Article infectious diseases

Herpes Simplex
Pamela Chayavichitsilp,*
Objectives After completing this article, readers should be able to:
Joseph Buckwalter V,
PhD,* Andrew C. 1. Characterize the epidemiology of herpes simplex virus (HSV) infection, including mode
Krakowski, MD,* Sheila F. of transmission, incubation period, and period of communicability.
Friedlander, MD* 2. Recognize the difference in clinical manifestations of HSV1 and HSV2 infection.
3. Diagnose various manifestations of HSV infection.
4. Describe the difference in the clinical manifestations and outcome of HSV infection in
Author Disclosure newborns and older infants and children.
Drs Chayavichitsilp, 5. Discuss the management of HSV infection.
Buckwalter, 6. List the indications and limitations of oral acyclovir treatment for HSV infection.
Krakowski, and
Friedlander have
disclosed no financial
Introduction
relationships relevant HSV causes a contagious infection that affects approximately 60% to 95% of adults
to this article. This worldwide. HSV1 and HSV2 primarily infect human populations. HSV1 is associated
commentary does chiefly with infections of the mouth, pharynx, face, eye, and central nervous system (CNS),
contain a discussion and HSV2 is associated primarily with infections of the anogenital region, although both
of an unapproved/ serotypes may infect any area. (1)
investigative use of a
commercial product/ Epidemiology
device. Most adults are infected with HSV and carry latent viruses, but the serotype, severity of
symptoms, and mode of transmission vary with age. Children are infected primarily with
orolabial HSV1 by 5 years of age, with infection rates of 33% in populations that are of
lower socioeconomic status and 20% in those who have improved socioeconomic status.
By adulthood, HSV1 affects 70% to 80% in the lower socioeconomic population and 40%
to 60% in the higher socioeconomic population. (1) Globally, the prevalence of HSV1
increases consistently with age, reaching 40% by age 15 years and increasing to 60% to 90%
in older adults. (2) In the United States, the prevalence of HSV1 increases consistently
with age, from 26.3% in 6- to 7-year-old children and 36.1% in 12- to 13-year-old children
to 90% among those older than 70 years. (2)(3) Of note, the
overall prevalence of HSV1 in the United States has been
shown to be decreasing over time. (3)
Abbreviations Worldwide, the prevalence of HSV1 infection is greater
CNS: central nervous system than HSV2 infection in most geographic areas. HSV2 pri-
CSF: cerebrospinal fluid marily is sexually transmitted and, therefore, is not as com-
DFA: direct fluorescent antibody mon in young children. However, HSV2 can be transmitted
HAEM: HSV-associated erythema multiforme from mother to neonate during pregnancy, with a neonatal
HHV: human herpesvirus incidence between 1 in 3,000 and 1 in 20,000 live births and
HSV: herpes simplex virus approximately 1,500 new cases in the United States annually.
IV: intravenous Approximately 2% of women acquire genital herpes during
PCR: polymerase chain reaction pregnancy, and about 20% to 30% of pregnant women are
SEM: skin, eye, and mouth seropositive for HSV2. (4) The prevalence of HSV2 varies
STI: sexually transmitted infection across country, sex, and age. HSV2 prevalence is highest in
VZV: varicella-zoster virus areas of sub-Saharan Africa and parts of Central and South
America. The prevalence usually is lower in western and

*Division of Pediatric and Adolescent Dermatology, Rady Children’s Hospital and University of California, San Diego, Calif.

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infectious diseases herpes simplex

southern Europe than in northern Europe and North refers to the presence of viruses outside of the cells on the
America. The lowest rates of HSV2 prevalence are found skin surface, despite the absence of clinical signs. (1)
in Asia. The initial or primary HSV1 or HSV2 infection usu-
Generally, the prevalence is higher in women than in ally has an incubation period of approximately 4 days, but
men and increases with age from negligible levels in can range from 2 to 12 days. This is followed by an active
children younger than 12 years to 20% to 40% by the age viral shedding period that lasts at least 1 week and up to
of 40 years and as high as 80% among higher-risk popu- several weeks. Most patients who are primarily infected
lations. (1)(2)(5)(6) In the United States, the prevalence with HSV are asymptomatic. Therefore, the virus still can
of HSV2 infection in African Americans is much higher be actively transmitted during the period of incubation
than in whites or Mexican Americans. Although time and viral shedding without the occurrence of active skin
trends in HSV prevalence are limited, most studies sug- lesions. (1)
gest that the prevalence of HSV2 has increased over the After initial infection, the virus usually remains latent,
past few decades in countries such as the United States persisting within the sensory ganglia of the autonomic
from 16.0% in the late 1970s to 20.8% in the early 1990s; nervous system, and the infection can be considered
in other populations, HSV2 prevalence has either re- incurable. Within the autonomic ganglia, the virus repli-
mained stable or decreased. (2) cates while evading detection by the host immune sys-
As stated previously, HSV2 is associated primarily tem. (1)(6) HSV1 resides most commonly within the
with infections of the anogenital region, whereas HSV1 trigeminal ganglion, due to its primary target site in and
is found extragenitally. Recent studies, however, have around the oral areas; HSV2 primarily remains in sacral
shown a 30% increase in the prevalence of HSV2 infec- ganglia after infection of the genital region. Once trig-
tion, (7) with HSV2 being as common as HSV1 in the gered to reactivate by an internal or external stimulus,
extragenital regions except for the orofacial area. Fur- including stress, exposure to sunlight, fever, and men-
thermore, HSV1 appears to be increasing in prevalence struation, the virus can travel along the sensory nerve and
in the anogenital region, previously known to be infected reactivate in the same mucocutaneous region as the
predominantly by HSV2. initial infection. Symptoms normally last for a shorter
period of time than for the initial infection, and viral
shedding only lasts 3 to 4 days. On average, reactivation
Etiology
of HSV occurs during approximately 1% of the days in
There are more than 80 herpesviruses, eight of which are
the life of patients infected previously. (8)
capable of infecting humans. In addition to HSV1 and
HSV2, varicella-zoster virus (VZV), cytomegalovirus,
Diagnosis
Epstein-Barr virus, human herpesviruses (HHV6 and
Several methods are employed to diagnose the presence
HHV7), and Kaposi sarcoma-associated herpesvirus
of HSV infection, each having varying degrees of selec-
(HHV8) can infect humans. All herpesviruses are envel-
tivity, sensitivity, cost, and utility. The main clinical
oped, double-stranded DNA viruses that have highly
method for diagnosing primary HSV1 infection is recog-
organized genomes encoding more than 84 polypep-
nizing the classic presentation of herpetic lesions in or
tides. (6) Although the DNA sequences of HSV1 and
around the oral cavity. Monomorphous, grouped vesi-
HSV2 are very similar, the proteins within the envelope
cles on an erythematous base evolve into coalescing,
allow serologic distinction between the two.
crusted papules and plaques within 1 to 3 days. The
lesions have a propensity to erode or ulcerate. Initial
Transmission infection can lead to an extensive gingivostomatitis. In
Infection is transmitted primarily through exposure to contrast to HSV1, the initial diagnosis for HSV2 can be
mucous membranes or skin that have active lesions or to more difficult because the classic signs of genital herpes,
mucosal secretions of an individual who has an active herpetic ulcers in and around the genital area, may not be
HSV infection. The virus is transmitted most easily present. In neonates, the presence of vesicular lesions
through saliva and can remain stable outside of the host should raise high suspicion for HSV infection.
for short periods of time, allowing transmission for some Laboratory evaluations can be used to confirm an
time after direct mucocutaneous contact with the virus. initial diagnosis or further investigate a suspicion of HSV
HSV also can be transmitted through respiratory drop- infection. The gold standard for laboratory diagnosis is
lets or by exposure to mucocutaneous secretions from an the viral culture. The viral culture technique can be
asymptomatic person who is shedding virus. Shedding employed only with active lesions and is obtained best by

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 infectious diseases herpes simplex

vigorously swabbing the base of an unroofed vesicle. The viral antigens. The antibody is tagged with fluorescent
swab is inoculated into a prepared cell culture, and the agent and forms an antigen-antibody complex with HSV
inoculated cells are observed for characteristics of HSV antigens present within a tissue or smear specimen. The
infection, including multinucleated giant cells and process can be performed with cytologic preparations,
desquamated epithelial cells with intranuclear inclusions. such as the Tzanck smear, as well as virally inoculated cell
Such findings usually are observed within 2 to 7 days after cultures. In addition, DFA may be employed to serotype
inoculation and can confirm the presence of HSV infec- the HSV infection. Because DFA testing is rapid, sensi-
tion. If the inoculated cell culture is devoid of character- tive, inexpensive, and virally selective, it often is used to
istic signs of HSV infections for more than 15 days, the substantiate clinical suspicion and determine serotype.
sample is reported as negative. Although this method A punch, shave, or wedge tissue biopsy also may be
offers a relatively rapid and effective method of diagnos- used to detect the presence of HSV infection and is
ing HSV infection, it can be limited by the quality of especially helpful when a suspicious lesion is old or
swabbing and culture techniques. atypical. The biopsied cells are observed microscopically
The Tzanck smear is a rapid and reasonably priced to detect degenerative cytopathologic changes com-
diagnostic test that can confirm the presence of HSV monly associated with the infection. The degenerative
infection. Cells scraped from the base of a freshly opened changes present in cells infected with HSV1 and HSV2
vesicle are stained and evaluated for the characteristic also are observed in cells infected with VZV. Thus, the
cytopathology of HSV infected cells, including multinu- specificity of the technique is low, and the test cannot be
cleated giant cells and eosinophilic intranuclear inclu- used to serotype the infection.
sions (Fig. 1). Although the test can confirm the presence Amplification of viral DNA using polymerase chain
of HSV or VZV, it cannot differentiate between the two reaction (PCR) is another method for detecting the
herpes serotypes and, therefore, cannot diagnose HSV1 putative presence of viral DNA. This method is particu-
or HSV2 infection definitively. In addition, the sensitiv- larly useful for detecting the presence of HSV in the
ity and specificity of the test are highly variable, depend- cerebrospinal fluid (CSF) of patients suspected of having
ing on the evaluator. An experienced clinician, such as an herpes encephalitis. As HSV PCR becomes more readily
infectious disease specialist or pathologist, should inter- available and less expensive, it has the potential to be-
pret test results because the findings may be subtle. With come the most widely used means of detecting HSV for
the increasing availability of the direct fluorescent anti- all types of infection because it is rapid, highly reliable,
body (DFA) technique, the Tzanck smear has decreased and valid.
in popularity as a diagnostic alternative. Serologic assays are employed to detect the presence
DFA testing is an immunohistochemistry technique of HSV antibodies when other techniques are impractical
that uses a specific antibody to identify the presence of or ineffective. Such assays take longer to complete than
other techniques and should be considered primarily for
diagnosing recurrent infections, in the presence of heal-
ing lesions and the absence of active lesions, or when
partners of persons who have clinical herpes are at risk.
Sera are collected at two separate times; acute serum is
obtained within 3 to 4 days after the onset of the initial
symptoms and convalescent serum is gathered several
weeks after the symptoms have abated. To confirm a
diagnosis of primary HSV infection, the acute sample
should be devoid of HSV-positive antibodies due to the
delayed humoral response, and the convalescent sample
should demonstrate the presence of both immunoglob-
ulin G and M antibodies to HSV proteins. If any quan-
tities of antibodies are observed in the acute sample,
primary infection is ruled out and the diagnosis is recur-
rent herpes infection. The absence of antibodies in both
Figure 1. A positive Tzanck smear showing a multinucleated samples indicates a negative test, which should be verified
giant cell and intranuclear inclusions (arrow). Courtesy of Dr later by another serologic assay. In the absence of her-
Robert O. Newbury. petic lesions, traditional serologic assays cannot deter-

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infectious diseases herpes simplex

mine the serotype or whether the site of infection is oral forme, pemphigus vulgaris, acute necrotizing ulcerative
or genital. However, newer type-specific serologic assays gingivitis, and most commonly, aphthous stomatitis.
can be performed to test for antibodies to both Aphthous stomatitis can be differentiated from herpetic
HSV1 and HSV2 proteins. gingivostomatitis by the absence of a vesicular stage,
Several transport media are available for effective viral prodrome, and systemic signs and symptoms. The major
transport after collection of the specimen, including complication of herpetic gingivostomatitis is dehydra-
swabs, liquid media, and cell cultures. Studies suggest tion in children whose painful lesions result in poor fluid
that although there are slight differences in the surviv- intake. Thus, pain control and sufficient rehydration
ability of both HSV1 and HSV2 in different media, most comprise the mainstay of management.
media are effective as long as the temperature is tightly
controlled, preferably at 39.2°F (4.0°C), and transport
Herpes Labialis
times are kept to a minimum, preferably less than
Herpes labialis is the most common manifestation of
24 hours and no greater than 48 hours. (9) Survival of
HSV1 infection. Because most initial infections are
the virus at temperatures greater than 39.2°F (4.0°C)
asymptomatic and may be unrecognized, recurrent oro-
and transport times greater than 48 hours for all trans-
facial herpes (commonly called fever blisters or cold
port media is variable and more dependent on viral
sores) typically is the initial manifestation in children and
concentration and accurate laboratory techniques.
young adults. The outer vermilion border is a common
location, and the crusted lesions often are confused with
Clinical Manifestations
staphylococcal or streptococcal impetigo (Figs. 2, 3).
The clinical presentation of HSV infection is variable and
Secondary bacterial infections with Staphylococcus or
dependent on method of transmission, age, and immu-
Streptococcus also may occur and are characterized by
nocompetency of the host. Cutaneous lesions usually
honey-colored crusting on top of the classic herpetic
consist of small, monomorphous vesicles on an erythem-
lesions. Treatment with oral acyclovir can be effective if
atous base that rupture into painful, shallow, gray ero-
started within 1 to 2 days of prodromal symptoms.
sions or ulcerations with or without crusting. (10) The
Chronic suppressive therapy with an oral antiviral medi-
skin lesions typically are preceded by prodromal symp-
cation can reduce the frequency of recurrences and is
toms such as burning and paresthesia at the site, lymph-
recommended for patients who experience six or more
adenopathy, fever, malaise, myalgia, loss of appetite, and
outbreaks per year. (8) Topical acyclovir is ineffective in
headaches. Most initial infections are subclinical and may
immunocompetent hosts and, therefore, is not recom-
be unrecognized. Recurrent infections due to reactiva-
mended.
tion of the latent viruses in the dorsal root ganglia are
more localized, milder, and shorter in duration. They
tend to occur following triggers such as stress, menstru- Genital Herpes
ation, exposure to sunlight, and fatigue. Both primary Genital herpes (Fig. 4) most commonly is caused by
and recurrent HSV infections can manifest on any mu- HSV2, although the proportion due to HSV1 has been
cocutaneous surface. Table 1 summarizes the clinical increasing recently. (1) This sexually transmitted infec-
manifestations, differential diagnoses, and recom- tion (STI) is associated with risk factors such as lower
mended treatments of herpetic infections occurring after socioeconomic status, sexual promiscuity, geography,
the neonatal period. race, and education. (1) Differential diagnoses include
other STIs such as syphilis, chancroid, condyloma acumi-
Herpetic Gingivostomatitis nate, and lymphogranuloma venereum, and non-STIs
Herpetic gingivostomatitis presents as multiple round such as Candida infection, scabies, lichen planus, lichen
ulcers or superficial erosions commonly affecting the sclerosis, Behçet syndrome, herpes zoster, and trauma.
palate, tongue, and gingivae. It is caused much more Sexual abuse must be suspected in prepubertal children
commonly by HSV1. Patients may present with the who develop genital herpes. Complications include uri-
typical prodromal symptoms, followed by classic vesicu- nary retention, psychological morbidity, and aseptic
loulcerative lesions. Children may present with diffuse meningitis. The pathogenesis of the spread to the CNS is
erythema and swelling of the gingiva, drooling, foul- unclear, but two routes are possible, including the hema-
smelling breath, and anorexia. Such nonspecific signs and togenous route and direct spread from mucocutaneous
symptoms can be caused by a wide range of conditions, sites through the peripheral nerves. Treatment with oral
including Coxsackievirus infections, erythema multi- antiviral medication can be effective if started early. For

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 infectious diseases herpes simplex

Clinical Manifestations, Differential Diagnoses, and Recommended

Table 1.

Treatments of Herpes Simplex Virus Infections

Clinical Manifestation Differential Diagnoses Recommended Treatment
Herpetic Gingivostomatitis • Herpangina • Pain control and rehydration
• Hand-foot-and-mouth disease • Insufficient data regarding response to
• Erythema multiforme antiviral treatment, but many experts treat
• Pemphigus vulgaris severe cases
• Acute necrotizing ulcerative gingivitis
• Aphthous stomatitis
Herpes Labialis • Impetigo • For primary disease and recurrences, oral
acyclovir has limited therapeutic benefits in
immunocompetent hosts, but many experts
treat severe cases
• Suppression for recurrent episodes*
Genital Herpes Sexually transmitted infections: • Primary: Oral acyclovir 1,000 to 1,200 mg/
• Syphilis day for 7 to 10 days
• Chancroid • Recurrences: Oral acyclovir 1,000 to
• Condyloma acuminatum 1,200 mg/day for 3 to 5 days
• Lymphogranuloma venereum • Suppression*
Non-sexually transmitted infections:
• Candida infections
• Scabies
• Lichen planus
• Lichen sclerosis
• Behçet syndrome
• Herpes zoster
• Trauma
Herpetic Keratoconjunctivitis • Scleritis • Prompt referral to ophthalmology
• Iritis • Trifluridine 1%, iododeoxyuridine 0.1%, and
• Glaucoma vidarabine 3% ophthalmic ointments
• Conjunctivitis • Suppression*
• Herpes zoster
Herpetic Whitlow • Bacterial felon • Supportive
• Paronychia • Antiviral therapy early in the course can be
• Blistering dactylitis considered
• Burn
• Impetigo
Herpes Gladiatorum • Atopic dermatitis • Avoid contact sports until lesions have
• Contact dermatitis become dry and firm and crusts are adherent
• Impetigo • Suppression throughout sports season is
• Tinea corporis controversial
Herpes Encephalitis • Other bacterial and viral encephalitis • Intravenous acyclovir for 21 days
Eczema Herpeticum • Atopic dermatitis flares • Intravenous acyclovir usually recommended
• Impetigo • Oral antibiotic therapy for secondary
bacterial infection
• Topical emollients
• Topical steroids as needed
• Avoid topical calcineurin inhibitors
*If recurrences involve six or more episodes per year, oral acyclovir 80 mg/kg per day or 800 to 1,200 mg/day continuously up to 12 months is
recommended.
Data from Red Book: 2006 Report of the Committee on Infectious Diseases. (8)

patients experiencing frequent recurrences (at least six Herpetic Keratoconjunctivitis

episodes per year), chronic suppressive therapy with an Ocular HSV infection is the second most common infec-
oral antiviral is recommended. (8) tious cause of blindness worldwide. HSV1 is the predom-

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infectious diseases herpes simplex

Figure 2. An early vesicle on an erythematous base at the

vermilion border in herpes labialis. Reprinted with permission
from Dr Sheila F. Friedlander.

inant cause. Vesicles, followed by erosion or ulceration of

the cornea, appear along with purulent conjunctivitis.
Differential diagnoses include scleritis, iritis, glaucoma,
conjunctivitis, and herpes zoster. Prompt referral to oph-
thalmology is recommended to prevent complications
such as permanent scarring, secondary bacterial infec-
tion, meningoencephalitis, and vision loss. Neonates af-
flicted with ocular HSV may have associated systemic or Figure 4. Multiple monomorphous vesicles on an erythema-
CNS disease. Treatment consists of both topical ophthal- tous base on the penile shaft and scrotum that are character-
mic antiviral (trifluridine, vidarabine, idoxuridine) and istic of genital herpes. Reprinted with permission from Dr
oral antiviral medications. Sheila F. Friedlander.

Herpetic Whitlow the distal phalanx of the hand (Fig. 5). This infection
Herpetic whitlow presents with deep-seated swelling, occurs commonly in patients who have primary oral or
erythema, and vesiculoulcerative lesions on the pulp of

Figure 3. Vesicles and crusting on the vermilion border, Figure 5. Herpetic whitlow, showing deep-seated vesicles
typical location of herpes labialis. Reprinted with permission grouped in clusters on the digit. Reprinted with permission
from Dr Victoria R. Barrio. from Dr Sheila F. Friedlander.

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 infectious diseases herpes simplex

genital herpes (due to autoinoculation) and health-care postinfectious encephalomyelitis. Therapy is less effective
workers. In children, digital/oral contact is the most in older adults than in children. Therefore, the recom-
common cause of herpetic whitlow. In adolescents and mended treatment for adults (parenteral acyclovir for
adults, digital/genital contact is more common, making 21 days) also is recommended for pediatric patients who
HSV2 the predominant infectious agent of herpetic have herpes infections of the CNS. (8)
whitlow. Differential diagnoses include bacterial felon or
paronychia, blistering dactylitis, burn trauma, and impe- Neonatal Herpes
tigo. (10) Oral antiviral medications are optional and are Neonatal herpes occurs in 1 in every 3,000 to 20,000 live
used in extensive disease. births and affects approximately 1,500 to 2,000 infants
per year in the United States. (8) In addition, 40% to 50%
Herpes Gladiatorum of infants born to mothers afflicted with primary genital
Herpes gladiatorum occurs in those involved in contact lesions are affected compared with only 2% to 3% of those
sports such as wrestling, boxing, football, soccer, and born to women undergoing recurrences. (10) Up to 70%
rugby. It most commonly affects exposed areas such as of infants who have neonatal herpes are born to asymp-
the face, ears, upper extremities, and neck. HSV1 is more tomatic mothers, adding to the difficulty in diagnosing
likely to be the agent than HSV2, due to the nature of this disease.
transmission. Differential diagnoses include atopic der- Neonatal herpes manifests in the first 4 weeks after
matitis, contact dermatitis, impetigo, and tinea corporis. birth and consists of three different types based on clin-
Patients who have herpes gladiatorum should avoid con- ical manifestations: 1) skin, eye, and mouth (SEM),
tact sports during outbreaks until the culture results are 2) CNS (often presenting with seizures, lethargy, and
negative. (11) Measures to prevent transmission also hypotonia), and 3) disseminated (including liver, adrenal
should be practiced and include examining athletes for glands, lungs). Classic cutaneous lesions generally are
active lesions and excluding them from competition and located on the scalp, mouth, nose, and eye, where the
cleaning wrestling mats with bleach for at least 15 sec- infant’s skin comes into contact with the mother’s genital
onds of contact time between matches. (8) The National lesions (Fig. 6). CNS infection presents with neurologic
Collegiate Athletic Association recommends that ath- signs such as seizures and accounts for 60% of the cases.
letes not be allowed to participate until the crusts are firm Skin lesions also are noted. Permanent neurologic dis-
and adherent. (11) If the lesions have not crusted over or ability can affect up to 40% of survivors. Disseminated
the crusts are not completely dry, the possibility is high neonatal HSV is a devastating manifestation that is asso-
that the patient still is infectious. Cultures to verify the ciated with a mortality rate of at least 50%. Infants
noninfectious state should be performed after the crusts present with multisystem involvement (shock, dissemi-
are dry, firm, and adherent. The family of an affected nated intravascular coagulation, and multiple organ sys-
patient must be informed and instructed to perform tem failure).
appropriate preventive measures. Suppressive therapy is
likely to be effective, but data about such therapy are
insufficient, and the family needs to be made aware of this
limitation before the initiation of therapy.

Herpes Encephalitis and Meningitis

HSV encephalitis can be a manifestation of primary or
recurrent infections. Patients present with nonspecific
CNS symptoms such as altered mental status, personality
changes, seizures, and focal neurologic findings. HSV
meningitis is characterized by CSF pleocytosis, with lym-
phocyte predominance and red blood cells in the CSF.
HSV also is believed to cause a rare form of aseptic
meningitis, termed Mollaret syndrome, consisting of Figure 6. Cluster of vesicles on the forehead and periocular
recurrent episodes of severe headache, meningismus, and area characteristic of neonatal herpes simplex. Reprinted with
fever that resolve spontaneously. permission from Friedlander SF, Bradley JS. Viral infections. In:
Complications include Bell palsy, atypical pain syn- Eichenfield LF, Frieden IJ, Esterly NB, eds. Neonatal Dermatol-
dromes, trigeminal neuralgia, ascending myelitis, and ogy. 3rd ed. Philadelphia, Pa: Saunders; 2008:193–197.

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infectious diseases herpes simplex

The differential diagnosis of neonatal HSV infection Treatment is similar to that for neonatal HSV, al-
includes bacterial sepsis and viral infections such as en- though the neurologic prognosis is poor, and virtually all
teroviruses, varicella, influenza A and B, parainfluenza, affected infants exhibit developmental delay.
and adenovirus. Incontinentia pigmenti and Langerhans
cell histiocytosis also may present with vesicles and must Eczema Herpeticum
be differentiated from HSV by using the diagnostic Eczema herpeticum also is known as Kaposi varicelliform
techniques described previously. eruption. It is characterized by HSV infections of skin
HSV is transmitted most commonly during delivery, from an underlying barrier defect caused by atopic der-
but also can be transmitted in utero or through postnatal matitis, pemphigus, Darier disease, burn trauma, and
contact with the mother or other caretakers. It is not cosmetic procedures. (1) The lesions tend to coalesce
transmitted through human milk. Higher risks of trans- into large, superficial erosions and often are disseminated
mission are associated with younger age of the mother, (Figs. 7 and 8). Differential diagnoses include atopic
maternal seronegativity, the presence of genital lesions dermatitis flares, impetigo, and secondarily infected le-
during vaginal delivery, and infant prematurity. sions. Management includes intravenous (IV) antiviral
Because of high rates of morbidity and mortality, therapy, antibiotic therapy for secondary bacterial infec-
timely diagnosis and prompt initiation of treatment are tion, and topical emollients. (10) Most experts use anti-
crucial. A high degree of suspicion is required in neonates inflammatory therapy such as topical corticosteroids in
who have vesicular skin lesions, sepsis syndrome with areas of atopic dermatitis once systemic antiviral therapy
negative bacteriologic culture results, severe liver dys- has been initiated. However, the use of calcineurin inhib-
function, fever, irritability, and abnormal CSF findings, itors is contraindicated in eczema herpeticum. (14)
particularly if seizures are present. Because of the low
toxicity profile of the antiviral medications and the po- Herpes in the Immunocompromised Host
tentially severe post-HSV sequelae, it always is better to HSV infections in immunocompromised individuals
institute therapy pending culture results if significant such as those who have hematologic malignancy, im-
suspicion exists. mune deficiencies, acquired immunodeficiency syn-
Prevention also is crucial, although there is no con- drome, and organ transplants tend to have higher risks of
sensus on the optimal prevention strategy. Pregnant dissemination and longer durations of outbreaks and are
mothers who are seronegative and have seropositive sex- less responsive to therapy. (10) Complications include
ual partners should be counseled to maintain abstinence esophagitis, tracheobronchitis, pneumonitis, hepatitis,
near term. For those who acquire primary genital HSV pancreatitis, and adrenal necrosis. The skin lesions often
during late pregnancy, the National Guideline Clearing-
house states, “Some specialists recommend acyclovir
therapy, some recommend routine cesarean section and
others recommend both.” (12) However, for those who
have a history of recurrent genital HSV, a Cochrane
review found insufficient data to support the use of
prophylactic acyclovir. (13)

Congenital HSV
Congenital HSV describes an HSV2 infection of the
fetus that has occurred prenatally. Infected fetuses often
die in utero. However, those that survive to term typi-
cally present with vesicular lesions, chorioretinitis, mi-
crophthalmia, microcephaly, and abnormalities on brain
scan.
Congenital HSV in neonates can be differentiated
from neonatal HSV by the absence of signs of systemic Figure 7. Eczema herpeticum, limited, showing vesicles and
toxicity and overwhelming sepsis in the former as well as crusts coalescing into plaques on underlying eczematous skin
the presence of both fetal and maternal antibodies in the popliteal fossa, a typical location affected by atopic
against HSV. Other differential diagnostic consider- dermatitis. Reprinted with permission from Dr Sheila F. Fried-
ations include congenital varicella syndrome and syphilis. lander.

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 infectious diseases herpes simplex

Figure 9. Target lesions of different sizes on palm that are

characteristic of erythema multiforme. Reprinted with permis-
sion of Drs Sheila F. Friedlander and Bari B. Cunningham.

Principles of Management
Management of HSV infections often incorporates both
treatment and prevention of recurrences. Because of the
infectious nature of the virus and the risk it poses to the
neonate and immunocompromised individuals, preven-
tion of recurrences is important and should be practiced
in every patient.
Figure 8. Eczema herpeticum, disseminated, showing rapidly
progressing vesicles over an erythematous base that coalesced Prevention
into plaques and then crusted over diffusely on the face of a Prevention of transmission is the first step in the manage-
young child who has underlying atopic dermatitis. Reprinted ment of HSV infections. Patients should be educated
with permission of Dr Sheila F. Friedlander. regarding the nature of the disease, transmission through
sexual and nonsexual contact, and asymptomatic shed-
ding of the virus. Patients who have active lesions on the
are atypical and can be extensively crusted, pustular,
necrotic, or exophytic. The differential diagnosis involves
herpes zoster and similar conditions, depending on the
location of the outbreak. Prompt therapy with parenteral
antiviral medications is critical.

HSV-associated Erythema Multiforme

HSV-associated erythema multiforme (HAEM) is a com-
plication of HSV outbreaks that induces erythema mul-
tiforme skin lesions. Patients commonly present with
fixed target or “bull’s eye” lesions distributed diffusely
on the body, with a predilection for palms and soles. The
lesions generally occur within 10 days of oral or genital
HSV reactivation (Figs. 9 and 10). (1) This condition
tends to resolve spontaneously without complications. Figure 10. Target lesions of different sizes on soles charac-
However, patients experiencing frequent outbreaks may teristic of erythema multiforme. Reprinted with permission of
benefit from chronic suppressive antiviral prophylaxis. Drs. Sheila F. Friedlander and Bari B. Cunningham.

Pediatrics in Review Vol.30 No.4 April 2009 127

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infectious diseases herpes simplex

skin should avoid direct contact with others. Precautions ORAL ANTIVIRAL MEDICATIONS. The first-line oral an-
include: 1) the use of condoms or other barrier methods tiviral medication for children is acyclovir. Alternatives
during sexual intercourse for genital HSV; 2) the avoid- include valacyclovir and famciclovir, although their use
ance of contact sports, examination and exclusion of in children had not been approved by the United States
athletes who have active lesions, and cleaning of wres- Food and Drug Administration as of July 2008. Oral
tling mats with bleach after every match for herpes gladi- acyclovir is indicated in primary genital HSV infection
atorum; and 3) the use of condoms or abstinence for when treatment is started within 6 days of disease onset
pregnant women who are seronegative whose partners and can shorten the duration by 3 to 5 days. In HSV
are seropositive to prevent primary HSV infections dur- recurrences, initiating oral acyclovir within 2 days of
ing the third trimester of the pregnancy. The multiple onset shortens the duration only by an average of 1 day.
risk factors that precipitate recurrence (eg, stress, expo- The recommended dose is 1,200 mg/day (maximum of
sure to sunlight, fever, menstruation, and trauma to the 80 mg/kg per day) for 7 to 10 days in initial infections
area such as dental procedures) should be addressed with and for 5 days in recurrences.
patients. Chronic suppressive therapy with oral acyclovir is
In a hospital, contact precautions should be practiced indicated for patients experiencing recurrence of genital,
by all health-care personnel for all patients possibly in- oral, or ocular HSV infection that involves six or more
fected with HSV except for those whose infections are episodes per year. The recommended pediatric dose is
limited to encephalitis and meningitis. These measures 80 mg/kg per day in three divided doses, with a maxi-
include providing the patient with a single-patient room mum of 1,000 mg/day for a maximum of 12 months.
when possible; using gloves at all times; washing hands One study has shown that acyclovir at a dose of 400 mg
after glove removal; and wearing gowns during direct twice a day chronically can suppress HAEM attacks in
contact with a patient, environmental surfaces, or items most patients. (15)
in the patient’s room. Acyclovir-resistant strains of HSV must be suspected
in patients experiencing worsening disease despite acy-
Treatment clovir therapy, particularly in immunocompromised pa-
The treatment of HSV infections does not result in cure, tients. Foscarnet is the recommended therapy in this
but can attenuate the duration of the clinical course, case.
decrease severity, prevent complications, and reduce the
frequency of recurrence. Current treatments include sup- PARENTERAL ANTIVIRAL MEDICATIONS. IV acyclovir
portive therapy and oral, parenteral, and topical antiviral therapy is reserved for cases having the potential for
medications. severe complications. Such situations include any neo-
nate who has HSV infection, mucocutaneous HSV infec-
SUPPORTIVE THERAPY. Supportive therapy encom- tions in immunocompromised hosts, eczema herpeti-
passes pain control and rehydration. Such support is cum, and HSV encephalitis. The recommended dose is
particularly important for children afflicted with herpes 60 mg/kg per day for 14 days in newborns who have
labialis and gingivostomatitis. Because of pain, patients SEM disease and 21 days in other neonatal HSV infec-
may refuse to eat or drink, resulting in dehydration. Pain tions and HSV encephalitis (Table 2).
control with local anesthetics and oral or IV rehydration Acyclovir is known to cause nephrotoxicity. There-
may be useful. fore, it is important to calculate the dose based on ideal

Table 2. Management of Neonatal Herpes

Manifestation Treatment
Skin, eyes, and mouth Intravenous acyclovir 60 mg/kg for 14 days
Disseminated and central nervous system Intravenous acyclovir 60 mg/kg for 21 days
Ocular involvement Add trifluridine 1%, iododeoxyuridine 0.1%, and vidarabine
3% ophthalmic ointments
Asymptomatic neonates born to mothers who had primary Empiric acyclovir therapy pending culture results*
genital infections
*Not approved by the United States Food and Drug Administration; some controversy exists.

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 infectious diseases herpes simplex

weight, hydrate the patient well, and monitor urine

output and serum creatinine values. Summary
TOPICAL ANTIVIRAL MEDICATIONS. Although com- • HSV infection is a multisystem disease characterized
monly prescribed by many physicians, topical antiviral by early and often classic skin manifestations.
Recognition of the common presentations of
medications such as acyclovir ointment are not recom- mucocutaneous HSV infections can lead to rapid
mended to treat most mucocutaneous HSV lesions be- diagnosis and timely treatment.
cause such therapy does not reduce the severity or dura- • The goal of management is to reduce disease
tion of infections in immunocompetent hosts. Topical severity and prevent recurrences as well as
therapy is recommended in immunocompromised pa- transmission to others through patient education
and antiviral therapy.
tients because it has been shown to accelerate the healing • HSV1 is associated primarily with infections of the
of lesions. mouth, pharynx, face, eye, and CNS; HSV2 is
Ophthalmic antiviral medications, including 1% triflu- associated primarily with infections of the
ridine, 0.1% iododeoxyuridine, and 3% vidarabine, are anogenital region, although both serotypes may
indicated for treatment of ocular HSV and neonatal HSV infect any area. (1)
• Based on strong research evidence, transmission of
with SEM involvement. HSV is primarily through exposure to mucocutaneous
surfaces with active lesions or viral shedding. (1)
• Based on strong research evidence, the primary
References method of diagnosis is recognition of the classic
1. Fatahzadeh M, Schwartz RA. Human herpes simplex virus in- presentation of herpetic lesions on mucocutaneous
fections: epidemiology, pathogenesis, symptomatology, diagnosis, surfaces, but the gold standard of diagnosis is viral
and management. J Am Acad Dermatol. 2007;57:737–763 culture. (1)
2. Smith JS, Robinson NJ. Age-specific prevalence of infection • Based on strong research evidence, empiric
with herpes simplex virus types 2 and 1: a global review. J Infect Dis. treatment of neonatal HSV with acyclovir is
2002; 186(suppl 1):S3–S28 recommended if there is a strong clinical suspicion
3. Xu F, Lee FK, Morrow RA, et al. Seroprevalence of herpes despite the absence of active lesions. (8)
simplex virus type 1 in children in the United States. J Pediatr. • Based on strong research evidence, suppression
2007;151:374 –377 therapy with oral acyclovir is beneficial for
4. Brown ZA, Gardella C, Wald A, Morrow RA, Corey L. Genital individuals who have six or more episodes per year
herpes complicating pregnancy. Obstet Gynecol. 2005;106: of herpes labialis, keratoconjunctivitis, or genital
845– 856 herpes. (8)
5. Kesson A. Management of neonatal herpes simplex virus infec- • Based on strong research evidence, parenteral
tion. Paediatr Drugs. 2001;3:81–90 acyclovir is recommended in neonatal HSV, HSV in
6. Whitley R, Roizman B. Herpes simplex virus infections. Lancet. immunocompromised patients, eczema herpeticum,
2001;357:1513–1518 and HSV encephalitis. (8)
7. Fleming D, McQuillan G, Johnson R, et al. Herpes simplex virus • Based on some research evidence, chronic
type 2 in the United States, 1976 to 1994. N Engl J Med. 1997; suppressive therapy with acyclovir is beneficial in
337:1105–1111 patients who have HAEM. (14)
8. American Academy of Pediatrics. Herpes simplex. In: Pickering
LK, Baker CJ, Long SS, McMillan JA, eds. Red Book: 2006 Report of
the Committee on Infectious Diseases. 27th ed. Elk Grove Village, Ill:
American Academy of Pediatrics; 2006:361–371 Prevention. Diseases characterized by genital ulcers. Sexually trans-
9. Dunn JJ, Billetdeaux E, Skodack-Jones L, Carroll KC. Evalua- mitted diseases treatment guidelines 2006. MMWR Morbid Mortal
tion of three Copan viral transport systems for the recovery of Wkly Rep. 2006;55(RR-11):14 –30
cultivatable, clinical virus isolates. Diagn Microbiol Infect Dis. 2003; 13. Hollier L, Wendel G. Third trimester antiviral prophylaxis for
45:191–197 preventing maternal genital herpes simplex virus (HSV) recurrences
10. Paller AS, Mancini AJ. Viral disease of the skin. In: Hurwitz and neonatal infection. Cochrane Database Syst Rev. 2008;1:
Clinical Pediatric Dermatology: A Textbook of Skin Disorders of CD004946
Childhood and Adolescence. 3rd ed. Philadelphia, Pa: Elsevier Saun- 14. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral infec-
ders; 2006:397– 422 tions in atopic dermatitis: pathogenic aspects and clinical manage-
11. Anderson BJ. The epidemiology and clinical analysis of several ment. J Allergy Clin Immunol. 2003;112:667– 674
outbreaks of herpes gladiatorum. Med Sci Sports Exerc. 2003;35: 15. Tatnall F, Schofield J, Leigh I. A double-blind, placebo-
1809 –1814 controlled trial of continuous acyclovir therapy in recurrent ery-
12. Workowski K, Berman S. Centers for Disease Control and thema multiforme. Br J Dermatol. 1995;132:267–270

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infectious diseases herpes simplex

PIR Quiz
Quiz also available online at pedsinreview.aappublications.org.

1. Which of the following statements about HSV is true?

A. Anogenital herpes infections always are caused by HSV2.
B. Infection is more common in patients who have a higher socioeconomic status.
C. Most initial infections do not cause symptoms.
D. Orofacial infections should be treated with topical acyclovir.
E. Viral shedding lasts longer in reactivation than in an initial infection.

2. You are evaluating a 4-year-old girl who has had blisters around her mouth for 3 days. She has been
immunized against VZV but recently was exposed to a child who has chickenpox. Physical examination
reveals clusters of vesicles on an erythematous base around her lips. You wonder if this is a primary HSV
infection or a mild VZV infection. Of the following, the test that is least likely to help you distinguish
between these two infections is:
A. HSV and VZV antibody titers.
B. HSV DFA.
C. HSV PCR.
D. Tzanck smear.
E. Viral culture.

3. You are seeing a 1-day old boy in the newborn nursery because of a rash. He was born at term to a mother
who had prenatal care and no history of STIs. He is sluggish at breastfeeding and appears ill. Physical
examination reveals several vesicles on his scalp and face. You suspect neonatal herpes infection. Of the
following, a true statement regarding this infant and his mother is that:
A. Acyclovir should be administered to the infant as soon as possible.
B. Administration of acyclovir to the mother during delivery could have prevented this infection.
C. Breastfeeding should be stopped to avoid additional spread of the infection.
D. His mother likely has a recent recurrence of a genital herpes infection.
E. His mother likely was infected with herpes in her first trimester.

4. Which of the following HSV infections is correctly matched with the appropriate treatment?
A. Genital herpes and topical acyclovir.
B. Gingivostomatitis and IV acyclovir.
C. Herpes gladiatorum and oral foscarnet.
D. Keratoconjunctivitis and topical vidarabine.
E. Neonatal herpes and oral acyclovir.

130 Pediatrics in Review Vol.30 No.4 April 2009

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 Herpes Simplex
Pamela Chayavichitsilp, Joseph V Buckwalter, Andrew C. Krakowski and Sheila F.
Friedlander
Pediatrics in Review 2009;30;119
DOI: 10.1542/pir.30-4-119

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 Herpes Simplex
Pamela Chayavichitsilp, Joseph V Buckwalter, Andrew C. Krakowski and Sheila F.
Friedlander
Pediatrics in Review 2009;30;119
DOI: 10.1542/pir.30-4-119

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located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/30/4/119

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