Viral Infections
Joyce Yang
EPSTEIN-BARR VIRUS
Epstein-Barr virus (EBV) is a common virus: most people
become infected sometime in their lives. The clinical syndrome
frequently associated with EBV is infectious mononucleosis, or
mono. In socioeconomically disadvantaged areas, infants and
children are most commonly affected, but adolescents are more
commonly affected in afuent areas.
ETIOLOGY AND PATHOGENESIS
EBV is transmitted by oral secretions and sexual intercourse,
thus requiring close contact for transmission. After infection,
the virus is excreted for many months and then intermittently
for life. The incubation period is usually 30 to 50 days.
The virus most likely spreads from the epithelial cells of the
buccal mucosa to B-lymphocytes and then disseminates to the
entire lymphoreticular system, including the liver and spleen.
Similar to other herpesviruses, EBV stays latent in the body
for life. EBV has been associated with a spectrum of prolif-
erative disorders such as hemophagocytic syndrome, nasopha-
ryngeal carcinoma, Burkitt lymphoma, and lymphoproliferative
disorders.
CLINICAL PRESENTATION
EBV infection causes a wide spectrum of clinical diseases. In
many infants and young children, the symptoms are mild or
unrecognized. The symptoms of infectious mononucleosis are
malaise, fatigue, prolonged fever, sore throat, headache, nausea,
and abdominal pain. Patients often have pharyngitis with exu-
dates, lymphadenopathy, hepatomegaly, or splenomegaly. The
incidence of dermatitis may be as high as 15% and is even more
pronounced in children who were treated with ampicillin or
amoxicillin; it is often called ampicillin rash (Figure 97-1).
Rare complications of mononucleosis include airway obstruc-
tion, central nervous system (CNS) disorders, splenic rupture,
thrombocytopenia, and hemolytic anemia.
EBV is also associated with Gianotti-Crosti syndrome
in which a symmetric rash is seen on the cheeks, extensor
surfaces, or buttocks with multiple erythematous papules,
which may coalesce into plaques. This may persist for 15 to
50 days and may sometimes look like atopic dermatitis (see
Figure 97-1).
DIFFERENTIAL DIAGNOSIS
Several other pathogens may cause a mononucleosis-like illness,
including cytomegalovirus (CMV), adenovirus, hepatitis viruses,
HIV, rubella, and Toxoplasma gondii. Another infection that
causes a similar clinical picture is streptococcal pharyngitis;
however, it usually is not associated with hepatosplenomegaly.
97
EVALUATION AND MANAGEMENT
In 90% of cases, there is leukocytosis of 10,000 to 20,000 cells/
mm3 with a predominance of lymphocytes with 20% to 40%
atypical lymphocytes. There may be a mild thrombocytopenia
but usually no purpura, and mild elevations of transaminases can
occur. A nonspecic test for heterophile antibodies (also called
Monospot) can be done. These are immunoglobulin M (IgM)
antibodies that agglutinate sheep or horse red blood cells (RBCs)
and usually appear during the rst 2 weeks of illness and gradu-
ally disappear over a 6-month period. This test result is often
negative in children younger than 4 years old. EBV can also
be detected by serologic antibody testing. In the acute phase,
there is a rapid immunoglobulin M (IgM) and IgG response to
viral capsid antigen (VCA) and IgG to early antigen(EA). Posi-
tive Epstein-Barr virus nuclear antigen (EBNA) (nuclear
antigen) antibody indicates past infection because this is not
usually present until several weeks to months after infection
(Table 97-1).
There is no specic treatment for infectious mononucleosis.
Patients should not participate in contact sports until they have
recovered or until the spleen normalizes. In severe cases with
complications, a short course of corticosteroids may be helpful;
however, there are no controlled data showing efcacy.
FUTURE DIRECTIONS
Further studies need to be done regarding the safety and efcacy
of corticosteroids for treating complicated EBV infections.
Research regarding treatment of EBV infections in immuno-
compromised patients is also needed. Investigations into asso-
ciations between EBV, malignancies, and lymphoproliferative
disorders will help elucidate these disease processes.
MEASLES
In the United States, the current rate of measles infection is
less than one case per million people; however, historically,
more than 90% of children were infected before the age of
15 years. This change is entirely attributable to the measles
vaccine that was introduced in 1963. An outbreak that occurred
between 1989 and 1991 resulted in 55,000 cases and prompted
implementation of the two-dose vaccine. The majority of cases
of measles are imported into the United States from abroad or
are import related.
ETIOLOGY AND PATHOGENESIS
Measles is transmitted by direct contact with large droplets or
small droplet aerosols that enter through the respiratory tract
or conjunctivae. Patients are contagious 3 days before the rash
 610 SECTION XV Infectious Disease

Periorbital edema

Encephalitis

Ampicillin rash
Transverse myelitis

Guillain-Barre syndrome

Splenomegaly (common)

Cholestatic hepatitis

Atypical lymphocytes
Gianotti-Crosti rash. Erythematous papules
with
E. Hatton (red bumps) on cheeks or extensor surfaces
Bone marrow (rare) Potential complications that coalesce into plagues.
Hemolytic anemia ITP and associated findings

2 Figure 97-1 Clinical presentation of Epstein-Barr virus.

and up to 4 to 6 days afterward. The incubation period is 8 to
12 days. It is very contagious and affects 90% of exposed indi-
viduals. The virus causes necrosis of epithelium and a small
vessel vasculitis of skin and oral mucosa. Infected cells fuse and
cause multinucleated giant cells called Warthin-Finkeldey giant
cells that are pathognomonic for measles.
CLINICAL PRESENTATION
There are four phases to the infection: incubation period,
prodrome, exanthem, and recovery. The prodrome period
begins with a mild fever that increases to 103 to 105F, con-
junctivitis, coryza, and cough. Koplik spots appear 1 to 4 days
before the rash. They appear as red lesions with a bluish white
spot in the center and are usually on the inner aspects of
the cheek. Rash usually appears after 2 to 4 days and begins
on the face as discrete erythematous patches and spreads
downward often becoming conuent (Figure 97-2). Lesions
are also seen on the palms and soles. Rash fades in about 7 days
and may leave desquamation of the skin. Cough can last up to
10 days.
Complications include otitis media, pneumonia, laryngotra-
cheobronchitis, seizures, and diarrhea. In rare cases, measles
may cause acute encephalitis and subacute sclerosing panen-
cephalitis (SSPE), a degeneration of the CNS usually occurring
an average of 7 years later.

Table 97-1 EBV Antibodies in EBV Infection

Viral Capsid Antigen Viral Capsid Antigen Epstein-Barr Virus
Infection Immunoglobulin G Immunoglobulin M Early Antigen Nuclear Antigen
No previous infection
Acute infection + + +/
Recent infection + +/ +/ +/
Past infection + +/ +

From Pickering LK: Red Book: 2006 Report of the Committee of Infectious Disease, ed 27. Elk Grove Village, IL, American Academy of
Pediatrics.

Measles:
Koplik spots
Figure 97-2 Koplik spots.
DIFFERENTIAL DIAGNOSIS
Measles may sometimes be confused with other viruses that
cause exanthems such as rubella, adenovirus, enterovirus, EBV,
human herpesvirus-6 (HHV-6), and parvovirus. Mycoplasma
pneumoniae and group A streptococci (GAS) can also produce
similar rashes. Several clinical ndings are similar in Kawasakis
disease, but there is a more prominent cough and no thrombo-
cytosis in measles. Drug reactions should also be in the differ-
ential diagnosis.
EVALUATION AND MANAGEMENT
The diagnosis of measles is usually clinical; however, laboratory
ndings can include decreased white blood cell count, and a
normal erythrocyte sedimentation rate and C-reactive protein.
IgM antibody can be detected 1 to 2 days after the onset of rash
and remains for 1 month and is therefore indicative of acute
infection. A fourfold increase in IgG antibodies after 2 to 4
weeks can also be diagnostic. There is no specic treatment for
measles; however, low vitamin A levels are associated with
increased morbidity and mortality. Therefore, vitamin A supple-
mentation is recommended. No antibiotic prophylaxis is
recommended.
PREVENTION
Vaccination is the best form of prevention. The rst dose is
recommended between 12 and 15 months followed by a second
dose at 4 to 6 years of age. Because the vaccine is a live-attenuated
vaccine, it should not be given to pregnant women or severely
immunocompromised children. The MMR (mumps, measles,
and rubella) vaccine can cause fever (6-12 days after), rash (7-12
CHAPTER 97 Viral Infections 611
days after) and rarely a transient thrombocytopenia. Fortu-
nately, several large and well-designed scientic studies have
convincingly shown that there is no evidence that the measles
vaccine causes autism.
Postexposure prophylaxis can be administered via vaccine if
it is less than 72 hours after exposure or immune globulin up to
6 days after exposure.
FUTURE DIRECTIONS
Continued educational efforts need to be undertaken to assure
parents about the necessity and the safety of the measles vaccine.
Preventing measles from becoming endemic again in the United
States will require maintenance of a high level of immunity
through vaccination. Eliminating measles from developing
countries through vaccines remains a continuing effort.
HERPES SIMPLEX VIRUS
There are 2 types of herpes simplex virus (HSV), type 1 and
type 2, that can cause a variety of illnesses depending on the
host and the site of infection. A primary herpes infection occurs
in those who have never been infected with either HSV-1 or
HSV-2. A nonprimary rst infection occurs when an individual
who was previously infected with one type of HSV then becomes
infected with another type. A recurrent infection is a reactiva-
tion of the virus from the latent state. HSV can also cause severe
neonatal infection (see Chapter 105).
ETIOLOGY AND PATHOGENESIS
HSV is ubiquitous and is transmitted through direct contact
with infected mucocutaneous surfaces. Even if a person is
asymptomatic, the virus can be intermittently shed; however, the
greatest concentration of virus is shed during symptomatic
primary infections. Although HSV-1 is thought to infect oral
mucosa and HSV-2 is thought to cause genital infections, either
type can cause initial infections in any mucosa surface. However,
HSV-1 is more likely to cause recurrent oral infections, and
HSV-2 is more likely to cause recurrent genital infections.
The virus enters through mucosal surfaces and then spreads
via nerve endings to sensory ganglia. Some viruses then establish
latency in these sensory neurons (Figure 97-3). The incubation
period is usually 2 days to 2 weeks.
CLINICAL PRESENTATION
The most common clinical manifestation of primary infection
in children is gingivostomatitis and is usually caused by HSV-1.
It causes sudden onset of pain in the mouth often manifested as
refusal to eat, drooling, and high fevers. The gums become very
swollen, and vesicles that are usually grouped on an erythema-
tous base are seen throughout the oral cavity, including the
gums, lips, tongue, palate, tonsils, and pharynx. The vesicles can
progress to ulcers, and lymphadenopathy is often seen (see
Figure 97-3). The illness usually resolves in 7 to 14 days.
Herpes labialis (common names include cold sores or fever
blisters) is a common manifestation of recurrent HSV-1
612 SECTION XV Infectious Disease

Ophthalmic Meningeal
branch branches

HSV Trigeminal
ganglion
Maxillary
branch

Mandibular
branch

CN-V

Primary Infection Latent Phase

Virus enters via cutaneous or mucosal surfaces Virus replicates in ganglia before
to infect sensory or autonomic nerve endings establishing latent phase.
with transport to cell bodies in ganglia.

Gingivostomatitis
caused by HSV
Eczema herpeticum

Figure 97-3 Pathogenesis and clinical presentation of herpes simplex viruses.

infections. Usually, a burning, tingling, itching sensation is felt
several hours or days before the development of a herpetic
lesion. It usually begins as a small grouping of erythematous
papules that progress to small, thin-walled vesicles. The vesicles
then form ulcers or become pustular. The most common site of
infection is the vermillion border of the lip. Symptoms usually
last 6 to 10 days.
HSV infections can occur on any skin surface that may have
breakdown or trauma. Herpetic whitlow is a term used for HSV
infections of the ngers or toes. Lesions and pain usually last
for 10 days, and complete recovery usually occurs in 18 to 20
days. Eczema herpeticum is described in patients with a history
of eczema who are superinfected with HSV (see Figure 97-3).
In addition to severe rash, patients can present with high fevers,
malaise, and lymphadenopathy. Other areas of the body that
may be affected by HSV include the conjunctiva, cornea, and
retina as well as the CNS, causing encephalitis and aseptic men-
ingitis. Thus, any vesicles around the eyes should prompt an
ophthalmologic examination. HSV has also been implicated in
erythema multiforme and Bells palsy.
DIFFERENTIAL DIAGNOSIS
When vesicular lesions are seen, the differential diagnosis
should always include infections caused by varicella zoster
(VZV). Gingivostomatitis can be confused with hand, foot, and
mouth disease caused by coxsackievirus or other causes of phar-
yngitis such as GAS and infectious mononucleosis. Widespread
eczema herpeticum can be confused with Stevens-Johnson
syndrome.
EVALUATION AND MANAGEMENT
The diagnosis of HSV infection can be made by detection of
viral antigen or viral DNA by polymerase chain reaction (PCR)
as well as by viral culture obtained by vigorous rubbing of
vesicular base. In HSV encephalitis, there is usually a pleocytosis
with predominance of lymphocytes. Electroencephalography
and magnetic resonance imaging may show temporal lobe
abnormalities as well.
The treatment of HSV includes three antiviral medications,
acyclovir, valacyclovir, and famciclovir. For gingivostomatitis,
acyclovir started within 72 hours of onset reduces the severity
and duration of illness. For herpes labialis, oral treatment can
shorten duration of the episode and can also be used to prevent
recurrences. Acyclovir has also been shown to be effective in the
treatment of eczema herpeticum.
FUTURE DIRECTIONS
Further studies need to be conducted regarding the efcacy of
acyclovir for prevention of recurrent HSV infections and
 CHAPTER 97 Viral Infections 613

treatment of various HSV infection. Currently, valacyclovir and

famciclovir have not been approved by the Food and Drug
Administration for use in children. If they are approved, alterna-
tives to acyclovir will be available and may be more effective in
the treatment of HSV infections in children.

VARICELLA ZOSTER VIRUS

VZV is a very contagious virus that causes chicken pox, and

similar to other members of the family Herpesviridae, then
remains latent in the body. It can be reactivated to cause herpes
zoster or shingles. Before the vaccine was introduced in 1995,
most children were infected by age 15 years. In healthy children,
chicken pox is usually a mild disease, but there is a higher mor-
bidity and mortality in adolescents, adults, infants, and immu-
nocompromised individuals.

ETIOLOGY AND PATHOGENESIS

The virus is spread through direct contact with respiratory
secretions or uid of skin lesions as well as by airborne
spread of respiratory secretions. The incubation period is 10
to 21 days after exposure. Patients are contagious 1 to 2 days
before the onset of rash until all of the vesicles have crusted over. Chickenpox
The virus then establishes a latent infection in the dorsal root
ganglia.

CLINICAL PRESENTATION
Chicken pox is characterized by fever, malaise, anorexia, head-
ache, and a classic rash that starts centrally and then spreads
outward. The rash begins as erythematous macules that then
become very pruritic and vesicular. It is often described as a
dew drop on a rose petal (Figure 97-4). Crusting of the lesions
then occurs as new ones arise, resulting in different stages of
rash. A child who has been previously vaccinated but infected
with VZV may have breakthrough varicella in which the
rash is more atypical. The rash may be maculopapular and less
vesicular with fewer lesions. Severe neonatal chicken pox can
develop if a mother develops the disease 5 days before delivery
or 2 days after.
Complications of varicella include bacterial superinfections Herpes zoster or shingles
of the skin, thrombocytopenia, arthritis, hepatitis, cerebellar
ataxia, encephalitis, meningitis, and glomerulonephritis. These Figure 97-4 Clinical presentations of varicella zoster virus.
complications are more common in adolescents, adults, infants,
and immunocompromised patients. The reactivation of latent
VZV causes zoster or shingles and manifests as grouped vesicles
within one or two dermatomes (see Figure 97-4). Although the
EVALUATION AND MANAGEMENT
lesions can cause intense pain in adults, children commonly have The diagnosis of VZV can be conrmed using direct uores-
a mild rash with minimal symptoms that usually resolve in 1 to cence antigen or PCR. Viral cultures can also be done from
2 weeks. tissue sample in 3 to 4 days. A fourfold increase in VZV IgG
titer can also be conrmatory. There is usually an initial leuko-
penia and then a lymphocytosis. In most cases, the liver enzymes
DIFFERENTIAL DIAGNOSIS are slightly elevated.
The differential diagnosis of varicella includes HSV and Acyclovir can be used to treat varicella infections but is
enterovirus caused by the vesicular lesions. It can often not currently recommended in healthy children. It can be
be confused with drug reactions, contact dermatitis, and given to adolescents, children older than 12 months old with
insect bites. skin or pulmonary disorders and children receiving chronic