# 86 - 197 Herpes Simplex Virus Infections

### 197 Herpes Simplex Virus Infections

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Section 12	 Infections Due to DNA Viruses
Lawrence Corey

Herpes Simplex 

Virus Infections
■
■DEFINITION
Herpes simplex viruses (HSV-1, HSV-2; Herpesvirus hominis) produce 
a variety of infections involving mucocutaneous surfaces, the periph­
eral nervous system (PNS), the central nervous system (CNS), and—on 
occasion—visceral organs. Prompt recognition and treatment reduce 
the morbidity and mortality rates associated with HSV infections.
■
■ETIOLOGIC AGENT
The genome of HSV is a 152-kb linear, double-stranded DNA 
molecule (molecular weight, ~100 × 106) that encodes >90 tran­
scription units with 84 identified proteins. The genomic structures 
of the two HSV subtypes are similar. The overall genomic sequence 
homology between HSV-1 and HSV-2 is ~50%, whereas the proteome 
homology is >80%. The homologous sequences are distributed over the 
entire genome map, and most of the polypeptides specified by one viral 
type are antigenically related to polypeptides of the other viral type. 
Many type-specific regions unique to HSV-1 and HSV-2 proteins do 
exist, and a number of them appear to be important in host immunity. 
These type-specific regions have been used to develop serologic assays 
that distinguish between the two viral subtypes. The most commonly 
used protein is glycoprotein G (US-4), which differs markedly in size 
and antigenic sites between HSV-1 and HSV-2. Either restriction endo­
nuclease analysis or sequencing of viral DNA can be used to distinguish 
between the two subtypes and among strains of each subtype. Recombi­
nant viruses (HSV-1/HSV-2) do circulate in nature. The variability of 
nucleotide sequences from clinical strains of HSV-1 and HSV-2 is such 
that HSV isolates obtained from two individuals can be differentiated by 
restriction enzyme patterns or genomic sequences. Epidemiologically 
related sources, such as sexual partners, mother–infant pairs, or persons 
involved in a common-source outbreak, can be inferred from such 

patterns. Deep sequencing of sequential isolates suggests that more 
than one variant of HSV-1 or HSV-2 can be found in a single individual 
and minor mutational changes do occur within anatomic sites and 
over time.

The viral genome is packaged in a regular icosahedral protein shell 
(capsid) composed of 162 capsomeres (Chap. 195). The outer covering 
of the virus is a lipid-containing membrane (envelope) acquired as the 
DNA-containing capsid buds through the inner nuclear membrane 
of the host cell. Between the capsid and lipid bilayer of the envelope 
is the tegument. Viral replication has both nuclear and cytoplasmic 
phases. Only four of the 12 glycosylated envelope proteins appear to 
be essential for cell entry: glycoprotein D (gD), gH, gL, and gB. gD 
binds to cellular co-receptors that belong to the heparin sulfate or 
tumor necrosis factor receptor family of proteins, the immunoglobulin 
superfamily (nectin family), triggering a conformational change that 
alters activation of the gH-gL heterodimer complex that then activates 
gB and the fusogen glycoprotein gC. The ubiquity of these receptors 
contributes to the wide host range of herpesviruses. HSV replication 
is highly regulated. After fusion and entry, the nucleocapsid enters the 
cytoplasm and several viral proteins are released from the virion. Some 
of these viral proteins shut off host protein synthesis (by increasing 
cellular RNA degradation), whereas others “turn on” the transcrip­
tion of immediate early genes of HSV replication. These immediate 
early gene products, designated α genes, are required for synthesis of 
the subsequent polypeptide group: the β polypeptides, many of which 
are regulatory proteins and enzymes required for DNA replication. 
Most current antiviral drugs interfere with β proteins, such as viral 
thymidine kinase (TK) and DNA polymerase. The third (γ) class of 
HSV genes encodes viral structural and tegument proteins and mostly 
requires viral DNA replication for expression. New antiviral drugs 
directed at viral assembly and release are under development.
CHAPTER 197
After viral genome replication and structural protein synthesis, 
nucleocapsids are assembled in the cell’s nucleus. Specific viral pro­
teases clip the end of the DNA into procapsid. In the nucleus, the 
nucleocapsid binds through the inner nuclear membrane to genetic 
vessels that fuse with the outer membrane and moves the capsid into 
the cytoplasm. 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. The cytoplasmic capsids move along microtubules to 
the Golgi network where a second round of envelopment occurs. The 
capsids acquire their lipid envelope and most of the tegument. Cellular 
machinery transports the infectious virus out of the cell.
Herpes Simplex Virus Infections 
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 pres­
ence 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 infec­
tious 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 noncod­
ing RNAs and micro-RNAs (miRNAs) collectively referred to as the 
latency-associated transcripts (LATs) are 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. About 10% of ganglionic 
neurons contain viral DNA and only about 1% of these neurons express 
LATs. 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 incompletely understood.

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 sub­
clinically. 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. Dur­
ing 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 periph­
eral 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 auto­
nomic 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.
PART 5
Infectious Diseases
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 reactiva­
tion. 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 gran­
zyme 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 sub­
sequent 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 iso­
lates 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 increas­
ingly 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. Immunocom­
promised 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. Experi­
mental 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 pro­
tection against subsequent neurologic disease or ganglionic latency, 
and reduced subsequent reactivation in animals model experiments. 
Human studies of monoclonal antibodies are underway. 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. Cellular 
and humoral immune responses to HSV have been detected both in 
human ganglia and in mucosal tissue at the site of reactivation. The 
HSV virion contains a variety of genes that are directed at the inhibi­
tion 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.
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 clini­
cal 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. The com­
munication with surrounding keratinocytes using cytokine release of 
interferon gamma initiates antiviral resistance mechanisms to HSV 
epithelial cell infection. Innate immunity also influences HSV infec­
tion. Severe HSV-1 infections occur in individuals with natural killer 
(NK) cell defects. Severe familial HSV-1 infections are associated with 
TLR3 polymorphisms, and the TLR signaling protein UNC93B and 
TLR2 polymorphisms influence disease reactivation. 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 world­
wide. The global prevalence of HSV-1 is estimated at 66% of the 
population (3.7 billion people), while 13.2% or 492 million people aged 
15–49 were estimated to live with HSV-2. The past 15 years have shown 
that the prevalence of HSV-2 is even higher in the developing than in 
the developed world. In sub-Saharan 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 ~23.9 million infections per year, with 491.5 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. pop­
ulation has antibodies to HSV-2. In most routine obstetric and family 
planning clinics, 15–30% 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 sexu­
ally 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 sero­
prevalence 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 popula­
tion 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. 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 hetero­
sexual women in sub-Saharan Africa. 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.

HSV-2 facilitates the spread of HIV into low-risk populations; prev­
alent HSV-2 appears to increase the risk of HIV infection by seven- to 
ninefold on a per-coital basis. In addition, HSV-2 is more frequently 
reactivated in and transmitted by persons co-infected 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 inflamma­
tory 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 subclini­
cal 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 ana­
tomic regions of the genital tract that are not easily visualized. Asymp­
tomatic 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 reac­
tivation of the virus from the genital tract have fostered the continued 
spread of genital herpes throughout the world.
CHAPTER 197
Herpes Simplex Virus Infections 
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. 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 once-daily sampling, 
HSV DNA can be detected on 20% of days by polymerase chain reac­
tion (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 people living with HIV, 
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, pri­
mary 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. Asymptom­
atic shedding rates follow the same pattern.

Oral–Facial Infections 
Gingivostomatitis and pharyngitis are the 
most common clinical manifestations of first-episode HSV-1 infec­
tion, 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, irritabil­
ity, 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 ulcer­
ative 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 clini­
cally 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 associ­
ated 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 infec­
tion 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.
PART 5
Infectious Diseases
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, and 
co-infections are common. 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 her­
peticum has resolved promptly with the administration of IV acyclovir. 
Erythema multiforme may also be associated with HSV infections 
(see Figs. 59-9 and A1-24); some evidence suggests that HSV infec­
tion 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 HSV-associated erythema multiforme are candi­
dates 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 reso­
lution 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.

FIGURE 197-1  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.)
Genital Infections 
First-episode primary genital herpes is char­
acterized by fever, headache, malaise, and myalgias. Pain, itching, 
dysuria, vaginal and urethral discharge, and tender inguinal lymph­
adenopathy are the predominant local symptoms. Widely spaced 
bilateral lesions of the external genitalia are characteristic (Fig. 197-1). 
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 associ­
ated 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. 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 recur­
rences, 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 dis­
charge 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 pros­
tatitis in men. About 15% of cases of HSV-2 acquisition are associated 
with nonlesional clinical syndromes, such as aseptic meningitis, cer­
vicitis, or urethritis. A more complete discussion of the differential 
diagnosis of genital herpes is presented in Chap. 141.
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 der­
matome or sacral autonomic ganglia 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 constipa­
tion. 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.
The recent outbreak of Mpox infections globally has made the dif­
ferentiation of HSV anal rectal infection from Mpox infection of clini­
cal and therapeutic importance. PCR-based assays clearly distinguish 
between the two entities. Acyclovir should be used for HSV-2 infection 
and tecovirimat for monkeypox 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; either viral type may be isolated from 
the lesion. 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 epi­
trochlear and axillary lymphadenopathy are common. The infection 
may recur. Prompt diagnosis (to avoid unnecessary and potentially 
exacerbating surgical therapy and/or transmission) is essential. Antivi­
ral 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. Outbreaks 
of HSV among competitive wrestlers 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 char­
acteristic 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 ther­
apy hasten 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 destruc­
tion 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 syn­
drome. Emergent ophthalmology consulta­
tion is recommended as residual blindness 
may occur; 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 neuro­
tropic spread from the periphery via the 
FIGURE 197-2  Computed tomography and diffusion-weighted magnetic resonance imaging scans of the brain of a 
patient with left-temporal-lobe herpes simplex virus encephalitis.

olfactory bulb. However, most adults with HSV encephalitis have clini­
cal 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 dem­
onstrated 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. Peripheralblood 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. 197-2); gadolinium enhancing lesions are seen 
in the temporal lobe by magnetic resonance imaging (MRI). Clinical 
differentiation of HSV encephalitis from other viral encephalitides, 
focal infections, or noninfectious processes is difficult. Elevated cere­
brospinal fluid (CSF) protein levels, leukocytosis (predominantly lym­
phocytes), and red blood cell counts due to hemorrhagic necrosis are 
common in HSV encephalitis. 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 HSV 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 
CHAPTER 197
Herpes Simplex Virus Infections

acyclovir to patients with presumed HSV encephalitis until the diag­
nosis 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 pre­
senting 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 
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 diagno­
sis. 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.
PART 5
Infectious Diseases
There is increasing experimental evidence suggesting an association 
between herpesvirus pathogens, specifically HSV-1, and the develop­
ment of sporadic Alzheimer’s disease (AD). HSV-1 DNA is detected in 
brain tissue of patients with AD, and epidemiologically, HSV-1 anti­
bodies 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 multicellu­
lar-like plaque structures associated with AD. There are no cogent data 
to indicate antiviral therapy would be of benefit to anyone with AD. An 
adequately powered prospective study of prolonged antiviral therapy 
has not been conducted.
HSV Lymphadenitis 
HSV-1 or HSV-2 lymphadenitis has been 
reported, with increasing frequency especially among patients with 
chronic lymphocytic leukemia. This condition represents a diagnos­
tic dilemma often confused with lymphomatous transformation and 
occurs absent of oral or genital lesions. One histologic hint between 
HSV and lymphoblastic transformation is the presence of necrosis in 
biopsy tissue in HSV lymphadenitis. Isolation of HSV or demonstra­
tion of HSV DNA in tissue confers the diagnosis. Concomitant HSV 
viremia may also be present. Intravenous acyclovir has been associated 
with resolution of infection and clinical improvement.
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 symp­
toms 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 usu­
ally reduces the severity and duration of symptoms and heals esopha­
geal ulcerations.
HSV pneumonitis is uncommon except in severely immunosup­
pressed patients and may result from extension of herpetic tracheo­
bronchitis 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 intu­
bation. 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 condi­
tions is unclear. HSV is an uncommon cause of hepatitis in immuno­
competent 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 monar­
ticular arthritis, adrenal necrosis, idiopathic thrombocytopenia, and 
glomerulonephritis. Disseminated HSV infection in immunocompe­
tent 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 dis­
semination, 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, neo­
nates (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. A recent 
review of U.S. Medicaid databases indicates a frequency of ~1000 
cases of neonatal HSV yearly, a rate of between 1 per 2000 and 1 per 
3000 live births. 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 through postnatal contact with immediate family members 
who have symptomatic or asymptomatic oral–labial HSV-1 infection 
or through nosocomial transmission within the hospital. All neonates 
with presumed herpes should be treated with IV acyclovir and then 
placed on maintenance oral antiviral therapy for the first 6–12 months 
of life. Antiviral chemotherapy with high-dose IV acyclovir (60 mg/kg 
per day) has reduced the mortality rate from neonatal herpes to ~15%.

However, rates of morbidity, especially among infants with HSV-2 
infection involving the CNS, are still very high.
HSV in Pregnancy 
In the United States, 21% of all pregnant 
women and 51% of non-Hispanic black pregnant women are seroposi­
tive for HSV-2. However, the risk of mother-to-child transmission of 
HSV in the perinatal period is highest when the infection is acquired 
near the time of labor—that is, in previously HSV-seronegative women. 
The clinical manifestations of recurrent genital herpes—including 
the frequency of subclinical versus clinical infection, the duration of 
lesions, pain, and constitutional symptoms—are similar in pregnant 
and nonpregnant women. Recurrences increase in frequency over 
the course of pregnancy. However, when women are seropositive for 
HSV-2 at the outset of pregnancy, no effect on neonatal outcomes 
(including birth weight and gestational age) is seen. First-episode 
infections in pregnancy have more severe consequences for mother 
and infant. Maternal visceral dissemination during the third trimester 
occasionally occurs, as does premature birth or intrauterine growth 
retardation. The acquisition of primary disease in pregnancy, whether 
related to HSV-1 or HSV-2, carries the risk of transplacental transmis­
sion of virus to the neonate and can result in spontaneous abortion, 
although this outcome is relatively uncommon. For newly acquired 
genital HSV infection during pregnancy, most authorities recommend 
treatment with acyclovir (400 mg three times daily) or valacyclovir 
(500–1000 mg twice daily) for 7–10 days. However, the impact of this 
intervention on transmission is unknown. The high HSV-2 prevalence 
rate in pregnancy and the low incidence of neonatal disease in these 
women (1 case per 6000–20,000 live births) indicate that only a few 
infants are at risk of acquiring HSV. Therefore, cesarean section is 
not warranted for all women with recurrent genital disease. Because 
intrapartum transmission of infection accounts for the majority of 
cases, abdominal delivery need be considered only for women who are 
shedding HSV at delivery. Several studies have shown no correlation 
between recurrence of viral shedding before delivery and viral shed­
ding at term. Hence, weekly virologic monitoring and amniocentesis 
are not recommended.
The frequency of transmission from mother to infant is markedly 
higher among women who acquire HSV near term (30–50%) than 
among those in whom HSV-2 infection is reactivated at delivery (<1%). 
Although maternal antibody to HSV-2 is protective, antibody to HSV-1 
offers little or no protection against neonatal HSV-2 infection. Primary 
genital infection with HSV-1 leads to a particularly high risk of trans­
mission during pregnancy and accounts for an increasing proportion 
of neonatal HSV cases. Moreover, during reactivation, HSV-1 appears 
more transmissible to the neonate than HSV-2. Only 2% of women 
who are seropositive for HSV-2 have HSV-2 isolated from cervical 
secretions at delivery, and only 1% of infants exposed in this man­
ner develop infection, presumably because of the protective effects of 
maternally transferred antibodies and perhaps lower viral titers during 
reactivation. Despite the low frequency of transmission of HSV in this 
setting, 30–50% of infants with neonatal HSV are born to mothers with 
established genital herpes.
Isolation of HSV by cervicovaginal swab at the time of delivery is the 
greatest risk factor for intrapartum HSV transmission (relative risk = 346); 
however, culture-negative, PCR-positive cases of intrapartum trans­
mission are well described. New acquisition of HSV (odds ratio [OR] = 
49), isolation of HSV-1 versus HSV-2 (OR = 35), cervical versus vulvar 
HSV detection (OR = 15), use of fetal scalp electrodes (OR = 3.5), and 
young maternal age confer further risk of transmission, whereas cesar­
ean delivery is protective (OR = 0.14). Physical examination poorly 
predicts the absence of shedding, and PCR far exceeds culture in terms 
of sensitivity and speed. Therefore, PCR detection at the onset of labor 
should be used to aid clinical decision-making for women with HSV-2 
antibody. Because cesarean section appears to be an effective means of 
reducing maternal–fetal transmission, patients with recurrent genital 
herpes should be encouraged to come to the hospital early at the time 
of delivery for careful examination of the external genitalia and cervix 
as well as collection of a swab sample for viral isolation. Women who 
have no evidence of lesions can have a vaginal delivery. The presence 

of active lesions on the cervix or external genitalia is an indication for 
cesarean delivery.

If first-episode exposure has occurred (e.g., if HSV serologies show 
that the mother is seronegative or if the mother is HSV-1-seropositive 
and the isolate at delivery is found to be HSV-2), many authorities 
would initiate antiviral therapy for the infant with IV acyclovir. At a 
minimum, samples for viral cultures and PCR should be obtained from 
the throat, nasopharynx, eyes, and rectum of these infants immediately 
and at 5- to 10-day intervals. Lethargy, skin lesions, or fever should be 
evaluated promptly. All infants from whom HSV is isolated 24 h after 
delivery should be treated with IV acyclovir at recommended doses.
■
■DIAGNOSIS
Both clinical and laboratory criteria are useful for diagnosing HSV 
infections. A clinical diagnosis can be made accurately when charac­
teristic multiple vesicular lesions on an erythematous base are present. 
However, herpetic ulcerations may resemble skin ulcerations of other 
etiologies and considerable overlap including coinfection between 
HSV and Mpox infections exist. Mucosal HSV infections may also 
present as urethritis or pharyngitis without cutaneous lesions. Thus, 
laboratory studies to confirm the diagnosis and to guide therapy are 
recommended. While staining of scrapings from the base of the lesions 
with Wright’s, Giemsa’s (Tzanck preparation), or Papanicolaou’s stain 
to detect giant cells or intranuclear inclusions of Herpesvirus infection 
is a well-described procedure, few clinicians are skilled in this tech­
nique, the sensitivity of staining is low (<30% for mucosal swabs), and 
these cytologic methods do not differentiate between HSV and VZV 
infections.
CHAPTER 197
HSV infection is best confirmed in the laboratory by detection of 
virus, viral antigen, or viral DNA in scrapings from lesions. HSV DNA 
detection by PCR is the most sensitive laboratory technique for detect­
ing mucosal or visceral HSV infections and is the recommended test 
for laboratory confirmation of a diagnosis. HSV causes a discernible 
cytopathic effect in a variety of cell culture systems, and this effect can 
be identified within 48–96 h after inoculation. Spin-amplified culture 
with subsequent staining for HSV antigen has shortened the time 
needed to identify HSV to <24 h. Culture is indicated when antiviral 
sensitivity testing is required. The sensitivity of all detection methods 
depends on the stage of the lesions (with higher sensitivity for vesicu­
lar than for ulcerative lesions), on whether the patient has a first or a 
recurrent episode of the disease (with higher sensitivity in first than 
in recurrent episodes), and on whether the sample is from an immu­
nosuppressed or an immunocompetent patient (with more antigen 
or DNA in immunosuppressed patients). Laboratory confirmation 
permits subtyping of the virus; information on subtype may be useful 
epidemiologically and may help to predict the frequency of reactivation 
after first-episode oral–labial or genital HSV infection.
Herpes Simplex Virus Infections 
Both type-specific and type-common antibodies to HSV develop 
during the first several weeks after infection and persist indefinitely. 
Serologic assays with whole-virus antigen preparations, such as com­
plement fixation, neutralization, indirect immunofluorescence, passive 
hemagglutination, radioimmunoassay, and enzyme-linked immuno­
sorbent assay, can differentiate uninfected (seronegative) persons from 
those with past HSV-1 or HSV-2 infection, but they do not reliably 
distinguish between the two viral subtypes or help establish an active 
clinical diagnosis of HSV-2. Serologic assays that identify antibodies to 
the type-specific glycoprotein G of the two viral subtypes (G1 and G2) 
are available commercially and can be used to distinguish between the 
human antibody responses to HSV-1 and HSV-2. Point-of-care assays 
that provide results from capillary blood or serum during a clinic 
visit are available. False-positive and false-negative assays do occur, 
and there is a need for commercially available assays to distinguish 
prevalent HSV-2 infection, especially on the backgroiund of earlier 
acquired HSV-1. A western blot assay that can detect several HSV 
type-specific proteins can also be used and is, at present, the best con­
firmatory assay. The presence of type-specific HSV-2 antibody implies 
past HSV-2 infection—i.e., latent infection, likely subclinical reactiva­
tion, increased risk of HSV-1 acquisition, and potential transmission 
to others.

PART 5
Infectious Diseases
Acute- and convalescent-phase serum samples can be useful in 
demonstrating seroconversion during primary HSV-1 or HSV-2 infec­
tion. However, few available tests report titers, and increases in index 
values do not reflect first episodes in all patients. Serologic assays based 
on type-specific proteins should be used to identify asymptomatic car­
riers of HSV-1 or HSV-2. No reliable IgM method for defining acute 
HSV infection is available.
Several studies have shown that persons with previously unrecog­
nized HSV-2 infection can be taught to identify symptomatic reactiva­
tions. Individuals seropositive for HSV-2 should be told about the high 
frequency of subclinical reactivation on mucosal surfaces that are not 
visible to the eye (e.g., cervix, urethra, perianal skin) or in microscopic 
ulcerations that may not be clinically symptomatic. Transmission of 
infection during such episodes is well established. HSV-2-seropositive 
persons should be educated about the high likelihood of subclinical 
shedding and the role that condoms (male or female) may play in 
reducing transmission. Antiviral therapy with valacyclovir (500 mg 
once daily) has been shown to reduce but not eliminate the transmis­
sion of HSV-2 between sexual partners.
TREATMENT
Herpes Simplex Virus Infections
Many aspects of mucocutaneous and visceral HSV infections are 
amenable to antiviral chemotherapy. For mucocutaneous infec­
tions, acyclovir and its congeners famciclovir and valacyclovir have 
been the mainstays of therapy. Several antiviral agents are available 
for topical use in HSV eye infections: idoxuridine, trifluorothymi­
dine, topical vidarabine, and cidofovir and, more recently, topical 
pritelivir. For HSV encephalitis and neonatal herpes, IV acyclovir is 
the treatment of choice.
Most licensed antiviral agents for use against HSV inhibit the 
viral DNA polymerase. One class of drugs, typified by the drug 
acyclovir, is made up of substrates for the HSV enzyme TK. Acyclovir, 
ganciclovir, famciclovir, and valacyclovir are all selectively phos­
phorylated to the monophosphate form in virus-infected cells. 
Cellular enzymes convert the monophosphate form of the drug to 
the triphosphate, which is then incorporated into the viral DNA 
chain. Acyclovir is the agent most frequently used for the treat­
ment of HSV infections and is available in IV, oral, and topical 
formulations. Valacyclovir, the valyl ester of acyclovir, offers greater 
bioavailability than acyclovir and thus can be administered less 
frequently. Famciclovir, the oral formulation of penciclovir, is clini­
cally effective in the treatment of a variety of HSV-1 and HSV-2 
infections. Ganciclovir is active against both HSV-1 and HSV-2; 
however, it is more toxic than acyclovir, valacyclovir, and famci­
clovir and generally is not recommended for the treatment of HSV 
infections. Anecdotal case reports suggest that ganciclovir may also 
be less effective than acyclovir for the treatment of HSV infections. 
All three recommended compounds—acyclovir, valacyclovir, and 
famciclovir—have proved effective in shortening the duration of 
symptoms and lesions of mucocutaneous HSV infections in both 
immunocompromised and immunocompetent patients (Table 197-1). 
IV and oral formulations prevent reactivation of HSV in sero­
positive immunocompromised patients during induction chemo­
therapy or in the period immediately after bone marrow or solid 
organ transplantation. Chronic daily suppressive therapy reduces 
the frequency of reactivation disease among patients with frequent 
genital or oral–labial herpes. Only valacyclovir has been subjected 
to clinical trials that demonstrated reduced transmission of HSV-2 
infection between sexual partners. IV acyclovir (30 mg/kg per day, 
given as a 10-mg/kg infusion over 1 h at 8-h intervals) is effective in 
reducing rates of death and morbidity from HSV encephalitis. Early 
initiation of therapy is a critical factor in outcome. The major side 
effect associated with IV acyclovir is transient renal insufficiency, 
usually due to crystallization of the compound in the renal paren­
chyma. This adverse reaction can be avoided if the medication is 
given slowly over 1 h and the patient is well hydrated. Because CSF 
levels of acyclovir average only 30–50% of plasma levels, the dos­
age of acyclovir used for treatment of CNS infection (30 mg/kg per 
day) is double that used for treatment of mucocutaneous or visceral 
disease (15 mg/kg per day). Even higher doses of IV acyclovir are 
used for neonatal HSV infection (60 mg/kg per day in three divided 
doses). Antiviral drugs neither eradicate latent infection nor affect 
the risk, frequency, or severity of subclinical or clinical recurrence 
after the drug is discontinued.
Increasingly, shorter courses of therapy are being used for recur­
rent mucocutaneous infection with HSV-1 or HSV-2 in immuno­
competent patients. One-day courses of famciclovir and valacyclovir 
are clinically effective, more convenient, and generally less costly 
than longer courses of therapy (Table 197-1). These short-course 
regimens should be reserved for immunocompetent hosts.
SUPPRESSION OF MUCOCUTANEOUS HERPES
Recognition of the high frequency of subclinical reactivation pro­
vides a well-accepted rationale for the use of daily antiviral therapy 
to suppress reactivations of HSV, especially in persons with frequent 
clinical reactivations (e.g., those with recently acquired genital HSV 
infection). Immunosuppressed persons, including those with HIV 
infection, may also benefit from daily antiviral therapy. Daily acy­
clovir and valacyclovir reduce the frequency of HSV reactivations 
among HIV-positive persons. Regimens used include acyclovir 
(400–800 mg twice daily), famciclovir (500 mg twice daily), and 
valacyclovir (500 mg twice daily); valacyclovir at a dose of 4 g/d 
was associated with thrombotic thrombocytopenic purpura in one 
study of HIV-infected persons. Daily acyclovir therapy is associated 
with a modest reduction in the titer of HIV RNA in plasma (0.5-log10 
reduction) and in the genital mucosa (0.33-log10 reduction). Epi­
sodes of subclinical reactivation still occur with chronic acyclovir 
or valaciclovir therapy.
REDUCED HSV TRANSMISSION TO SEXUAL PARTNERS
Once-daily valacyclovir (500 mg) has been shown to reduce trans­
mission of HSV-2 between sexual partners. Transmission rates are 
higher from males to females and among persons with frequent 
HSV-2 reactivation. Serologic screening can be used to identify 
at-risk couples. Daily valacyclovir appears to be more effective at 
reducing subclinical shedding than daily famciclovir.
ACYCLOVIR RESISTANCE
Clinically relevant acyclovir-resistant strains of HSV do occur. 
Most of these strains have an altered substrate specificity for phos­
phorylating acyclovir. Thus, cross-resistance to famciclovir and 
valacyclovir is usually found. Occasionally, an isolate with altered 
TK specificity arises and is sensitive to famciclovir but not to acy­
clovir. In some patients infected with TK-deficient virus, higher 
doses of acyclovir are associated with clearing of lesions. In others, 
clinical disease progresses despite high-dose therapy. The major­
ity of clinically significant acyclovir resistance has been seen in 
immunocompromised patients. HSV-2 isolates appear to be more 
resistant than HSV-1 strains. The frequency of acyclovir resistance 
is not systematically monitored; the lack of appreciable change in 
the frequency of acyclovir resistance in the general population past 
45 years probably reflects the reduced transmission of TK-deficient 
mutants. Isolation of HSV from lesions persisting despite adequate 
dosages and blood levels of acyclovir should raise the suspicion of 
acyclovir resistance. Clinical management of acyclovir resistance 
can be challenging. Therapy with the antiviral drug foscarnet 
(40–80 mg/kg IV every 8 h until clinical resolution) is the only cur­
rently well demonstrated approach (Chap. 196). Because of its toxic­
ity and cost, this drug is usually reserved for patients with extensive 
mucocutaneous infections. Cidofovir is a nucleotide analogue and 
exists as a phosphonate or monophosphate form. Most TK-deficient 
strains of HSV are sensitive to cidofovir. Cidofovir ointment speeds 
healing of acyclovir-resistant lesions, but the topical drug itself 
can cause mucocutaneous ulcerations. No well-controlled trials 
of systemic cidofovir have been reported. Occasional cases may 
respond to topical imiquimod. Anecdotal case reports of successful

TABLE 197-1  Antiviral Chemotherapy for Herpes Simplex Virus (HSV) Infection
I.  Mucocutaneous HSV infections
A.	 Infections in immunosuppressed patients
1.	 Acute symptomatic first or recurrent episodes: IV acyclovir (5 mg/kg q8h) or oral acyclovir (400 mg qid), famciclovir (500 mg bid or tid), or valacyclovir 

(500 mg bid) is effective. Treatment duration may vary from 7 to 21 days. IV therapy may be given for 2–10 days until clinical improvement and followed by 
oral therapy.
2.	 Suppression of reactivation disease (genital or oral–labial): IV acyclovir (5 mg/kg q8h) or oral valacyclovir (500 mg bid) or acyclovir (400–800 mg 3–5 times 
per day) prevents recurrences during the 30-day period immediately after transplantation. Longer-term HSV suppression is often used for persons with 
continued immunosuppression. In bone marrow and renal transplant recipients, oral valacyclovir (2 g/d) is also effective in reducing cytomegalovirus 
infection. Oral valacyclovir at a dose of 4 g/d has been associated with thrombotic thrombocytopenic purpura after extended use in HIV-positive persons. In 
HIV-infected persons, oral acyclovir (400–800 mg bid), valacyclovir (500 mg bid), or famciclovir (500 mg bid) is effective in reducing clinical and subclinical 
reactivations of HSV-1 and HSV-2.
B.	 Infections in immunocompetent patients
1.	 Genital herpes
a.	 First episodes: Oral acyclovir (200 mg 5 times per day or 400 mg tid), valacyclovir (1 g bid), or famciclovir (250 mg tid) for 7–14 days is effective. IV acyclovir 
(5 mg/kg q8h for 5 days) is given for severe disease or neurologic complications such as aseptic meningitis.
b.	 Symptomatic recurrent genital herpes: Short-course (1- to 3-day) regimens are preferred because of low cost, likelihood of adherence, and convenience. 
Oral acyclovir (800 mg tid for 2 days), valacyclovir (500 mg bid for 3 days), valacyclovir (1 g orally once a day for 3 days), or famciclovir (750 or 1000 mg 
bid for 1 day, a 1500-mg single dose, or 500 mg stat followed by 250 mg q12h for 2 days) effectively shortens lesion duration. Other options include oral 
acyclovir (200 mg 5 times per day), valacyclovir (500 mg bid), and famciclovir (125 mg bid for 5 days).
c.	 Suppression of recurrent genital herpes: Oral acyclovir (400–800 mg bid) or valacyclovir (500 mg daily) is given. Patients with >9 episodes per year should 
take oral valacyclovir (1 g daily or 500 mg bid) or famciclovir (250 mg bid or 500 mg bid).
2.	 Oral–labial HSV infections
a.	 First episode: Oral acyclovir is given (200 mg 5 times per day or 400 mg tid); an oral acyclovir suspension can be used (600 mg/m2 qid). Oral famciclovir 

(250 mg bid) or valacyclovir (1 g bid) has been used clinically. The duration of therapy is 5–10 days.
b.	 Recurrent episodes: If initiated at the onset of the prodrome, single-dose or 1-day therapy effectively reduces pain and speeds healing. Regimens include 
oral famciclovir (a 1500-mg single dose or 750 mg bid for 1 day) or valacyclovir (a 2-g single dose or 2 g bid for 1 day). Self-initiated therapy with 6-timesdaily topical penciclovir cream effectively speeds healing of oral–labial HSV infection. Topical acyclovir cream has also been shown to speed healing or 
single dose oral amenamevir 1200 mg.
c.	 Suppression of reactivation of oral–labial HSV: If started before exposure and continued for the duration of exposure (usually 5–10 days), oral acyclovir 
(400 mg bid) prevents reactivation of recurrent oral–labial HSV infection associated with severe sun exposure.
3.	 Surgical prophylaxis of oral or genital HSV infection: Several surgical procedures, such as laser skin resurfacing, trigeminal nerve-root decompression, and 
lumbar disk surgery, have been associated with HSV reactivation. IV acyclovir (3–5 mg/kg q8h) or oral acyclovir (800 mg bid), valacyclovir (500 mg bid), or 
famciclovir (250 mg bid) effectively reduces reactivation. Therapy should be initiated 48 h before surgery and continued for 3–7 days.
4.	 Herpetic whitlow: Oral acyclovir (200 mg) is given 5 times daily (alternative: 400 mg tid) for 7–10 days.
5.	 HSV proctitis: Oral acyclovir (400 mg 5 times per day) is useful in shortening the course of infection. In immunosuppressed patients or in patients with severe 
infection, IV acyclovir (5 mg/kg q8h) may be useful.
6.	 Herpetic eye infections: In acute keratitis, topical trifluorothymidine, vidarabine, idoxuridine, acyclovir, penciclovir, and interferon are all beneficial. 
Debridement may be required. Topical steroids may worsen disease.
II.  Central nervous system HSV infections
A.	 HSV encephalitis: IV acyclovir (10 mg/kg q8h; 30 mg/kg per day) is given for 10 days or until HSV DNA is no longer detected in cerebrospinal fluid.
B.	 HSV aseptic meningitis: No studies of systemic antiviral chemotherapy exist. If therapy is to be given, IV acyclovir (15–30 mg/kg per day) should be used.
C.	 Autonomic radiculopathy: No studies are available. Most authorities recommend initial therapy with IV acyclovir (5–10 mg/kg q8h) followed by oral therapy for 
21 days.
III.  Neonatal HSV infections: IV acyclovir (60 mg/kg per day, divided into 3 doses) is given. The recommended duration of IV treatment is 21 days. Monitoring for 
relapse should be undertaken. Continued suppression with oral acyclovir suspension should be given for 3–4 months.
IV.  Visceral HSV infections
A.	 HSV esophagitis: IV acyclovir (15 mg/kg per day) is given. In some patients with milder forms of immunosuppression, oral therapy with valacyclovir or 
famciclovir is effective.
B.	 HSV pneumonitis and lymphadenitis: No controlled studies exist. IV acyclovir (15 mg/kg per day) should be considered.
V.  Disseminated HSV infections: No controlled studies exist. IV acyclovir (5 mg/kg q8h) should be tried. Adjustments for renal insufficiency may be needed. No 
definite evidence indicates that therapy will decrease the risk of death.
VI.  Erythema multiforme associated with HSV: Anecdotal observations suggest that oral acyclovir (400 mg bid or tid) or valacyclovir (500 mg bid) will suppress 
erythema multiforme.
VII.  Infections due to acyclovir-resistant HSV: IV foscarnet (40 mg/kg IV q8h) should be given until lesions heal. The optimal duration of therapy and the usefulness 
of its continuation to suppress lesions are unclear. The helicase-primase inhibitor pritelivir, 400 mg oral loading dose on day 1 followed by 100 mg once daily for 
21–28 days, has reported effectiveness. Some patients may benefit from cutaneous application of trifluorothymidine or 1% cidofovir gel, both of which must be 
compounded at a pharmacy. These preparations should be applied once daily for 5–7 days. Topical imiquimod can be considered. IV cidofovir (5 mg/kg weekly) 
may be considered.
VIII.  Acyclovir and pregnancy: No adverse effects to the fetus or newborn have been attributable to acyclovir. Acyclovir can be used in all stages of pregnancy and 
among women who are breastfeeding (the drug can be found in breast milk). Suppressive acyclovir treatment in late pregnancy (acyclovir 400 mg orally tid or 
valacyclovir 500 mg orally bid from ~34 weeks until delivery) reduces the frequency of cesarean delivery among women with recurrent genital herpes. Such 
treatment may not protect against transmission to neonates.
treatment of acyclovir resistant HSV with oral pritelivir have been 
reported in immunocompetent persons. Drugs from a new class 
that inhibit HSV-specific helicase/primase activity, amenamevir 
and pritelivir, are under clinical investigation and appear to offer a 
better toxicity profile for the treatment of acyclovir-resistant strains 
of HSV. Amenamevir is licensed for varicella-zoster infections in 

CHAPTER 197
Herpes Simplex Virus Infections 
Japan, and a recent study has shown promise in recurrent oral–
labial HSV.
ACYCLOVIR EFFICACY IN THE DEVELOPING WORLD
Initial studies of acyclovir-like drugs were performed solely in the 
developed world. While acyclovir, valacyclovir, and famciclovir are