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Clinical Manifestations and Treatment Considerations of Herpes Simplex

Virus Infection
Anthony Simmons

Childrens Hospital, University of Texas Medical Branch at Galveston

Herpes simplex viruses (HSV) types 1 and 2 cause infections manifesting as dermatologic,
immunologic, and neurologic disorders. Some of the most important manifestations and
complications of HSV infection are considered here in a neuroanatomic context. This discussion should aid in understanding the pathogenesis and, in some cases, diagnosis and management of associated HSV-related diseases. The sensory nervous system, rather than skin
and mucous membranes, is the primary target of HSV infection. With the intention of extending the benefits of acyclovir, valacyclovir is now being explored in a number of HSVrelated conditions. This review extends contemporary thinking about how new antiherpetic
drugs might be put to greater therapeutic use in the future.

Financial support: GlaxoWellcome (now GlaxoSmithKline; consultant),

SmithKlineBeecham, Wyeth-Lederle, 3M, Merck.
Reprints or correspondence: Dr. Anthony Simmons, 2.330 Childrens
Hospital, University of Texas Medical Branch at Galveston, 301 University
Blvd., Galveston, TX 77555-0373 (ansimmon@utmb.edu).
The Journal of Infectious Diseases 2002; 186(Suppl 1):S717
2002 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2002/18608S-0009$15.00

numerous HSV-related conditions (table 1). More recently,

newer nucleoside analogues have been investigated as treatments for HSV infections with the aim of building upon the
success of acyclovir [9]. Valacyclovir is an oral prodrug formulation of acyclovir that provides up to 5 times greater acyclovir bioavailability [10]. Although not discussed in this review,
another new medication for herpesvirus infections is famciclovir. In this review of HSV infections (predominantly in immunocompetent hosts), I discuss the thought that HSV infections are a cause of disease primarily of the nervous system
rather than of skin. I also describe the many manifestations of
HSV infection in a neuroanatomic framework to aid in the
understanding of their pathogenesis and management.
Throughout I discuss how newer antiherpetic compounds such
as valacyclovir or famciclovir might help in the discovery of
new associations between HSV and disease.

Infections of the Peripheral Nervous System

The peripheral nervous system is bilaterally symmetric and
segmental in its organization, with a defined dermatome innervated by each cutaneous sensory nerve. An association between HSV and the peripheral sensory nervous system has been
recognized for some time. Attributing herpetic lesions to individual dermatomes on the limbs can pose some difficulties
because the distribution of individual nerve roots on the limbs
is less straightforward than on the trunk, owing to rotation of
the limbs during embryogenesis. The simplest way to correct
for the effects of this rotation is to picture the body in the
quadruped position, in which the dermatomes return to a logical, sequential arrangement (figure 1).
Recurrences of HSV infection tend to be confined to the
dermatome of primary infection but do not necessarily occur
at precisely the same anatomic location. In the case of perioral
disease, for example, primary infection is usually inside the
mouth (gingivostomatitis), whereas spread of HSV within the
trigeminal ganglion means that recurrent disease is most com-

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Worldwide, 60%95% of the population is infected by one or

more viruses of the herpes viridae family [1]. In an immunocompetent host, herpesvirus infections can often cause debilitating
diseases, which may have psychological and physical sequelae in
persons with frequent recurrences [2]. Herpesviruses have two
unique biologic properties: the ability to invade and replicate in
the host nervous system and the ability to establish a site of latent
infection. The neurovirulent properties of herpes simplex virus
(HSV) enable the virus to cause a disease primarily of the sensory
nervous system rather than of the skin [3].
The ability of HSV to lytically infect cells of the central
nervous system (CNS) is illustrated by sporadic cases of potentially fatal HSV encephalitis. In more usual circumstances,
however, the peripheral nervous system is the main target of
the virus [3, 4]. During primary infection, virus is transported
via sensory ganglia to establish a chronic latent infection, most
commonly in the trigeminal, cervical, or lumbosacral ganglia
[5]. Retrograde transport of HSV along nerves and the establishment of latency are not dependent on viral replication in
the skin or neurons [6] and it therefore follows that neurons
can be infected in the absence of symptoms.
Periodically, HSV may reactivate from its latent state and
virus particles then travel along sensory neurons to the skin
and other mucosal sites to cause recurrent disease episodes.
Recurrent mucocutaneous shedding of HSV can be associated
with lesions or asymptomatic shedding and in either scenario
is allied with a period when virus can be transmitted to a new
host [7, 8]
Acyclovir has been evaluated and is widely used to treat

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Simmons

JID 2002;186 (Suppl 1)

monly associated with lesions on the lip (cold sores). Frequency

of recurrence can also depend on the virus subtype (HSV type
1 or type 2) and anatomic sites of infection [11].

Infections of the Trigeminal Nerve

Table 1.

tion of valacyclovir during the prodromal period [21]. In contrast to the equivocal efficacy of episodic oral acyclovir treatment, suppressive acyclovir (400 mg twice/day) is useful in
preventing recurrent cold sores [22]. Recent data also show that
oral valacyclovir, administered more conveniently as 500 mg
once a day over 4 months, effectively suppresses recurrent herpes labialis outbreaks [23].
Recurrences of HSV infection in the distribution of the trigeminal nerve have greater impact in circumstances where mu-

HSV infections of the peripheral sensory nervous system

Disease manifestation

Trigeminal nerve

7th cranial nerve

Cervical and thoracic sensory nerves
Lumbosacral sensory nerves
Complications

Figure 1. Human cervical (C), thoracic (T), lumbar (L), and sacral
(S) dermatomes illustrate the segmental and bilateral symmetric structure of the peripheral sensory nervous system (shown in quadruped
position).

Gingivostomatitis
Recurrent cold sores
Corneal infections
Facial resurfacing
a
HSV gladiatorum
Facial paralysis
Herpetic whitlow
Nipple infection
Genital herpes
Eczema herpeticum
Erythema multiforme;
Stevens-Johnson
syndrome

Can also affect cervical and thoracic sensory nerves.

Acyclovir effective?

Potential for valacyclovir?

Possible, pediatric formulation required

Controlled trial data available
Possible
Possible, limited data available
Possible, limited data available
Possible
Possible
Possible
Controlled trial data available
Possible, anecdotal evidence
Possible

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Gingivostomatitis and orolabial HSV infection. Gingivostomatitis is a symptomatic primary HSV-1 infection, usually
occurring in children, and characterized by lesions in and
around the oral cavity. Children are often unable to swallow
because of the associated pain and may become dehydrated.
In severe cases hospitalization may be required and occasionally
autoinoculation can result in conjunctivitis and keratitis. Oral
acyclovir treatment (acyclovir suspension 15 mg/kg 5 times/day
for 7 days) started within the first 3 days of onset of symptoms
shortens the duration of all clinical manifestations by about
50% [12]. Most cases of gingivostomatitis go untreated, undiagnosed, or even unrecognized; the condition is not normally
considered serious.
HSV-1 commonly reactivates from the trigeminal ganglion
to cause the cutaneous and mucocutaneous manifestations of
recurrent facial herpes or cold sores. Cold sores are usually
preceded by prodromal symptoms (e.g., tingling, pain, burning
sensation, or itching at the site of reactivation), which are
thought to be due to early viral replication at sensory nerve
endings and in the epidermis or mucosa [13]. Early initiation
of antiviral therapy is essential since the therapeutic window is
narrow. Ideally, treatment should begin before a lesion is apparent [14, 15].
Cold sores are a common manifestation of HSV infection;
symptomatic outbreaks are estimated to affect 20%40% of
adults [16, 17]. Although clinical symptoms are considered mild,
frequently recurrent outbreaks are associated with significant
morbidity [15]. The benefit of topical treatment of facial herpes
outbreaks with acyclovir cream is only modest [18, 19]. Similarly, oral acyclovir appears to offer only limited efficacy on
lesion healing [20]. The greater bioavailability of valacyclovir
may, however, translate into an improved clinical benefit in that
some lesions can be aborted by patients initiating administra-

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Scope of HSV Infections

ating valacyclovir for the acute treatment or prevention of ocular HSV outbreaks are warranted.
Herpetic facial paralysis. Reactivation of HSV-1 from the
geniculate ganglion has been implicated in the pathogenesis of
idiopathic facial palsy or Bells palsy. During the acute phase
of the disease, shedding of HSV-1 into saliva was detectable by
polymerase chain reaction in 40% (n p 47) of cases examined
[33]. Inflammation appears also to play a major role in pathogenesis of facial paralysis, and corticosteroids have been a
mainstay of therapy, although views on efficacy remain
controversial.
One study compared acyclovir (400 mg 5 times/day) and
placebo given in combination with oral prednisone and concluded that the combination of acyclovir and prednisone was
more efficacious than oral prednisone alone [34]. A recent metaanalysis of prospective trials of steroids, acyclovir, and surgery
for facial palsy identified the complete absence of any adequately powered study. The analysis concluded that, from available evidence, steroids were probably effective and acyclovir
(with prednisone) was possibly effective in improving facial
function outcome [35]. Clearly, there is a role for antiherpes
therapy in the treatment of this disease; however, several issues
need clarification, including the determination of the proportion of facial palsies attributable to HSV and how they can be
differentiated at the outset from idiopathic (Bells) palsy. Further prospective trials are needed that substitute valacyclovir
for acyclovir so as to offer a less cumbersome dosing schedule.
Such a study might also be designed to formally assess the
contribution of corticosteroids in herpetic facial paralysis.
HSV gladiatorum.
Another cutaneous manifestation of
HSV infection affecting persons who participate in contact
sports (e.g., wrestling or rugby football) is herpes gladiatorum
[36]. This disease may involve the trigeminal, cervical, or lumbosacral dermatomes and is arbitrarily considered here. Commonly, HSV-1 is inoculated via abraded skin during the lock
position and lesions appear in 12 weeks. Recurrences are
frequent enough to be troublesome and may be unsightly, particularly when on the face, neck, and ears. Prophylactic use of
valacyclovir (500 or 1000 mg once or twice/day) during the
sports season has been helpful in such cases. The higher dose
regimen should be considered in cases of more recent primary
acquisition of infection (unpublished data) [37, 38].

Cervical and Thoracic Sensory Nerves Infections

Herpetic whitlow. This condition, caused by HSV-1 or -2,
is a painful infection of the digits seen predominantly in health
care professionals [39] (figure 2). Rowe et al. [40] reported that
the incidence of the disease is higher in dental personnel than
in the general population [40], although their study was done
before the routine use of disposable gloves in dental clinics.
Another study reported that of 46 patients seen by a dental

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cocutaneous immune defenses are locally impaired. For example, severe recurrences of HSV infection may complicate
laser-resurfacing surgery. Gilbert and McBurney [24], in an uncontrolled study, found that prophylactic valacyclovir (500 mg
twice/day) started either the day before or the day of facial
resurfacing and continued for 14 days thereafter almost completely eliminated the risk of HSV recurrence following this
procedure. Further controlled trials are needed to optimize the
duration and start time of therapy, together with a dosage regimen of valacyclovir [25].
Ocular HSV infections. HSV is a major cause of corneal
scarring and visual loss, the result not only of a direct viral
cytopathic effect but also an immune-mediated response [26].
In contrast to early antiviral agents, which demonstrated unacceptably high levels of systemic toxicity, acyclovir, when introduced almost 20 years ago, was shown to be highly selective
for herpesviruses with low systemic toxicity. Although originally developed as an ophthalmic ointment formulation outside
the United States, subsequent studies with oral acyclovir
showed good intraocular and tissue penetration [27, 28]. The
low systemic toxicity of acyclovir also made it an ideal candidate for long-term use in patients experiencing frequent ocular HSV recurrences.
More recently, a large controlled study investigating longterm suppressive oral acyclovir therapy for recurrences of HSV
epithelial keratitis and stromal keratitis was reported [29, 30].
This randomized, placebo-controlled trial concluded that acyclovir (400 mg twice/day for 12 months) was effective in reducing the rate of recurrences, especially in persons with a prior
history of HSV stromal keratitis. Continuous suppression
rather than intermittent dosing was suggested as the preferred
therapeutic option.
Oral valacyclovir administration provides improved bioavailability of acyclovir, suggesting that valacyclovir should be
evaluated as therapy for ocular HSV infections. In a randomized study in which patients about to undergo cataract surgery
received valacyclovir (1000 mg 3 times/day) or acyclovir (800
mg 5 times/day) to achieve steady-state concentrations, acyclovir concentrations in aqueous humor were about 40% of those
in plasma at the same, near maximum, time point [31]. Thus,
intraocular acyclovir concentrations appear to rise in parallel
with plasma concentrations.
Aqueous humor concentrations of acyclovir after valacyclovir administration were almost twice those found after oral
acyclovir (mean SD, 9.18 3.17 vs. 4.59 2.97 mM) and
after valacyclovir dosing exceeded the value of 7.5 mM previously reported for acyclovir ophthalmic ointment [32]. While
corneal tissue concentrations of acyclovir would be more relevant for assessing the potential efficacy of valacyclovir in ocular HSV disease, acyclovir penetration into ocular fluids after
valacyclovir administration should ensure a substantial excess
given the in vitro IC50 acyclovir susceptibility range of 1 mM
for most HSV-1 strains. Randomized controlled trials evalu-

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Simmons

hygienist over 4 days, 20 contracted gingivostomatitis. The hygienist was subsequently found to have herpetic whitlow [41].
Primary and recurrent herpetic whitlows are often associated
with painful neuritis in the affected digit and forearm. The
condition may last 3 weeks or more and patients may benefit
from episodic or suppressive acyclovir. Several cases have been
successfully treated with intravenous acyclovir regimens, including a 13-month-old girl [42] and a 35-year-old male dentist
[43]. While there have been no appropriate controlled clinical
trials with oral acyclovir or valacyclovir, the increased bioavailability of valacyclovir can be expected to offer advantages
in dosage and perhaps efficacy in treating herpetic whitlow.
HSV infection of the nipple. Reports of HSV infection of
the nipple, while extremely uncommon, most often relate to
transmission of HSV from infant to mother during breast-feeding [44]. Although treatment has not been defined in the literature, there is no reason to infer that acyclovir or valacyclovir
would be ineffective. If treatment of the mother were considered, dosages would be those recommended for HSV management at other anatomic sites. Transfer of acyclovir to the infant
via breast milk should be recognized [45] but not be considered
a contraindication to treatment when the infection is severe.
HSV Infections of the Lumbosacral Sensory Nerves
Of primary importance in the neuroanatomic context is how
the organization of the peripheral sensory nervous system relates not only to the pathogenesis but also to the diagnosis of
genital herpes. The sensory nerves arising from the sacral and
lower lumbar spinal segments innervate the genitalia in males
and females as well as a substantial part of the lower body,
including the buttocks, thighs, and perianal mucosa (figure 1).
As a consequence, when the lumbosacral ganglia become infected with HSV, lesions can occur at seemingly very different
anatomic sites. The buttocks, thighs, and perianal mucosa are
common sites of recurrent blistering that may not always be
recognized as genital herpes without an understanding of the

neuroanatomy involved. This is further compounded by the

fact that lesions are often atypical in appearance. In order to
maximize the chances of correct diagnosis and treatment, recurrent itching, burning, blistering, or erythema at any site
below the waist should be regarded as genital HSV infection
until proven otherwise. A swab taken from a recent eruption
is essential for confirmatory diagnosis. Serologic testing may
provide useful insight in diagnosing recurrent genital discomfort when the classic vesicular lesions of genital herpes are not
apparent. HSV-2 seroprevalence minimum estimates for general
adult populations, suggesting genital HSV infection, are about
5%25% in Western countries [46].
Two issues should be highlighted. First, perianal herpes does
not necessarily imply direct anal inoculation of HSV given infection in lumbosacral sensory nerves. Second, symptomatic
herpes in the sacral dermatome may sometimes be accompanied
by asymptomatic shedding from the genital mucosa. The importance of asymptomatic HSV reactivation and shedding in
sexual transmission of genital herpes and public health is reviewed elsewhere [47, 48].
To extend the neuroanatomic theme further, several cases
have been reported of HSV infections affecting the toes [42,
49, 50]. While it was generally assumed that autoinoculation
was the source of infection, it is likely that the sacral nerves of
the toes were responsible for the location of the lesions.
The role of antivirals in the management of genital herpes,
which effectively includes all HSV infections below the waist,
is discussed in detail elsewhere [51]. There have been several
recent advances in nucleoside analogues used for the treatment
of primary and recurrent genital herpes. In particular, valacyclovir was found to be as effective as acyclovir in the acute
treatment of primary and recurrent infections, with the advantage of a more convenient, twice daily dosing regimen [52, 53].
In addition, valacyclovir is effective when administered once
daily for suppressive management of recurrent genital herpes
[54, 55]. Ongoing research initiatives for new therapeutic strategies in genital herpes focus on modification of the immune
response (e.g., by therapeutic vaccination or local immune response modification) [56, 57] and on the potential for suppressive antiviral therapy to influence sexual HSV transmission
risk [47].
Neonatal HSV infections, although rare, can have grave consequences. Infection occurs via three distinct routes: in utero
infection, intrapartum contact, and postnatal acquisition. In
each case, although the mother is the most common source of
infection [3], there is usually no evidence of shedding at the
time of delivery [58]. Shedding may also occur from the uterine
cervix where lesions, if present, are hidden from view. Although
the safety and ease of administration of intravenous acyclovir
(10 mg/kg every 8 h) make it the treatment of choice for neonatal HSV infection, recent discussions have identified the
ideal of prevention of infection [59]. Although it has been suggested that prophylaxis with an antiviral agent should be of-

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Figure 2. Herpetic whitlow, an infection of the digits, seen primarily

in health care professionals.

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Scope of HSV Infections

S75

fered to pregnant women who have a history of genital herpes

or are seropositive for HSV-2, this strategy highlights areas
where information is needed on the ability of nucleoside analogues to interrupt vertical transmission of HSV infection and
on the safety of prolonged exposure of the preterm fetus to
antivirals.

Complications of HSV Infections of the Peripheral

Sensory Nervous System

HSV Infections of the CNS

Herpes simplex encephalitis is a life-threatening manifestation of infection usually caused by HSV-1 [64]. In neonates,
encephalitis accounts for 35% of babies with HSV infection

Figure 3.
infection.

Eczema herpeticum, a potentially serious and widespread

[65]. Progressive neurologic impairment is recognized as a sequel to herpes simplex encephalitis [64]. It has been hypothesized that this occurs as a result of accumulating damage caused
by frequent reactivations of HSV in the brain. This issue is
being studied in adults in a randomized controlled trial by
following the initial intravenous treatment of encephalitis with
a prolonged course of oral suppressive valacyclovir therapy
(Whitley R, personal communication). Two anecdotal reports
hint at the potential of this approach with valacyclovir for
prevention of further seizures [66, 67].
The possibility of an association between acute episodes of
multiple sclerosis (MS) and reactivations of herpesviruses continues to be a topic of interest. HSV, Epstein-Barr virus, and
human herpesvirus type 6 are all implicated [68]. In one study,
HSV-1 was detected in the blood of MS patients only during
acute episodes of the disease [65], suggesting that this virus
reactivates during acute exacerbations of MS. However, it is
unclear whether herpesvirus reactivation might precipitate the

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Eczema herpeticum. HSV infection is a particularly troublesome complication of atopic eczema [60] and frequently affects the head and neck if associated with autoinoculation from
orolabial herpes (figure 3). Eczema herpeticum is a potentially
serious and progressive disease for which suppressive therapy
with acyclovir may be indicated. In some patients, recurrences
are so severe that they cannot be suppressed adequately with
acyclovir. Some cases have been managed successfully with suppressive valacyclovir (1000 mg twice/day) (unpublished data).
Erythema multiforme and Stevens-Johnson syndrome. Erythema multiforme, an acute, usually self-limiting inflammatory syndrome, and Stevens-Johnson syndrome (SJS) are recognized as being part of a continuum of immunologically
mediated diseases of the skin. SJS is at the more severe end of
the spectrum. SJS is defined as erythema multiforme associated
with mucosal involvement, visceral involvement, or both, and
can be fatal. Viral infections including HSV-1 are recognized
as triggers for these severe cutaneous conditions [61]. The efficacy of continuous acyclovir therapy (600 mg twice/day for
6 months) in preventing outbreaks was demonstrated for recurrent erythema multiforme and in some cases resulted in complete disease remission [61, 62].
Choy et al. [63] used suppressive acyclovir (200 mg twice/
day) following acute treatment (200 mg 5 times/day) at the onset
of herpetic oral lesions to treat a patient with recurrent HSVassociated SJS. The interval between the onset of herpetic lesions and erythema multiforme prior to acyclovir intervention
was 713 days. The patient was followed for 6 months (FebruaryJuly) and, following acyclovir intervention, erythema
multiforme did not occur in April, May, or July despite oral
herpetic lesions in March, April, May, and July. Single-case
statistical analysis demonstrated a reduction of the HSV lesions
and erythema multiforme with acute and prophylactic acyclovir
regimens. Although effective, the acyclovir regimens evaluated
in erythema multiforme and SJS might be improved by the
greater bioavailability of valacyclovir, which offers more convenient dosing and better control of HSV reactivation.

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Simmons

episode. Further trials of antiviral compounds in MS patients

with dosage regimens that facilitate CNS penetration of active
compounds seem warranted.

15.
16.

Conclusions

17.

18.
19.
20.

21.

22.

23.

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An intimate relationship with the sensory nervous system is

the common thread linking many manifestations of HSV infection. Acyclovir has been used to treat herpesvirus infections
for about 20 years and knowledge regarding its clinical utility
is well documented. Acyclovir is highly specific for herpesvirusinfected cells and sets the standards for efficacy and safety. The
development of valacyclovir should ensure a less onerous treatment schedule and better compliance, without loss in clinical
benefit, alongside maintenance of the highly acceptable safety
profile of acyclovir. Future strategies for combating HSV are
likely to continue through the search for effective vaccines and
immune modifying agents and ideally will target the control of
HSV infection at the level of the sensory nerve ganglia.

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Scope of HSV Infections

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