Herpes simplex virus type 1 (HSV-1)
and herpes simplex virus type 2 (HSV-2) belong to a family of DNA
viruses that include cytomegalovirus (CMV), varicella-zoster virus
(VZV), Epstein-Barr virus (EBV), and human herpesviruses 6, 7, and
8 (Table 309-1). Following primary infection,
herpes simplex viruses establish a latent state, in general, HSV-1
in the trigeminal ganglion and HSV-2 in the sacral ganglion. From
time to time, the viruses may be reactivated, resulting in recurrent
infections that may or may not be associated with symptoms. HSV-1
is usually transmitted in oral secretions, whereas HSV-2 is most
often transmitted through sexual activity. HSV-1 infections occur
most frequently during childhood and usually affect body sites above
the waist (mouth, lips, eyes, face). HSV-2 infections occur most
often during adolescence and adulthood, and involve body sites below
the waist (genitalia, buttocks, thighs). Historically, the majority
of infections in newborns is transmitted from the maternal genital
tract and is usually caused by HSV-2.1 However,
because the prevalence of genital infection with HSV-1 in the United
States is increasing, a greater proportion of neonatal infections
may be due to HSV-1.2,3
Humans are the only natural reservoirs of herpes simplex virus
(HSV). Infections caused by HSV have no seasonal predilection; however, geographic
location, socioeconomic status, age, and race influence the prevalence
of infection. Children of lower socioeconomic classes and those
from developing countries contract HSV-1 earlier in life than children
of more affluent socioeconomic classes and children from developed
countries. Increased direct person-to-person contact occurring in crowded
living conditions probably accounts for these differences.
Primary infection with herpes simplex virus type 1 (HSV-1) usually
occurs in infancy or childhood, whereas primary infection with herpes
simplex virus type 2 (HSV-2) occurs after the onset of sexual activity.
Acquisition of infection follows intimate mucocutaneous contact
(eg, kissing, sexual intercourse) between a susceptible host and
one shedding virus. The incubation period for most HSV infections
ranges from 2 to 7 days. More recent seroepidemiologic studies reveal
that the prevalence of HSV-1 in the general US population is around
60%, and the prevalence of HSV-2 is approximately 20%.3 In
another more recent study, about 25% of children were infected
with HSV-1 by the age of 12 years.4
The most devastating form of HSV infection in pediatric patients
is neonatal herpes, occurring at an estimated rate of 1 in 3500
to 5000 deliveries. Genital HSV infection in pregnant women is the
major source of virus for the newborn. Most infected infants contract
HSV at the time of delivery through an infected birth canal.
Herpes simplex viruses are 150 to 200 nm in diameter and consist
of a core of linear double-stranded DNA surrounded by an icosahedral
capsid, a fibrillous tegument, and a lipid envelope. There is extensive
homology between HSV-1 and HSV-2, rendering serologic distinction
difficult. There are at least 60 proteins specified by the virus.
Mucocutaneous epithelial cells provide the presumed initial target
for viral infection, whereas neural cells in trigeminal
and sacral root ganglia constitute the site of latent infection.
Infection of the susceptible host results when herpes simplex
virus (HSV) penetrates through abraded skin or mucosal surfaces.
After minimal local replication at the site of inoculation, virus
migrates along innervating axons to the sensory ganglia where infectious virus
is synthesized. Visible lesions result after the virus returns to
the inoculation site via peripheral sensory nerves. Vesicular lesions appear
between epidermal and dermal layers and contain large amounts of
virus, cell debris, and inflammatory cells. When the host is unable
to limit viral replication, such as in newborns and the immunocompromised,
viremia may result in multiorgan involvement.
Establishment of latency, punctuated by episodes of recrudescence,
characterizes infections caused by HSV. During latency, the HSV
genome is maintained in a repressed, noninfectious, “static” state.
Periodic reactivation of HSV and spread down the neuraxis is associated
with the development of recurrent lesions or asymptomatic viral
excretion. A number of stimuli, including direct trauma to ganglia,
exposure to ultraviolet lights, stress, hormonal changes, administration
of immunosuppressive agents, and serious infection, may precipitate
The specific immunologic factors that influence the clinical
course of HSV infections are not completely understood. Humoral,
cell-mediated, and innate immune responses are important in influencing
the acquisition of disease, severity of infection, and frequency
of recurrences. The important role of antibody in HSV infections
is evident by investigations of neonates exposed to HSV at the time
of delivery; those exposed to virus in the presence of transplacentally
acquired neutralizing antibodies are significantly less likely to
contract infection. Humoral immunity also influences the course
of HSV infections beyond the neonatal period. For example, antibodies
against herpes simplex virus type 1 (HSV-1) reduce the risk of contracting
herpes simplex virus type 2 (HSV-2) infection by about 50%,
and a first episode of genital infection caused by HSV-2 is less
severe in patients with preexisting HSV-1 antibodies than in patients
Cellular immunity is also critical for the control of HSV infections.
Clinically severe HSV infections are more common among patients
with compromised cellular immunity than among normal hosts, especially
in those with impairment of CD4 T cells.
Patients with genetic defects in specific components of their
innate immune system, namely, Toll-like receptor 3 and UNC93-B,
have been found to be susceptible to herpes encephalitis.6,7 The
recognition of these patients underscores the importance of these
immune mechanisms in controlling herpes virus.
Most herpes simplex virus (HSV) infections in normal children
are asymptomatic or of mild-to-moderate severity. When associated with
symptoms, primary infections tend to be more severe than recurrent
infections. In contrast, HSV infections in immunocompromised children,
even if recurrent, may result in extensive local disease with substantial
Herpes labialis is the most common herpes simplex virus (HSV)
infection of childhood, with peak incidence at 1 to 5 years of age.
Oral herpes infections are usually caused by herpes simplex virus
type 1 (HSV-1); however, oral-genital sexual practices may result
in herpes simplex virus type 2 (HSV-2) infection in the oral cavity.
Most primary oral infections are subclinical, although careful examination
may detect a few oral ulcers (Fig. 309-1).
When symptomatic, the severity and sites of lesions vary: buccal
mucosa, tongue, palate, and face may be affected; the gums may also
be inflamed and bleed readily. Spread of infection from the oral
mucosa to the lips, skin around the mouth, and eyes may occur. Children who
frequently suck their fingers may develop concomitant infections
of their digits (herpetic whitlow). Submandibular adenopathy, high
fever, and irritability often accompany symptomatic oral infection.
The most common reason for hospital admission is dehydration resulting
from reduced eating and drinking.
Herpes simplex with multiple oral ulcers.
(Source: Reproduced, with permission, from Bondi
EE, Jegasothy BV, Lazarus GS, eds. Dermatology: Diagnosis
& Treatment. Orginally published by Appleton &
Lange. Copyright © 1991 by The McGraw-Hill Companies, Inc.)
The lips are the most common site of oral HSV-1 recurrences.
Factors associated with recurrent bouts of herpes labialis (cold
sores or fever blisters) include intense exposure to sun and/or
wind (eg, skiing) and stressful life events. Labial herpes is commonly
heralded by a burning sensation or itching 1 to 2 days before lesions
develop. In the compromised host, the lips and adjacent facial areas
may be involved for prolonged periods. The usual differential diagnosis
of herpes labialis includes aphthous stomatitis, herpangina, infectious
mononucleosis, and impetigo. Pharyngitis, which
cannot be distinguished clinically from other viral and bacterial causes
of infection, is a common manifestation of primary HSV infection
in older children.
Primary and recurrent herpes simplex virus (HSV) infections may
cause skin vesicles and ulcers on almost any part of the body. Primary skin
infections may be accompanied by deep burning pain, edema, lymphadenopathy,
and fever. Vesicles may appear singly or in clusters; they tend
to become pustular, crust over, and heal within a week, usually
leaving no scars. Herpetic whitlow is an eruption
that typically occurs on the fingers (Fig. 309-2).
It is often painful, and it is easily confused with bacterial infection. Herpes
gladiatorum develops in skin area abraded during the course
of wrestling after contact with someone who has oral HSV infection.
Skin infections also have resulted from other contact sports such
Herpetic whitlow with pustules superimposed on erythema
and edema of the finger.
(Source: From McPhee SJ, Papadakis MA. Current
Medical Diagnosis & Treatment 2010. 49th ed. http://www.accessmedicine.com.
Copyright © The McGraw-Hill Companies, Inc. All rights
HSV cutaneous infection can be particularly severe among patients
with burns, diaper rash, or underlying eczema (eczema herpeticum).
Erythema multiforme may be associated with either primary or recurrent
HSV. The lesions of erythema multiforme can recur with each recrudescence
of herpetic infection.
HSV infections of the skin are sometimes difficult to diagnose, particularly when the patient is
not seen until the lesions are crusted or pustular, or when the
affected skin area is denuded. When HSV skin lesions assume a dermatomal
distribution they may be mistaken for herpes zoster.
Herpetic involvement of the eye is of particular concern because
it can cause loss of vision. Primary infections may be accompanied
by conjunctivitis and tender preauricular nodes, with or without
associated keratitis. Conjunctivitis sometimes occurs with recurrent
infection, but the most common recurrent form is herpetic keratitis.
This entity is readily diagnosed clinically because of the characteristic dendritic,
branched, fluorescent-staining corneal ulcers. Deeper ocular involvement,
including stromal keratitis and iridocyclitis, occurs occasionally.
Corticosteroids, in the absence of antiviral drugs, are contraindicated because
they may contribute to deeper ocular involvement.
Genital herpes infection is a common sexually transmitted disease,
and at least one third of these infections occur in people 19 years
old or younger. Herpes simplex virus type 2 (HSV-2) remains the
most common cause of genital herpes in the United States, but an
increasing proportion is caused by herpes simplex virus type 1 (HSV-1).
In some countries, HSV-1 has actually become the predominant cause
of genital herpes infections. Seroepidemiologic studies show that
17% of adults in the United States are seropositive for
HSV-2; however, only 10% to 25% of people with
HSV-2 antibodies have a history of genital herpes. Thus, most genital herpes
infections are asymptomatic. When associated with symptoms, primary
infections are usually more severe than recurrent infections.8
Over approximately 10 days, genital lesions associated with primary
infection evolve from vesicles and pustules to ulcers, and then crust
and heal during the subsequent 10 days. Lesions are distributed
over the labia majora, labia minora, mons pubis, vaginal mucosa, and
cervix in women. In men, lesions are typically found on the penile
shaft. Local symptoms of itching and pain may precede visible lesions
by 1 to 2 days. Tender inguinal adenopathy typically appears during
the second or third week of illness and tends to be the last sign
to resolve. Constitutional symptoms, including headache, fever,
myalgias, and backache, often accompany symptomatic primary genital
herpes infection. Extragenital complications of primary HSV infections
include aseptic meningitis, mucocutaneous lesions beyond the genital
area, pharyngitis, and visceral dissemination.
Most recurrences of genital herpes are asymptomatic. About 50% of
individuals with symptomatic recurrences have local prodromal complaints
for several hours to 3 days before the appearance of visible lesions.
Sparse genital lesions typically increase in size over the first
3 days, reach a plateau at 6 days, and resolve rapidly. Factors
implicated in precipitating recurrences include emotional stress, menses,
and sexual intercourse. Of note, about 1% of individuals
previously infected with HSV-2 have active viral shedding without symptoms
on any given day.9
Herpes simplex virus (HSV) infections are associated with a variety
of neurologic manifestations, including encephalitis, meningitis,
radiculitis, and myelitis. HSV is the most important cause of life-threatening
sporadic encephalitis; almost 75% of patients die if untreated.
Beyond the newborn age group, HSV encephalitis is caused by herpes
simplex virus type 1 (HSV-1).
Patients with Compromised Immunity
Herpes simplex virus (HSV) infection may cause severe localized
disease, contiguous infection (eg, esophagitis or pneumonia in those with
oral infection), or, rarely, disseminated infection in immunologically
impaired persons, such as those with malignancy, congenital immunologic
deficiencies, or AIDS, and in severely malnourished children. The
basic defect common to these conditions has not been ascertained,
although a common denominator may be a defect in cellular immunity.
Herpes infections in the neonate may be localized or disseminated.
At onset, about 40% of infections are localized to the
skin, eyes, and mucosa (SEM), 35% are localized to the
central nervous system (CNS), and 25% are disseminated.
Neonatal SEM infection typically presents during the first 1
to 2 weeks of life. Skin lesions characteristically evolve rapidly
from macules to vesicles on a red base, but rapid ulceration and
skin denudation may confuse the diagnosis. Skin lesions tend to
appear at sites of trauma such as the site of attachment of fetal
scalp electrodes, the margin of the eyes, or over the presenting
body part. Herpes simplex virus (HSV) infection should be considered whenever
any vesicle appears on a neonate. Lesions of mucous membranes other
than the eye are not common initial sites. Involvement of the eye
may be unilateral or bilateral. Conjunctivitis, keratitis, or chorioretinitis
may occur. Outcome of SEM disease is excellent if diagnosis is made
promptly and antiviral therapy is administered. However, if untreated, SEM
infection can progress to encephalitis or disseminated disease in
75% of cases. Recurrent skin lesions commonly occur periodically throughout
the first 1 to 2 years of life.
Patients with HSV encephalitis often present with fever, lethargy,
irritability, and seizures. Untreated, CNS disease has a mortality
of 50%. Although high-dose acyclovir therapy has resulted
in a marked decrease in mortality, many surviving infants have significant neurologic
Disseminated HSV infection is associated with sepsis and coagulopathy.
It is often indistinguishable from neonatal bacterial sepsis. In
addition to hypoxemia, coagulopathy, and hepatitis, significant
respiratory compromise can occur. Chest radiographs are characterized
by a diffuse, interstitial pattern that can progress to hemorrhagic
pneumonitis.10 Despite high-dose acyclovir therapy,
mortality is still ~30%.
The definitive diagnosis of herpes simplex virus (HSV) is made
by viral culture. HSV can be readily isolated in a number of tissue-culture
systems, and cytopathic effects can be detected within 1 to 2 days.
The presence of intranuclear inclusions and multinucleated giant
cells seen in Papanicolaou-stained smears, or in Tzank preparations
of cells obtained by scraping the base of a suspicious lesion, support
the diagnosis of HSV infection. However, because these morphologic
tests are only about 67% as sensitive as virologic methods, they
should not be relied on in the management of potentially life-threatening
infections. Immunofluorescence methods are much more sensitive than
histologic methods for diagnosing HSV infection and are more rapid
than viral culture.
Polymerase chain reaction (PCR) is a very sensitive technique
for amplifying HSV DNA from cerebrospinal fluid and other body secretions.
Laboratory standardization and false-positive reactions are potential
challenges to the interpretation of polymerase chain reaction results.
Many serologic assays demonstrate antibodies to HSV. A primary
infection is diagnosed by finding no HSV antibodies in the acute
serum and a detectable HSV titer in the convalescent serum obtained
after at least 1 week. A fourfold rise in titer may be observed with
recurrent infections, and does not distinguish between primary and
recurrent infection. IgM or IgA antibodies cannot be used to diagnose
primary HSV infection because such antibodies also can be found
with recurrent infections.
The similarity of herpes simplex virus type 1 (HSV-1) and herpes
simplex virus type 2 (HSV-2) proteins produces extensive cross-reactivity
of antibodies to these viruses in older serologic assays. However,
more recently the US Food and Drug Administration (FDA) approved
glycoprotein G-based type-specific assays, which reliably distinguish HSV-1
and HSV-2 antibodies. Because the clinical diagnosis of genital
herpes is unreliable, these newer serologic tests are a useful tool
in confirming infection with HSV.11
Certain preventive measures can be used to reduce the likelihood
of contracting herpes simplex virus (HSV) infection. For example, exposure
of neonates to active maternal genital HSV infection may be reduced
by cesarean delivery, especially if performed before or soon after
rupture of membranes. Precautions should also be taken to prevent
postnatal contact between a neonate and caregivers with nongenital
herpetic lesions. Infants with suspected neonatal herpes should
Treatment with antiviral agents for herpes simplex infections
depends on the severity of infection and underlying host factors. Dosages
for common treatment scenarios can be found in Table
245-1. In general, primary herpes simplex infections are more
serious and may require more aggressive treatment. Recurrences are
usually self-limited, although treatment can reduce duration of
symptoms and viral shedding. Mild gingivostomatitis requires no
therapy other than maintenance of proper oral hygiene and perhaps
the application of a topical anesthetic. If these infections are
severe, antiviral therapy with acyclovir may be indicated. Orally
administered acyclovir, valacyclovir, or famciclovir is effective
in the treatment and prevention of genital HSV infections. In addition,
these agents can be used for treatment and suppression of recurrent
genital lesions.12 Consultation with an ophthalmologist
is advisable for children with ocular herpes. Systemic administration
of high-dose acyclovir has been shown to reduce the mortality and
morbidity of HSV encephalitis and neonatal herpes. Similarly, HSV
infections in immunocompromised hosts should be treated with intravenous