Herpes Simplex

AT-A-GLANCE

 Herpes simplex viruses (HSVs) are common human DNA viral pathogens that
intermittently reactivate. After replication in the skin or mucosa, the virus infects the
local nerve endings and ascends to the ganglia where it becomes latent until
reactivation.

 There are two types of HSV: HSV-1 and HSV-2. HSV-1 is mostly associated with
orofacial disease, whereas HSV-2 usually causes genital infection, but both can infect
oral and genital areas and cause acute and recurrent infections.

 Most of the adult population is seropositive for HSV-1, and the majority of infections
are acquired in childhood. About one-fourth of adults are infected with HSV-2 in the
United States. Acquisition of HSV-2 correlates with sexual behavior.

 Most primary HSV infections are asymptomatic or not recognized, but they can also
cause severe disease. Most recurrences are not symptomatic and most transmissions
occur during asymptomatic shedding.

 Genital herpes is the most prevalent sexually transmitted disease worldwide and is
the most common cause of ulcerative genital disease; it is an important risk factor
for acquisition and transmission of HIV.

 HSV can cause diseases involving the eye, CNS, and neonatal infection. Cellular
immunity defects are a risk factor for severe and disseminated disease.

 Diagnosis is made by polymerase chain reaction, viral culture, or serology, depending

on the clinical presentation.

 Treatment is with acyclovir, valacyclovir, or famciclovir. Regimens and dosages vary

with the clinical setting. Resistance is rare, other than in immunocompromised
patients.

 Herpes simplex virus (HSV) infections are common worldwide and are caused by 2
closely related types of HSV. Their main clinical manifestations are mucocutaneous
infections, with HSV Type 1 (HSV-1) being mostly associated with orofacial disease,
and HSV Type 2 (HSV-2) usually being associated with genital infection. HSV-1 is
increasingly becoming a more common cause of genital mucosal infections in young
women in the United States than HSV-2.1
EPIDEMIOLOGY
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The incidence of primary infection with HSV-1, which is responsible for the vast majority of
recurring labial herpes, is greatest during childhood, when 30% to 60% of children are
exposed to the virus. Rates of infection with HSV-1 increase with age and reduced
socioeconomic status. From 20% to 40% of the population has had episodes of herpes
labialis. The frequency of recurrent episodes is extremely variable, and, in some studies,
averages approximately once per year. From 2005 to 2010 the seroprevalence of HSV-1 in
the United States was 30% in persons 14 to 19 years of age, 50% in persons 20 to 29 years of
age, and 62% in persons 30 to 39 years of age.2 The rate of HSV-1 declined by 7% from 1999-
2004 to 2005-2010.

Acquisition of HSV-2 correlates with sexual behavior and the prevalence of infection in one’s
potential sexual partners. Antibodies to HSV-2 are rare in people before the onset of
intimate sexual activity and rise steadily thereafter. From 2005 to 2010 the seroprevalence
of HSV-2 in the United States was 1.2% in persons 14 to 19 years of age, 9.9% in persons 20
to 29 years of age, and 19% in persons 30 to 39 years of age. 2 The rate of HSV-2
seropositivity did not change significantly from 1999-2004 to 2005-2010. Although most
persons infected with HSV-1 or HSV-2 are asymptomatic, they still can transmit the
virus.3 Even though HSV-2–asymptomatic persons shed virus less frequently than
symptomatic persons, the amount of HSV-2 shed during asymptomatic shedding is similar in
symptomatic and asymptomatic groups.4 In one study, 21% of genital swabs were positive
for HSV by polymerase chain reaction (PCR) in persons who were HSV-2 seropositive, and
12% of oral swabs were positive for HSV by PCR in persons who were HSV-1 seropositive. 5 It
is estimated that more than 70% of HSV-2 transmission is associated with asymptomatic
shedding. The rate of transmission is no higher in persons with frequent symptomatic
recurrences than it is in persons with infrequent recurrences. The average risk of
transmission for couples discordant for genital herpes (ie, one partner has genital herpes
and the other does not) varies from 5% to 10% per year.6 As with other sexually-transmitted
infections, the rate of acquisition of HSV-2 infection is higher for women than for men.
Asymptomatic HSV-2 infection is more common among men and persons who are also
seropositive for HSV-1, suggesting that prior infection with HSV-1 reduces one’s likelihood of
experiencing symptomatic HSV-2 infection.7 Studies show that genital HSV infections
significantly increase the risk for acquisition and transmission of HIV. Randomized trials
with acyclovirreduced the frequency of genital ulcers and slightly reduced HIV viral loads,
but did not reduce transmission of HIV

CLINICAL FINDINGS
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CUTANEOUS FINDINGS
The clinical manifestations of HSV infection depend on the site of infection and the immune
status of the host. Primary infections with HSV, namely those that develop in persons
without preexisting immunity to either HSV-1 or HSV-2, are usually more severe, frequently
involve systemic signs and symptoms, and have a higher rate of complications, compared to
episodes associated with reactivation of HSV.
OROFACIAL INFECTIONS
Herpetic gingivostomatitis (Fig. 164-1) and pharyngitis are most commonly associated with a
primary HSV-1 infection. The symptoms of primary oral herpes may resemble those of
aphthous stomatitis and include ulcerative lesions involving the hard and soft palate,
tongue, and buccal mucosa, as well as neighboring facial areas. Patients with pharyngitis
exhibit ulcerative and exudative lesions of the posterior pharynx that can be difficult to
differentiate from streptococcal pharyngitis. Other common symptoms include fever,
malaise, myalgias, pain on swallowing, irritability, and cervical adenopathy.

FIGURE 164-1
Primary herpetic gingivostomatitis. (Used with permission from Clyde S. Crumpacker, MD.)

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Reactivation of virus from these primary infections involves the perioral facial area, mainly
the lips, with the outer one-third of the lower lip being the most commonly affected area
(Fig. 164-2). Other facial locations include the nose, chin, and cheek, and account for fewer
than 10% of cases (Fig. 164-3). Two-thirds of labial lesions involve the vermilion border, and
the rest occur at the junction of the border with the skin. In patients with frequent
recurrences, lesions may differ slightly in location with each episode. Immunocompetent
patients tend not to experience recurrent intraoral lesions, but can present with clusters of
tiny vesicles and ulcers, or linear fissures on the gingivae and anterior hard palate that are
mildly symptomatic. Prodromal symptoms precede herpes labialis in 45% to 60% of
episodes. Patients experience pain, burning, or itching at the site of the subsequent
eruption. Even in the immunocompetent patient, the severity of recurrent herpes labialis is
extremely variable and may vary from that of prodromal symptoms alone without the
subsequent development of lesions (aborted episodes) to extensive disease induced by
severe local sunburn.

FIGURE 164-2
Herpes simplex virus infection. Erythema and early vesicles caused by recurrent herpes
labialis of the upper lip. (Used with permission of the William Weston Collection.)

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FIGURE 164-3
Recurrent facial herpes simplex with grouped vesicles and crusting. (Used with permission
from Clyde S. Crumpacker, MD.)
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The progression of classical herpes lesions has been divided according to the following
stages based on their features: prodromal, erythema, and papule (the developmental
stage); vesicle, ulcer, and hard crust (disease stage); followed by dry flaking and residual
swelling (resolution stage). The lesions usually resolve within 5 to 15 days.

Triggers for oral herpes recurrences include emotional stress, illness, exposure to sun,
trauma, fatigue, menses, chapped lips, and the season of the year. Other well-documented
triggers include exposure to ultraviolet irradiation, trigeminal nerve surgery, oral trauma,
epidural administration of morphine, and abrasive, laser, and chemical facial cosmetic
procedures. The exact mechanism by which these diverse factors trigger HSV reactivation is
unknown.

HSV-2 causes a primary orofacial infection that is indistinguishable from that associated with
HSV-1, except that it is usually in adolescents and young adults, following genital–oral
contact. HSV-2 orolabial infections are 120 times less likely to reactivate than orolabial HSV-
1 disease.

GENITAL INFECTIONS
Genital herpes is the major clinical presentation of HSV-2 infection, but HSV-1 is becoming a
more common cause of genital herpes in young women.9,10 Because of their epidemiology,
acquisition of HSV-1 in a person with prior HSV-2 infection is unusual, but HSV-2 acquisition
in the presence of previous HSV-1 infection is common, and infection of the genital tract
with both HSV-1 and HSV-2 has been described. Patients with previously known HSV-1
genital infection who develop frequent genital herpes recurrences should be tested for HSV-
2 infection. Viremia occurs in approximately 25% of persons during primary genital herpes.

The clinical course of acute first-episode genital herpes among patients with HSV-1 and HSV-
2 infections is similar. These infections are associated with extensive genital lesions in
different stages of evolution, including vesicles, pustules, and erythematous ulcers that may
require 2 to 3 weeks to resolve (Fig. 164-4). In males, lesions commonly occur on the glans
penis or the penile shaft; in females, lesions may involve the vulva, perineum, buttocks,
vagina, or cervix. There is accompanying pain, itching, dysuria, vaginal and urethral
discharge, and tender inguinal lymphadenopathy. Systemic signs and symptoms are
common and include fever, headache, malaise, and myalgias. Herpetic sacral
radiculomyelitis with urinary retention, neuralgias, and constipation, can occur. HSV
cervicitis occurs in more than 80% of women with primary infection. It can present as
purulent or bloody vaginal discharge; examination reveals areas of diffuse or focal friability
and redness, extensive ulcerative lesions of the exocervix, or, rarely, necrotic cervicitis.
Cervical discharge is usually mucoid, but it is occasionally mucopurulent.

FIGURE 164-4
A, Primary genital herpes with vesicles. (Used with permission from Clyde S. Crumpacker,
MD.) B, Primary herpetic vulvitis.
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The rates of recurrence for genital HSV-2 infections vary greatly among individuals and over
time within the same individual. Infections caused by HSV-2 reactivate approximately 16
times more frequently than HSV-1 genital infections, and average 3 to 4 times per year, but
may appear virtually weekly. Recurrences tend to be more frequent in the first months to
years after initial infection. The classical clinical manifestations of recurrent HSV-2 infection
include multiple small, grouped, vesicular lesions in the genital area (Fig. 164-5), but which
can occur anywhere in the perigenital region, including the groin, buttocks, and thighs; the
lesions may recur at the same site or change location. The recurrence of genital lesions may
be heralded by a prodrome of tenderness, itching, burning, or tingling, and the outbreaks
are less severe than primary infection. Without treatment, the lesions usually heal in 6 to 10
days. Herpetic cervicitis is less common in recurrent disease, occurring in 12% of patients. It
may present without external lesions. Signs and symptoms that are less classical for genital
HSV infection and that can divert one from the correct diagnosis include small erythematous
lesions, fissures, pruritus, and urinary symptoms. HSV can cause urethritis, usually
manifested only as a clear mucoid discharge, dysuria, and frequency. Occasionally, HSV can
be associated with endometritis, salpingitis, or prostatitis. Symptomatic or asymptomatic
rectal and perianal infections are common. Herpetic proctitis presents with anorectal pain,
anorectal discharge, tenesmus, and constipation, with ulcerative lesions of the distal rectal
mucosa. Genital herpes can recur at nongenital sites as well.
FIGURE 164-5
A, Genital herpes. Recurrent infection of the penis. Group of vesicles with early central
crusting on a red base arising on the shaft of the penis. This “textbook” presentation,
however, is much less common than small asymptomatic erosions or fissures. B, Genital
herpes. Recurrent vulvar infection. Large, painful erosions on the labia. Extensive lesions
such as these are uncommon in recurrent genital herpes in an otherwise healthy individual.

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OTHER CUTANEOUS FINDINGS
HSV can infect any skin site (Fig. 164-6). The common theme among virtually all of these
cutaneous presentations is the requirement that virus have penetrated otherwise normal
and well-keratinized tissues. Herpetic whitlow (Fig. 164-7) is infection of the fingers by HSV
acquired by direct inoculation or by direct spread from mucosal sites at the time of primary
infection. Whitlow occurs in children who suck their fingers during a primary
gingivostomatitis outbreak. It is also a well documented occupational hazard for medical
personnel. It is usually caused by HSV-1, but HSV-2 whitlow may develop as a manifestation
of primary inoculation following manual–genital contact with an infected partner. The
infected region becomes erythematous and edematous. Lesions are usually present at the
fingertip and can be pustular and very painful. Fever and local lymphadenopathy are
common. Whitlow is often misdiagnosed as a bacterial paronychial infection, but surgical
drainage, often needed for a bacterial infection, is unnecessary and potentially harmful,
while antiviral therapy speeds healing. Whitlow may recur.
FIGURE 164-6
Recurrent genital herpes on the abdomen (zosteriform herpes simplex).

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FIGURE 164-7
Herpes simplex virus infection. Herpetic whitlow. Painful, grouped, confluent vesicles on an
erythematous, edematous base at the distal finger where the first (and presumed primary)
symptomatic infection occurred.
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Cutaneous herpes can be transmitted between athletes involved in contact sports, such as
wrestling (herpes gladiatorum) and rugby (herpes rugbiorum or scrum pox), and may occur
as outbreaks or small epidemics among team members. In these instances, multiple
herpetic lesions may appear across the thorax, ears, face, arms, and hands, in which
infection is facilitated by trauma to the normally-keratinized skin during sport activities (Fig.
164-8). Concomitant ocular herpes can occur.
FIGURE 164-8
Herpes simplex gladiatorum with lesions on the neck.

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Eczema herpeticum (Kaposi varicelliform eruption; Fig. 164-9) results from widespread
infection following inoculation of virus to skin damaged by eczema. It is usually a
manifestation of primary HSV-1 infection in a child with atopic dermatitis; the expression of
antimicrobial peptides in the skin may be a factor in controlling susceptibility to eczema
herpeticum in these patients. Cathelicidin and beta-defensins are antimicrobial peptides
that inhibit HSV replication. Skin lesions from patients with eczema herpeticum have lower
levels of cathelicidin and beta-defensins than do skin lesions from persons with atopic
dermatitis or psoriasis.11 Mycosis fungoides, Sézary syndrome, Darier disease, various
bullous diseases of the skin (particularly if patients are receiving immunosuppressive
therapy), and second-degree and third-degree burns also can be complicated by cutaneous
dissemination of HSV. The severity of eczema herpeticum ranges from mild to fatal, with
mortality rates of up to 10% being reported before antiviral therapy was available. Mortality
was primarily caused by bacterial superinfection and bacteremia. Common pathogens
include Staphylococcus aureus, beta-hemolytiic Streptococcus, and Pseudomomas
aerugionosa. In a typical severe primary attack, vesicles develop in large numbers over areas
of active or recently healed atopic dermatitis, particularly the face, several days after
exposure and continue to appear in crops for several more days. The vesicles become
pustular and markedly umbilicated and quickly progress to monomorphic erosions. Patients
commonly have high fever and adenopathy. Viremia with infection of internal organs can be
fatal. Recurrences are usually far milder than the first infection. Arriving at the correct
diagnosis can be delayed because of secondary impetigo involving the lesions, but it should
be considered in children with infected eczema, particularly if the child is more systemically
ill than one might anticipate with impetigo. Eczema herpeticum of the young infant is a
medical emergency, and early treatment with acyclovir can prove lifesaving.

FIGURE 164-9
Two examples of eczema herpeticum. Confluent and discrete crusted erosions associated
with erythema and edema of the face of a child (A) and man (B) with atopic dermatitis. Note
the monomorphic vesicles and punched out erosions. (Image A, Used with permission from
Anna L. Bruckner, MD.)

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Recurrent HSV infection is the most common precipitating event in cases of recurrent
erythema multiforme (see Chap. 43). HSV-associated erythema multiforme is usually an
acute, self-limited, recurrent disease, that lasts approximately 3 weeks. The lesions are
usually symmetric, occurring on acral extremities and the face, and there is grouping of
lesions over the elbow and knees as well as nailfold involvement. Mucosal involvement is
usually mild and restricted to the mouth. Constitutional symptoms are rare, and the skin
lesions heal without scarring.

NEONATAL HERPES
The neonate is a special category of immunodeficient host. The prevalence of neonatal
herpes varies from 1 case per 12500 to 1700 live births. 12 Primary maternal genital herpes is
associated with a risk of neonatal infection of 25% to 50% for vaginally-delivered babies, and
accounts for 50% to 80% of cases of neonatal HSV infection. In contrast, recurrent maternal
infection is associated with a risk of transmission of less than 3%, and transplacental
antibodies likely play a role in decreasing the risk of infection. 13 Other risk factors for
development of neonatal herpes include vaginal delivery, presence of cervical HSV infection,
use of invasive monitors, isolation of HSV from the genital tract, and prolonged rupture of
membranes.

Neonatal herpes infections manifest in 1 of 3 forms: skin, eye, and mouth involvement;
encephalitis; or disseminated disease (Fig. 164-10). The encephalitic and disseminated
disease forms account for more than 50% of cases of neonatal herpes. It is important to
remember that more than 20% of neonates with neurologic and disseminated disease do
not develop cutaneous vesicles. Without therapy, the overall mortality of neonatal herpes is
65%, and fewer than 10% of untreated neonates with CNS infection will develop normally.
With current therapeutic modalities, most babies with skin, eye, and mouth disease survive
and have normal development at age 1 year. For treated babies with encephalitis, mortality
is 64%, with approximately 30% developing normally within 2 years after infection.
Suppressive oral acyclovir for 6 months in neonates who survive CNS disease results in
improved neurologic outcomes.14 For treated babies with disseminated disease, mortality is
30%, with approximately 80% of the survivors apparently developing normally within 2
years after infection.12

FIGURE 164-10
Neonatal herpes simplex virus Type-2.
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NONCUTANEOUS FINDINGS
OCULAR INFECTIONS
HSV is a leading cause of recurrent keratoconjunctivitis and its associated corneal
opacification and visual loss. It is usually caused by HSV-1, except in neonates in whom HSV-
2 is more prevalent. The majority of HSV eye disease is caused by reactivation of the virus in
the trigeminal ganglia, but primary infections of the eye can also occur. Usually, the initial
manifestation of herpetic eye disease is a superficial infection of the eyelids and conjunctiva
(blepharoconjunctivitis), or corneal surface (dendritic or geographic epithelial ulcer with
pain and blurred vision). Deeper involvement of the cornea (stromal keratitis) or anterior
uvea (iritis) represents more serious forms of the disease and can cause permanent visual
loss. Acute retinal necrosis is a rare but rapidly progressive disease characterized by retinal
arteriolar sheathing, uveitis, and peripheral retinal opacification with variable pain and
visual loss. Retinal detachment is common and it is usually associated with HSV-1 infection.

NEUROLOGIC DISORDERS
All HSV infections involve the nervous system, as neurons are the sole proven site of virus
latency. HSV meningitis is manifested by headache, fever, stiff neck, and mild photophobia
with lymphocytic pleocytosis in the cerebrospinal fluid. Most cases result from HSV-2
infection, which resolve spontaneously in 2 to 7 days. HSV infection may involve the sacral
nerves with autonomic nervous system dysfunction, numbness, pelvic pain, tingling, urinary
retention, constipation, and cerebrospinal fluid pleocytosis. Symptoms usually resolve in a
few days, but in some cases, the neurologic residua take weeks to months to disappear,
occasionally becoming permanent. Reactivation of HSV or varicella-zoster virus is associated
with Bell’s palsy with acute, peripheral facial paresis caused by compression of the facial
nerve in the temporal bone. HSV encephalitis is the most commonly identified acute,
sporadic viral encephalitis in the United States, accounting for 10% to 20% of all cases.
Nearly all of the cases arising after the neonatal period are caused by HSV-1. HSV
encephalitis usually presents with acute focal neurologic symptoms, fever, and involvement
of the temporal lobe. PCR of the cerebrospinal fluid for HSV DNA is the most common
diagnostic technique.

COMPLICATIONS
All manifestations of HSV infection seen in the immunocompetent host also can be seen in
immunocompromised patients, but they are usually more severe, more extensive, and more
difficult to treat; for many of them, recurrences are more frequent. Patients with defects in
T-cell immunity, such as those with AIDS or transplantation recipients, are at particular risk
for progressive mucocutaneous or visceral infections, but the degree of dissemination
depends on the level of immunodeficiency of the host. Recurrent and persistent ulcerative
HSV lesions are among the most common and defining opportunistic infections in patients
with AIDS.15 Genital herpes is very common in patients with HIV and can be persistent and
severe. Oropharyngeal HSV in immunocompromised patients can present with widespread
involvement of skin (Fig. 164-11), the mucosa, and extremely painful, friable, hemorrhagic,
and necrotic lesions, similar to mucositis caused by cytotoxic agents. The lesions can spread
locally to involve the esophagus. Esophagitis presents with odynophagia, dysphagia,
substernal pain, and multiple ulcerative lesions. Esophagitis can also arise directly by
reactivation of HSV and its spread to the esophagus via the vagus nerve. Tracheobronchitis
and pneumonitis can also occur by spreading of the virus from oropharyngeal HSV.

FIGURE 164-11
Herpes simplex virus infection. Chronic ulcer in an immunocompromised host. Multiple,
slowly spreading, deep ulcers with central necrosis and hemorrhagic crusts on the lips,
cheeks, and nose of a woman with leukemia.
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HSV can reactivate from visceral ganglia of the autonomic nervous system or disseminate
hematogenously to other visceral organs (causing pneumonitis, hepatitis, pancreatitis, or
meningitis) and the GI tract. Most of these severe infections are caused by HSV-1, but HSV-2
can cause them as well.

ETIOLOGY AND PATHOGENESIS

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RISK FACTORS
The risk of severe HSV disease and the recurrence rate correlate with the level of cellular
immune competence of the host. Patients with mild decreases in cellular immunity may
experience only an increased number of recurrences and a slower resolution of lesions,
while severely compromised patients are more likely to develop disseminated, chronic, or
drug-resistant infections. CD8+ and CD4+ T-lymphocyte subsets, natural killer cells, and
inflammatory cytokines like interferon-γ are important in mediating protection against HSV.
Innate immunity is also important and polymorphisms in TLR2 are associated with increased
rates of genital lesions in seropositive persons. 16 Mutations in proteins important for
interferon responses, including STAT1, TYK2, and UNC-93B, are associated with herpes
simplex encephalitis.17 Constant immune surveillance and engagement are required to
maintain latency, mainly by HSV-specific CD8+ lymphocytes. T-cells reactive to HSV-1 are
clustered around latently infected neurons in ganglia from HSV-1 seropositive persons.
Dendritic cells and HSV-2–specific CD8+ lymphocytes localize to sites of reactivation, rapidly
contain virus-infected cells,18 and persist in the skin for weeks after lesions are
cleared.19These virus-specific CD8 cells are oligoclonal CD8αα+ cells that persist in the
dermal–epidermal junction, and produce cytotoxic granules. 20

Patients with defects in humoral immunity have no increase in HSV disease severity, but the
humoral immune response is important in reducing virus titers at the site of inoculation and
in regional neural tissues during primary infection. The transfer of HSV-specific antibodies
from mother to child is a key factor in protecting against neonatal herpes.

DIAGNOSIS
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LABORATORY TESTING
The method of choice for diagnosis of HSV infection depends on the clinical presentation. In
many instances, the history and clinical findings may be sufficient, but the social, emotional,
and therapeutic implications of a diagnosis dictate that it be confirmed by laboratory testing
when possible. For patients with active lesions, virus can be isolated in cell culture. In
culture, HSV causes typical cytopathic effects, and most specimens will prove positive within
48 to 96 hours after inoculation. The sensitivity of culture depends on the quantity of virus
in the specimen. Even in the most experienced centers, only approximately 60% to 70% of
fresh genital lesions are culture positive. Isolation of virus is most successful when lesions
are cultured during the vesicular stage and when specimens are taken from
immunocompromised patients or from patients suffering from a primary infection.

PCR is more sensitive than viral isolation and has become the preferred method for
diagnosis. PCR has been extensively used for the diagnosis of CNS infections and neonatal
herpes. It is also useful for the detection of HSV in late-stage ulcerative lesions. Both viral
culture and PCR assays enable typing of the isolate as HSV-1 or HSV-2. This information
helps to predict the frequency of reactivation after a first episode of HSV infection.

Serologic detection of IgG antibodies to HSV can be helpful in certain settings, but the
results are often misinterpreted. The main function of serologic testing is to differentiate a
primary episode from a recurrent infection (Table 164-1). A positive serologic test result can
be useful in patients with recurrent, genital lesions that are not present at the time of
examination, thereby making a positive culture unobtainable. Serologic testing also can be
helpful for counseling patients with initial episodes of disease and their partners, especially
during pregnancy, and in counseling partners of patients with genital herpes about their risk
of acquiring HSV.

TABLE 164-1Classification of Herpes Simplex Infections According to Viral Isolation and

Paired Serologic Test Results
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Type-specific serologic assays are based on antigenic differences between HSV-1 and HSV-2
glycoprotein G. These tests are often used to counsel patients about the meaning of the test
results in terms of the natural history of the disease, disease transmission, and the
emotional and social implications of the diagnosis.

PATHOLOGY
Direct fluorescent antibody staining of lesion scrapings also can be used, but its sensitivity is
lower than that of viral culture. The Tzanck test is helpful in rapid diagnosis of herpesvirus
infections, but it is less sensitive than culture and staining with fluorescent antibody, with
positive results in fewer than 40% of culture-proven cases. It is performed by scraping the
base of a freshly-ruptured vesicle and staining the slides with Giemsa or Wright stain (the
Papanicolaou staining method also can be used), followed by examination for
multinucleated giant cells that are diagnostic of herpetic infection (Fig. 164-12). Both HSV
and varicella-zoster virus will cause these changes. In skin biopsy specimens, epithelial cells
are enlarged, swollen, and often separated. Multinucleated cells with intranuclear
eosinophilic inclusion bodies can be seen.

FIGURE 164-12
Herpes simplex virus: Positive Giemsa smear for Tzanck cells. A giant, multinucleated
keratinocyte on a Giemsa-stained smear obtained from a vesicle base. Compare size of the
giant cell to that of neutrophils also seen in this smear.
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DIFFERENTIAL DIAGNOSIS
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The differential diagnosis of orolabial herpes includes aphthous ulcers, syphilis, and
herpangina. Diseases that can mimic genital herpes include chancroid, syphilis, and
lymphogranuloma venereum 
CLINICAL COURSE AND PROGNOSIS
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Although most patients with HSV infections are asymptomatic, primary infections can be
severe. Most recurrences are asymptomatic, but symptomatic recurrences are milder than
symptomatic primary infections. The frequency and severity of recurrent HSV-1 and HSV-2
disease decrease over time; therefore, the need for continued suppressive therapy should
be reevaluated.

MANAGEMENT
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INTERVENTIONS
COUNSELING
All sexually-active persons should be educated regarding the nature and risks of acquiring
and transmitting sexually-transmitted infections, including HSV. Studies show that
approximately one-half of patients with asymptomatic HSV-2 infection have mild,
unrecognized disease and can be taught to recognize the symptoms and signs of genital
herpes. Also, patients should be counseled regarding safer sex practices. It must be
emphasized that the majority of transmission occurs in asymptomatic phases and from
people who have no classical lesions. Patients with genital herpes should be counseled to
refrain from sexual intercourse during outbreaks and for 1 to 2 days after, and to use
condoms between outbreaks. Suppressive antiviral therapy is also an option for individuals
concerned about transmission to a partner.
Pregnant women who are known to have genital herpes should be reassured that the risk of
transmitting herpes to the baby during childbirth is extremely low. Recommendations for
the management of pregnant women with recurrent genital herpes include clinical
evaluation at delivery, with delivery by cesarean section indicated if there are signs and
symptoms of active infection (including prodrome). But cesarean section delivery may not
reliably prevent neonatal HSV infection when membranes are ruptured for long periods (≥24
hours). Women with primary HSV infection during pregnancy should be treated with
antiviral therapy. For women at or beyond 36 weeks of gestation who are at risk for
recurrent HSV infection, suppressive antiviral therapy has been recommended, as this
decreases viral shedding, the incidence of active lesions near term, and the need for
cesarean delivery because of HSV.21 Close followup; sequential PCR or cultures for HSV of
infants born to seropositive mothers who are shedding virus at the time of delivery;
prophylactic therapy with intravenous acyclovir for infants born to mothers with primary
infection; and intravenous acyclovir, if HSV is detected in infants of seropositive mothers, all
have been suggested.12

Women who are known by history and serologic tests not to have genital herpes should be
counseled about signs and symptoms of HSV and how to avoid acquiring the infection
during pregnancy. Serology is helpful in counseling a couple in which the male partner has
recurrent genital herpes and the pregnant wife is susceptible.

MEDICATIONS
Many HSV infections require no specific treatment (SEE Chap. 191). Keeping lesions clean
and dry while they heal by themselves may be all that is required. Treatment is warranted
for infections that are likely to prove protracted, highly symptomatic, or
complicated. Acyclovir has a highly favorable therapeutic index because of its preferential
activation in infected cells and preferential inhibition of the viral DNA polymerase. It must
be phosphorylated to be active, and it requires the viral thymidine kinase for
phosphorylation. Acyclovir inhibits HSV-1 and HSV-2 replication by 50% at a concentration
of 0.1 and 0.3 µg/mL (range: 0.01 to 9.9 µg/mL), respectively, but is toxic at concentrations
of greater than 30 µg/mL. Any strain that requires more than 3 µg/mL of acyclovir to be
inhibited is said to be relatively drug resistant.

Valacyclovir, the L-valyl ester of acyclovir, is an oral prodrug of acyclovir that achieves 3- to

5-fold higher bioavailability after oral administration, and can be used in a more convenient
dosage regimen. Famciclovir is the well absorbed oral form of penciclovir. Similar
to acyclovir, famciclovir is converted by phosphorylation to its active
metabolite penciclovirtriphosphate. The efficacy and adverse effect profile of famciclovir is
comparable to that of acyclovir. Penciclovir 1% cream is approved by the U.S. Food and Drug
Administration (FDA) for the treatment of herpes simplex labialis. Docosanol 10% cream is
approved by the FDA for nonprescription treatment of recurrent herpes labialis. Docosanol
is a long-chain saturated alcohol that inhibits entry of lipid-enveloped virus into the cell. It
decreases healing time by 18 hours when compared with placebo.

The current recommendations for antiviral treatment depend on the clinical disease, on
host immune status, and whether one is treating a primary or recurrent episode or
considering suppressive therapy (Tables 164-3, 164-4, 164-5).22 For disseminated or severe
herpes infections, the treatment of choice remains intravenous acyclovir 10 to 15 mg/kg
every 8 hours. The dose of intravenous acyclovir for neonatal herpes is 20 mg/kg per dose
given every 8 hours.

TABLE 164-3Recommended Regimens for the Treatment of Orofacial Herpes Simplex

Infections
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TABLE 164-4Recommended Regimens for the Treatment of Genital Herpes Simplex
Infections
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TABLE 164-5Recommended Regimens for Other Herpes Cutaneous Diseases
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For first episodes of genital HSV-2 infections, oral acyclovir, famciclovir, or valacyclovir all
speed healing and resolution of symptoms, and decrease viral shedding. When compared
with placebo, acyclovir decreases time to healing from 16 to 12 days, the duration of pain
from 7 to 5 days, and the duration of constitutional symptoms from 6 to 3 days. Valacyclovir
was compared with acyclovir in the treatment of primary episodes and shown to be
equivalent. Antiviral treatment of initial herpes episodes does not decrease subsequent
recurrences, probably because HSV establishes latent infection within hours after infection
and days before symptoms evolve.

Treatment of recurrent episodes of genital herpes with famciclovir, acyclovir, or valacyclovir

reduces the time of healing from approximately 7 to 5 days, time of cessation of viral
shedding from 4 to 2 days, and duration of symptoms from 4 to 3 days when compared with
placebo. Valacyclovir and acyclovir are equivalent; valacyclovir was similar to famciclovir in
one study, but slightly superior to famciclovir to suppress genital herpes in another study.
For persons with frequent or complicated genital recurrences, long-term suppressive
therapy with acyclovir or its analogs is the most effective management strategy. Suppressive
therapy was effective during the first year after acquisition of genital herpes. Suppressive
therapy reduces the rate of shedding in healthy persons and those with HIV. Suppressive
therapy with valacyclovir was more effective to reduce the burden of genital herpes disease
than episodic therapy. Because genital herpes is not progressive in the normal host and
because the rate of recurrences varies over time and may decrease after some years, it is
wise to recommend a “holiday” from treatment every year or so to reassess the continuing
need for treatment. Sunscreen has shown benefit in some, but not all trials, but there is no
evidence for lysine or gammaglobulin.23 Novel antivirals that inhibit the HSV helicase–
primase complex24,25 were effective for treatment of recurrent genital herpes in Phase II
trials, but are not licensed.

The use of antiviral suppressive therapy during the late phase of pregnancy to avoid
neonatal herpes also has been advocated, but a formal study of the approach would require
a very large number of participants because of the rare incidence of neonatal herpes. A
more achievable goal is to decrease the need for cesarean deliveries caused by herpes
recurrences during labor. Studies show that antiviral therapy in late pregnancy (beginning at
36 weeks) prevents clinical recurrences, cesarean sections associated with genital herpes,
and the risk of HSV-viral shedding at delivery.

Orolabial HSV infections warrant antiviral treatment less often than do genital infections.
Primary HSV gingivostomatitis should be treated with oral acyclovir. The pediatric dose is 15
mg/kg of acyclovir suspension orally 5 times a day for 7 days. When it is started within 3
days of onset of the disease, this regimen decreases the duration of oral and extraoral
lesions, fever, and eating and drinking difficulties. Valacyclovir and famciclovir may be
equally effective, but they have not been studied in this setting and are not currently
approved for use in children. Severely ill children may need to be hospitalized for hydration,
and IV acyclovir may be necessary.

Treatment of recurrent herpes labialis with antiviral drugs in immunocompetent hosts has
shown only modest benefits.23 Oral infections are inherently briefer and less symptomatic
than genital herpes. Treatment is only effective if used very early in the disease, especially in
the prodromal or erythema lesion stages. Patients who wish treatment should have the
medication available and be vigilant for the earliest signs and symptoms of a recurrence.
When treatment is thought to be required, penciclovir 1% cream every 2 hours while awake,
for 4 days can be used. Treatment should be initiated as early as possible. When initiated
within 1 hour of first symptoms of recurrence, penciclovir sped the healing of lesions (4.8
days vs 5.5 days) and decreased the duration of pain (3.5 days vs 4.1 days). This regimen is
approved by the FDA. Docosanol 10% cream is approved by the FDA for nonprescription
treatment of herpes simplex labialis. It is applied 5 times a day at the first sign of recurrence
of herpes simplex labialis. There has been no direct comparison with topical penciclovir.
Oral acyclovir, 400 mg 5 times a day for 5 days, affords marginal benefit if begun in the
earliest hour or two of the outbreak. Famciclovir, 500 mg 3 times a day for 5 days, when
started within 48 hours after experimental ultraviolet radiation, decreased the median time
to healing from 6 to 4 days, but is not useful for the more usual sporadic cases of herpes
labialis. Valacyclovir (2 g twice daily for 1 day) decreased the mean duration of cold sore
episodes by 1 day when compared with placebo, if started in the prodrome period.
Similarly, a single dose of famciclovir (1500 mg) reduced time to healing of herpes labialis
lesions by approximately 2 days compared with placebo. Creams and ointments containing
5% and 10% acyclovir are not beneficial in recurrent herpes labialis.

The use of suppressive acyclovir for herpes labialis is controversial. In one small study,

oral acyclovir, 400 mg twice a day, was effective in decreasing recurrences of herpes labialis.
In another study, suppressive therapy with valacyclovir was more effective than episodic
therapy with valacyclovir for herpes labialis. In studies with skiers (who have significant sun
exposures), acyclovir 400 mg twice a day, was shown to reduce recurrences in one study,
whereas acyclovir, 800 mg twice daily, failed to prevent recurrences in another study. Both
perioperative famciclovir (125 or 250 mg orally twice daily given 1 to 2 days before to 5 days
after the procedure) and valacyclovir (500 mg twice daily for 14 days, starting either a day
before or the day of the procedure) appeared to reduce the recurrence of orofacial HSV in
patients undergoing facial laser resurfacing. Valacyclovir also suppresses recurrences of
herpes gladiatorum.

Herpetic eye disease should always be treated in consultation with an ophthalmologist.

Options usually involve topical antivirals, including vidarabine, trifluridine, acyclovir,
or ganciclovir. Topical antivirals are effective in shortening the duration of dendritic and
geographic keratitis, and are used to prevent corneal epithelial disease in patients with
blepharitis and conjunctivitis, as well as patients on topical steroid therapy for corneal
stromal inflammation and iridocyclitis. Oral acyclovir is also effective for dendritic and
geographical epithelial keratitis. Suppressive antiviral therapy reduces the rates of all types
of recurrent ocular HSV disease, and it is most important for patients with a history of HSV
stromal keratitis because it can prevent additional episodes and potential loss of vision.
 Antiviral Resistance
Virtually all clinically relevant drug resistance has been seen in immunocompromised
patients. The primary mechanism of acyclovir resistance is selection of viral mutants
defective or deficient in thymidine kinase expression. Most mutants that are thymidine
kinase deficient are somewhat attenuated for virulence in vivo.

The treatment of resistant HSV infection is complicated. Very few people who claim to be
“resistant” to one of the antiviral drugs actually harbor resistant virus. There is a common
misconception that treatment prevents all recurrences. One should suspect resistance only
in people who continue to have culture-proven or PCR-proven outbreaks of unaltered
frequency and severity, especially if the lesions do not heal by themselves. When resistance
is suspected, virus should be cultured and tested for sensitivity to acyclovir. These tests are
expensive but are available through commercial reference laboratories. Foscarnet does not
require activation by HSV thymidine kinase and is usually effective in the treatment of
acyclovir-resistant HSV. The drug requires IV therapy and can cause numerous adverse
reactions, including nephrotoxicity, electrolyte disturbances, anemia, and seizures. Rare
foscarnet-resistant HSV strains have been reported.

Cidofovir also does not require activation by HSV thymidine kinase. Cidofovir has been used
in cases of acyclovir-resistant HSV and topical cidofovir has been used with success to treat
progressive herpetic lesions. Intravenous cidofovir is associated with considerable
nephrotoxicity and requires the coadministration of saline hydration and probenecid. A few
patients with acyclovir-resistant genital herpes have responded to imiquimod 5% cream.
Imiquimod causes severe inflammation in some patients with recurrent herpes labialis.
Resiquimod reduced the rate of new lesions in 1 study of persons without drug-resistant
virus, but had no effect on genital herpes in 4 other studies. Continuous
intravenous acyclovir also has been used to treat acyclovir-resistant HSV. Long-term
suppressive acyclovir therapy reduced the rate of drug-resistant HSV disease in
hematopoietic stem cell transplant recipients.

PREVENTION
Strategies to prevent HSV infection have proved inadequate. HSV infection can be
prevented by total abstinence, as indicated by very low seroprevalence rates in cloistered
nuns. Condoms reduce rates of transmission if used routinely. Male circumcision reduced
the rate of HSV-2 infection in one study, but not in another study. Other than these public
health approaches, most efforts involve antiviral therapy and vaccines directed at genital
herpes.

Antiviral Therapy
Acyclovir, famciclovir, and valacyclovir all decrease both symptomatic and subclinical
shedding of HSV-2, from approximately 8% of the days in the placebo group to 0.3% to 0.6%
of the days in the treatment group, when assessed by culture. Once-daily valacyclovir
reduced shedding by PCR from 14% to 3% in patients with newly diagnosed genital herpes.
Valacyclovir 500 mg once daily was effective in reducing the transmission of HSV-2 between
partners by 48%, and reduced clinical disease in the susceptible partner by 7% in a
randomized, placebo-controlled trial involving immunocompetent, heterosexual couples in
stable relationships.6 This therapy can be recommended for individuals concerned about
transmission to a partner, in conjunction with the use of condoms. Frequency of HSV-2
shedding was reduced with high-dose acyclovir (800 mg 3 times daily) or high-dose
valacyclovir (1 g 3 times daily) compared with standard dose valacyclovir (500 mg daily);
however, the high-dose therapies did not reduce recurrence rates compared with standard
dose valacyclovir.26 Tenofovir gel applied vaginally within 12 hours before and 12 hours after
coitus reduced the incidence of HSV-2 by approximately 50%.27 Oral tenofovir and
emtricitabine-tenofovir had a modest effect on reducing acquisition of HSV-2. 28 Vaginal
microbicides are also being studied, mostly focusing on decreasing HIV transmission, but
some of the compounds also have anti-HSV activity and may also affect HSV transmission.

Vaccines
No vaccine is licensed to protect against acquisition of HSV (prophylactic) or to reduce the
number of recurrent episodes (therapeutic).29 A recombinant HSV-2 glycoprotein D vaccine
was ineffective at preventing genital herpes disease, infection, or HSV shedding. 30 Several
candidate vaccines are under development to prevent recurrent genital HSV. 31 A replication-
defective mutant, deleted for 2 essential viral proteins, is currently in a clinical trial. Initial
results with a subunit vaccine containing HSV-2 gD2 and ICP4 protein showed a 50%
reduction in HSV-2 genital shedding after vaccination. A Phase II study of a vaccine
consisting of HSV-2 peptides linked to heat shock protein with an adjuvant, showed a 15%
reduction in HSV-2 genital shedding.
Herpes
Herpes merupakan nama kelompok virus herpesviridae yang dapat menginfeksi manusia.
Infeksi virus herpes dapat ditandai dengan munculnya lepuhan kulit dan kulit kering. Jenis
virus herpes yang paling terkenal adalah herpes simplex virus atau HSV. Herpes simplex
dapat menyebabkan infeksi pada daerah mulut, wajah, dan kelamin (herpes genitalia).

Pembagian kelompok virus herpesviridae adalah sebagai berikut:

 Alfa herpesvirus. Kelompok virus ini memiliki siklus hidup untuk menggandakan diri
yang pendek, serta berpotensi menjadi tersembunyi dan infeksi muncul kembali
(infeksi laten) di sel saraf. Contoh alfa herpesvirus adalah HSV tipe 1 dan 2, serta
virus varicella-zoster.
 Beta herpesvirus. Kelompok virus ini memiliki siklus hidup untuk menggandakan diri
yang panjang dan infeksi virus ini berjalan lambat dalam tubuh manusia. Contoh beta
herpesvirus adalah cytomegalovirus, serta herpesvirus 6 dan 7.
 Gamma herpesvirus. Contohnya adalah Epstein-Barr virus dan human herpesvirus 8.

Tahapan Infeksi Herpes

Infeksi herpes yang muncul biasanya terjadi dalam beberapa tahapan. Rincian tahapan
infeksi herpes adalah sebagai berikut:

 Stadium primer. Stadium primer terjadi pada hari kedua hingga kedelapan setelah
terjadinya infeksi herpes. Gejala yang muncul adalah blister (kulit yang melepuh)
berukuran kecil, namun menyakitkan. Blister biasanya berisi cairan berwarna bening
atau keruh, dan dapat pecah serta menimbulkan luka terbuka. Daerah di sekitar
blister akan berwarna kemerahan.
 Stadium laten. Pada stadium ini, gejala herpes seperti blister dan koreng akan
mereda. Tetapi pada stadium ini, sebetulnya virus sedang menyebar ke saraf dekat
saraf tulang belakang melalui kulit.
 Stadium peluruhan. Pada stadium ini, virus mulai berkembang biak pada ujung-
ujung saraf organ tubuh. Jika ujung saraf yang terinfeksi terletak pada organ tubuh
yang menghasilkan cairan, seperti testis atau vagina, virus herpes dapat terkandung
dalam cairan tubuh seperti semen dan lendir Biasanya tidak terjadi gejala yang
terlihat, namun sebenarnya sedang terjadi perkembangbiakan virus di dalam tubuh.
  Stadium rekurensi (muncul kembali). Pada stadium ini, blister pada kulit yang terjadi
di stadium pertama dapat muncul kembali. Biasanya tidak separah lepuhan dan
koreng yang sebelumnya. Gejala yang umumnya muncul pada stadium rekurensi ini
adalah gatal, kesemutan, dan nyeri di daerah yang terkena infeksi pada stadium
pertama.

Virus Penyebab dan Gejala Herpes

Artikel ini akan fokus membahas kelompok alfa herpesvirus yang paling sering
menyebabkan infeksi.
HSV 1
Herpes simplex virus tipe 1 (HSV 1) merupakan virus yang dapat menyebar dengan cepat,
dan umumnya menyebabkan herpes oral (mulut). Akan tetapi HSV 1 juga dapat
menyebabkan terjadinya herpes kelamin (genital) jika menyebar dari mulut ke alat kelamin
pada saat melakukan hubungan seksual melalui oral. HSV 1 dapat menular melalui kontak
langsung sederhana dari penderita herpes ke orang yang sehat. Contohnya adalah lewat
berciuman (termasuk saat mencium bayi), berbagai pakai peralatan makan atau lipstik dan
kosmetik. HSV 1 bahkan dapat ditularkan dari seseorang yang mengalami infeksi HSV 1
namun tanpa gejala.
Gejala yang dapat ditimbulkan oleh infeksi HSV 1 atau herpes oral adalah:

 Diawali dengan demam, nyeri otot, dan lemas.

 Muncul rasa nyeri, gatal, rasa terbakar atau ditusuk pada tempat infeksi.
 Kemudian timbul blister, yaitu lesi kulit seperti melepuh yang pecah dan mengering
dalam beberapa hari.
 Blister yang pecah tersebut mengakibatkan luka dengan rasa nyeri. Bila terjadi di
mulut, bisa mengganggu makan.

HSV 2
Herpes simplex virus tipe 2 (HSV 2) merupakan penyebab penyakit herpes genital. Virus ini
menyebar melalui kontak dengan luka pada penderita herpes, misalnya saat hubungan
seksual. Selain itu, HSV 2 juga dapat ditularkan dari ibu kepada bayinya pada saat
persalinan.
Baik HSV 1 maupun HSV 2 dapat menjadi infeksi laten di sel saraf dan berisiko muncul
kembali saat seseorang mengalami demam, cedera, stres, dan menstruasi. HSV 2 sendiri
dapat lebih mudah menginfeksi seseorang jika:

 Berjenis kelamin perempuan.

 Bergonta-ganti pasangan seksual.
 Memiliki sistem kekebalan tubuh yang rendah.
 Sedang mengalami penyakit menular seksual selain herpes.
 Melakukan hubungan seksual di usia muda.

Beberapa gejala yang umumnya muncul pada penderita herpes genital, antara lain:
 Gatal.
 Sakit pada saat buang air kecil.
 Keluarnya cairan dari vagina.
 Munculnya benjolan di selangkangan.
 Munculnya koreng yang menyakitkan pada kemaluan, pantat, anus, atau paha.
 Pada pria, herpes dapat menyebabkan kulit penis kering, perih, dan gatal.