1471CHAPTER 192 Herpes Simplex Virus Infections

After viral genome replication and structural protein synthesis,

nucleocapsids are assembled in the cell’s nucleus. Envelopment occurs

as the nucleocapsids bud through the inner nuclear membrane into the

perinuclear space. In some cells, viral replication in the nucleus forms

two types of inclusion bodies: type A basophilic Feulgen-positive bodies that contain viral DNA and eosinophilic inclusion bodies that are

devoid of viral nucleic acid or protein and represent a “scar” of viral

infection. Enveloped virions are then transported via the endoplasmic

reticulum and the Golgi apparatus to the cell surface.

Viral genomes are maintained by some neuronal cells in a repressed

state called latency. Latency, which is associated with transcription of

only a limited number of virus-encoded RNAs, accounts for the presence of viral DNA and RNA in neural tissue at times when infectious

virus cannot be isolated. Maintenance and growth of neural cells from

latently infected ganglia in tissue culture result in production of infectious virions (explantation) and in subsequent permissive infection of

susceptible cells (co-cultivation). Activation of the viral genome may

then occur, resulting in reactivation—the normal pattern of regulated

viral gene expression and replication and HSV release. The release

of virions from the neuron follows a complex process of anterograde

transport down the length of neuronal axons. In experimental animals,

ultraviolet light, systemic and local immunosuppression, and trauma to

the skin or ganglia are associated with reactivation.

A noncoding region of the viral genome initially felt to be three

noncoding regions and now felt to be a more diverse set of noncoding RNAs and micro-RNAs (miRNAs) collectively referred to as the

latency-associated transcripts (LATs) is found in the nuclei of latently

infected neurons, and deletion mutants of the LAT region exhibit

reduced efficiency in their later reactivation. HSV DNA copy number

is highly variable between neurons, with no direct correlation between

HSV DNA copy numbers and LAT positivity. Substitution of HSV-1

LATs for HSV-2 LATs induces an HSV-1 reactivation pattern, suggesting this region of the genome apparently maintains—rather than

establishes—latency. Viral miRNA appears to silence expression of the

key neurovirulence factor infected-cell protein 34.5 (ICP34.5) and to

bind in an antisense configuration to the immediate-early protein ICP0

messenger RNA to prevent expression, which is vital to HSV reactivation. While certain viral transcripts are known to be necessary for

reactivation from latency, the molecular mechanisms of HSV latency

are not fully understood, and strategies to interrupt or maintain latency

in neurons are in developmental stages.

While latency is the predominant state of virus on a per-neuron

basis, the high frequency of oral and genital tract reactivation for

HSV-1 and HSV-2 suggests that the viruses are rarely quiescent within

the entire biomass of ganglionic tissue. The virus appears to be in a

dynamic state—“mostly suppressed”—but with continual individual

cells showing various degrees of viral transcriptional activity, and only

a few of these infected neurons giving rise to actual reactivation. There

is increasing recognition that HSV infection of the autonomic ganglia

plays an important role in both initial and reactivation infections.

In fact, deaths of animals from HSV-2 infection appear to be related

to autonomic dysfunction of the bowel. Both HSV-1 and HSV-2 are

shed subclinically. Most persons infected with HSV-2 and HSV-1 have

frequent subclinical bursts of reactivation lasting 2–6 h, and the host

tissue-based immune system can contain viral reactivation in the tissue

before the development of clinical reactivation.

■ PATHOGENESIS

Exposure to HSV at mucosal surfaces or abraded skin sites permits

entry of the virus into cells of the epidermis and dermis and initiation of viral replication therein. HSV infections are usually acquired

subclinically. Whether clinical or subclinical, HSV acquisition is associated with sufficient viral replication to permit infection of sensory

and/or autonomic nerve endings. On entry into the neuronal cell, the

virus—or, more likely, the nucleocapsid—is transported intra-axonally

to the nerve cell bodies in ganglia. Viral particles tether onto cellular

proteins that motor along microtubules from axon tips (neurite endings) to neuronal cell bodies. In humans, the transit interval of spread

to the ganglia after virus inoculation into peripheral tissue is unknown.

During the initial phase of infection, viral replication occurs in ganglia

and contiguous neural tissue. Virus then spreads to other mucocutaneous surfaces through centrifugal migration of infectious virions via

peripheral nerves. This mode of spread helps explain the large surface

area involved, the high frequency of new lesions distant from the initial

crop of vesicles that is characteristic in patients with primary genital or

oral–labial HSV infection, and the ability to recover virus from neural

tissue distant from neurons innervating the inoculation site. Contiguous spread of locally inoculated virus also may take place and allow

further mucosal extension of disease. Recent studies have demonstrated HSV viremia—another mechanism for extension of infection

throughout the body—in ~30–40% of persons with primary HSV-2

infection; latent infection with both viral subtypes in both sensory

and autonomic ganglia has been demonstrated. For HSV-1 infection,

trigeminal ganglia are most commonly infected, although extension

to the inferior and superior cervical ganglia also occurs. With genital infection, sacral nerve root ganglia (S2–S5) are most commonly

affected. Autonomic ganglia, pelvic nerves, and vaginal nerve roots are

commonly infected.

After resolution of primary disease, infectious HSV can no longer be

cultured from the ganglia; however, neuronal infection, as defined by

the presence of viral DNA, persists in ganglionic cells in the anatomic

regions of the initial infection. The mechanism of reactivation from

latency is unknown, although increasingly evidence of limited viral

genes or miRNAs is identified in latently infected neurons. Evidence

exists for viral antigen and activated host T cells at the ganglia and

periphery, and immune responses in ganglia as well as peripheral

tissue appear to influence the frequency and severity of HSV reactivation. HSV-specific T cells have been recovered from peripheral

nerve root ganglia. Many of these resident CD8+ T cells are juxtaposed

with latently HSV-1-infected neurons in the trigeminal ganglia and

can block reactivation with both interferon (IFN) γ release and granzyme B–mediated degradation of the immediate-early protein ICP4.

In addition, there appears to be a latent viral load in the ganglia that

correlates positively with the number of neurons infected and the rate

of reactivation but inversely with the number of T cells present. It is not

known whether reactivating stimuli transiently suppress these immune

cells, independently upregulate transcription of lytic genes, or both.

Moreover, host containment in the mucosa has been demonstrated.

Once virus reaches the dermal–epidermal junction, there are three

possible outcomes: (1) rapid host containment of infection near the site

of reactivation; (2) spread of small amounts of virus into the epidermis,

with a micro-ulceration associated with low-titer subclinical shedding;

and (3) widespread replication and necrosis of epithelial cells and subsequent clinical recurrence (the latter defined clinically by a skin blister

and ulceration). Histologically, herpetic lesions involve a thin-walled

vesicle or ulceration in the basal region, multinucleated cells that may

include intranuclear inclusions, necrosis, and an acute inflammatory

response. Re-epithelialization occurs once viral replication is restricted,

almost always in the absence of a scar.

Analysis of the DNA from sequential isolates of HSV or from isolates from multiple infected ganglia in any one individual has revealed

similar, if not identical, restriction endonuclease or DNA sequence

patterns in most persons. As more sensitive genomic technologies are

developed, evidence of multiple strains of the same subtype is increasingly being reported. For example, infection of individual neurons with

multiple strains of drug-susceptible and drug-resistant virus in severely

immunosuppressed patients indicates that ganglia can be reseeded

during chronic infection. Because exposure to mucosal shedding is

relatively common during a person’s lifetime, current data suggest that

exogenous infection with different strains of the same subtype does

occur. The role strain variation plays in the varied reactivation pattern

of disease is unknown.

■ IMMUNITY

Host responses influence the acquisition of HSV disease, the severity of

infection, resistance to the development of latency, the maintenance of

latency, and the frequency of recurrences. Both antibody-mediated and

cell-mediated reactions are clinically important. Immunocompromised

1472 PART 5 Infectious Diseases

patients with defects in cell-mediated immunity experience more

severe and more extensive HSV infections than those with deficits

in humoral immunity, such as agammaglobulinemia. Experimental

ablation of lymphocytes indicates that T cells play a major role in

preventing lethal disseminated disease, although antibodies help

reduce titers of virus in neural tissue. Some clinical manifestations of

HSV appear to be related to the host immune response (e.g., stromal

opacities associated with recurrent herpetic keratitis). The surface viral

glycoproteins have been shown to be targets of antibodies that mediate

neutralization and immune-mediated cytolysis (antibody-dependent

cell-mediated cytotoxicity [ADCC]). Monoclonal antibodies to HSV

viral glycoproteins have, in experimental infections, conferred protection against subsequent neurologic disease or ganglionic latency,

and controlled studies in humans of monoclonal antibodies on disease

reactivation are not available. Multiple cell populations, including

neutrophils, macrophages, and a variety of T lymphocytes, play a role

in host defenses against HSV infections, as do lymphokines generated

by T lymphocytes. In animals, passive transfer of primed lymphocytes

confers protection from subsequent HSV challenge. Maximal protection usually requires the activation of multiple T-cell subpopulations,

including cytotoxic T cells and T cells responsible for delayed hypersensitivity. The latter may confer protection by the antigen-stimulated

release of lymphokines (e.g., IFNs), which in turn have a direct antiviral

effect and both activate and enhance a variety of specific and nonspecific effector cells. The HSV virion contains a variety of genes that are

directed at the inhibition of host responses. These include gene ICP47,

which can bind to the cellular transporter-activating protein TAP-1

and reduce the ability of this protein to bind HSV peptides to human

leukocyte antigen class I, thereby reducing recognition of viral proteins

by cytotoxic T cells of the host. This effect can be overcome by the

addition of IFN-γ, but this reversal requires 24–48 h; thus, the virus

has time to replicate and invade other host cells. Entry of infectious

HSV-1 and HSV-2 inhibits several signaling pathways of both CD4+

and CD8+ T cells, leading to their functional impairment in killing and

influencing the spectrum of their cytokine secretion. Therapeutic vaccination with a replication-defective HSV lacking gD, the major neutralizing protein, produced enhanced ADCC activity and subsequent

reduction in reactivation in the guinea pig model of HSV-2, suggesting

that immune responses to cell-associated virus may play an important

role in disease resolution.

HSV-specific CD8+ T-cell responses appear to be an important

component in viral clearance from lesions. Immunosuppressed patients

with frequent and prolonged HSV lesions have fewer functional CD8+

T cells directed at HSV. HSV-specific CD8+ T cells have been shown to

persist in the genital skin at the dermal–epidermal junction contiguous

to nerve endings for months after lesion resolution. Even during clinical quiescence, these CD8+ T cells make both antiviral and cytotoxic

proteins indicative of immune surveillance. These resident memory

CD8+ T cells appear to be “first responders” capable of controlling

viral reactivation at the site of viral release into the dermis. This rapid

“on and off ” interplay between the virus and the host helps explain the

variability in clinical disease severity between episodes in any single

individual. Differences of 30–60 min in host responses can result in

100- to 1000-fold differences in viral levels and can determine whether

an episode of disease is subclinical or clinical.

There is a strong association between the magnitude of the CD8+

T-lymphocyte response and the clearance of virus from genital lesions.

The location, effectiveness, and longevity of the CD8+ T lymphocytes

(and other influencers of immune effector functions such as natural

killer or CD4+ T-cell responses) may be important in the expression of

disease and the likelihood of transmission over time.

■ EPIDEMIOLOGY

Seroepidemiologic studies have documented HSV infections worldwide. The past 15 years have shown that the prevalence of HSV-2 is

even higher in the developing than in the developed world. In subSaharan Africa, HSV-2 seroprevalence among pregnant women may

approach 60%, and annual acquisition rates among teenage girls may

verge on 20%. The global incidence has been estimated at ~23.6 million

infections per year, with >490 million infected persons worldwide. As

in the developed world, the rate of HSV-2 coital acquisition as well as

the serologic prevalence are higher among women than among men.

Most of this HSV-2 acquisition is preceded by acquisition of HSV-1;

the frequency of genital HSV-1 in middle- and low-income countries

is low at present.

Infection with HSV-1 is acquired more frequently and earlier in life

than infection with HSV-2. From 70 to 90% of adults have antibodies to

HSV-1 by the fifth decade of life. In populations of low socioeconomic

status, most persons acquire HSV-1 infection before the third decade

of life. Antibodies to HSV-2 are not detected routinely until puberty.

Antibody prevalence rates correlate with past sexual activity and vary

greatly among different population groups. There is evidence that the

prevalence of HSV-2 has decreased slightly over the past decade or so

in the United States. Serosurveys indicate that 15–20% of the U.S. population has antibodies to HSV-2. In most routine obstetric and family

planning clinics, 15 to 30% of women have HSV-2 antibodies, although

only 10% of those who are seropositive for HSV-2 report a history

of genital lesions. As many as 50% of heterosexual adults attending sexually transmitted disease clinics have antibodies to HSV-2.

A wide variety of serologic surveys has catalogued the widespread

epidemic of HSV-2 in Central America, South America, and Africa. In

Africa, HSV-2 seroprevalence has ranged from 40 to 70% in obstetric

and other sexually experienced populations. Antibody prevalence rates

average ~5–10% higher among women than among men.

Many studies continue to show that both incident and—more

importantly—prevalent HSV-2 infection enhances the acquisition rate

of HIV-1. More specifically, HSV-2 infection is associated on a population basis with a two- to fourfold increase in HIV-1 acquisition. This

association has been amply demonstrated in heterosexual men and

women in both the developed and developing worlds. Epidemiologically, regions of the world with high HSV-2 prevalence and selected

populations within such regions have a higher population-based incidence of HIV-1.

An important observation is that HSV-2 facilitates the spread of

HIV into low-risk populations; prevalent HSV-2 appears to increase

the risk of HIV infection by seven- to ninefold on a per-coital basis.

Mathematical models suggest that ~33–50% of HIV-1 infections may

be attributable to HSV-2 both in men who have sex with men (MSM)

and in heterosexual women in sub-Saharan Africa. In addition, HSV-2

is more frequently reactivated in and transmitted by persons coinfected with HIV-1 than in persons not co-infected. Thus, most areas

of the world with a high HIV-1 prevalence also have a high HSV-2

prevalence. The shedding of HIV-1 virions from herpetic lesions in

the genital region facilitates the spread of HIV through sexual contact.

HSV-2 reactivation is associated with a localized persistent inflammatory response consisting of high concentrations of CCR5-enriched

CD4+ T cells as well as inflammatory dendritic cells in the submucosa

of the genital skin. These cells can support HIV infection and replication and thus are likely to account for the increased risk of HIV

acquisition among persons with genital herpes. Unfortunately, antiviral

therapy does not reduce this subclinical postreactivation inflammation,

probably because of the inability of current antiviral agents to prevent

the release of small amounts of HSV antigen into the genital mucosa.

Several studies suggest that many cases of “asymptomatic” genital

HSV-2 infection are, in fact, simply unrecognized or confined to anatomic regions of the genital tract that are not easily visualized. Asymptomatic seropositive persons shed virus on mucosal surfaces almost as

frequently as do those with symptomatic disease. This large reservoir

of unidentified carriers of HSV-2 and the frequent asymptomatic reactivation of the virus from the genital tract have fostered the continued

spread of genital herpes throughout the world.

HSV infections occur throughout the year. Transmission can result

from contact with persons who have active ulcerative lesions or with

persons who have no clinical manifestations of infection but who are

shedding HSV from mucocutaneous surfaces. HSV reactivation on

genital skin and mucosal surfaces is common. In fact, recent studies

indicate that most HSV-1 and HSV-2 episodes last 2–6 h; thus, replication of the virus and clearance by the host are rapid. Even with

1473CHAPTER 192 Herpes Simplex Virus Infections

once-daily sampling, HSV DNA can be detected on 20–30% of days by

polymerase chain reaction (PCR). Corresponding figures for HSV-1 in

oral secretions are similar. Rates of shedding are highest during the initial years after acquisition, with viral shedding occurring on as many as

30–50% of days during this period. Immunosuppressed patients shed

HSV from mucosal sites at an even higher frequency (20–80% of days).

These high rates of mucocutaneous reactivation suggest that exposure

to HSV from sexual or other close contact (kissing, sharing of glasses

or silverware) is common and help explain the continuing spread and

high seroprevalence of HSV infections worldwide. Reactivation rates

vary widely among individuals. Among HIV-positive patients, a low

CD4+ T-cell count and a high HIV-1 load are associated with increased

rates of HSV reactivation. Daily antiviral chemotherapy for HSV-2

infection can reduce shedding rates but does not eliminate shedding,

as measured by PCR or culture.

■ CLINICAL SPECTRUM

HSV has been isolated from nearly all visceral and mucocutaneous

sites. The clinical manifestations and course of HSV infection depend

on the anatomic site involved, the age and immune status of the host,

and the antigenic type of the virus. Primary HSV infections (i.e., first

infections with either HSV-1 or HSV-2 in which the host lacks HSV

antibodies in acute-phase serum) are frequently accompanied by

systemic signs and symptoms. Compared with recurrent episodes, primary infections, which involve both mucosal and extramucosal sites,

are characterized by a longer duration of symptoms and virus isolation

from lesions. The incubation period ranges from 1 to 26 days (median,

6–8 days). Both viral subtypes can cause genital and oral–facial infections, and the infections caused by the two subtypes are clinically

indistinguishable. However, the frequency of reactivation of infection

is influenced by anatomic site and virus type. Genital HSV-2 infection

is twice as likely to reactivate and recurs 8–10 times more frequently

than genital HSV-1 infection. Conversely, oral–labial HSV-1 infection

recurs more frequently than oral–labial HSV-2 infection. Asymptomatic shedding rates follow the same pattern.

Oral–Facial Infections Gingivostomatitis and pharyngitis are the

most common clinical manifestations of first-episode HSV-1 infection, whereas recurrent herpes labialis is the most common clinical

manifestation of reactivation HSV-1 infection. HSV pharyngitis and

gingivostomatitis usually result from primary infection and are most

common among children and young adults. Clinical symptoms and

signs, which include fever, malaise, myalgias, inability to eat, irritability, and cervical adenopathy, may last 3–14 days. Lesions may involve

the hard and soft palate, gingiva, tongue, lip, and facial area. HSV-1 or

HSV-2 infection of the pharynx usually results in exudative or ulcerative lesions of the posterior pharynx and/or tonsillar pillars. Lesions

of the tongue, buccal mucosa, or gingiva may occur later in the course

in one-third of cases. Fever lasting 2–7 days and cervical adenopathy

are common. It can be difficult to differentiate HSV pharyngitis clinically from bacterial pharyngitis, Mycoplasma pneumoniae infections,

and pharyngeal ulcerations of noninfectious etiologies (e.g., StevensJohnson syndrome). No substantial evidence suggests that reactivation

of oral–labial HSV infection is associated with symptomatic recurrent

pharyngitis.

Reactivation of HSV from the trigeminal ganglia may be associated with asymptomatic virus excretion in the saliva, development of

intraoral mucosal ulcerations, or herpetic ulcerations on the vermilion

border of the lip or external facial skin. About 50–70% of seropositive

patients undergoing trigeminal nerve-root decompression and 10–15%

of those undergoing dental extraction develop oral–labial HSV infection a median of 3 days after these procedures. Clinical differentiation

of intraoral mucosal ulcerations due to HSV from aphthous, traumatic,

or drug-induced ulcerations is difficult.

In immunosuppressed patients, HSV infection may extend into mucosal

and deep cutaneous layers. Friability, necrosis, bleeding, severe pain,

and inability to eat or drink may result. The lesions of HSV mucositis

are clinically similar to mucosal lesions caused by cytotoxic drug

therapy, trauma, or fungal or bacterial infections. Persistent ulcerative

HSV infections are among the most common infections in patients

with AIDS. HSV and Candida infections often occur concurrently.

Systemic antiviral therapy speeds the rate of healing and relieves the

pain of mucosal HSV infections in immunosuppressed patients. The

frequency of HSV reactivation during the early phases of transplantation or induction chemotherapy is high (50–90%), and prophylactic systemic antiviral agents such as intravenous (IV) acyclovir and

penciclovir or the oral congeners of these drugs are used to reduce

reactivation rates. Patients with atopic eczema may also develop

severe oral–facial HSV infections (eczema herpeticum), which may

rapidly involve extensive areas of skin and occasionally disseminate to

visceral organs. Extensive eczema herpeticum has resolved promptly

with the administration of IV acyclovir. Erythema multiforme may

also be associated with HSV infections (see Figs. 56-9 and A1-24);

some evidence suggests that HSV infection is the precipitating event

in ~75% of cases of cutaneous erythema multiforme. HSV antigen

has been demonstrated both in circulatory immune complexes and in

skin lesion biopsy samples from these cases. Patients with severe HSVassociated erythema multiforme are candidates for chronic suppressive

oral antiviral therapy.

HSV-1 and varicella-zoster virus (VZV) have been implicated in the

etiology of Bell’s palsy (flaccid paralysis of the mandibular portion of

the facial nerve). Some but not all trials have documented quicker resolution of facial paralysis with the prompt initiation of antiviral therapy,

with or without glucocorticoids. However, other trials have shown little

benefit. There are advantages to the use of both antiviral drugs and

glucocorticoids for moderate to severe Bell’s palsy. Some experts feel

glucocorticoids alone are preferred for mild disease.

Genital Infections First-episode primary genital herpes is characterized by fever, headache, malaise, and myalgias. Pain, itching, dysuria,

vaginal and urethral discharge, and tender inguinal lymphadenopathy

are the predominant local symptoms. Widely spaced bilateral lesions

of the external genitalia are characteristic (Fig. 192-1). Lesions may be

present in varying stages, including vesicles, pustules, or painful erythematous ulcers. The cervix and urethra are involved in >80% of women

with first-episode infections. First episodes of genital herpes in patients

who have had prior HSV-1 infection are occasionally associated with

systemic symptoms: prior HSV-1 infection is associated with faster

healing than true primary genital herpes. Detection of HSV DNA in

serum has been found in ~30% of cases of true primary genital herpes.

FIGURE 192-1 Genital herpes: primary vulvar infection, with multiple, extremely

painful, punched-out, confluent, shallow ulcers on the edematous vulva and

perineum. Micturition is often very painful. Associated inguinal lymphadenopathy

is common. (Reprinted with permission from K Wolff et al: Fitzpatrick’s Color Atlas &

Synopsis of Clinical Dermatology, 5th ed. New York, McGraw-Hill, 2005.)

1474 PART 5 Infectious Diseases

The clinical courses of acute first-episode genital herpes are similar for

HSV-1 and HSV-2 infection. However, the recurrence rates of genital

disease differ with the viral subtype: the 12-month recurrence rates

among patients with first-episode HSV-2 and HSV-1 infections are

~90% and ~55%, respectively (median number of recurrences, 4 and

<1, respectively). Recurrence rates for genital HSV-2 infections vary

greatly among individuals and over time within the same individual.

HSV has been isolated from the urethra and urine of men and women

without external genital lesions. A clear mucoid discharge and dysuria

are characteristics of symptomatic HSV urethritis. HSV has been isolated from the urethra of 5% of women with the dysuria–frequency

syndrome. Occasionally, HSV genital tract disease is manifested by

endometritis and salpingitis in women and by prostatitis in men. About

15% of cases of HSV-2 acquisition are associated with nonlesional

clinical syndromes, such as aseptic meningitis, cervicitis, or urethritis.

A more complete discussion of the differential diagnosis of genital

herpes is presented in Chap. 136.

Both HSV-1 and HSV-2 can cause symptomatic or asymptomatic

rectal and perianal infections. HSV proctitis is usually associated with

rectal intercourse. However, subclinical perianal shedding of HSV is

detected in women and men who report no rectal intercourse. This

phenomenon is due to the establishment of latency in the sacral dermatome from prior genital tract infection, with subsequent reactivation

in epithelial cells in the perianal region. Such reactivations are often

subclinical. Symptoms of HSV proctitis include anorectal pain, anorectal discharge, tenesmus, and constipation. Sigmoidoscopy reveals

ulcerative lesions of the distal 10 cm of the rectal mucosa. Rectal biopsies show mucosal ulceration, necrosis, polymorphonuclear and lymphocytic infiltration of the lamina propria, and (in occasional cases)

multinucleated intranuclear inclusion-bearing cells. Perianal herpetic

lesions are also found in immunosuppressed patients receiving cytotoxic therapy. Extensive perianal herpetic lesions and/or HSV proctitis

is common among patients with HIV infection.

Herpetic Whitlow Herpetic whitlow—HSV infection of the

finger—may occur as a complication of primary oral or genital herpes by inoculation of virus through a break in the epidermal surface

or by direct introduction of virus into the hand through occupational or some other type of exposure. Clinical signs and symptoms

include abrupt-onset edema, erythema, and localized tenderness of

the infected finger. Vesicular or pustular lesions of the fingertip that

are indistinguishable from lesions of pyogenic bacterial infection are

seen. Fever, lymphadenitis, and epitrochlear and axillary lymphadenopathy are common. The infection may recur. Prompt diagnosis (to

avoid unnecessary and potentially exacerbating surgical therapy and/

or transmission) is essential. Antiviral therapy is usually recommended

(see below).

Herpes Gladiatorum HSV may infect almost any area of skin.

Mucocutaneous HSV infections of the thorax, ears, face, and hands

have been described among wrestlers. Transmission of these infections

is facilitated by trauma to the skin sustained during wrestling. Several

recent outbreaks have illustrated the importance of prompt diagnosis

and therapy to contain the spread of this infection.

Eye Infections HSV infection of the eye is the most common

cause of corneal blindness in the United States. HSV keratitis presents

as an acute onset of pain, blurred vision, chemosis, conjunctivitis, and

characteristic dendritic lesions of the cornea. Use of topical glucocorticoids may exacerbate symptoms and lead to involvement of deep

structures of the eye. Debridement, topical antiviral treatment, and/or

IFN therapy hastens healing. However, recurrences are common, and

the deeper structures of the eye may sustain immunopathologic injury.

Stromal keratitis due to HSV appears to be related to T-cell–dependent

destruction of deep corneal tissue. An HSV-1 epitope that is autoreactive with T cell–targeting corneal antigens has been postulated to be

a factor in this infection. Chorioretinitis, usually a manifestation of

disseminated HSV infection, may occur in neonates or in patients with

HIV infection. HSV and VZV can cause acute necrotizing retinitis as

an uncommon but severe manifestation. While VZV infection is the

most common cause of acute retinal necropsy, both HSV-1 and HSV-2

may also be associated with this syndrome. Emergent ophthalmology

consultation is recommended; both systemic and intravitical antiviral

therapy is recommended.

Central and Peripheral Nervous System Infections HSV

accounts for 10–20% of all cases of sporadic viral encephalitis in the

United States. The estimated incidence is ~2.3 cases per 1 million

persons per year. Cases are distributed throughout the year, and the age

distribution appears to be biphasic, with peaks at 5–30 and >50 years of

age. HSV-1 causes >95% of cases.

The pathogenesis of HSV encephalitis varies. In children and

young adults, primary HSV infection may result in encephalitis;

presumably, exogenously acquired virus enters the CNS by neurotropic spread from the periphery via the olfactory bulb. However, most

adults with HSV encephalitis have clinical or serologic evidence of

mucocutaneous HSV-1 infection before the onset of CNS symptoms. In

~25% of the cases examined, the HSV-1 strains from the oropharynx

and brain tissue of the same patient differ; thus, some cases may result

from reinfection with another strain of HSV-1 that reaches the CNS.

Two theories have been proposed to explain the development of

actively replicating HSV in localized areas of the CNS in persons whose

ganglionic and CNS isolates are similar. Reactivation of latent HSV-1

infection in trigeminal or autonomic nerve roots may be associated

with extension of virus into the CNS via nerves innervating the middle

cranial fossa. HSV DNA has been demonstrated by DNA hybridization

in brain tissue obtained at autopsy—even from healthy adults. Thus,

reactivation of long-standing latent CNS infection may be another

mechanism for the development of HSV encephalitis. Recent studies

have identified genetic polymorphisms among families with a high

frequency of HSV encephalitis. Peripheral-blood mononuclear cells,

fibroblasts, and neurons from these patients (predominantly children)

appear to secrete reduced levels of IFN in response to HSV. Genetic

mutations in TLR3 documented in patients with HSV encephalitis

suggest that some cases of sporadic HSV encephalitis may be related to

host genetic determinants.

The clinical hallmark of HSV encephalitis has been the acute onset

of fever and focal neurologic symptoms and signs, especially in the

temporal lobe (Fig. 192-2). Clinical differentiation of HSV encephalitis from other viral encephalitides, focal infections, or noninfectious

processes is difficult. Elevated cerebrospinal fluid (CSF) protein levels,

leukocytosis (predominantly lymphocytes), and red blood cell counts

due to hemorrhagic necrosis are common. While brain biopsy has been

the gold standard for defining HSV encephalitis, a highly sensitive and

specific PCR for detection of HSV DNA in CSF has largely replaced

biopsy for defining CNS infection. Although titers of antibody to HSV

in CSF and serum increase in most cases of HSV encephalitis, they

rarely do so earlier than 10 days into the illness and, therefore, although

useful in retrospect, generally are not helpful in establishing an early

clinical diagnosis. In rare cases, demonstration of HSV antigen, HSV

DNA, or HSV replication in brain tissue obtained by biopsy is highly

sensitive; examination of such tissue also provides the opportunity to

identify alternative, potentially treatable causes of encephalitis. Antiviral therapy with acyclovir reduces the rate of death from HSV encephalitis. Most authorities recommend the administration of IV acyclovir

to patients with presumed HSV encephalitis until the diagnosis is confirmed or an alternative diagnosis is made. All confirmed cases should

be treated with IV acyclovir (30 mg/kg per day in three divided doses

for 14–21 days). After the completion of therapy, the clinical recurrence of encephalitis requiring more treatment has been reported.

For this reason, some authorities prefer to treat initially for 21 days,

and many continue therapy until HSV DNA has been eliminated from

the CSF. Even with therapy, neurologic sequelae are common, especially among persons >50 years of age.

HSV DNA has been detected in CSF from 3 to 15% of persons presenting to the hospital with aseptic meningitis. HSV meningitis, which

is usually seen in association with primary genital HSV infection, is

an acute, self-limited disease manifested by headache, fever, and mild

photophobia and lasting 2–7 days. Lymphocytic pleocytosis in the

1475CHAPTER 192 Herpes Simplex Virus Infections

FIGURE 192-2 Computed tomography and diffusion-weighted magnetic resonance imaging scans of the brain of a

patient with left-temporal-lobe herpes simplex virus encephalitis.

CSF is characteristic. Neurologic sequelae of HSV meningitis are rare.

HSV is the most commonly identified cause of recurrent lymphocytic

meningitis (Mollaret’s meningitis). Demonstration of HSV antibodies

in CSF or persistence of HSV DNA in CSF can establish the diagnosis. For persons with frequent recurrences of HSV meningitis, daily

antiviral therapy has reduced the frequency of recurrent episodes of

symptomatic meningitis.

Autonomic nervous system dysfunction, especially of the sacral

region, has been reported in association with both HSV and VZV

infections. Numbness, tingling of the buttocks or perineal areas, urinary

retention, constipation, CSF pleocytosis, and (in males) impotence may

occur. Symptoms appear to resolve slowly over days or weeks. Occasionally, hypoesthesia and/or weakness of the lower extremities persists for

many months. Transitory hypoesthesia of the area of skin innervated by

the trigeminal nerve and vestibular system dysfunction (as measured by

electronystagmography) are the predominant signs of disease. Rarely,

transverse myelitis, manifested by a rapidly progressive symmetric paralysis of the lower extremities or Guillain-Barré syndrome, follows HSV

infection. Similarly, PNS involvement (Bell’s palsy) or cranial polyneuritis may be related to reactivation of HSV-1 infection.

There is increasing experimental evidence suggesting an association

between herpesvirus pathogens, specifically HSV-1, and the development of sporadic Alzheimer’s disease (AD). HSV-1 DNA is detected in

brain tissue of patients with AD, and epidemiologically, HSV-1 antibodies are a significant risk factor for later AD onset. A wide variety

of models of AD indicate that HSV-1 infection can induce neuronal

death, tau phosphorylation, and intracellular expression of isoforms of

amyloid precursor protein cleavage products that produce multicellular-like plaque structures associated with AD. There are no cogent data

to indicate antiviral therapy would be of benefit to anyone with AD.

Visceral Infections HSV infection of visceral organs usually

results from viremia, and multiple-organ involvement is common.

Occasionally, however, the clinical manifestations of HSV infection

involve only the esophagus, lung, or liver. HSV esophagitis may

result from direct extension of oral–pharyngeal HSV infection into

the esophagus or may occur de novo by reactivation and spread of

HSV to the esophageal mucosa via the vagus nerve. The predominant

symptoms of HSV esophagitis are odynophagia, dysphagia, substernal

pain, and weight loss. Multiple oval ulcerations appear on an erythematous base with or without a patchy white pseudomembrane. The

distal esophagus is most commonly involved. With extensive disease,

diffuse friability may spread to the entire

esophagus. Neither endoscopic nor barium

examination can reliably differentiate HSV

esophagitis from Candida esophagitis or

from esophageal ulcerations due to thermal injury, radiation, or corrosives. Endoscopically obtained secretions—for cytologic

examination and culture or DNA detection by

PCR—provide the most useful material for

diagnosis. Systemic antiviral therapy usually

reduces the severity and duration of symptoms and heals esophageal ulcerations.

HSV pneumonitis is uncommon except

in severely immunosuppressed patients and

may result from extension of herpetic tracheobronchitis into lung parenchyma. Focal

necrotizing pneumonitis usually ensues.

Hematogenous dissemination of virus from

sites of oral or genital mucocutaneous disease may also occur, producing bilateral

interstitial pneumonitis. Bacterial, fungal,

and parasitic pathogens are commonly present in HSV pneumonitis. The mortality rate

from untreated HSV pneumonia in immunosuppressed patients is high (>80%). HSV

has also been isolated from the lower respiratory tract of persons with acute respiratory

distress syndrome and prolonged intubation. Most authorities believe

that the presence of HSV in tracheal aspirates in such settings is due

to reactivation of HSV in the tracheal region and localized tracheitis in

persons with long-term intubation. Such patients should be evaluated

for extension of HSV infection into the lung parenchyma. While retrospective reviews of HSV tracheitis in intensive care unit patients suggest

benefit from antiviral therapy, well-powered controlled trials assessing

the role of antiviral agents used against HSV in ventilation-associated

morbidity and mortality have not been conducted. The role of lower

respiratory tract HSV infection in overall rates of morbidity and mortality associated with these conditions is unclear. HSV is an uncommon

cause of hepatitis in immunocompetent patients. HSV infection of the

liver is associated with fever, abrupt elevations of bilirubin and serum

aminotransferase levels, and leukopenia (<4000 white blood cells/μL).

Disseminated intravascular coagulation may also develop.

Other reported complications of HSV infection include monarticular arthritis, adrenal necrosis, idiopathic thrombocytopenia, and

glomerulonephritis. Disseminated HSV infection in immunocompetent patients is rare. In immunocompromised patients, burn patients,

or malnourished individuals, HSV occasionally disseminates to other

visceral organs, such as the adrenal glands, pancreas, small and large

intestines, and bone marrow. Dissemination, even recurrent dissemination, is being increasingly recognized in persons with chronic

lymphocytic leukemia. Rarely, primary HSV infection in pregnancy

disseminates and may be associated with the death of both mother

and fetus. This uncommon event is usually related to the acquisition of

primary infection in the third trimester. Disseminated HSV infection is

best detected by the presence of HSV DNA in plasma or blood.

Neonatal HSV Infections Of all HSV-infected populations, neonates (infants <6 weeks) have the highest frequency of visceral and/

or CNS infection. Without therapy, the overall rate of death from

neonatal herpes is 65%; <10% of neonates with CNS infection develop

normally. Although skin lesions are the most commonly recognized

features of disease, many infants do not develop lesions at all or do

so only well into the course of disease. Neonatal infection is usually

acquired perinatally from contact with infected genital secretions at

delivery. Congenitally infected infants have been reported. Of neonatal

HSV infections, 30–50% are due to HSV-1 and 50–70% to HSV-2.

The risk of developing neonatal HSV infection is 10 times higher

for an infant born to a mother who has recently acquired HSV than

for other infants. Neonatal HSV-1 infections may also be acquired