viral diseases of the oral mucosa
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very good to know about viral diseases affecting oral cavityTRANSCRIPT
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Viral diseases of the oral mucosa
Bethany R. Hairston, MDa, Alison J. Bruce, MDb,c,*, Roy S. Rogers III, MDb,c
aDepartment of Dermatology, Mayo Graduate School of Medicine, Rochester, MN 55905, USAbDepartment of Dermatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
cDepartment of Dermatology, Mayo Medical School, Rochester, MN 55905, USA
The oral mucosa is often involved in diseases
caused by viral pathogens. Viruses isolated from the
oral cavity may be direct causative agents, adjuncts in
the disease process, or superinfection of a separate
primary process. Viruses have variable mucosal pro-
cesses and stages of evolution, and many viruses have
similar clinical presentations. Often, the investigator
must consider the oral lesions in the context of the
general clinical presentation and use laboratory tests
for diagnosis. Both DNA and RNAviral families have
been implicated in oral mucosal diseases.
DNA viruses
Human herpesvirus
Multiple human herpesvirus (HHV) serotypes are
associated with oral diseases (Table 1). All HHVs
consist of double-stranded DNA. The viruses replicate
in the host cell, causing both cytopathic and inflam-
matory-mediated cell damage.
Human herpesvirus 1 and human herpesvirus 2
( herpes simplex viruses)
Herpes simplex virus (HSV)-1 and HSV-2 are
associated with primary and recurrent mucocutaneous
disease. The location of the disease depends on the
site of inoculation. HSV-1 is responsible for more than
90% of the lesions caused by HSV in the oral mucosa
[1]. More than 85% of the worlds population has
serologic evidence of previous HSV-1 exposure [2].
Most persons are exposed to the virus during child-
hood by mucocutaneous contact with another infected
person. A primary infection is the first infection with
HSV in a seronegative patient; many people have
asymptomatic primary infections and are unaware that
they harbor the virus.
Primary exposure to HSV-1 and, less commonly,
HSV-2 results in the syndrome known as primary, or
acute, herpetic gingivostomatitis. The disease is most
common in children 1 to 5 years old or young adults,
and the onset is approximately 5 to 10 days after
intimate mucocutaneous exposure to HSV. The virus
must come into contact with the mucosa or abraded
skin for infection to occur [3]. Fever, sore throat, and
painful vesicles that progress to erosions and ulcer-
ations may be present. Most commonly, lesions are
located on the buccal and gingival mucosa, hence, the
term gingivostomatitis (Fig. 1). Both keratinized and
nonkeratinized oral mucosa may be involved [4]. In
severe cases, dysphagia and lymphadenopathy may be
present. The episode usually lasts 10 to 14 days.
Primary infections in adults are less likely to result
in gingivostomatitis; however, HSV-associated phar-
yngitis may be a component of a mononucleosis-like
syndrome (Fig. 2) [5].
Following primary infection, HSV migrates by
retrograde axonal flow to the sensory ganglion inner-
vating the primary lesion [6]. An eruption that occurs
after latency is known as reactivated or recurrent
infection and occurs in approximately 40% of those
harboring HSV-1 [7,8]. HSV-2 recurrences in the oral
mucosa are less common than HSV-1 recurrences [9].
Recurrences generally are milder and of shorter dura-
tion than primary episodes in immunocompetent hosts
0733-8635/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S0733 -8635 (02 )00056 -6
* Corresponding author. Department of Dermatology,
Mayo Clinic, 200 First Street Southwest, Rochester,
MN 55905.
E-mail address: [email protected] (A.J. Bruce).
Dermatol Clin 21 (2003) 1732
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and typically occur three or four times per year.
Activation of the virus with subsequent anterograde
migration along the sensory nerve usually is heralded
by a tingling, itching, or burning sensation at the
vermilion border. Clustered lesions progress from
erythematous papules to vesicles and may ulcerate,
producing the characteristic lesions of herpes labialis
(Fig. 3). Recurrent intraoral HSV with vesicles and
ulcers on the gingivae and hard palate may occur
alone or in parallel with herpes labialis (Fig. 4).
Healing generally occurs in 8 to 10 days.
Recurrences may be spontaneous or associated
with multiple factors, including emotional stress,
fatigue, illness, dental trauma [10], neurosurgical
axonal injury [11], orofacial fracture [12], and ultra-
violet light [10,13,14]. Immune system compromise
from malignancy or immunosuppressive therapy
[15,16], radiation therapy [17], transplantation regi-
mens [1820], and HIV infection [21,22] may result
in more frequent and more severe recurrences, with
potential extension into the deep mucosal and cuta-
neous layers of the skin [23].
Recurrent erythema multiforme has been linked to
preceding HSV infection and is known as herpes-
associated erythema multiforme (Fig. 5) [24,25]. In a
British study that reviewed recurrent erythema multi-
forme, approximately 71% of cases had previous HSV
infection. Oral erosions or ulcerations were common
Table 1
Herpetic infections of the oral mucosa
Oral disease Etiology
Herpetic gingivostomatitis HSV-1, HSV-2
Herpes labialis HSV-1, HSV-2
Varicella HHV-3 (varicella-zoster virus)
Herpes zoster HHV-3 (varicella-zoster virus)
Mononucleosis HHV-4 (Epstein-Barr virus)
Oral hairy leukoplakia HHV-4 (Epstein-Barr virus)
Cytomegalovirus HHV-5
Exanthema subitum HHV-6
Kaposis sarcoma HHV-8
Abbreviations: HHV, human herpesvirus; HSV, herpes
simplex virus.
From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and
management of oral viral infections. Dermatologic Therapy
2002;15:27187: with permission.
Fig. 1. Primary herpetic gingivostomatitis. (A) Vesicles and erosions of palate. (B) Well-circumscribed erosions of tongue.
(C) Vesicles and erythema of gingivae and interdental papillae. (D) Labial mucosal vesicles and erosions. [(A) and (D) From
Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatol Ther 2002;15:27187. By
permission of Blackwell Publishing, Inc: with permission.]
B.R. Hairston et al / Dermatol Clin 21 (2003) 173218
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(69%), especially of the buccal mucosa and palate
[24]; targetoid lesions of the lips have also been
described [25].
Diagnosis of primary and recurrent HSV is aided
by the location and configuration of the lesions and
associated clinical features. Differentiation of herpetic
lesions from the herpetiform variant of recurrent aph-
thosis may be difficult [26]. Typically, aphthous ulcer-
ations occur predominantly on the nonkeratinized
mucosa, whereas recurrent HSV generally is found
on keratinized mucosa overlying bony prominences
(ie, alveolar ridges and the hard palate) [26,27].
Multiple laboratory tests are available to assist in
the diagnosis of herpetic infection (Table 2). Under
ideal conditions, the Tzanck smear is positive in
approximately 50% of HSVinfections [28]. Histologic
examination demonstrates a combination of direct
cytopathic effect and inflammatory response [3]. Tra-
ditionally, the reference standard of diagnosis has been
culture, with sensitivity increased in early vesicular
lesions, primary disease, and immunosuppressed per-
sons [23]. The polymerase chain reaction (PCR)
detects specific DNA sequences in HSV infection
and herpes-associated erythema multiforme [25,29]
and is more sensitive than cell culture for detecting
HSV [3032]. Direct immunofluorescence [33] and in
situ hybridization (ISH) [34] demonstrate HSV in
cutaneous specimens. Serologic testing is useful in
identifying past infection but has little value in dia-
gnosing acute mucocutaneous HSV infection because
titers are slow to rise [23].
Mouth rinses containing topical anesthetic agents
(viscous lidocaine [Xylocaine]) or diphenhydramine
(Benadryl) plus coating agents (magnesium-contain-
ing antacids) are helpful in relieving oral discomfort in
severe herpetic gingivostomatitis [4]. Fluid and elec-
trolyte balance should be maintained in infants and
children. In a randomized, placebo-controlled clinical
trial, oral acyclovir was effective for herpetic gingivo-
stomatitis in children, but it has not been approved by
the US Food and Drug Administration (FDA) for this
indication [35].
Topical agents are often used to treat recurrent
herpes labialis. In a recent double-blind, placebo-
controlled study of recurrent herpes labialis, docosanol
10% cream, a 22-carbon, saturated, primary alcohol
available as an over-the-counter medication (Abreva),
was found to be clinically efficacious in decreasing the
mean time to healing and the duration of symptoms
[36]. Penciclovir (Denavir) is a topical nucleoside ana-
logue superior to both placebo [37] and acyclovir for
treatment of recurrent herpes labialis [38]; it has been
approved by the FDA for recurrent disease. Topical
Fig. 2. Herpes pharyngitis, with erythema and erosions of
posterior oropharynx.
Fig. 3. (A) Recurrent herpes labialis of lower lip. (B) Well-circumscribed erosions of lateral tongue in association with lip lesions.
[(A) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy
2002;15:27187: with permission.]
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 19
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acyclovir cream and ointment have been less effective
for the treatment and suppression of recurrent HSV,
likely because of poor absorption through perioral
skin [14]. These three topical agents were compared
recently in an animal model (guinea pig) of cutaneous
HSV, and the efficacy of penciclovir was greater than
that of acyclovir cream, which was greater than or
equal to that of acyclovir ointment; the efficacy of all
compared agents was superior to that of docosanol
cream [39]. Protection of the lips from ultraviolet
exposure with sunscreen is also beneficial [13].
Oral antiviral therapy has not been approved by the
FDA for either the treatment or suppression of herpes
labialis in immunocompetent persons; however, acy-
clovir has proved to be efficacious in decreasing
lesion size and healing time without decreasing the
number of lesions if treatment is started in the pro-
drome or erythema stage [14]. Famciclovir (Famvir),
the well-absorbed oral prodrug of penciclovir, has
been shown clinically to decrease lesion size and time
to healing in herpes labialis induced by ultraviolet
light [40]. Acyclovir prophylaxis against herpes labi-
alis has been demonstrated to decrease the frequency
of recurrent episodes [41,42]. The effects from the
therapy do not seem to be long-lasting, however,
because the pretreatment recurrence rate returns after
cessation of acyclovir treatment [41].
Acyclovir is the treatment of choice for immuno-
suppressed persons; oral, intravenous, and topical
ointment formulations have been approved by the
FDA [43]. Intravenous foscarnet (Foscavir) is recom-
mended for acyclovir-resistant disease [44]. Suppres-
sive therapy with acyclovir is commonly used in
transplantation and chemotherapeutic regimens [45].
Famciclovir is indicated for the treatment of recurrent
herpes labialis in HIV because it is as effective and
well-tolerated as high-dose acyclovir [46]. Famci-
clovir also has been shown to decrease the frequency,
duration, and severity of HSV recurrences in HIV-
infected persons, but it has not been approved by the
FDA for this indication [47].
Human herpesvirus 3 (varicella-zoster virus)
Primary infection with varicella-zoster virus
(VZV), resulting in varicella, occurs through direct
contact with lesions or inhalation of infective respi-
ratory droplets. Varicella is primarily a disease of
childhood, with 90% of cases occurring in children
younger than 10 years [48]. One study has demon-
strated a nearly 99% rate of serologic immunity
among adults [49]. The disease generally is more
severe and prolonged in older persons [50].
After a 14- to 16-day incubation period following
exposure to VZV, a generalized pruritic eruption with
crops of erythematous maculae, papules, vesicles,
pustules, and crusted lesions begins on the face and
spreads rapidly to the trunk, with relative sparing of
the extremities. Oral lesions may coincide in onset
with the cutaneous eruption. Painful vesicles that may
ulcerate are found most commonly on the palate or
buccal or pharyngeal mucosa (Fig. 6) [51].
Fig. 4. Recurrent intraoral herpes simplex virus in patient
with hairy cell leukemia.
Fig. 5. Herpes-associated erythema multiforme. (A) Hemorrhagic crusting of lower lip. (B) Targetoid papules of palm.
B.R. Hairston et al / Dermatol Clin 21 (2003) 173220
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Similar to HSV, VZV establishes latency in sen-
sory ganglia. Recurrent disease occurs in the derma-
tome innervated by the affected sensory ganglion. A
recurrent episode is known as herpes zoster. Among
multiple predisposing factors for herpes zoster are
HIV [22,5254], malignancy [55,56], iatrogenic
immunosuppression with corticosteroids [57], trans-
plantation regimens [50,58], and senescence of the
cellular immune system related to aging [59].
The clinical features of herpes zoster include a
dermatomal eruption heralded by segmental neuralgia
and pruritus, followed by herpetiform vesicles and
erythema with progression to pustules and crusting in
7 to 10 days. Cephalic zoster involves the second and
third divisions of the trigeminal nerve and may present
with oral cavity vesicles on an erythematous base,
with erosions, ulceration, and crusting preceded by
odontalgia (Fig. 7) [60]. Tooth exfoliation and man-
dibular necrosis are reported complications [54,61].
Ramsay Hunt syndrome, with neuritic involvement
and inflammation of cranial nerves VII and VIII, may
result in tinnitus, vertigo, otalgia, ageusia, hearing
loss, and mucosal lesions on the palate and anterior
two thirds of the tongue [62]. Facial palsy and deaf-
ness are potential complications.
Table 2
Diagnostic tools for detection of herpetic infections
Test Method Medium Comments
Histopathology Hematoxylin and eosin stain Tissue Ballooning and reticular
epidermal degeneration with
multinucleated keratinocytes
in HSV, VZV [3]
Cytomegalic nuclear and
cytoplasmic inclusions in
CMV [94]
Direct
immunofluorescence
Epifluorescence microscopy
following monoclonal antibody
application [33]
Tissue Useful for HSV, VZV [33],
and EBV [84]
Culture Cell culture growth to detect
cytopathic change [28]
Tissue, vesicular fluid Reference standard of detection
for all herpesviruses
Polymerase
chain reaction
Identification of viral nucleic acid Tissue, vesicular fluid,
paraffin-embedded
Most sensitive means of detecting
HSV [3032] and VZV [28,64]
tissue [65] Effective for all herpesviruses
In situ hybridization
Serology
Tzancks smear
Fluorescein-labeled DNA probe
visualized with antifluorescein
antibody [66]
Detection of antibodies
Characteristic viral cytopathic changes
Tissue, paraffin-
embedded tissue
Serum
Vesicle base scraping
Demonstrates location of virus
in tissue
Useful for HSV [34], VZV [66],
EBV [75,83], and CMV [94]
Correlation with past infection
Rapid, inexpensive
Multinucleated keratinocytes in
HSV and VZV [28,63]
Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; VZV, varicella-zoster virus.
From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management of oral viral infections. Dermatologic Therapy
2002;15:27187: with permission.
Fig. 6. Varicella infection with vesicles and surrounding
palatal erythema. (From Bruce AJ, Hairston BR, Rogers RS
III. Diagnosis and management of oral viral infections.
Dermatologic Therapy 2002;15:27187: with permission.)
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 21
-
The diagnostic methods for VZV are similar to
those for HSV. The Tzanck smear is positive in ap-
proximately 75% to 80% of cases of herpes zoster and
viral cultures are positive in 44% to 60%, reflecting
the difficulty with culturing VZV [28,63]. PCR is
more sensitive than viral culture [28,64] and can detect
VZV in formalin-fixed tissue specimens, vesicle fluid
swabs, crusts, and Tzanck smear debris [65]. Neither
PCR nor culture reliably demonstrate VZV from oral
samples in primary varicella, however, because the
virus is not harbored in the oropharynx after the
incubation period [64]. Direct immunofluorescence
[33] and ISH [66] also distinguish VZV from HSV.
Positive serology correlates with immunity [67].
Acyclovir has been shown to decrease both the
duration and severity of varicella in children [68];
however, it has not been approved by the FDA nor
widely used in clinical practice because of the benign
course of the disorder in immunocompetent hosts,
financial considerations, and concern for emergence
of acyclovir resistance. Painful oral lesions may
respond to topical anesthetic mouth rinses [69]. Acy-
clovir is the drug of choice for adults and immunosup-
pressed persons. The live, attenuated OKA varicella
vaccine has been approved by the FDA and is given to
persons older than 12 months, those with chronic dis-
ease, and those who are immunosuppressed [48,70].
Intraoral herpes zoster generally is more severe
and painful than oral varicella; oral analgesics admin-
istered in combination with topical anesthetic prepa-
rations may be needed. Acyclovir, famciclovir, and
valacyclovir (Valtrex) have all received FDA approval
for treatment of herpes zoster because the three agents
have comparable efficacy and safety profiles [7173].
Corticosteroids generally are not necessary for ad-
junctive treatment in herpes zoster except in Ramsay
Hunt syndrome, for which the combination of acy-
clovir and prednisone has been shown to reduce facial
nerve degeneration [74].
Human herpesvirus 4 (Epstein-Barr virus)
Epstein-Barr virus (EBV)induced diseases with
oral manifestations include infectious mononucleosis,
oral hairy leukoplakia, and Burkitts and nasopha-
ryngeal lymphomas. EBV infects multiple cell lines,
including B and T lymphocytes and squamous epithe-
Fig. 7. Herpes zoster. (A) Unilateral erythema, erosions, and crusting of upper lip and cheek. (B) Erosion of palate. (C) Unilateral
erosion and fissuring of tongue (arrow). [(A) and (B) From Bruce AJ, Hairston BR, Rogers RS III. Diagnosis and management
of oral viral infections. Dermatologic Therapy 2002;15:27187: with permission.]
B.R. Hairston et al / Dermatol Clin 21 (2003) 173222
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lial cells of the oropharyngeal and nasopharyngeal
mucosa [75]. The virus establishes latency in B lym-
phocytes andmay be reactivated in immunodeficiency.
Infectious mononucleosis is associated with palatal
petechiae, pharyngeal erythema, and tonsillar hyper-
trophy. These are nonspecific findings that may be
seen in many infections of the upper respiratory tract.
Fever, cervical lymphadenopathy, and a morbilliform,
erythematous exanthem may be present. The cuta-
neous features are more common in childhood. In a
severe case, infectious mononucleosis may be associ-
ated with necrotic gingival tissue [69]. The diagnosis is
based on clinical symptoms, hematologic findings,
and the presence of heterophil antibodies. Detection
of EBV-specific antibody is confirmatory [76]. Be-
cause the disease is self-limited, treatment is usually
symptomatic. Acyclovir is not effective [77]. Coinfec-
tion with b-hemolytic streptococci should be ruled outand, if present, treated with antibiotics; however,
neither ampicillin (Omnipen, Principen) nor amoxicil-
lin (Amoxil, Augmentin) should be used because of
the potential for generalized morbilliform eruptions in
patients with mononucleosis treated with these medi-
cations [78,79].
Oral hairy leukoplakia is a benign, asymptomatic
white patch or plaque of hyperplasia most commonly
located on the lateral border of the tongue (Fig. 8).
Extension to the dorsal and ventral tongue, buccal
mucosa, palate, and tonsillar region has been described
[80]. It occurs most often in persons immunocompro-
mised from HIV infection, but it has been reported in
transplant recipients [81] and in patients with renal
failure associated with Fabrys disease [82]. Oral hairy
leukoplakia may be the first clinical sign of HIV
infection in more than 5% of cases [22]. Diagnosis is
aided by histopathologic examination; EBV may be
identified with ISH (Fig. 9) [75,83], Southern blot
hybridization, direct immunofluorescence, or electron
microscopy [84]. Treatment with acyclovir is success-
ful but has been associated with recurrence [85,86].
Other measures reported to improve the leukoplakia
during treatment include antiretroviral therapy for
HIV-associated disease [87], topical 0.1% vitamin A
acid [86], and topical podophyllum resin [88].
EBV has been identified as an etiologic factor in
Burkitts lymphoma by serologic tests [89] and ISH
[83]; this disease is divided into African endemic [83]
and nonendemic forms [89]. Nonendemic forms,
however, are less likely to be associated with EBV
[89,90]. Burkitts lymphoma is the most common
childhood cancer in tropical Africa [75]. The char-
acteristic features are palpable jaw masses, cervical
lymphadenopathy, sore throat, loosened teeth, and
odontalgia. The disease is responsive to chemother-
apy. EBV is also associated with nasopharyngeal
carcinoma, which most commonly presents with
metastatic disease-containing lymphadenopathy.
EBV-related nasopharyngeal carcinoma is the most
common cancer in parts of southern Asia; 75% of
nasopharyngeal carcinomas in the United States are
induced by EBV [75].
Human herpesvirus 5 (cytomegalovirus)
Primary infection with cytomegalovirus is usually
subclinical and asymptomatic, although patients
may have a mononucleosis-like syndrome with fever,
lymphadenopathy, pharyngitis, and inflamed salivary
glands. Cytomegalovirus persists in a latent phase,
but reactivation rarely affects the skin and mucous
membranes. Oropharyngeal ulcerations caused by
cytomegalovirus have been described in iatrogenic
Fig. 8. Oral hairy leukoplakia with typical corrugated
white plaque on lateral tongue. (From Bruce AJ, Hairston
BR, Rogers RS III. Diagnosis and management of oral
viral infections. Dermatologic Therapy 2002;15:27187:
with permission.)
Fig. 9. Epstein-Barr virus demonstrated with in situ hybrid-
ization in the epidermis of patient with oral hairy leukoplakia.
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 23
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immunosuppression [91], HIV infection [22,92], and
bone marrow [93] and organ transplantation [92].
Cytomegalovirus may be cultured in fibroblast
media. Characteristic histopathologic features include
basophilic intranuclear inclusions and granular cy-
toplasmic inclusions, thus the name cytomegalic
inclusion disease. Serologic testing, ISH, or PCR
identifies the virus [94]. Ganciclovir has been effec-
tive in the treatment of cytomegalovirus-related oro-
pharyngeal disease [92].
Human herpesvirus 6
HHV-6 is responsible for exanthema subitum (ros-
eola infantum), the most common infectious exan-
them during the first 2 years of life [95,96]. The virus
remains latent in the salivary gland and can be
transmitted by oropharyngeal secretions. The enan-
them consists of erythematous maculae on the soft
palate. It may precede cutaneous exanthem of dis-
crete, 1- to 2-mm pink- to rose-colored maculae that
originate on the trunk following defervescence [97].
Serologic testing may detect antibody to HHV-6 [96].
Treatment is supportive.
Human herpesvirus 8
Kaposis sarcoma is a vascular neoplasm with
several clinical variants: classic, African endemic,
iatrogenic immunosuppression, and epidemic HIV-
associated. HHV-8 has been isolated from all subtypes
of Kaposis sarcoma, although its specific role in the
pathogenesis of the disease is unknown [98,99]. Oral
Kaposis sarcoma lesions are often the first indication
of HIV infection [22]. Erythematous to violaceous
maculae, patches, plaques, and nodules occur on the
palate, gingiva, and tongue (Figs. 10 and 11). Gen-
erally, Kaposis sarcoma of the oral cavity is asymp-
tomatic, although bleeding, pain, and ulceration may
occur. Because HHV-8 is not exclusive to Kaposis
sarcoma lesions, other pathogenic factors may con-
tribute to the development of the sarcoma [98].
In conjunction with histologic examination,
HHV-8 may be identified by PCR. Specific treatment
options for oral Kaposis sarcoma include local
excision [22], cryotherapy [100], injection of a scle-
rosing agent [101], intralesional interferon alfa-2b
[102], intralesional vinblastine [103], or site-directed
radiotherapy [104]. Radiotherapy must be used with
caution to avoid secondary mucositis [105]. Systemic
chemotherapy generally is reserved for patients with
rapidly progressive or disseminated disease or a high
tumor burden. Antiretroviral therapy in HIV-associ-
ated cases may interfere with immune deterioration
and prevent or reverse Kaposis sarcoma [106]. No
treatment has been approved specifically by the FDA
for Kaposis sarcoma of the oral cavity.
Human papillomavirus
Human papillomavirus (HPV) is a nonenveloped,
double-stranded DNA virus with at least 80 different
genotypes [107]. Diseases of the oral cavity induced
by HPV include squamous papilloma, oral verruca
vulgaris, condyloma acuminatum, and focal epithelial
hyperplasia (Table 3). Several subtypes of HPV have
been linked to the induction of malignancy [107,108]
but further study is needed to determine the role of
HPV in the etiology of oral squamous cell carcinoma.
Squamous papillomas and oral verrucae
Squamous papillomas and oral verrucae are com-
monly referred to as oral warts. Both lesions are
Fig. 10. Violaceous plaques with erosion on hard palate,
representing HIV-associated Kaposis sarcoma. (From Bruce
AJ, Hairston BR, Rogers RS III. Diagnosis and management
of oral viral infections. Dermatologic Therapy 2002;15:
27187: with permission.)
Fig. 11. Violaceous exophytic and fungating plaque on hard
palate, with violaceous macules and papules of lips in
person with classic Kaposis sarcoma.
B.R. Hairston et al / Dermatol Clin 21 (2003) 173224
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typically exophytic, verrucous papules or plaques
located on any oral mucosal surface, including the
lips. A distinguishing feature between these two dis-
eases is that squamous papillomas tend to be small and
pedunculated, whereas the verrucae are more sessile
[4]. Koilocytes are more common in oral verrucae
than in squamous papillomas [108].
Condyloma acuminatum
Condyloma acuminatum is predominantly an ano-
genital disease; however, lesions of the palate and
tongue have been reported [109,110]. Oral lesions
likely are acquired by sexual transmission, hematog-
enous spread, or autoinoculation by the hands from
primary genital lesions. Oral condyloma acuminatum
typically consists of multiple, small, white- to flesh-
colored, soft exophytic papules that enlarge to plaques
with a pebbled surface.
Focal epithelial hyperplasia (Heck disease)
Focal epithelial hyperplasia occurs most com-
monly in Native Americans and Eskimos of Green-
land [111]. It also has been described in cases of HIV
infection [112]. Because the disease is relatively
isolated to these subgroups of the population, a
genetic predisposition and inheritance pattern are
likely factors. The disease usually is located on the
buccal mucosa or lips as asymptomatic solitary or
multiple whitish papules; HPV DNA has been iden-
tified with ISH [113] and PCR in lesions of the oral
mucosa [114]. Lesions often remit spontaneous-
ly. Mucosal involvement may be extensive and pain-
ful, however, and may be treated with surgical
excision, cryotherapy, or laser ablation [22]. Topical
interferon-b [115] and carbon dioxide laser [114]therapies have been described.
Poxvirus
Molluscum contagiosum
Poxvirus, responsible for molluscum contagiosum,
is a DNA virus that replicates in the cytoplasm of
infected cells. Oral molluscum contagiosum presents
as flesh-colored, dome-shaped, smooth-surfaced or
umbilicated papules and is most commonly found in
immunocompromised persons. Sites reported to be
Table 3
Benign HPV-associated oral diseases
Oral manifestation Predominant HPV genotype Lesion
Squamous papilloma HPV-6, HPV-11 [108,126] Pedunculated, pink papule on palatine,
buccal, labial mucosa
Verruca vulgaris HPV-2, HPV-4 [108,125] Sessile, papillomatous, pink papule of
lips, gingivae
Condyloma acuminatum HPV-6, HPV-11 [108,126] Multiple, soft, sessile, pink coalescing
papules of palate, tongue
Focal epithelial hyperplasia HPV-11, HPV-13, HPV-32 [108,113115] Multiple, soft, pink papules of lips,
buccal mucosa
Abbreviations: HPV, human papillomavirus.
Table 4
Oral infections caused by RNA viruses
Oral infection Etiology Transmission Lesion
Measles Paramyxovirus Infectious respiratory
droplets, saliva
Kopliks spots on buccal mucosa,
Herrman spots on tonsils
Mumps Paramyxovirus Infectious respiratory
droplets, saliva
Edema and erythema of salivary
gland orifices
Rubella Togavirus Infectious respiratory
droplets, saliva
Forschheimer sign of palate
Hand-foot-
and-mouth disease
Picornavirus Saliva, feces Vesicles, erosions, or ulcerations of
palate, buccal mucosa, tongue
Herpangina Picornavirus Saliva, feces Vesicle or ulcerations with surrounding
erythema of palate, tonsillar fauces, uvula
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 25
-
affected include the lips, buccal mucosa, and palate
[116]. Large intracytoplasmic inclusion bodies (Hen-
derson-Paterson bodies) are a characteristic histologic
feature [117]. ISH demonstrates the poxvirus in clin-
ical specimens [118]. Treatment of the oral lesions is
with cryotherapy or excision [22].
RNA viruses
All the RNA viruses that affect the oral mucosa
consist of a single-stranded nucleic acid molecule.
RNA viral enanthems may be associated with a
cutaneous exanthem except for the paramyxovirus
that causes mumps. Diseases caused by RNA viruses
are listed in Table 4.
Paramyxovirus
Measles
Paramyxoviridae-associated infections include
measles (rubeola) and mumps [95]. A prodrome of
fever, malaise, cough, coryza, and conjunctivitis may
occur in measles, followed by a generalized ery-
thematous morbilliform exanthem. Kopliks spots,
pathognomonic for measles, are discrete, bluish white
punctate mucosal maculae surrounded by a rim of
erythema; they represent foci of epithelial necrosis
(Fig. 12). The most common location of this enanthem
is the buccal mucosa, where the lesions may resemble
grains of salt sprinkled on an erythematous back-
ground [95]. Pharyngeal erythema and bluish gray to
Fig. 12. Measles infection with Kopliks spots having
progressed to extensive necrosis, erosions, and ulceration of
buccal mucosa. (FromBruce AJ, Hairston BR, Rogers RS III.
Diagnosis and management of oral viral infections. Dermato-
logic Therapy 2002;15:27187: with permission.)
Fig. 13. Hand-foot-and-mouth disease. (A) Pinpoint vesicle with surrounding erythema of buccal mucosa. (B) Discrete
erythematous papules with vesiculation on both palms. (C) Similar erythematous papules and vesicles on dorsum of both feet.
B.R. Hairston et al / Dermatol Clin 21 (2003) 173226
-
white maculae (Herrman spots) may be present on the
tonsils. Herrman spots are not specific for the measles
virus [119]. Oropharyngeal disease may present 24 to
48 hours before the cutaneous exanthem.
Measles is usually diagnosed clinically; serologic
test results confirm the disease. Treatment generally is
symptomatic, with analgesics, antipyretics, and main-
tenance of adequate hydration. Immune serum globu-
lin treatment may be necessary for disease in children
younger than 12 months, in pregnant women, and
in immunosuppressed persons; it is best given within
6 days after exposure. The disease may be prevented
with the measles-mumps-rubella (MMR) vaccine
according to guidelines recommended by the Centers
for Disease Control and Prevention [95,119].
Mumps
Mumps is characterized by salivary gland swelling
and tenderness, particularly of the parotid gland.
Sublingual orifices, Stensens duct on the buccal
mucosa, and Whartons duct at the base of the tongue
may be edematous and erythematous. Serologic tests
or culturing the orifice of Stensens duct confirms the
diagnosis. Mumps may be prevented with the MMR
vaccine [120].
Togavirus
Rubella
Togavirus is responsible for rubella, or German
measles. Infection with togavirus during pregnan-
cy may lead to serious fetal infection and congeni-
tal rubella syndrome. A prodrome is less common
than in measles, but symptoms may occur in older
children and adults. The fine, pale pink maculopap-
ular exanthem spreads in a cephalocaudad pattern
and may be followed by fine desquamation. The en-
anthem of erythematous, pinpoint, petechial-appear-
ing maculae occurs on the soft palate and uvula.
This nonpathognomonic enanthem is known as the
Forschheimer sign [95]. It occurs in the prodrome or
early rash in up to 20% of cases of rubella [69].
Marked lymphadenopathy, typically of the cervical
and postauricular nodes, is often an accompanying
feature. Diagnosis of rubella is more difficult than
measles because it has no pathognomonic features
and a low incidence with the widespread use of the
MMR vaccine. Serologic testing is especially impor-
tant in women of childbearing age and those who are
pregnant to determine the status of immunity. In most
persons, rubella is essentially benign, and treatment
is symptomatic.
Picornavirus
Hand-foot-and-mouth disease and herpangina are
picornavirus-associated diseases with characteristic
Fig. 14. Vesicles and erosions of hard palate and poste-
rior oropharynx in herpangina. (From Bruce AJ, Hairston
BR, Rogers RS III. Diagnosis and management of oral
viral infections. Dermatologic Therapy 2002;15:27187:
with permission.)
Fig. 15. Perioral and labial erosions and crusting of
recurrent herpes simplex labialis associated with chronic
lymphocytic leukemia.
B.R. Hairston et al / Dermatol Clin 21 (2003) 1732 27
-
features that allow a specific diagnosis. Type-specific
immunity is established in both herpangina and hand-
foot-and-mouth disease; however, recurrences of the
clinical syndromes are possible because both diseases
may be caused by various members of the Picorna-
virus family.
Hand-foot-and-mouth disease
Hand-foot-and-mouth disease is most commonly
caused by coxsackievirus serotype A16 or enterovirus
71 [121,122]. The disease usually occurs in small
epidemics among groups of children and is quite
contagious. Typical features include a short prodrome
of upper respiratory symptoms and low-grade fever,
followed by mucosal and cutaneous lesions. Shallow
erosions and ulcerations with surrounding erythema
are most common on the palate, tongue, and buccal
mucosa (Fig. 13A). Erythematous papules, vesicles,
or ulcers occur on the dorsal and palmoplantar sur-
faces of the hands and feet either concomitantly with
the mucosal lesions or shortly thereafter (Fig. 13B
and C). Picornaviridae may be cultured from the sa-
liva or feces. PCR detects viral DNA in vesicles and
defines the specific serotype [121]. Serologic testing
also detects antibodies to the specific coxsackie-
virus [122].
Symptomatic therapy for hand-foot-and-mouth
disease is usually sufficient. Oral analgesics and
anesthetic mouth rinses alleviate stomatodynia. Com-
plications of hand-foot-and-mouth disease are rare;
however, enterovirus 71 was associated with central
nervous system disease, including meningitis, enceph-
alitis, and flaccid monoparesis, in 24% and 8% of
afflicted patients in the 1973 and 1978 hand-foot-and-
mouth disease outbreaks, respectively, in Japan [122].
Herpangina
Herpangina is induced most commonly by cox-
sackievirus [123] and is characterized by the sudden
onset of fever without a prodrome. Pain and dysphagia
are associated with small erythematous papules,
vesicles, or ulcerations covered by a pseudomem-
brane. Typical locations of these lesions are the tonsils
and tonsillar fauces, palate, and uvula (Fig. 14) [4].
The virus may be isolated from vesicles of the throat
or fecal culture [123]. Because herpangina may be
associated with high fever, febrile seizure is a rare
potential complication. Otherwise, therapy is usually
supportive, with hydration, analgesics, antipyretics,
and topical oral anesthetics.
HIV
HIV is an RNA retrovirus with the reverse tran-
scriptase enzyme responsible for conversion of RNA
to DNA. Oral lesions often are the indication for initial
HIV testing, and oral diseases are more common as
the CD4 + count decreases [21]. The acute serocon-
version syndrome following HIV infection is associ-
ated with oral erythema and ulcerations in up to 30%
of patients [124]. Similar to the more severe and
frequent herpetic viral infections in malignancy and
during immunosuppressive therapy (Fig. 15) [3], viral
pathogens often display a more aggressive and pro-
tracted course in HIV-infected persons (Table 5).
Summary
A wide variety of both DNA and RNA viruses
affect the oral cavity. When considered in conjunction
with cutaneous features, careful examination of the
oral mucosa and oropharynx aids the clinician in
making a diagnosis. Examination of the oral cavity
should be incorporated as a regular component of the
dermatologic examination because diagnostic clues
are readily available to assist in the evaluation of
infectious processes.
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Viral diseases of the oral mucosa in HIV infection
Viral disease Etiology
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