V J Differentiating Herpes Simplex Virus and
Recurrent Aphthous Ulcerations
By JoAnn R. Gurenlian, RDH, PhD
Abstract
Recurrent oral ulcerations are commonly seen in
dental office settings and arc a source of discomfort and
frustration for clients, lr is often a challenge to distin-
guish one type of ulccration from another. Recurrent
herpes simplex virus (HSV) and recurrent aphthous
stomatitis (RAS) represent a classic example of lesions
that arc similar in clinical presentation and course.
Because they share more similarities than differences clin-
ically, they are easy to misdiagnose. This article discusses
the features of both ulcerative conditions.
Introduction
In the course of a career, dental hygienists and den-
tists are likely to encounter numerous oral ulcerative con-
ditions, clinically. Some of them are easily identified; oth-
ers share similar characteristics and histories, making it
difFtcuk to determine an accurate diagnosis without fur-
ther diagnostic study. Recurrent herpes simplex virus
(HSV) and recurrent aphthous stomatitis (RAS) share
similar clinical features; however, one represents an infec-
tious process, while
the other remains an
Recurrent hemes simplex virus (HSV) enigma in terms of
and recurrent aphttious stomatitis (HAS) etiology. Differentia-
share simtiar citnicai features. However, ting between HSV
and RAS is impor-
one represents an intectious process, tant in terms of client
while the other remains an enigma in education, health care
provider infection con-
terms of etiology.
trol, and treatment
considerations. The
purposes of this paper are to highlight clinical character-
istics of HSV and RAS and to describe treatment consid-
erations for each disease.
Herpes Simplex Virus
There are rv/o types of herpes simplex virus: herpes
simplex virus type I (HSV-1) and herpes simplex virus
type 2 (HSV-2). While the viruses are similar, HSV-1
30 FEBRUARY 2003
typically causes oral disease while HSV-2 causes genital
disease; however, both can cause oral or genital disease.
HSV-1 is the dominant viral serotype that causes oral and
perioral tissue recurrences and is Frequently referred to as
"cold sores" or "fever blisters." Recurrent HSV-1 infec-
tions of the lip and perioral areas occur in 20-^0% of the
population worldwide.' Approximately 4 0 - 6 3 % of the
U.S. population is seropositive for HSV-1 .^ An estimated
20-40% of individuals suffer from recurrent outbreaks of
HSV-1.^
Transmission of HSV is by person-to-person con-
tact. Infection is most commonly acquired in infancy or
childhood through contact with relatives. The virus may
be shed despite the absence of typical cold-sore symptoms
at the time of transmission. Further, it is possihie to shed
infectious virus particles in saliva without the presence of
noticeable symptoms.
Once the virus is transmitted, the incubation period
for oral lesions varies from rwo co 12 days. Primary oral
infection is usually asymptomatic in the beginning stages.
When symptoms do occur they tend to present with sys-
temic features including fever, malaise, anorexia, lym-
phadenopathy, sore throat, and gingivoscomatitls. All
surfaces of the mouth may be involved, beginning with a
vesicular rash that ulcerates. This condition l;ists for
10-14 days and then resolves spontaneously. Primary oral
infection may prevent eating and drinking, which when
combined with fever and malaise may lead to dehydra-
tion. In an immunocompromised individual, primary
herpes infection can cause severe illness and may lead to
herpetic hepatitis or encephalitis. These conditions may
be fatal. Although the oral symptoms resolve in time,
shedding of the virus after primary infection may continue
for up to three weeks.
Following primary infection, neutralizing antibodies
to HSV develop that protect against funher exposure to
HSV. However, these antibodies do not prevent reactiva-
tion of latent HSV. Up to 40% of individuals with anti-
bodies to HSV develop secondary or recurrent herpes
infections.''
In addition, after the primary infection, the virus
migrates along a sensory nerve ending to a nerve ganglion
where it establishes a latent infection. During this latent
period, there are no clinical signs of infection. It has been
suggested that HSV is present in the trigeminal ganglia in
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almost 20% of individuals younger than 20 years and in most common and occur in approximately 80% of cases.
almost 100% of persons 60 years of age.* Major aphthous ulcerations occur in approximately 10% of
It is not known why some individuals with normal the affected population and the remaining individuals have
immune function develop recurrent HSV while others do the herpetiform type of aphthous ulcerations.
not. The virus may reactivate at any time. Usually, a "trigger" Minor RAS lesions arise typically on nonkeratinized
such as fever, exposure to ultraviolet light, stress, menstrua- mucosa and exhibit the shortest duration. The lesions devel-
tion, trauma (Including dental procedures), immune sup- op an erythematous macule and may have prodromal symp-
pression, or cancer therapy stimulates reactivation and recur- toms of burning, itching, swelling, or stinging. The macule
rent HSV lesions. develops an ulceration covered by a yellow-white, removable
Recurrent herpetic infection occurs in several stages. fibrinous membrane encircled by an erythematous halo. The
Typically, clients report a prodromal period. Symptoms size of minor ulcers varies from <1 to 10 mm in diameter.
include tingling, burning, itching, or pain. This period They tend to heal without scarring in seven to 14 days. One
reflects the virus replication in sensory nerve endings. tofiveulcers may be present during each occurrence, and the
Within 24 hours, erythematous maculopapular lesions lesions tend to be extremely painful in comparison to their
appear that rapidly develop into small vesicles or blisters. size. The buccal and labial mucosa are the most commonly
The vesicles expand and coalesce and then rupture. Ulcers involved sites for minor RAS. Figure 2 illustrates a clinical
form, followed by crusting, which can remain for five to six presentation of RAS.
days. When the crust is shed, there may be some residual Major RAS lesions are larger than minor aphthous
skin flaking or transient swelling noted. Healing is consid- ulcerations and have the longest duration per episode. Major
ered complete when the crust is lost and the skin reepithe- RAS IS the most severe
lializes, typically within 10 to 14 days.^''"" form of aphthous
While recurrent HSV mainly affects the lip (herpes labi- stomatitis. Lesions
aJis—Figure 1), lesions may appear on the cheeks, chin, and may vary in number
nose. In addition, recurrent HSV can cause intraoral ulcera- from one to 10, and
tions affecting both keratinized and nonkeratinized tissues.'^ measure from 1 - 3
In approximately one-fourth of cases, individuals with cm in diameter. The
prodromal symptoms will find that the process is aborted. labial mucosa, soft
They may experience itching and tingling, but no vesicles or palate, and tonsillar
ulcers form.'^ It has been suggested that therapeutic inter- fauces are the most
vention early in the prodromal stage can abort some episodes commonly affected
that would otherwise progress to the characteristic herpes sites. Lesions take
lesion or reduce the duration of episodes and healing two to six weeks to Figure 1.
heal, and may cause
scarring.
Recurrent Aphthous Stomatitis Herpetiform RAS
tends to have small
Recurrent aphthous stomatitis (RAS), often referred to multiple lesions rang-
as "canker sores," is one of the most common nontraumatic ing from 1—3 mm in
ulcerative conditions of the oral mucosa. Incidence varies, diameter. The lesions
ranging from 1 5-60%, depending on the population stud- bear a superficial re-
ied. Remissions and rates of recurrence vary. semblance to primary
The etiology of RAS remains unknown; however, mul- HSV, but are not
tiple factors have been implicated. Heredity, immunology, preceded by vesicle
allergic responses, trauma, stress, hormonal changes in formation. Lesions
women, chemical irritants, nutrition deficiency, and genetics often coalesce into
have all been suggested as contributing factors to or poten- larger irregular ulcera- Figure 2.
tial causes of RAS.'"•'"*•'* These various catises tend to repre- tions. Any oral mucosa
sent three processes: primary immunodysregulation with aT may be involved, although nonkeratinized, movable mucosa
cell-mediated immunologic reaction, decrease of the mucos- is most frequendy affected. The ulcerations tend to heal
al barrier, and increase in antigenic exposure.''' Systemic dis- within seven to 10 days.
eases have also been associated with aphthouslike ulcera-
tions, including Behcet's disease, celiac disease, cyclic neu-
tropenia, IgA deficiency, inflammatory bowel disease, and Diagnosis of HSV and RAS
immunocompromising conditions including HIV disease.
There are three clinical subgroups of RAS: minor, Diagnosis of HSV and RAS is frequently made based on
major, and herpetiform. Minor aphthous ulcerations are the the client's history and clinical presentation. Clinical distinc-

access FEBRUARY 2003 31

 tions between RAS and recurrent HSV may be based on
vesicles preceding ulcens, clustering of ulcers, and location.
The differential diagnosis of primary HSV includes
streptococcal pharyngitis, erythema multiforme, and Vincents
infection. Differential diagnosis of recurrent HSV includes
trauma, chemical bums, contaa stomatitis, impetigo, herpan-
gina, and RAS. The differential diagnosis for RAS consists of
ctauma, ulcer from odontogenic infection, nutritional defi-
ciency, squamous cell carcinoma, chancre, and systemic dis-
eases such as Behcet's Syndrome or celiac disease.^''•'•"
No laboratory procedures provide a defmitive diagnosis
for RAS. However, there are laboratory studies that can be
used to defmitivcly diagnose HSV The difficulty with diag-
nostic studies is that the viruses are shed quickly after vesi-
cles rupture. Timing is critical to
obtaining accurate information.
flitflCUtty with Culturing is one method to determine
cUagnosdc studies is ^^"^^ -^^ '"^^" ^^''^''^'' unroofbd and
^ - -. ^ _- vesicle fluid is collected on a sterile
that tlie viruses are ^^^^ ^-^^ ^^^j, .^ p,^^j -^ „ ,„,,„,,
QlltCUy after medium. It may take up to two weeks
Dre. for results to be obtained. A fresh blis-
is CrrflCal to '^' '^^^ ^^ evaluated using a Tzanck
. smear, a polymerase chain reaction
accurate ^p^^^,^ and direct immunotluores-
cence antibody studies of scrapings
from the base of an unroofed vesicle
can be performed. Scrologic tests for HSV antibodies can be
performed and will be positive four to eight days after initial
exposure. Antibody titers are useful in documenting past
exposure to HSV.
Treatment Considerations
Treatment of HSV includes palliative measures and
medication management- For cases of primary HSV, sup-
portive management may include the use of topical anes-
thetics, analgesics, and nutrition supplements. Topical anes-
thetics may include a rinse with diphenydramine mixed with
Kaopectate or Maalox, or a solution of dyclonine HCX. If
dehydration and difficulty eating are concerns, nutrition
supplements (e.g.. Ensure) can be recommended. In cases in
which the client is experiencing significant discomfort, acet-
aminophen can be prescribed. For more severe pain, aceta-
minophen with codeine may be needed. If the client is seen
in the early stages of the disease and clinical severity warrants
it, acyciovir can be prescribed. The typical dosage is 200 mg
five times daily for 1 0 days. Although acyciovir may shorten
the clinical course of the di.sease, it does not reduce the inci-
dence of recurrent HSV. Presently, the U.S. Food and Drug
Administration (FDA) recommends that systemic acyciovir
be used to treat oral herpes only in immunocompromised
individuals.
Recurrent HSV therapy consists of a wide variety of pal-
liative agents. Treatments have included the use of ice
32 FEBRUARY 2003
applied during che prodromal stage or with early lesions,
over-the-counter (OTC) products, lysine ingestion, and
alcohol. Topical therapy is often used to treat recurrent infec-
tion. Symptomatic types of topical treatment include the tise
of O T C products such as Orabase and Zilactin.
Two newer topical agents tbat have demonstrated effi-
cacy in the treatment of HSV include Abteva (docosanol
10% cream) and Denavir (penciclovir cream). Docosanol Is
a saturated 22-carbon primary alcohol that acts by inhibit-
ing viral encry into epithelial cells, thus inhibiting viral
replication. This mode of action is advantageous in that
drug resistance with docosanol is unlikely to occur since the
product does not interact directly wich viral proteins or
nucleic acid. Clinical trials using randomized, double-blind,
placebo-controlled designs involving the use of docosanol
cream have demonstrated clinical efflcacy.^"'^' Reduced
times have been noted for cessation of prodromal and clin-
ical symptoms. Abreva (10% docosanol cream) is the first
and only O T C produce that is approved by FDA. Because it
is available OTC, clients have the added advantage of not
having to wait for a prescription to be called in and pre-
pared.
Penciclovir cream (Denavir) is an acyclic guanine ana-
log that works in a manner similar to acyciovir (Zovirax)
to inhibit DNA synthesis and viral replication. A report of
a randomized, multicenter, double-blind, placebo-con-
trolled clinical trial indicates thai favorable outcomes were
found with respect to healing time, duration of pain, and
duration of viral shedding when compared with the vehi-
cle control."
If a recurrence of herpes labialis is triggered by exposure
to ultraviolet light, the lesion may be prevented by use of top-
ical application of sun-block with a high skin protection fac-
tor of SPF 13 or higher. When frequent recurrences occur
associated with immunocompromised individuals, use of sys-
temic acyciovir, valacyclovir (Valtrex), or famciclovir (Famvir)
may be used either as a therapeutic or prophylactic agent.
However, indi.scriminate use of systemic antiviral medications
for mild cases of recurrent HSV is inappropriate.
Because HSV represents an infectious process, clients
need to be educated concerning preventive behaviors.
Individuals with HSV should be advised that their cold sores
are highly contagious from the prodromal stage until the
blisters are completely healed. Dental and dental hygiene
treatment should be postponed when clients present with
evidence of primary or recurrent herpes simplex infection.
Clients should be instructed to resist contact with active
lesions to prevent it from spreading to other sites and other
people. Auto inoculation can occur and cause permanent
damage and even blindness when the eyes are affected. If
individuals find themselves touching their cold sore, they
should be instructed to thoroughly wash their hands with
soap and water. Individuals should be cautioned to resist
sharing items that come in contact with the lesion, such as
drinking glasses, straws, eating utensils, lipstick, toothbrush-
es, and washcloths. With respect to sexual practices, clients
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should avoid kissing and engaging iti oral sex utitil the cold
sore is completely healed.
Oral health care providers need to he astute about rec-
ognizing HSV and taking appropriate precautions in clinical
practice. Shedding of the virus can he expected during active
stages of the disease, as well as during asymptomatic periods;
therefore, dental personnel are at an increased risk of con-
tracting HSV from their clients. Since the timespan for
asymptomatic shedding of virus particles in the saliva
varies,^ ' it may be helpful to develop an office policy to
promote safety of practitioners. One approach may be to
postpone all dental treatment in clients with evidence of
HSV until two weeks after the lesion has completely healed.
Clients can be instructed to contact the ofFicc when the
lesion has completely resolved, so that they can be resched-
uled accordingly.
As with HSV, treatment of RAS is most effective
when initiated early in the course of the lesion. However,
no medication provides complete relief or can cure the
condition. A review of the client's medical history should
be performed to identify signs and symptoms of systemic
disease that may be associated with apbthous ulcerations.
If medical conditions or nutrition deficiencies are suspect-
ed, referrai to a primary care provider or medical specialist
is indicated.
For cases oi mild or minor RAS, periodic topical thera-
py is used to minimize the frequency and severity of occur-
rences. As with the treatment of HSV, there are numerous
OTC, products that can be used to palliate symptoms. Little,
et al. recommend the use of 5% amlexanox oral paste
(Apbtbasol) for treatment of RAS." Amlexanox is a ben-
zopyrano-bipyridine carboxylic acid derivative that has anti-
inflammatory and antiallergenic properties. Studies of 5%
amlexanox paste have demon.strated that it accelerates the
resolution of pain and healing of aphthous ulcers and is clin-
ically safe.'^^
Major RAS is more difficult to treat than minor aph-
thae. Therapies attempted with limited and varying results
included acyciovir, amlexanox, chlorhexidine, gamma globu-
lin, and interferon-a. Examples of topical steroids used to
treat major apbthae include triamcinolone acetonidc in
Orabase 0.1% and dexamethasone (Decaderon) elixir.
Systemic medications used to treat major RAS include
thalidomide, azathioprine, cyciosporin, colchicines, and
dapsone. These therapeutic agents are toxic and require spe-
ciali.st supervision.
Herpetiform aphthous ulcerations appear to be best
managed with a tetracyclme mouth rinse. The contents of a
250 mg capsule can be mixed in water and used to rinse the
mouth for two to three minutes, three times daily.''' For
clients susceptible to fungal infection when using antibiotics,
an antifungal agent may be prescribed to prevent suprainfec-
tion by Candida albicans.
For a summary of the therapeutic management of HSV
and RAS, Little, et aJ. provide a ready reference concerning
products, dosage, and administration.^''
access
Conclusion
Although HSV and RAS may be difficult to differenti-
ate clinically, there are distinctions in history and clinical
presentation as well as laboratory testing that allow for defin-
itive diagnosis. Careful que.stioning of and follow-up with
the client and thorough documentation of findings for
future reference are important
considerations in caring for indi-
viduaLs witb tbese ulcerative con- " mCHiCal GOnditJOnS Or
ditions. Distinguishing i u s and nutntlon deficJencies are
HSV will allow the oral health SUSP^tCd, refeiTal tO 3
professional an opportunity to primarv cafc provider OT
better educate clients concerning
appropriate prevention and treat- '"CdiCal SPeCiBllSt IS
indicated.
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JoAnn R. Gurenlian. RDH, PhD, is an internationally recog-
nized authar, research consultant, and speaker. Gurenlian is
the owner of Gurenlian and Associates, offering consulting
and continuing education services to health care profes-
sionals. In addition to having clinical experience in peri-
odontal, general, pediatric, and orttiodontic practices, she
cunently works part-time in a medical practice enhancing
her assessment and diagnostic skills.
Correspondence regarding "DHDx and Oral Medicine" may
besentby fax to 312/467-1702 oremailtodhdx@adha.net.
access