%
aspirates, stool,
or vesicular fluid
Echo- CSF, serum, stool 2-6 d for Results Blood Not routinely e e CSF, serum, stool RT-PCR
virus or rectal swabs, S: 19% used samples, and S: 94.7%
throat swabs, throat swabs SP: 97.4%
or urine

CHIKV, Chikungunya virus; CMV, cytomegalovirus; CSF, cerebrospinal fluid; EBNA, Epstein Barr nuclear antigen; HHV-6, human herpesvirus-6; HHV-7, human herpesvirus-7; HIV, human
immunodeficiency virus; NAAT, nucleic acid amplification testing; PCR, polymerase chain reaction; PBMCs, peripheral blood mononuclear cells; Ref, references; RT, reverse transcription; S, sensitivity;
SP, specificity; VCA, viral capsid antigen.
*Commonly a send-out test.
y
Should be sent to the Centers for Disease Control and Prevention.

J AM ACAD DERMATOL
MARCH 2017
J AM ACAD DERMATOL Korman, Alikhan, and Kaffenberger 547
VOLUME 76, NUMBER 3

take to a commercial laboratory for peripheral blood and hepatitis are more common in adults.83
to be sent to the CDC; this test is free for the patient.73 Complications of infection include arthralgia,
A single laboratory RT-PCR test is now available arthritis, and encephalitis. Serologic diagnosis of
through the CDC to evaluate for presence of Zika rubella virus is available with high sensitivity and
virus, CHIKV, or dengue virus infection. specificity, and is the most common diagnostic
method.84 Similar to measles, the measurement of
UNDERIMMUNIZED OR UNIMMUNIZED IgM antibodies should be performed, as the
STATUS presence of IgG antibodies is indicative of earlier
Measles virus immunization. RT-PCR can diagnose rubella virus
Antivaccination sentiment and travel abroad has infection but is usually reserved for prenatal
fueled a resurgence in measles cases in the United diagnosis of congenital rubella syndrome, and is
States in recent years, with a record 667 cases in 2014, not widely available.
the highest number since measles was officially Serologic diagnosis of rubella infection should be
eliminated in the United States in 2000.74 Most cases performed in the nonpregnant adult.
were adults, with approximately 20% previously
vaccinated, suggesting waning immunity.74 ACRAL/ORAL INVOLVEMENT
Measles virus infection classically causes high The nonpolio enteroviruses include entero-
fever, cough, conjunctivitis, and coryza followed by viruses, Coxsackie viruses (CV), and echoviruses.
the development of rash.75 The typical exanthem of
measles arises 2 to 4 days after onset of fever and Enterovirus
consists of a morbilliform, blanching rash, which Enteroviruses are the most commonly implicated
begins on the face and spreads cephalocaudally and viruses in morbilliform eruptions associated with
centrifugally to involve the neck, upper and aseptic meningitis, accounting for about 70% of
lower aspect of the trunk, and extremities.76 Koplik cases.85 They are the most commonly implicated
spots, guttate minute white macules on the buccal viruses in hand-foot-and-mouth disease (HFMD).86
mucosa, are pathognomonic. Infection is more
severe in adults, who more commonly experience Coxsackie virus
postinfectious encephalitis, hepatitis, hypocalcemia, Classic HFMD manifests with fever and a nonspe-
or pancreatitis. Infection is particularly severe in cific morbilliform or vesicular eruption classically
immunocompromised patients who can experience limited to the hands, feet, and oral mucosa.
a severe desquamative rash.77 However, 87.6% of patients will have lesions in other
Serologic diagnosis of measles virus should be areas, including the buttocks, legs, arms, and trunk.87
performed because of its availability and high CV-A16 is the most common subtype of CV to cause
sensitivity and specificity.78 Measurement of IgM classic HFMD and second most common cause
antibodies should be performed, as the presence of overall. Recently, however, CV-A6 has been
IgG antibodies is indicative of earlier immunization. recognized as the cause of atypical HFMD, which is
A send-out RT-PCR is available through the CDC with associated with widespread, severe vesiculobullous
high sensitivity and specificity.79,80 disease, localization to areas of atopic dermatitis
(so-called eczema coxsackium), high rates of
Rubella virus onychomadesis, and a perioral eruption, unlike
Although eliminated in the United States, CV-A16.87-89 Although HFMD occurs primarily in
imported cases of rubella continue to occur, with children, it can occur in adults as well.90 Since 2008,
about 10 cases per year from 2004 to 2013.81 Thus, there have been increasing reports of HFMD in
rubella should be considered in recent, underimmu- adults caused by the more virulent CV-A6.91
nized or unimmunized travelers who fit the classic
presentation. Echovirus
Rubella infection causes a prodrome of low-grade Echovirus can cause HFMD in children and can
fever, lymphadenopathy, malaise, and upper cause aseptic meningitis, encephalitis, or more
respiratory tract infection symptoms, preceding the rarely, pleurodynia, in adults.92-94 In these settings,
classic rash, which is morbilliform and begins on the it can cause a morbilliform rash 6 petechiae or
face before spreading cephalocaudally.82 It is vesicles, the latter of which can be disseminated or
occasionally pruritic and is usually fainter than the localized.95
exanthem of measles. Red petechiae on the soft Serologic diagnosis of enterovirus demonstrates
palate (Forchheimer spots) are seen in 20% of cases. high sensitivity and specificity.96 Serologic diagnosis
High-grade fever, subconjunctival hemorrhage, of CV is available with high sensitivity and specificity
548 Korman, Alikhan, and Kaffenberger J AM ACAD DERMATOL
MARCH 2017

but does not detect CV-A6,97 and thus RT-PCR 9. Forman ML, Cherry JD. Enanthems associated with uncom-
is often a better testing modality.98 RT-PCR can mon viral syndromes. Pediatrics. 1968;41:873-882.
10. Kudesia G, Wreghitt T. Clinical and diagnostic virology. Cam-
diagnose enterovirus, CV, and echovirus infection bridge, UK: Cambridge University Press; 2009:9-10.
with high sensitivity and specificity,99-101 and its use 11. Keyes A, Mathias M, Boulad F, et al. Cutaneous
has been associated with decreased duration of involvement of disseminated adenovirus infection in an
unnecessary antimicrobial therapy and length of allogeneic stem cell transplant recipient. Br J Dermatol.
hospital stay.102 2016;174:885-888.
12. Layman CP, Gordon SM, Elegino-Steffens DU, Agee W, Barnhill J,
Conclusion Hsue G. Rapid multiplex PCR assay to identify respiratory viral
Although dermatologists encounter morbilliform pathogens: moving forward diagnosing the common cold.
Hawaii J Med Public Health. 2013;72:24-26.
eruptions regularly, oftentimes the cause can be 13. Raboni SM, Siqueira MM, Portes SR, Pasquini R. Comparison of
difficult to ascertain. It is essential to first understand PCR, enzyme immunoassay and conventional culture for
clues that support either viral cause or drug eruption adenovirus detection in bone marrow transplant patients
(Table I). Once a viral cause is suspected, the with hemorrhagic cystitis. J Clin Virol. 2003;27:270-275.
14. Levent F, Greer JM, Snider M, Demmler-Harrison GJ.
dermatologist can further narrow down the
Performance of a new immunochromatographic assay for
exact causal agent based on dermatologic and detection of adenoviruses in children. J Clin Virol. 2009;44:
nondermatologic features (Table II) and choose the 173-175.
appropriate laboratory tests and procedures to 15. Cooper RJ, Yeo AC, Bailey AS, Tullo AB. Adenovirus polymer-
confirm the diagnosis (Table III). All of the labora- ase chain reaction assay for rapid diagnosis of conjunctivitis.
tory tests recommended above are available at the Invest Ophthalmol Vis Sci. 1999;40:90-95.
16. Rosenberg M, Tram C, Kuper A, Daneman N. Rash associated
authors’ institutions and are widely available, except with pandemic (H1N1) influenza. CMAJ. 2010;182:E146.
for the test for HHV-6/7, which is commonly a send- 17. Fretzayas A, Moustaki M, Kotzia D, Nicolaidou P. Rash, an
out test, and the tests for CHIKV, dengue virus, and uncommon but existing feature of H1N1 influenza among
Zika virus, which should be sent to the CDC. children. Influenza Other Respir Viruses. 2011;5:223-224.
Although this review serves as a first step in 18. Landry ML, Cohen S, Ferguson D. Real-time PCR compared to
Binax NOW and cytospin-immunofluorescence for detection
discussing the viral causes of morbilliform eruptions, of influenza in hospitalized patients. J Clin Virol. 2008;43:
more studies are needed to define subtle morpho- 148-151.
logical clues, distinguishing characteristics, and 19. Boivin G, Cote S, Dery P, De Serres G, Bergeron MG. Multiplex
reactivation patterns of these viruses. Furthermore, real-time PCR assay for detection of influenza and human
respiratory syncytial viruses. J Clin Microbiol. 2004;42:45-51.
studies are needed to examine the costs accrued and
20. Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in
avoided with testing for viral causes of morbilliform adults and childrenediagnosis, treatment, chemoprophy-
eruptions. laxis, and institutional outbreak management: clinical
practice guidelines of the Infectious Diseases Society of
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