Ulcerative, Vesicular,

and
Bullous Lesions
Lecture 1
Assistant professor Dr. Ameena Ryhan
Dermatologic lesions are classified according to their clinical appearance
Frequently used terms that are applicable in the oral mucosa are:

• 1. Macules. Lesions that are flush with the adjacent mucosa and that are
noticeable because of their difference in color from normal skin or mucosa. They
may be red due to increased vascularity or inflammation, or pigmented due to
the presence of melanin, hemosiderin, and foreign materials (including the
breakdown products of medications).
• A good example in the oral cavity is the melanotic macule.
• 2. Papules. These are lesions raised above the skin or mucosal surface that are
smaller than 1.0 cm in diameter (some use 0.5 cm for oral mucosal lesions).
• They may be slightly domed or flat-topped.
• Papules are seen in a wide variety of diseases, such as the yellow-white papules of
pseudomembranous candidiasis.
• 3. Plaques. These are raised lesions that are greater than 1 cm in diameter; they
are essentially large papules.
• 4. Nodules. These lesions are present within the dermis or mucosa. The lesions
may also protrude above the skin or mucosa forming a characteristic dome-
shaped structure.
• A good example of an oral mucosal nodule is the irritation fibroma.
5. Vesicles. These are small blisters containing clear fluid that are less than 1 cm in
diameter.
6. Bullae. These are elevated blisters containing clear fluid that are greater than 1 cm
in diameter
7. Erosions. These are red lesions often caused by the rupture of vesicles or bullae, or
trauma. May also result from thinning or atrophy of the epithelium in inflammatory
diseases such as lichen planus. These should not be mistaken for ulcers that are covered
with fibrin and are yellow although erosions may develop into ulcers.

8. Pustules. These are blisters containing purulent material and appear yellow.

9. Ulcers. These are well-circumscribed, sometimes depressed lesions with an

epithelial defect that is covered by a fibrin clot, resulting in a yellow-white appearance,
such as aphthous.
10. Purpura. reddish to purple discolorations caused by blood from vessels leaking
into the connective tissue.
These lesions do not blanch when pressure is applied and are classified by size as
petechiae (less than 0.3 cm), purpura (0.4–0.9 cm), or ecchymoses (greater than 1 cm).
 Ulcerative, Vesicular, and Bullous Lesions

Classified into :
1. The Patient with Acute Multiple Ulcers
2. The Patient with Chronic Multiple Ulcers
3. The Patient with Recurring Oral Ulcers
4. The Patient with Single Ulcers
 1. The Patient with Acute Multiple Ulcers
The major diseases that cause acute multiple oral ulcers include:
Viral and bacterial stomatitis, allergic and hypersensitivity reactions
(particularly erythema multiform and contact allergic stomatitis), and
lesions caused by medications (such as cancer chemotherapy).

1. Herpes Simplex Virus Infections

2. Varicella-Zoster Virus Infections
3. Cytomegalovirus Infections
4. Coxsackievirus Infection (CV Infections)
5. Necrotizing Ulcerative Gingivitis and Necrotizing
Ulcerative Periodontitis
6. Erythema Multiforme
7. Stevens–Johnson Syndrome and Toxic Epidermal
Necrolysis
8. Plasma Cell Stomatitis and Oral Hypersensitivity
Reactions
1. Herpes Simplex Virus Infection

Etiology and Pathogenesis

 The primary infection, which occurs on initial contact with the
virus, is acquired by inoculation of the mucosa, skin, and eye with
infected secretions.
The virus then travels along the sensory nerve axons and establishes
chronic, latent infection in the sensory ganglion (trigeminal ganglion).

Extraneuronal latency (HSV remaining latent in cells other than

neurons such as the epithelium) may play a role in recurrent lesions
of the lips.
Recurrent HSV results when HSV reactivates at latent sites and
travels centripetally to the mucosa or the skin, where it is directly
cytopathic to epithelial cells, causing recrudescent HSV infection in
the form of localized vesicles or ulcers.
The most common sites of infection are the oral, genital mucosa and
the eye.
 In general, infections above the waist are caused by HSV‐1 and
those below the waist by HSV‐2, although with changing sexual
practices, it is not uncommon to culture HSV‐2 from oral lesions
and vice versa.

• HSV infection of the cornea (keratitis) is a

major cause of blindness in the world.

• HSV-1 or -2 may cause herpes whitlow, an

infection of the fingers when virus is inoculated
into the fingers through a break in the skin.

• This was a common occupational hazard

(including within the dental profession) before
the widespread use of gloves.
Other HSV-1 infections include
Herpes gladiatorum (infections of the skin spread through the sport of wrestling)
Herpes encephalitis
HSV esophagitis
HSV pneumonia and neonatal and disseminated infection.
HSV is an important etiologic agent in erythema multiforme
HSV has been recovered in the endoneurial fluid of of patients with Bell palsy.

(endoneurium a layer of delicate connective tissue around the myelin sheath of

each myelinated nerve fiber)
However, varicella‐zoster virus(VZV) has also been strongly implicated in
the development of Bell palsy.

Treatment with antiviral therapy (especially with corticosteroids) within the first
48 hours resulted in better outcomes further supporting the concept of
herpesvirus involvement in the pathogenesis of Bell palsy.

However, a recent study showed that approximately 60% of cases of Bell palsy
were associated with Human herpesvirus (HHV6), and only 13% with HSV.
 Primary Gingivostomatitis
Clinical Manifestations

 The majority of primary HSV-1 infections are

subclinical and generally occur in children and
teenagers, and young Adults
 There is a 1-3-day viral prodrome of fever, loss of
appetite, malaise, and myalgia that may also be
accompanied by headache and nausea.
 Oral pain leads to poor oral intake, and patients may
require hospitalization for hydration.
 The disease is self-limiting in otherwise normal
patients and resolves within 10–14 days, typical for a
viral illness.
Oral Findings
 Within a few days of the prodrome, erythema and clusters of
vesicles and/or ulcers appear on the keratinized mucosa of
the hard palatal mucosa, attached gingiva and dorsum of the
tongue, and the nonkeratinized mucosa of the buccal and
labial mucosa, ventral tongue, and soft palate.

 Vesicles break rapidly down to form ulcers that are usually 1–

5 mm and coalesce to form larger ulcers with scalloped
borders and marked surrounding erythema.
 The gingiva is often erythematous,and the mouth is extremely
painful, causing difficulty with eating.
 Pharyngitis causes swallowing difficulties.

Primary HSV infection in adults follows a similar pattern

 Primary herpetic gingivostomatitis

Clustered vesicles of recrudescent herpes labialis on vermilion.

Recrudescent (renewing) Oral HSV Infection

 Reactivation of HSV may lead to asymptomatic shedding

of HSV, in the saliva and other secretions, an important
risk factor for transmission; it may also cause ulcers to form.
• Asymptomatic shedding of HSV is not associated with systemic
signs and symptoms and occurs in 8-10% of patients following
dental treatment.
 Reactivation of HSV-1 on the oral mucosa is common and usually
asymptomatic. However, HSV-1 is rarely found in tears and nasal
mucosa. Frequent oral shedding of HSV-1 may increase the risk for
transmitting the virus to both oral and genital mucosa of sexual
partners
 The term recrudescent HSV should be used to refer to the actual
ulcerations caused by reactivated virus.
 Fever, ultraviolet radiation, trauma, stress, and menstruation are
important triggers for reactivation of HSV.

 Recrudescent HSV on the lips is called recurrent herpes labialis (RHL)

and occurs in 20- 40% of the young adult population.
 These are associated with a prodrome of itching, tingling, or burning
approximately 50% of the time, followed by the appearance of papules,
vesicles, ulcers, crusting, and then resolution of lesions.

 Pain is generally present only within the first two days.

 There is a suggestion that patients who do not experience a prodrome

develop lesions from extraneural latent HSV within the epithelium and
these lesions are less responive to topical therapy.

Recrudescent intraoral HSV (RIH) in the immunocompetent host

• Occurs chiefly on the keratinized mucosa of the hard palatal
mucosa, attached gingiva, and dorsum of the Tongue.
• They present as 1–5 mm single or clustered painful ulcers with a
bright erythematous border.
• One common presentation is the complaint of pain in the gingiva 1-2
days after a scaling and prophylaxis or other dental treatment.
 Lesions appear as 1–5 mm painful vesicles but more often ulcers on
the marginal gingiva.
HSV in Immunocompromised Patients
• In immunocompromised patients (such as those undergoing
chemotherapy, who have undergone organ transplantation,
or who have acquired immune deficiency syndrome (AIDS).
• May occur at any site intraorally and may form ulcers that may be
several centimeters in size and may last several weeks or months if
undiagnosed and untreated
• Single Recurrent intraoral herpes (RIH) ulcers are clinically
indistinguishable from recurrent aphthous ulcers if they occur on a
nonkeratinized site.
• These ulcers are painful and similar to those seen in immunocompetent
patients except that they may be larger and often occur on
• non-keratinized sites.
• They appear slightly depressed with raised borders.
• The presence of 1–2 mm vesicles or satellite ulcers at the edges of the
main ulcer is a helpful sign.
If undiagnosed and left untreated, RIH infection may disseminate to other
sites and cause severe infections in the immunocompromised population.
This is a particular problem in patients undergoing hematopoietic stem
cell transplantation, where reactivation of HSV occurs in approximately
70% of patients.
Laboratory Diagnosis

HSV isolation by cell culture is the gold standard test for the diagnosis
since it grows readily in tissue culture.
A single swab of the oral ulcers is performed.
More recently, polymerase chain reaction (PCR) from swabs has been
shown to detect HSV antigen 3 to 4 times more often than culture
real-time PCR has also been shown to be highly sensitive and specific.

 Primary HSV infection is associated with elevated immunoglobulin

(Ig)M titers that occur within days
 Followed several weeks later by permanent IgG titers, that indicate
previous infection but confer no protection against reactivation.
 Recurrent infection is associated with a rise in IgG antibody
titer in acute and convalescent sera, but a four-fold rise (a
criterion that indicates active infection) is seen in only 5% of
patients.

 The assay for HSV IgM is not particularly reliable for diagnostic
purposes, and overall, the use of serology alone to diagnose
recurrent infection is not advised.

HSV lesions are not generally biopsied

because the clinical appearance and history
are characteristic, and infection is readily
confirmed with a culture or cytology specimen
when necessary.
Management
Primary HSV Infection
Management is directed toward
1. Pain control,
2. Supportive care,
3. Definitive treatment.
In the past, healthy patients with primary herpetic gingivostomatitis were
treated only with hydration and supportive measures.
However, since the acyclovir family of medication is inexpensive, safe,
and readily available, it is appropriate to treat even primary infections
definitively because it reduces viral shedding and infectivity.

Acyclovir inhibits viral replication and is activated by virally produced

thymidine kinase. As such, it has little activity against non-virally infected
cells.
The use of acyclovir at 15 mg/kg five times a day in children reduces the
duration of fever, reduces HSV shedding, stops the progress of lesions,
improves oral intake, and reduces the incidence of hospital admissions.

Valacyclovir, a prodrug of acyclovir, has 3 to 5 times the bioavailability

of acyclovir and, together with famciclovir, is now widely used.
Recrudescent HSV
Recurrent herpes labialis can often be suppressed by reducing tissue damage,
such as using sunscreen.
Although RHL is self-limiting, the use of topical antiviral medications reduces
shedding, infectivity, pain, and the size and duration of lesions.
Topical antiviral medications such as 5% acyclovir cream, 1% penciclovir
cream, and 10% docosanol cream are efficacious if applied 5 to 8 times a
day at the first prodrome or sign of a lesion.

Systemic therapy with valacyclovir (2 g every 12 hours for one day) or

famciclovir (1500 mg single dose) are both effective in treating active lesions
of RHL

For intraoral lesions, treatment is with 500–1000 mg valacyclovir three

times a day or 400–800 mg of acyclovir for 7–10 days.

Suppression of HSV infection in patients who develop Frequent Episodes,

Large Lesions, Or Erythema Multiforme is effected with variable doses of
acyclovir, valacyclovir, and famciclovir.
Similar suppressive regimens can be used for patients susceptible
to recrudescent HSV after dental procedures.
HSV in Immunocompromised Patients

 HSV infections should be treated with systemic antivirals to prevent

dissemination to other sites (e.g., HSV esophagitis) or systemically.
 The primary pathogen for herpes encephalitis& herpes pneumonitis
is HSV-1.
 For patients undergoing hematopoietic cell transplantation, antiviral
therapy such as acyclovir or valacyclovir at suppressive doses should
be initiated for all patients who are HSV seropositive
(acyclovir 400 mg three times a day or 500 mg valacyclovir twice a day).
 Acyclovir-resistant HSV is most frequently seen in this group of
patients, where the virally derived thymidine kinase that activates
acyclovir is mutated.
 In such cases, foscarnet or cidofovir is effective.

The dosage of the acyclovir family should be adjusted for Age and
Renal Health.

A number of vaccines and new therapies against HSV are currently

under development.
 2. Varicella-Zoster Virus Infection
Etiology and Pathogenesis
 Primary infection with varicella zoster virus (VZV), an α-herpesvirus, leads to varicella
(chicken pox).
 The virus then becomes latent, usually in the dorsal root ganglia or ganglia of the
cranial nerves.
 Reactivation produces herpes zoster infection (HZI), commonly called shingles.
• The incidence of HZI increases with age and the degree of immunosuppression.
this increases to 10 per 1000 in those older than the age of 75 years.
 Therefore, it is not uncommon to see HZI
 in the elderly,
 in patients undergoing cancer chemotherapy,
 in patients on chronic immunosuppressive therapy and in patients with AIDS.

As with HSV, this virus is cytopathic to the epithelial cells of the skin and mucosa,
causing blisters and ulcers.
Transmission is usually by the respiratory route, with an incubation period of 2 to 3
weeks.
Post herpetic neuralgia,
a morbid sequela of HZI, is a neuropathy resulting from peripheral and central
nervous system injury and altered central nervous system processing.
Clinical Findings

 Primary VZV infection generally occurs in the first two decades of life.
 The disease begins with a low-grade fever, malaise, and the development of
an intensely pruritic, maculopapular rash, followed by vesicles that have
been described as “dewdrop-like.”
 These vesicles turn cloudy and pustular, burst, and scab, with the crusts
falling off after one to two weeks.
 Lesions begin on the trunk and face and spread centrifugally.
 Central nervous system involvement may result in cerebellar ataxia and
encephalitis.
 Other complications of varicella include pneumonia, myocarditis, and
hepatitis.

Immunocompromised hosts usually experience more severe disease with

more blisters, a prolonged course, and, not infrequently, involvement of the
lungs, central nervous system, and liver; there is a significantly higher
mortality rate.
Secondary bacterial infection by gram-positive cocci may have severe septic
consequences
HZI of the skin (shingles) occurs in adults and starts with a prodrome of deep,
aching, or burning pain. There is usually little to no fever or lymphadenopathy.
This is followed within 2 to 4 days by the appearance of crops of vesicles in a
dermatomal or “zosteriform” pattern. This pattern describes the unilateral, linear,
and clustered distribution of the vesicles, ulcers, and scabs in a dermatome
supplied by one nerve.
Thoracic/lumbar dermatomes are the most frequently involved, followed by the
craniofacial area.
Lesions heal within 2 to 4 weeks, often with scarring and hypopigmentation.

Occasionally, HZI may occur without the appearance of dermatomal lesions

(zoster sine eruptione or zoster sine herpete), which makes the diagnosis
of this condition challenging; these patients often present with facial palsy.

 VZV has been detected in up to 20% of patients with Bell palsy.

 A serious and occasional side effect of HZI is acute retinal necrosis.

One of the most important complications of HZI is postherpetic

neuralgia, defined as pain that remains for 120 days after the
onset of the acute rash.
Facial lesions of herpes zoster involving the third division of the trigeminal nerve
 Patients older than age 50, up to 70% developed postherpetic neuralgia
and up to 50% have debilitating pain, usually of a sharp, stabbing, burning
or gnawing nature lasting more than one month.

 Some unfortunate patients experience pain for years.

 Predisposing factors include older age, prodromal pain, and more severe
clinical disease during the acute rash phase.

Immunocompromised patients often experience more severe VZI that may

appear atypical, be bilateral, and involve multiple dermatomes; retinitis,
pneumonitis, and encephalitis have been reported as complications in this
patient population.

On rare occasions, HZI may involve not just the dorsal root ganglion
but also the anterior horn cells, leading to paralysis.
 Oral Manifestations
 Primary VZV infection presents as acute-onset ulcerations in the mouth
that often pale
 In recurrent VZV infection, the ophthalmic division of the trigeminal (V)
nerve is the cranial nerve most often affected (herpes zoster
ophthalmicus).
 Corneal involvement may lead to blindness.
 Involvement of this nerve (V) leads to lesions on the upper eyelid,
forehead, and scalp with V1; midface and upper lip with V2; and lower
face and lower lip with V3 .
 With the involvement of V2, patients experience a prodrome of pain,
burning, and tenderness, usually on the palate on one side.

This is followed several days later by the appearance of painful, clustered

1–5 mm ulcers (rarely vesicles, which break down quickly) on the hard
palatal mucosa or even buccal gingiva, in a distinctive unilateral distribution.

These ulcers heal within 10–14 days, and post herpeticneuralgia in the oral
cavity is uncommon. Involvement of V results in blisters and ulcers on the
mandibular gingiva and tongue.
Palatal lesions of herpes zoster involving the second division of
the trigeminal nerve V2; note unilateral distribution.
 An uncommon complication of HZI involving the
geniculate ganglion: is Ramsay Hunt syndrome.
Patients develop Bell palsy, vesicles of the external ear,
and loss of taste sensation in the anterior two‐thirds of
the tongue.

 HZI has been reported to cause resorption and

exfoliation of teeth and osteonecrosis of the
jawbones, especially in patients with HIV disease.
Laboratory Findings

As with HSV infection, an oral swab for viral isolation using cell culture is still
the best way to confirm a diagnosis of VZV infection, although VZV is more
difficult to culture, but this does not distinguish between HSV and VZV.

Direct fluorescent antibody testing using a smear has greater sensitivity.

This test uses a smear obtained by scraping the lesion and staining it with
antibody against VZV conjugated to a fluorescent compound.

The use of PCR and real-time PCR to detect viral antigen is expensive and
highly sensitive, but the presence of VZV antigen does not always equate with
active infection.
In HZI, there is inflammation of peripheral nerves leading to demyelination
and wallerian degeneration, as well as degeneration of the dorsal horn cells
of the spinal cord.
Management
Management of oral lesions of varicella and HZI is directed toward
 pain control (particularly, the prevention of postherpetic neuralgia),
 supportive care,
 hydration
 definitive treatment to minimize the risk for dissemination, particularly
in immunocompromised patients.

 Aspirin use, especially in children with VZV infection or influenza,

may be associated with the development of Reye syndrome, which
is potentially fatal, and is contraindicated; characterized by fatty
degeneration of the liver and encephalopathy.
 Ibuprofen is the preferred analgesic.
Treatment of primary VZV infection includes the use of :
 Acyclovir (800 mg five times a day).
 This reduces infectivity, severity of lesions, and hospitalization for
complications. However, acyclovir has poor bioavailability.
 Valacyclovir (1000 mg 3 times a day)
or Famciclovir (500 mg) 3 times a day) for 7 days is effective in treating
HZI and should be started within 72 hours of disease onset.

These medications also reduce the incidence of postherpetic neuralgia

compared with acyclovir.
The first line of treatment for postherpetic neuralgia is
 Gabapentin,
 5% lidocaine patch,
 and 0.025 – 0.8% topical capsaicin

The second line of treatment is

with tricyclic antidepressants and corticosteroids

The use of corticosteroids and antiviral therapy together in an attempt to

reduce post herpetic neuralgia has not proved effective, although early
treatment with famciclovir or valacyclovir may prevent it.

Other modalities of treatment in Case reports suggest that

 Botulinum toxin may provide relief.
 Attenuated vaccine for the prevention of VZV infection has been shown
to reduce the incidence of varicella outbreaks.

But because it establishes latency may be associated with increased

zoster incidence.
Vaccination of older adults using:
 ZostavaxTM (live, attenuated virus),
 or ShingrixTM (recombinant VZV antigen) reduces incidence
of HZI significantly and the latter, post‐herpetic neuralgia.

The use of recombinant virus in a vaccine is more appropriate

for use in immunocompromised hosts.

Recombinant virus :
When viruses of two different parent strains coinfect the
same host cell and interact during replication to generate virus
progeny that have some genes from both parents.