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31
:: Adriana R. Marques & Jeffrey I. Cohen
HERPES SIMPLEX AT A GLANCE EPIDEMIOLOGY
Herpes simplex viruses (HSVs) are Herpes simplex virus (HSV) infections are common
common human DNA viral pathogens that worldwide and are caused by two closely related types
intermittently reactivate. After replication of HSV. Their main clinical manifestations are muco-
in the skin or mucosa, the virus infects cutaneous infections, with HSV type 1 (HSV-1) being
the local nerve endings and ascends to mostly associated with orofacial disease, whereas HSV
the ganglia where it becomes latent until type 2 (HSV-2) is usually associated with genital and
reactivation. perigenital infection.
Chapter 193
The incidence of primary infection with HSV-1,
There are two types of HSV: HSV-1 and HSV- which is responsible for the vast majority of recur-
2. HSV-1 is mostly associated with orofacial ring labial herpes, is greatest during childhood, when
disease, whereas HSV-2 usually causes 30%60% of children are exposed to the virus. Rates
genital infection, but both can infect oral and of infection with HSV-1 increase with age and reduced
genital areas and cause acute and recurrent socioeconomic status, the majority of persons age 30 or
::
infections. older are seropositive for HSV-1.1,2 From 20% to 40%
Herpes Simplex
of the population have had episodes of herpes labia-
Most of the adult population is seropositive lis.3 The frequency of recurrent episodes is extremely
for HSV-1, and the majority of infections are variable, and, in some studies, averages about once
acquired in childhood. About one-fourth of per year,4 but there is evidence that the frequency and
adults are infected with HSV-2 in the United severity of recurrent HSV-1 disease decrease over time.
States. Acquisition of HSV-2 correlates with Acquisition of HSV-2 correlates with sexual behav-
sexual behavior. ior and the prevalence of the infection in the pool of
ones potential sexual partners. Antibodies to HSV-2
Most primary HSV infections are are rare in people before the onset of intimate sexual
asymptomatic or not recognized, but activity and rise steadily thereafter. HSV-2 seropreva-
they can also cause severe disease. lence in the United States is 22% in persons 12 years of
Most recurrences are not symptomatic age or older.5 The rate of HSV-2 seropositivity declined
(asymptomatic shedding), with most in the United States from 21% in 19881994 to 17% in
transmissions occurring by asymptomatic 19992004, and rate of HSV-1 seropositivity declined
shedding. from 62% to 58% during the same period.6
Although most patients infected with HSV-1 or
Genital herpes is the most prevalent sexually HSV-2 are asymptomatic, they still can transmit the
transmitted disease worldwide and is the virus. Studies using DNA polymerase chain reaction
most common cause of ulcerative genital (PCR) assays show that rates of detecting HSV-2 DNA
disease, and it is an important risk factor in genital secretions of people who have never recog-
for acquisition and transmission of human nized herpes outbreaks (asymptomatic persons) are
immunodeficiency virus. similar to the rates of shedding viral DNA in people
who have experienced symptomatic genital herpes
HSV can cause diseases involving the but who are not symptomatic at the moment of test-
eye, central nervous system, and neonatal ing (subclinical shedding).7 In one study, 21% of geni-
infection. Cellular immunity defects are tal swabs were positive for HSV-2 by PCR and 12% of
a risk factor for severe and disseminated oral swabs were positive for HSV-1 PCR in HSV-2 and
disease. HSV-1 seropositive persons, respectively.8 It is esti-
mated that more than 70% of transmission of HSV-2
Diagnosis is made by polymerase chain is associated with asymptomatic and subclinical reac-
reaction, viral culture, or serology, tivation and shedding. The rate of transmission is no
depending on the clinical presentation. higher is persons with frequent symptomatic recur-
rences than those with infrequent recurrences.9 The
Treatment is with acyclovir, valacyclovir, average risk of transmission for couples discordant for
or famciclovir. Regimens and dosages genital herpes (i.e., one partner has genital herpes and
vary with the clinical setting. Resistance is the other does not) varies from 5% to 10% per year.10,11
rare in other than immunocompromised As with other sexually transmitted infections, the rate
patients. of acquisition of HSV-2 infection is higher for women
than for men (6.8 vs. 4.4 cases per 100 person-years;
2367
31 relative risk, 1.55). Asymptomatic HSV-2 infection is
more common among men and persons who are also
IMMUNE RESPONSE
seropositive for HSV-1, suggesting that prior infection
Host immunity to HSV clearly influences the risk of
with HSV-1 reduces ones likelihood of experiencing
acquiring the infection, the severity of disease, and the
symptomatic HSV-2 infection.12 Studies have shown
frequency of recurrences. The risk of severe HSV dis-
that genital HSV infections significantly increase the
ease and the recurrence rate correlates with the level of
risk for acquisition and transmission of human immu-
cellular immune competence of the host. Patients with
nodeficiency virus (HIV). Randomized trials with
mild decreases in cellular immunity may experience
acyclovir reduced the frequency of genital ulcers and
only an increased number of recurrences and a slower
slightly reduced HIV viral loads, but did not reduce
resolution of lesions, whereas severely compromised
transmission of HIV.13,14
patients are more likely to develop disseminated,
chronic, or drug-resistant infections.
ETIOLOGY AND PATHOGENESIS Studies of humans and mice have implicated a
role for both CD8+ and CD4+ T lymphocyte subsets,
Section 31
infect multiple cell types in culture, grow rapidly, and Patients with defects in humoral immunity have
efficiently destroy the host cells. Infection in the natural no increase in HSV disease severity, but the humoral
host is characterized by lesions in the epidermis, often immune response is important in reducing virus titers
involving mucosal surfaces, with spread of virus to the at the site of inoculation and in regional neural tissues
nervous system and establishment of latent infections during primary infection. Animals are effectively pro-
in neurons, from which virus periodically reactivates. tected from disseminated and neurologic disease by
HSV-1 and HSV-2 have a high degree of genetic and passive transfer of polyclonal or monoclonal antibod-
antigenic homology. An analysis of herpesvirus phy- ies and by antibody responses elicited actively through
logeny estimated that the two HSV types diverged vaccination. Moreover, the transfer of HSV-specific
from an ancestral protoherpesvirus approximately antibodies from the mother to the child is a key factor
8 million years ago.15 in protecting against neonatal herpes.
Herpesvirus replication is a carefully regulated pro- The mechanisms of immunity required to sustain
cess. Shortly after infection, immediate-early genes are latency and limit reactivation of HSV are less clear.
transcribed whose proteins upregulate expression of There is evidence that constant immune surveillance
early proteins that are required for genome replication. and engagement are required to maintain latency,
The late [HSV-2HSV] genes encode virion structural mainly by HSV-specific CD8+ lymphocytes and low
components including the glycoproteins. levels of viral proteins produced in neurons.18 T cells
In vivo, HSV infections can be divided into three reactive to HSV-1 are clustered around latently infected
stages: (1) acute infection, (2) establishment and main- neurons in ganglia from HSV-1 seropositive persons.19
tenance of the latency, and (3) reactivation of virus. HSV-specific CD8+ lymphocytes localize to site of reac-
During acute infection, virus replicates at the site of tivation and persist in the skin for weeks after lesions
inoculation on mucocutaneous surfaces, resulting in are cleared.20
primary lesions from which virus rapidly spreads to
infect sensory nerve terminals, where it travels by ret-
rograde axonal transport to neuronal nuclei in regional CLINICAL FINDINGS
sensory ganglia. In a subset of infected neurons, a
latent infection is established in which viral DNA is The clinical manifestations of HSV infection depend
maintained as an episome and HSV gene expression on the site of infection and, as indicated in Immune
is severely restricted: of all of the viral genes, only one Response (above), the immune status of the host. Pri-
is abundantly transcribed during latency. In the last mary infections with HSV, namely those that develop
stage, replication reactivates with concomitant antero- in persons without preexisting immunity to either
grade axonal transport of newly assembled virus to a HSV-1 or HSV-2, are usually more severe, frequently
peripheral site, at or near the original portal of entry with systemic signs and symptoms, and they have a
(see eFig. 193-0.1 in online edition). higher rate of complications, than recurrent episodes.
HSV-1 reactivates most efficiently and frequently
from trigeminal ganglia, whereas HSV-2 reactivates
primarily from sacral ganglia. The rate of reactiva- OROFACIAL INFECTIONS
tion of HSV appears to be influenced by the quantity
of latent viral DNA in the ganglia.16 Reactivation is Herpetic gingivostomatitis (Fig. 193-1) and pharyngitis
induced in experimentally infected animals by expo- are most commonly associated with a primary HSV-1
sure to ultraviolet irradiation, by hyperthermia, by infection. The symptoms of primary oral herpes may
2368 local trauma, and by other physiologic stressors. resemble those of aphthous stomatitis and include
31
Chapter 193
Figure 193-1 Primary herpetic gingivostomatitis. (Used
with permission from Clyde S. Crumpacker, MD.)
::
Figure 193-3 Recurrent facial herpes simplex with
Herpes Simplex
grouped vesicles and crusting. (Used with permission
ulcerative lesions involving the hard and soft palate,
from Clyde S. Crumpacker, MD.)
tongue, and buccal mucosa, as well as neighboring
facial areas. Patients with pharyngitis exhibit ulcer-
ative and exudative lesions of the posterior pharynx episodes. Patients experience pain, burning, or itch-
that can be difficult to differentiate from streptococcal ing at the site of the subsequent eruption. Even in the
pharyngitis. Other common symptoms are fever, mal- immunocompetent patient, the severity of recurrent
aise, salivation, myalgias, pain on swallowing, irrita- herpes labialis is extremely variable and may vary
bility, and cervical adenopathy. from that of prodromal symptoms alone without the
Reactivation of virus from these primary infections subsequent development of lesions (aborted episodes)
involves the perioral facial area, mainly the lips, with to extensive disease induced by severe local sunburn.
the outer one-third of the lower lip being the most The progression of the classical herpes lesions has
commonly affected (Fig. 193-2 and see eFig. 193-2.1 been divided according to the following stages based
in online edition). Other facial locations include the on their features: prodromal, erythema, and papule
nose, chin, and cheek, and account for less than 10% (the developmental stages); vesicle, ulcer, and hard
of the cases (Fig. 193-3). Two-thirds of labial lesions crust (disease stages); followed by dry flaking and
involve the vermilion border, whereas the rest occur residual swelling (resolution stages). The lesions usu-
at the junction of the border with the skin. In patients ally resolve within 515 days.
with frequent recurrences, lesions may differ slightly Trigger factors for oral herpes recurrences include
in location with each episode. Immunocompetent emotional stress, illness, exposure to sun, trauma,
patients tend not to experience recurrent intraoral fatigue, menses, chapped lips, and the season of
lesions, but can present with clusters of tiny vesicles the year.21 Other well-documented triggers include
and ulcers, or linear fissures on the gingivae and ante- exposure to ultraviolet irradiation, trigeminal nerve
rior hard palate that are mildly symptomatic. Prodro- surgery, oral trauma, epidural administration of mor-
mal symptoms precede herpes labialis in 45%60% of phine, 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 and following genitaloral contact. Moreover,
HSV-2 orolabial infections are 120 times less likely to
reactivate than is orolabial HSV-1 disease. For the dif-
ferential diagnosis of orofacial herpes see Box 193-1.
GENITAL INFECTION
Genital herpes is the major clinical presentation of
HSV-2 infection, but it may also result from HSV-1
Figure 193-2 Herpes simplex virus infection: recurrent in 10%40% of the cases, primarily following oral
herpes labialis. genital contact.22 Because of their epidemiology, 2369
31 Box 193-1 Differential Diagnosis
HSV-1 genital infection who develop frequent genital
herpes recurrences should be tested for HSV-2 infec-
of Orolabial and Genital Herpes tion.23 Viremia occurs in about 25% of persons during
primary genital herpes.24
Differences from Orolabial The clinical course of acute first-episode genital her-
Disease Herpes pes among patients with HSV-1 and HSV-2 infections
Aphthous ulcers Not preceded by vesicles, is similar. These infections are associated with exten-
only on mucosa sive genital lesions in different stages of evolution,
Syphilis Painless, not preceded by including vesicles, pustules, and erythematous ulcers
that may require 23 weeks to resolve (Fig. 193-4). In
vesicles
males, lesions commonly occur on the glans penis or
Herpangina Posterior portion of mouth
the penile shaft; in females, lesions may involve the
(soft palate, tonsils)
vulva, perineum, buttocks, vagina, or cervix. There is
Stevens Johnson Disseminated lesions
accompanying pain, itching, dysuria, vaginal and ure-
syndrome thral discharge, and tender inguinal lymphadenopa-
Section 31
Differences from Genital thy. Systemic signs and symptoms are common and
Disease Herpes include fever, headache, malaise, and myalgias. Her-
Chancroid Deep ulceration with petic sacral radiculomyelitis, with urinary retention,
neuralgias, and constipation, can occur. HSV cervici-
exudate
tis occurs in more than 80% of women with primary
::
A B
Figure 193-4 A. Primary genital herpes with vesicles. (Used with permission from Clyde S. Crumpacker, MD.) B. Primary
2370 herpetic vulvitis.
31
Chapter 193
A B
::
Figure 193-5 A. Genital herpes: recurrent infection of the penis. Group of vesicles with early central crusting on a red
Herpes Simplex
base arising on the shaft of the penis. This textbook presentation, however, is much less common than small asymptom-
atic 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.
of recurrent HSV-2 infection include multiple small but thritis, usually manifested only as a clear mucoid dis-
grouped vesicular lesions in the genital area (Fig. 193- charge, dysuria, and frequency. Occasionally, HSV can
5), but it can occur anywhere in the perigenital region, be associated with endometritis, salpingitis, or pros-
including the abdomen, groin, buttocks, and thighs tatitis. Symptomatic or asymptomatic rectal and peri-
(Fig. 193-6), and the lesions may recur at the same site anal infections are common. Herpetic proctitis presents
or change location. The recurrence of genital lesions with anorectal pain, anorectal discharge, tenesmus, and
may be heralded by a prodrome of tenderness, itch- constipation, with ulcerative lesions of the distal rectal
ing, burning, or tingling, and the outbreaks are less mucosa. Genital herpes can recur at nongenital sites as
severe than primary infection. Without treatment, the well. For the differential diagnosis of genital herpes, see
lesions usually heal in 610 days. Herpetic cervicitis is Box 193-1.
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 OTHER CUTANEOUS INFECTIONS
infection, and which may divert one from the correct
diagnosis include small erythematous lesions, fissures, HSV can infect any skin site (Fig. 193-6). The common
pruritus, and urinary symptoms. HSV can cause ure- theme among virtually all of these cutaneous presenta-
tions is the requirement that virus has penetrated oth-
erwise normal and well-keratinized tissues. Herpetic
whitlow (Fig. 193-7) is infection of the fingers by HSV
acquired by direct inoculation or by direct spread from
mucosal sites at the time of primary infection. Thus, a
typical presentation of whitlow would be in children
who suck their fingers during a primary gingivosto-
matitis outbreak. It is also a well-documented occu-
pational hazard for medical personnel. It is usually
caused by HSV-1, but HSV-2 whitlow may develop
as a manifestation of primary inoculation following
manualgenital contact with an infected partner. The
infected region becomes erythematous and edema-
tous. Lesions are usually present at the fingertip and
can be pustular and very painful. Fever and local
lymphadenopathy are common. Whitlow is often mis-
diagnosed as a bacterial paronychial infection, but the
surgical drainage, often needed for a bacterial infec-
Figure 193-6 Recurrent genital herpes on the abdomen tion, is unnecessary and potentially harmful, while
(zosteriform herpes simplex). antiviral therapy speeds healing. Whitlow may recur. 2371
31 Eczema herpeticum (Kaposi varicelliform eruption;
Fig. 193-8B and eFig. 193-8.1 in online edition) results
from widespread infection following inoculation of
virus to skin damaged by eczema. It is usually a mani-
festation of primary HSV-1 infection in a child with
atopic dermatitis, and the expression of cathelicidins in
the skin may be a factor in controlling susceptibility to
eczema herpeticum in these patients.25 Mycosis fungoi-
des, Szary syndrome, Darier disease, various bullous
diseases of the skin (particularly if patients are receiv-
ing immunosuppressive therapy), and burns of second
or third degree can also be complicated by cutaneous
dissemination of HSV. The severity of eczema herpe-
ticum ranges from mild to fatal, with mortality rates
of up to 10% being reported before antiviral therapy
Section 31
A B
Figure 193-8 A. Herpes simplex gladiatorum with lesions on the neck. B. Herpes simplex virus infection: eczema herpe-
ticum on face. Confluent and discrete crusted erosions associated with erythema and edema of the face of a man with
2372 atopic dermatitis.
3 weeks. The lesions are usually disseminated and
symmetric, occurring on acral extremities and the face,
31
and there is grouping of the lesions over the elbow
and knees, as well as nail fold involvement. Muco-
sal involvement is usually mild and restricted to the
mouth. Constitutional symptoms are rare, and the skin
lesions heal without scarring.
LABORATORY TESTS
The method of choice for diagnosis of HSV infec-
tion depends on the clinical presentation. In many Figure 193-9 Herpes simplex virus: positive Tzanck smear.
instances, the history and clinical findings may A giant, multinucleated keratinocyte on a Giemsa-stained
Chapter 193
be sufficient, but the social, emotional, and thera- smear obtained from a vesicle base. Compare size of the
peutic implications of a diagnosis dictate that it be giant cell to that of neutrophils also seen in this smear.
confirmed by laboratory testing when possible. For Another smaller multinucleated acantholytic keratinocyte
patients with lesions, virus can be isolated in cell is seen as well as acantholytic keratinocytes. Identical find-
culture. In culture, HSV causes typical cytopathic ings are present in lesions caused by varicella-zoster virus.
effects, and most specimens will prove positive
::
within 4896 hours after inoculation. The sensitivity sensitivity is lower than viral culture.26 The Tzanck
of the culture depends on the quantity of the virus in smear can be helpful in the rapid diagnosis of herpes-
Herpes Simplex
the specimen. Even in the most experienced centers, virus infections, but it is less sensitive than culture and
only approximately 60%70% of fresh genital lesions staining with fluorescent antibody, with positive results
are culture-positive. Isolation of the virus is most in fewer than 40% of culture-proven cases. It is per-
successful when lesions are cultured during their formed by scraping the base of a freshly ruptured vesi-
vesicular stage and when specimens are taken from cle and staining the slides with Giemsa or Wright stain
immunocompromised patients or from patients suf- (the Papanicolaou staining method can also be used),
fering from a primary infection. followed by examination for the multinucleated giant
PCR is more sensitive than viral isolation and has cells that are diagnostic of herpetic infection (Fig. 193-9).
become the preferred method for diagnosis. PCR has Both HSV and varicella-zoster virus (VZV) will cause
been extensively used for the diagnosis of central ner- these changes. In skin biopsy specimens, epithelial cells
vous system infections and in neonatal herpes. It is are enlarged, swollen, and often separated. Multinucle-
also useful for the detection of HSV in late-stage ulcer- ated cells with intranuclear eosinophilic inclusion bod-
ative lesions. Both viral culture and PCR assays enable ies (Cowdry type A inclusions) can be seen.
typing of the isolate as HSV-1 or HSV-2. This informa- Serologic detection of antibodies to HSV can be help-
tion helps to predict the frequency of reactivation after ful in certain settings, but the results are often misinter-
a first-episode of HSV infection. preted. Its main function is in differentiating a primary
Direct fluorescent antibody staining of lesion scrap- episode from a recurrent infection (Table 193-1). A pos-
ings and antigen detection assays can also be used but itive serologic test result can be useful in patients with
TABLE 193-1
Classification of Herpes Simplex Infections According to Viral Isolation and Paired
Serologic Test Results
COMPLICATIONS
IMMUNOCOMPROMISED HOST
::
Viral and Rickettsial Diseases
Chapter 193
HSV encephalitis is the most commonly identi-
fied acute, sporadic viral encephalitis in the United
States, accounting for 10%20% of all cases. Nearly
all of the cases arising after the neonatal period (see
Section Neonatal Herpes) are caused by HSV-1.
HSV encephalitis usually presents with acute onset
::
of focal neurologic symptoms and fever. Involvement
Herpes Simplex
of the temporal lobe is a characteristic feature of this
disease, but overall, it is difficult to differentiate HSV Figure 193-11 Neonatal herpes simplex virus 2.
encephalitis clinically from other viral encephalitides.
PCR of the CSF for HSV DNA is the most sensitive
noninvasive technique to help in the diagnosis, but it with central nervous system infection will develop
can occasionally be negative very early in the course of normally. With current therapeutic modalities, most
the disease.32 Patients with presumed HSV encephali- babies with skin, eye, and mouth disease survive and
tis should be treated empirically with intravenous acy- have normal development at 1 year. For treated babies
clovir until the diagnosis is confirmed or an alternative with encephalitis, mortality is 6%, with about 30%
diagnosis is made. However, even with therapy, neu- developing normally after 1 year. For babies with dis-
rologic sequelae are frequent.33 seminated disease, mortality is 30%, with about 80%
of the survivors apparently developing normally after
1 year.34
NEONATAL HERPES
The neonate is a special category of immunodeficient TREATMENT
host. The incidence of neonatal herpes varies from 1
case per 12,500 to 1 per 1,700 live births.34 The category All sexually active persons should be educated regard-
of maternal infection plays a significant role in defin- ing the nature and risks of acquiring and transmitting
ing the risk of neonatal herpes. Primary genital herpes sexually transmitted infections, including HSV. Studies
is associated with a risk of neonatal infection of 25% show that about one-half of the patients with asymp-
50% for vaginally delivered babies, and accounts for tomatic HSV-2 infection have mild, unrecognized dis-
50%80% of cases of neonatal HSV infection. In con- ease and can be taught to recognize their symptoms
trast, recurrent maternal infection is associated with a and signs of genital herpes. Also, patients should be
risk of transmission of less than 3%, and transplacental counseled regarding safer sex practices. It must be
antibodies are likely to play a role in decreasing the emphasized that the majority of transmission occurs
risk of infection.35 Other risk factors for development in asymptomatic phases and from people who have no
of neonatal herpes include vaginal delivery, presence classical lesions. Patients with genital herpes should
of cervical HSV infection, use of invasive monitors, be counseled to refrain from sexual intercourse during
and isolation of HSV from the genital tract.36 Prolonged outbreaks and for 12 days after and to use condoms
rupture of the membranes is also a risk factor. between outbreaks. Suppressive antiviral therapy is
Neonatal herpes infections manifest in one of the also an option for individuals concerned about trans-
three forms: (1) skin, eye, and mouth involvement; (2) mission to a partner (see Section Antiviral Therapy
encephalitis; or (3) disseminated disease (Fig. 193-11). under Prevention).
The latter two forms account for more than 50% of cases Pregnant women who are known to have genital
of neonatal herpes. It is important to remember that herpes should be reassured that the risk of trans-
more than 20% of neonates with neurologic and dis- mitting herpes to the baby during childbirth is
seminated disease do not develop cutaneous vesicles. extremely low. Recommendations for the manage-
Without therapy, the overall mortality of neonatal her- ment of pregnant women with recurrent genital
pes is 65%, and fewer than 10% of untreated neonates herpes include clinical evaluation at delivery, with
2375
31 delivery by Cesarean section indicated if there are
signs and symptoms of active infection (including
inhibits entry of lipid-enveloped virus into the cell.
It decreased the healing time by 18 hours when com-
prodrome). But Cesarean section delivery may not pared with placebo.39
reliably prevent neonatal HSV infection when mem- The current recommendations for antiviral
branes are ruptured for long periods (24 hours). treatment depend on the clinical disease, on host
Women with primary HSV infection during preg- immune status, and whether one is treating a pri-
nancy should be treated with antiviral therapy. For mary or recurrent episode or considering suppres-
women at or beyond 36 weeks of gestation who sive therapy (Boxes 193-2, 193-3, 193-4, and 193-5).84
are at risk for recurrent HSV infection, suppressive For disseminated or severe herpes infections, the
antiviral therapy has been recommended, (1) as this treatment of choice remains intravenous acyclovir
decreases viral shedding, the incidence of active 510 mg/kg every 8 hours. Some experts use acyclovir
lesions near term, and the need of Cesarean delivery 15 mg/kg intravenously every 8 hours for life-threat-
due to HSV.37,38 Close follow-up, sequential70 PCR ening HSV infection, including encephalitis. The dose
or cultures for HSV of infants born to seropositive of intravenous acyclovir for neonatal herpes is 20 mg/
mothers who are shedding virus at the time of deliv- kg per dose given every 8 hours.
Section 31
ery, prophylactic therapy with intravenous acyclovir For first episodes of genital HSV-2 infections, oral
for infants born to mother with primary infection, acyclovir, famciclovir, and valacyclovir all speed the
and intravenous acyclovir if HSV is detected in healing and resolution of symptoms, and decrease
infants of seropositive mothers have also been sug- viral shedding. When compared with placebo, acy-
gested.34 clovir decreases time of healing from 16 to 12 days,
::
Women who are known by history and serologic the duration of pain from 7 to 5 days, and the dura-
Viral and Rickettsial Diseases
tests not to have genital herpes should be counseled tion of constitutional symptoms from 6 to 3 days.51
about signs and symptoms of HSV and how to avoid Valacyclovir was compared with acyclovir in the
acquiring the infection during pregnancy. Serology is treatment of primary episodes and shown to be
helpful in counseling a couple in which the male part- equivalent.52 Antiviral treatment of initial herpes
ner has recurrent genital herpes and the pregnant wife episodes does not decrease subsequent recurrences,
is susceptible. probably because HSV establishes latent infection
within hours after inoculation and days before symp-
toms evolve.
ANTIVIRAL THERAPY Treatment of recurrent episodes of genital herpes
with famciclovir, acyclovir, or valacyclovir has been
(See Chapter 231) shown to reduce the time of healing from about 7 to
Many HSV infections require no specific treatment 5 days, time of cessation of viral shedding from 4 to
at all. Keeping the lesions clean and dry while they 2 days, and duration of symptoms from 4 to 3 days
heal by themselves may be all that is required. Treat- when compared with placebo. Valacyclovir and acy-
ment is warranted for infections that are likely to prove clovir are equivalent54,56; valacyclovir was similar to
protracted, highly symptomatic, or complicated. Acy- famciclovir in one study,57 but slightly superior to fam-
clovir, an acyclic guanosine analogue, has a highly ciclovir to suppress genital herpes in another study.67
favorable therapeutic index because of its preferential A regimen of patient-initiated, 1-day famciclovir
activation in infected cells and preferential inhibition of 1,000 mg twice daily was not different from placebo
the viral DNA polymerase. It must be phosphorylated in immunocompetent black adults in a recent study,
to be active, and it requires the viral thymidine kinase but this finding warrants further investigation.85 For
(TK) for initial phosphorylation. Acyclovir inhibits persons with frequent or complicated genital recur-
HSV-1 and HSV-2 replication by 50% at a concentration rences, long-term suppressive therapy with acyclovir
of 0.1 and 0.3 g/mL (range, 0.019.9 g/mL), respec- or its analogues is the most effective management
tively, but is toxic at concentrations of >30 g/mL. Any strategy.71,86,87 Suppressive therapy was effective dur-
strain that requires more than 3 g/mL of acyclovir to ing the first year after acquisition of genital herpes.69,70
be inhibited is said to be relatively drug resistant. Suppressive therapy reduces the rate of shedding in
Valacyclovir, the l-valyl ester of acyclovir, is an healthy persons and those with HIV.60,70,88,89 Suppres-
oral prodrug of acyclovir that achieves three- to five- sive therapy with valacyclovir was more effective
fold higher bioavailability after oral administration, to reduce the burden of genital herpes disease than
and it can be used in a more convenient dosage regi- episodic therapy.90 Because genital herpes is not pro-
men. Famciclovir is the well-absorbed oral form of gressive in the normal host and because the rate of
the related guanosine analogue penciclovir. Similar recurrences varies over time and may decrease after
to acyclovir, famciclovir is converted by phosphoryla- some years, it is wise to recommend a holiday from
tion to its active metabolite penciclovir triphosphate. treatment every year or so to reassess the persons
The efficacy and adverse effect profile of famciclovir is continuing need for treatment.
comparable to that of acyclovir. Penciclovir 1% cream The use of antiviral suppressive therapy during
is approved by the U.S. Food and Drug Administra- the late phase of pregnancy to avoid neonatal her-
tion (FDA) for the treatment of herpes simplex labia- pes has also been advocated, but a formal study of
lis. Docosanol 10% cream is approved by the FDA for the approach would require a very large number of
over-the-counter treatment of recurrent herpes labia- participants because of the rare incidence of neona-
2376 lis. Docosanol is a long-chain saturated alcohol that tal herpes. A more achievable goal is to decrease the
Box 193-2 Recommended Regimens for the Treatment of Orofacial Herpes
31
Simplex Infections
Acceptable Regimen Alternativesa
Primary infec- Acyclovir, 200 mg orally five 15 mg/kg of acy- 710 days or until IV acyclovir for
tion times a day. clovir orally five resolution of severely ill individuals.
Acyclovir, 400 mg orally three times a day.40 symptoms. No studies have been
times a day. done in adults: regi-
Valacyclovir, 1,000 mg orally mens are extrapolated
two times a day. from their effective-
Famciclovir, 250 mg orally ness in primary geni-
Chapter 193
three times a day. tal herpes.
Recurrent infec- Topical penciclovir, 1% cream 45 days or until Generally not war-
tion: episodic q2h while awake.41 lesions are healed. ranted.
treatment Topical docosanol 10% cream Valacyclovir and
five times a day.39 famciclovir were
::
Acyclovir, 400 mg orally five used for only 1
Herpes Simplex
times a day.42 day.
Famciclovir, 500 mg orally two
or three times a day.43,44
Valacyclovir, 2,000 mg orally
twice a day for 1 day.45
Famciclovir, 1,500 mg single
dose or 750 mg twice a day for
1 day.46
Recurrent infec- Acyclovir, 400 mg orally twice Start just before and
tion: prophy- a day.47 during precipitat-
laxis ing event, such as
intensive ultraviolet
exposure.
Recurrent Acyclovir, 400 mg orally twice There are no pedi-
infection: sup- a day.48 atric studies, but
pression of con- Valacyclovir 500 mg once a children with con-
firmed frequent day.49 firmed frequent
recurrences Valacyclovir 1,000 mg once a recurrences may
day.50 benefit from sup-
pressive oral acy-
clovir therapy.
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
Note: Neither valacyclovir nor famciclovir is approved by the US Food and Drug Administration for use in children.
need for Cesarean deliveries caused by herpes recur- days. When it is started within 3 days of onset of the
rences during labor. Studies have shown that antivi- disease, this regimen decreases the duration of oral
ral therapy in late pregnancy (beginning at 36 weeks) and extraoral lesions, fever, and eating and drink-
prevent clinical recurrences, Cesarean sections due to ing difficulties. Valacyclovir and famciclovir may be
genital herpes, and the risk of HSV viral shedding at equally effective, but they have not been studied in
delivery.91 this setting and are not currently approved for use in
Orolabial HSV infections warrant antiviral treat- children. Severely ill children may need to be hospi-
ment less often than do the genital infections. Pri- talized for hydration, and intravenous acyclovir may
mary HSV gingivostomatitis should be treated with be necessary.
oral acyclovir. The pediatric dose is 15 mg/kg of Treatment of recurrent herpes labialis with anti-
acyclovir suspension orally five times a day for 7 viral drugs in immunocompetent hosts has shown 2377
31 Box 193-3 Recommended Regimens for the Treatment of Genital Herpes
Simplex Infections
Acceptable Regimen Alternativesa
a day.
Recurrent Acyclovir, 400 mg orally three times a For children 12 510 days or
infection day. years of age: until clinical res-
Acyclovir, 200 mg orally five times a acyclovir, 200 mg olution occurs.
day.54 orally five times
::
2378
Box 193-4 Recommended Regimens for the Treatment of Ocular and Other
31
Cutaneous Herpes Simplex Infections
Acceptable Regimen Alternativesa
Chapter 193
days)
3% vidarabine ointment
q3h during day (five times
daily); after reepithelializa-
tion, treat for an additional
::
7 days at a reduced dose
Herpes Simplex
(such as twice daily)
Acyclovir 3% ophthalmic
ointment five times daily for
710 days
Ganciclovir ophthalmic gel
0.15% 1 drop into affected
eye five times daily until
healed; then 1 drop three
times daily for 7 days
Acyclovir, 400 mg orally five
times a day.
Valacyclovir, 1,000 mg orally
two times a day.79
Suppres- Acyclovir, 400 mg orally For children Undertake in consulta-
sion of twice a day.81,82 12 years of tion with an ophthal-
recurrences Valacyclovir 500 mg daily81 age: acyclovir, mologist.
400 mg orally
twice a day.53
Other Treatment Acyclovir, 200 mg orally five Acyclovir, 710 days or No studies have been
cutaneous times per day. 480 mg/kg/ until resolu- done. Regimens are
herpes Acyclovir, 400 mg orally day orally tion of symp- extrapolated from the
(herpes three times a day. divided into toms. treatment of genital
gladi- Valacyclovir, 1,000 mg orally three to four herpes. Consider sup-
atorum, twice a day. doses pressive antiviral ther-
herpetic Famciclovir, 250 mg orally (maximum apy for patients with
whitlow, three times a day. 1 g/day)53 frequent recurrences.
etc.)
a
The doses are for patients with normal renal function.
b
Oral dosage of acyclovir in children should not exceed 80 mg/kg/day. Children 40 kg and above should receive the adult dose.
c
Human immunodeficiency virus patients.
d
The high once-a-day and twice-daily doses of valacyclovir are more effective in patients who present with more than 10 recurrences per year.
Note: Neither valacyclovir nor famciclovir is approved by the U.S. Food and Drug Administration for use in children.
2379
31 Box 193-5 Recommended Regimens for the Treatment of Neonatal Herpes,
Disseminated Infection, Encephalitis and Eczema Herpeticum
Acceptable Regimen Alternativesa
infection
Encepha- IV acyclovir, 1015 mg/ IV acyclovir, 1520 mg/ 1421 days.
litis kg three times a day. kg three times daily.53
Eczema Acyclovir, 200 mg orally Acyclovir, 4080 mg/ 1421 days. No studies have
::
herpeticum five times a day. kg/ day orally divided been done. Use IV
Viral and Rickettsial Diseases
only modest benefits so far. The infections are inher- the median time of healing from 6 to 4 days43 but is
ently briefer and less symptomatic than genital her- not useful for the more usual sporadic cases of her-
pes. Treatment is only effective if used very early in pes labialis. A 1-day regimen of valacyclovir (2 g twice
the disease, especially in the prodromal or erythema daily for 1 day) decreased the mean duration of cold
lesion stages. Patients who wish treatment should sore episodes by 1 day when compared with placebo,
have the medication available and be vigilant for the if started in the prodrome period. Similarly, a single
earliest signs and symptoms of recurrence. When dose of famciclovir reduced time of healing of herpes
treatment is felt to be required, the therapy of choice is labialis lesions by approximately 2 days compared
penciclovir 1% cream every 2 hours while awake, for with placebo.46 Creams and ointments containing 5%
4 days.41 Treatment should be initiated as early as pos- and 10% acyclovir are not beneficial in recurrent her-
sible. When initiated within 1 hour of first symptoms pes labialis.
of recurrence, penciclovir sped the healing of lesions The use of suppressive acyclovir for herpes labia-
(4.8 days vs. 5.5 days) and decreased the duration of lis is controversial. In one small study, oral acyclovir,
pain (3.5 days vs. 4.1 days). This regimen is approved 400 mg twice a day, was effective in decreasing recur-
by the FDA. Docosanol 10% cream is approved by the rences of herpes labialis.48 In another study, suppres-
FDA for over-the-counter treatment of herpes simplex sive therapy with valacyclovir was more effective than
labialis. It is to be applied five times a day at the first episodic therapy with valacyclovir for herpes labialis.50
sign of recurrence of herpes simplex labialis. There In studies with skiers (who have significant sun expo-
has been no direct comparison with topical penci- sures), acyclovir 400 mg twice a day, was shown to
clovir. Oral acyclovir, 400 mg five times a day for 5 reduce recurrences in one study,47 whereas acyclovir,
days, affords marginal benefit if begun in the earliest 800 mg bid, failed to prevent recurrences in another
hour or two of the outbreak. Famciclovir, 500 mg three study.92 Both perioperative famciclovir (125 or 250 mg
times a day for 5 days, when started within 48 hours orally twice daily given 12 days before to 5 days after
2380 after experimental ultraviolet radiation, decreased 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
some patients with recurrent herpes labialis.98 Resiqui-
mod reduced the rate of new lesions in one study of
31
of orofacial HSV in patients undergoing facial laser persons without drug-resistant virus,99 but had no
resurfacing.93,94 Valacyclovir has also been shown to effect on genital herpes in another study.100 Long-term
suppress recurrences of herpes gladiatorum.95 suppressive acyclovir therapy reduced the rate of
Herpetic eye disease should always be treated in drug-resistant HSV disease in hematopoietic stem cell
consultation with an ophthalmologist. Options usu- transplant recipients.101
ally involve topical antivirals, including vidarabine,
trifluridine, acyclovir, or ganciclovir. Topical antivirals
are effective in shortening the duration of dendritic PREVENTION
and geographic keratitis, and are used to prevent cor-
neal epithelial disease in patients with blepharitis and
Strategies to prevent HSV infection have proved
conjunctivitis, as well as patients on topical steroid
inadequate. HSV infection can be prevented by total
therapy for corneal stromal inflammation and iridocy-
abstinence, as indicated by very low seroprevalence
clitis.80 Oral acyclovir is also effective for dendritic and
Chapter 193
rates in cloistered nuns. Condoms reduce rates of
geographical epithelial keratitis. Suppressive antiviral
transmission if used routinely.102,103 Male circumci-
therapy reduces the rates of all types of recurrent ocular
sion reduced the rate of HSV-2 infection from 10%
HSV disease, and it is most important for patients with
in the control group to 7.8% in the circumcised
a history of HSV stromal keratitis because it can pre-
group.103 Other than these public health approaches,
vent additional episodes and potential loss of vision.81,82
most efforts involve antiviral therapy and vaccines
::
directed at genital herpes.
Herpes Simplex
ANTIVIRAL RESISTANCE
ANTIVIRAL THERAPY
Virtually all clinically relevant drug resistance has been
seen in immunocompromised patients. The primary Acyclovir, famciclovir, and valacyclovir decrease
mechanism of acyclovir resistance is selection of viral both symptomatic and subclinical shedding of HSV-
mutants defective or deficient in TK expression. Most 2, from about 8% of the days in the placebo group to
mutants that are TK deficient are somewhat attenuated 0.3%0.6% of the days in the treatment group, when
for virulence in vivo. assessed by culture.67,74,88,104,105 Once daily valacyclovir
The treatment of resistant HSV infection is compli- reduced shedding by PCR from 14% to 3% in patients
cated. First, one must make the diagnosis. Very few with newly diagnosed genital herpes.106 Valacyclovir
people who claim to be resistant to one of the anti- 500 mg once daily was shown to be effective in reduc-
viral drugs actually harbor resistant virus. There is a ing the transmission of HSV-2 between partners by
common misconception that treatment prevents all 48%, and reduced clinical disease in the susceptible
recurrences. One should suspect resistance only in partner by 75% in a randomized, placebo-controlled
people who continue to have culture-proven outbreaks trial involving immunocompetent, heterosexual
of unaltered frequency and severity, especially if the couples in stable relationships.11 This therapy can be
lesions do not heal by themselves. When resistance is recommended for individuals concerned about trans-
suspected, virus should be recovered and tested specif- mission to a partner, in conjunction with the use of
ically for sensitivity to acyclovir. These tests are expen- condoms. Regarding other groups (e.g., homosexual
sive but are available through commercial reference couples, nonmonogamous individuals, immunocom-
laboratories. Second, the options for patients with true promised, and persons with asymptomatic HSV-2
resistance are few and far from ideal due to the lack of infection), it is uncertain if the use of antiviral therapy
alternatives that are safe and easy to administer. Fos- (and which regimen) would be adequate to decrease
carnet inhibits replication of all known herpesviruses transmission.
in vitro and does not require activation by TK or other Vaginal microbicides are also being studied, mostly
kinases, and therefore can be effective in the treat- focusing on decreasing HIV transmission, but some of
ment of acyclovir-resistant HSV. Foscarnet requires the compounds also have anti-HSV activity and may
intravenous therapy and can cause numerous adverse also affect HSV transmission.107
reactions including nephrotoxicity, electrolyte distur-
bances, anemia, and seizures. Also, foscarnet-resistant
HSV strains have been described. VACCINES
Cidofovir does not require the viral TK for its intra-
cellular phosphorylation to the active form. Cidofovir The best public health strategy to reduce infection and
has been tested in cases of acyclovir-resistant HSV and morbidity associated with HSV infection is develop-
topical cidofovir has been used with success to treat ment of effective vaccines. Unfortunately, no vaccine
progressive herpetic lesions.96 Intravenous cidofovir has proved to protect adequately against acquisition of
is associated with considerable nephrotoxicity and HSV (prophylactic) or to reduce the number of recur-
requires the coadministration of saline hydration and rent episodes (therapeutic), although there are hopeful
probenecid. A few patients with acyclovir-resistant developments in these directions.
genital herpes have responded to imiquimod 5% Recombinant glycoprotein vaccines containing
cream.97 Imiquimod caused severe inflammation in immunogenic HSV proteins have been developed and 2381
31 tested by multiple pharmaceutical and biotechnologi-
cal companies. In a preliminary study, a recombinant
mal models, but resulted in very limited induction of
HSV-specific cellular immune responses in a phase I
HSV-2 glycoprotein D vaccine with alum adjuvant human study.112
decreased the frequency of symptomatic outbreaks in
patients with genital herpes. A modified form of the
vaccine (with added glycoprotein B and a lipid emul- ACKNOWLEDGMENT
sion adjuvant known as MF59) did not decrease the
number of recurrences in patients with genital her- This chapter is dedicated to the memory of Stephen
pes, but did decrease the duration and severity of a E. Straus, a coauthor of this chapter in the seventh
subsequent study outbreak of genital herpes.108 Two edition.
phase III studies of the effect of this vaccine (one in
monogamous seronegative partners of individuals
with genital herpes, and the other in seronegative KEY REFERENCES
persons attending clinics for sexually transmitted dis-
eases) failed to prevent acquisition of genital herpes Full reference list available at www.DIGM8.com
Section 31
infection or disease.109 A recombinant gD2 vaccine that DVD contains references and additional content
uses monophosphoryl lipid-A as adjuvant was pro-
tective against HSV-2 genital disease (but had limited 6. Xu F et al: Trends in herpes simplex virus type 1 and type
protection against infection) in HSV-1 and HSV-2 sero- 2 seroprevalence in the United States. JAMA 296(8):964-
973, 2006
negative women but not in males or HSV-1 seroposi-
::
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