Ulceratif

50 50
ULCERATIVE, VESICULAR, AND

BULLOUS LESIONS
MARTIN S. GREENBERG, DDS
A clinician attempting to diagnose an ulcerative or vesiculobul-
lous disease of the mouth is confronted with the fact that many
diseases have a similar clinical appearance. The oral mucosa is
thin, causing vesicles and bullae to break rapidly into ulcers,
and ulcers are easily traumatized from teeth and food, and they
become secondarily infected by the oral ora. These factors may
cause lesions that have a characteristic appearance on the skin
to have a nonspecic appearance on the oral mucosa.
Mucosal disorders may occasionally be correctly diagnosed
from a brief history and rapid clinical examination, but this
approach is most often insufcient and leads to incorrect diag-
nosis and improper treatment. The history taking is frequently
underemphasized, but, when correctly performed, it gives as
much information as does the clinical examination. A detailed
history of the present illness is of particular importance when
attempting to diagnose oral mucosal lesions. A complete
review of systems should be obtained for each patient, includ-
ing questions regarding the presence of skin, eye, genital, and
rectal lesions. Questions should also be included regarding
symptoms of diseases associated with oral lesions; that is, each
patient should be asked about the presence of symptoms such
as joint pains, muscle weakness, dyspnea, diplopia, and chest
pains. The clinical examination should include a thorough
inspection of the exposed skin surfaces; the diagnosis of oral
lesions requires knowledge of basic dermatology because many
disorders occurring on the oral mucosa also affect the skin.
Dermatologic lesions are classied according to their clinical
appearance and include the following basic lesions:
1. Macules. Well-circumscribed, flat lesions that are
noticeable because of their change from normal skin
color. They may be red due to the presence of vascular
lesions or inammation, or pigmented due to the pres-
ence of melanin, hemosiderin, and drugs.
THE PATIENT WITH ACUTE MULTIPLE
LESIONS
Herpesvirus Infections
Primary Herpes Simplex Virus Infections
Coxsackievirus Infections
Varicella-Zoster Virus Infection
Erythema Multiforme
Contact Allergic Stomatitis
Oral Ulcers Secondary to Cancer Chemotherapy
Acute Necrotizing Ulcerative Gingivitis
THE PATIENT WITH RECURRING ORAL
ULCERS
Recurrent Aphthous Stomatitis
Behets Syndrome
Recurrent Herpes Simplex Virus Infection
THE PATIENT WITH CHRONIC MULTIPLE
LESIONS
Pemphigus
Subepithelial Bullous Dermatoses
Herpes Simplex Virus Infection in Immunosuppressed Patients
THE PATIENT WITH SINGLE ULCERS
Histoplasmosis
Blastomycosis
Mucormycosis
Ulcerative, Vesicular, and Bullous Lesions 51
2. Papules. Solid lesions raised above the skin surface that
are smaller than 1 cm in diameter. Papules may be seen
in a wide variety of diseases including erythema mul-
tiforme simplex, rubella, lupus erythematosus, and sar-
coidosis.
3. Plaques. Solid raised lesions that are over 1 cm in diam-
eter; they are large papules.
4. Nodules. These lesions are present deep in the dermis,
and the epidermis can be easily moved over them.
5. Vesicles. Elevated blisters containing clear uid that are
under 1 cm in diameter.
6. Bullae. Elevated blisterlike lesions containing clear uid
that are over 1 cm in diameter.
7. Erosions. Moist red lesions often caused by the rupture
of vesicles or bullae as well as trauma.
8. Pustules. Raised lesions containing purulent material.
9. Ulcers. A defect in the epithelium; it is a well-circum-
scribed depressed lesion over which the epidermal layer
has been lost.
10. Purpura. Reddish to purple at lesions caused by blood
from vessels leaking into the subcutaneous tissue.
Classified by size as petechiae or ecchymoses, these
lesions do not blanch when pressed.
11. Petechiae. Purpuric lesions 1 to 2 mm in diameter.
Larger purpuric lesions are called ecchymoses.
A detailed history of the present illness is essential in mak-
ing the diagnosis of oral mucosal disease. Three pieces of
information that should be obtained early in the history will
help the clinician rapidly categorize a patients disease and
simplify the diagnosis: length of time the lesions have been pre-
sent (acute or chronic lesions), past history of similar lesions
(primary or recurrent disease), and number of lesions present
(single or multiple). In this chapter, the diseases are grouped
according to the information just described. This information
serves as an excellent starting point for the student who is just
learning to diagnose these disorders, as well as the experienced
clinician who is aware of the potential diagnostic pitfalls.
The rst section of this chapter describes acute multiple
lesions that tend to occur only once, the second portion of the
chapter covers recurring oral mucosal syndromes, and the third
portion presents the patient with chronic multiple lesions. The
nal section describes diseases that present as chronic single
lesions. It is hoped that classifying the disorders in this way will
help the clinician avoid the common diagnostic problem of
confusing viral infections with recurring oral syndromes, such
as recurrent aphthous stomatitis, or disorders that present as
chronic progressive disease, such as pemphigus and pemphoid.
THE PATIENT WITH ACUTE
MULTIPLE LESIONS
The major diseases that cause acute multiple oral lesions
include viral stomatitis, allergic reactions (particularly ery-
thema multiforme and contact allergic stomatitis), and lesions
caused by cancer chemotherapy or blood dyscrasias.
Herpesvirus Infections
There are 80 known herpesviruses, and eight of them are
known to cause infection in humans: herpes simplex virus
(HSV) 1 and 2, varicella-zoster virus, Cytomegalovirus,
Epstein-Barr virus, and human herpesvirus 6 (HHV6). All
herpesviruses contain a deoxyribonucleic acid (DNA) nucleus
and can remain latent in host neural cells, thereby evading the
host immune response.
1
HHV6, a herpesvirus discovered in
1986, has been shown by seroprevalence studies to infect over
80% of the population by adult life. Two variants, HHV6A and
HHV6B have been identied. The virus is commonly isolated
from saliva and causes roseola infantum (exanthema subi-
tum), a common childhood illness that is characterized by
fever and a rash. The virus also is a cause of a mononucleosis-
like syndrome in older children and adults. In immunocom-
promised patients, HHV6 can cause interstitial pneumonitis
and bone marrow suppression.
2
HHV7, which is commonly
isolated from saliva, is presently not associated with a specic
disease, whereas HHV8 has been closely associated with
Kaposis sarcoma in human immunodeficiency virus
(HIV)infected patients. There is also evidence linking HHV8
to forms of lymphoma and Castlemans disease.
HSV1, HSV2, and varicella-zoster are viruses that are
known to cause oral mucosal disease. Cytomegalovirus is an
occasional cause of oral ulceration in immunosuppressed
patients, and it is suspected as a cause of salivary gland disease
in HIV-infected patients.
3
The herpes simplex virus is composed of four layers: an
inner core of linear double-stranded DNA, a protein capsid, a
tegument, and a lipid envelope containing glycoproteins that
is derived from the nuclear membrane of host cells. The two
major types, HSV1 and 2, can be distinguished serologically or
by restriction endonuclease analysis of the nuclear DNA.
Classically, HSV1 causes a majority of cases of oral and pha-
ryngeal infection, meningoencephalitis, and dermatitis above
the waist; HSV2 is implicated in most genital infections.
Although this distinction applies to a majority of cases, chang-
ing sexual habits are making that distinction less important.
Both types can cause primary or recurrent infection of either
the oral or the genital area, and both may cause recurrent dis-
ease at either site.
1
Primary infection may also occur concur-
rently in both oral and genital sites from either HSV1 or
HSV2,
4
although HSV1 recurs more frequently in the oral
region and HSV2 more frequently in the genital region.
5,6
Humans are the only natural reservoir of HSV infection,
and spread occurs by direct intimate contact with lesions or
secretions from an asymptomatic carrier. This latter method
of spread of HSV is common; between 2 and 9% of asympto-
matic individuals shed HSV in saliva or genital secretions.
79
Latency, a characteristic of all herpesviruses, occurs when
the virus is transported from mucosal or cutaneous nerve end-
ings by neurons to ganglia where the HSV viral genome
remains present in a nonreplicating state.
10
During the latent
phase, herpes DNA is detectable, but viral proteins are not
produced.
11
Reactivation of the latent virus occurs when HSV
switches to a replicative state; this can occur as a result of a
number of factors including peripheral tissue injury from
trauma or sunburn, fever, or immunosuppression.
12
The concept that HSV is a possible cause of Bells palsy was
initially suggested in 1972,
13
but recent evidence using genetic
and molecular techniques has demonstrated that reactivation
of HSV is the most common cause of this disorder.
14,15
There is evidence linking HSV to carcinogenesis.
16
Epidemiologic studies have demonstrated an increased inci-
dence of HSV2 serum antibodies or positive HSV2 cultures in
patients with cervical carcinoma. Animal studies on hamster
cheek pouches show an enhanced development of invasive
squamous cell carcinoma when HSV1 infection is combined
with topical snuff.
17
Primary Herpes Simplex Virus Infections
There are approximately 600,000 new cases of primary HSV
infections per year in the United States. Primary HSV infection
occurs in patients who do not have immunity resulting from
previous contact with the virus. HSV is contracted after inti-
mate contact with an individual who has active HSV primary
or recurrent lesions. Primary HSV may also be spread by
asymptomatic shedders with HSV present in salivary secre-
tions. The majority of oral HSV infections is caused by HSV1,
but primary oral HSV2 infections may also occur chiey as a
result of oral-genital contact.
11
Infection of the ngers (her-
petic whitlows) of health professionals may occur during treat-
ment of infected patients. Dentists may experience primary
lesions of the ngers from contact with lesions of the mouth
or saliva of patients who are asymptomatic carriers of HSV,
although the incidence of this disorder should be minimal if
gloves are worn (Figure 4-1).
18
Use of gloves should also pre-
vent the spread of HSV from the ngers of health care work-
ers infected with herpetic whitlows to patients.
Primary HSV infection of the newborn was previously
believed to be caused by direct contact with vaginal HSV
lesions during birth, but it has now been established that a
majority of mothers giving birth to children with primary
HSV are asymptomatic carriers without lesions.
19
These infec-
tions of the newborn result in viremia and disseminated infec-
tion of the brain, liver, adrenals, and lungs.
20
52 Diagnosis and Management of Oral and Salivary Gland Diseases
Newborns of mothers with antibody titers are protected by
placentally transferred antibodies during the rst 6 months of
life. After 6 months of age, the incidence of primary HSV1
infection increases. The incidence of primary HSV1 infection
reaches a peak between 2 and 3 years of age. Incidence of pri-
mary HSV2 infection does not increase until the age when
sexual activity begins. Studies of neutralizing and comple-
ment-xing antibodies to HSV have shown a continual rise in
the percentage of patients who have had contact with the virus
until 60 years of age, demonstrating that although the pri-
mary infection with HSV1 is chiey a disease of infants and
children, new cases continue to appear during adult life. This
is consistent with the many reports of adults with primary
herpetic gingivostomatitis.
The incidence of primary herpes infection has been shown
to vary according to socioeconomic group. In lower socioeco-
nomic groups, 70 to 80% of the population have detectable
antibodies to HSV by the second decade of life, indicating
prior HSV infection, whereas, in a group of middle class indi-
viduals, only 20 to 40% of the patients in the same age group
have evidence of contact with HSV.
21,22
A significant percentage of cases of primary herpes are
subclinical, although the apparently low incidence of a history
of classic primary herpetic gingivostomatitis is also inuenced
by the young age of patients who develop the infection, by the
improper diagnosis of some cases, and by the cases of primary
herpetic pharyngitis that cannot be clinically distinguished
from other causes of viral pharyngitis.
CLINICAL MANIFESTATIONS OF PRIMARY ORAL HERPES
The patient usually presents to the clinician with full-blown
oral and systemic disease, but a history of the mode of onset
is helpful in differentiating lesions of primary HSV infection
from other acute multiple lesions of the oral mucosa. The
incubation period is most commonly 5 to 7 days but may
range from 2 to 12 days.
Patients with primary oral herpes have a history of gener-
alized prodromal symptoms that precede the local lesions by
1 or 2 days. This information is helpful in differentiating this
viral infection from allergic stomatitis or erythema multi-
forme, in which local lesions and systemic symptoms appear
together. These generalized symptoms include fever, headache,
malaise, nausea, and vomiting. A negative past history of recur-
rent herpes labialis and a positive history of direct intimate
contact with a patient with primary or recurrent herpes are
also helpful in making the diagnosis.
Approximately 1 or 2 days after the prodromal symptoms
occur, small vesicles appear on the oral mucosa; these are
thin-walled vesicles surrounded by an inflammatory base
(Figure 4-2). The vesicles quickly rupture, leaving shallow
round discrete ulcers. The lesions occur on all portions of the
mucosa. As the disease progresses, several lesions may coa-
lesce, forming larger irregular lesions.
An important diagnostic criterion in this disease is the
appearance of generalized acute marginal gingivitis. The
entire gingiva is edematous and inamed (Figures 4-3, A and FIGURE 4-1 Primary herpetic whitlow on the nger of a dentist.
B, and 4-4). Several small gingival ulcers are often present.
Examination of the posterior pharynx reveals inammation,
and the submandibular and cervical lymph nodes are char-
acteristically enlarged and tender. On occasion, primary HSV
may cause lesions of the labial and facial skin without intra-
oral lesions.
Primary HSV in otherwise healthy children is a self-limit-
ing disease. The fever ordinarily disappears within 3 or 4 days,
and the lesions begin healing in a week to 10 days, although
HSV may continue to be present in the saliva for up to a month
after the onset of disease.
LABORATORY DIAGNOSIS
The diagnosis of primary herpetic gingivostomatitis is straight-
forward when patients present with a typical clinical picture of
generalized symptoms followed by an eruption of oral vesicles,
round shallow symmetric oral ulcers, and acute marginal gin-
givitis. Laboratory tests are rarely required in these cases. Other
patients, especially adults, may have a less typical clinical pic-
ture, making the diagnosis more difcult. This is especially
important when distinguishing primary herpes from erythema
multiforme since proper therapy differs signicantly.
The following laboratory tests are helpful in the diagnosis
of a primary herpes infection.
Cytology. For cytology, a fresh vesicle can be opened and a
scraping made from the base of the lesion and placed on a
microscope slide. The slide may be stained with Giemsa,
Wrights, or Papanicolaous stain and searched for multinu-
cleated giant cells (Figure 4-5), syncytium, and ballooning
degeneration of the nucleus. Fluorescent staining of cytology
smears has been shown to be more sensitive (83%) compared
with routine cytology (54%); it is the cytologic test of choice,
when available.
23
HSV Isolation. Isolation and neutralization of a virus in tis-
sue culture is the most positive method of identication and
has a specicity and sensitivity of 100%.
23
A clinician must
remember that isolation of HSV from oral lesions does not
necessarily mean that HSV caused the lesions. Patients who
have lesions from other causes may also be asymptomatic
shedders of HSV.
Antibody Titers. Conclusive evidence of a primary HSV
infection includes testing for complement-xing or neutraliz-
ing antibody in acute and convalescent sera. However, it is
rarely necessary in routine clinical situations and is often not
helpful since the results are not available until the infection is
gone. In special circumstances, such as immunocompromised
FIGURE 4-2 A 12-year-old female with primary herpetic gingivosto-
matis causing discrete vesicles and ulcers surrounded by inammation.
FIGURE 4-3 Acute marginal gingivitis characteristic of primary HSV infection. A, mandibular anterior gingiva; B, vesicles and inammation around
mandibular molars.
FIGURE 4-4 Primary herpes infection in a 17-year-old male. Note the
unruptured palatal vesicles and intense marginal gingivitis.
A B
patients, an acute serum specimen should be obtained within
3 or 4 days of the onset of symptoms. The absence of detectable
antibodies plus the isolation of HSV from lesions is compati-
ble with the presence of a primary HSV infection. Antibody to
HSV will begin to appear in a week and reach a peak in 3
weeks. A convalescent serum can conrm the diagnosis of pri-
mary HSV infection by demonstrating at least a fourfold rise
in anti-HSV antibody. If anti-HSV antibody titers are similar
in both the acute and convalescent sera, then the lesions from
which HSV was isolated were recurrent lesions.
TREATMENT
A signicant advance in the management of herpes simplex
infections was the discovery of acyclovir, which has no effect
on normal cells but inhibits DNA replication in HSV-infected
cells.
24
Acyclovir has been shown to be effective in the treat-
ment of primary oral HSV in children when therapy was
started in the rst 72 hours. Acyclovir signicantly decreased
days of fever, pain, lesions, and viral shedding.
25
Newer anti-
herpes drugs are now available, including valacyclovir and
famciclovir. The advantage of the newer drugs is increased
bioavailability, allowing for effective treatment with fewer
doses.
26
Milder cases can be managed with supportive care
only. The use of antiviral drugs in the management of recur-
rent disease or in immunocompromised patients is discussed
later in this chapter in sections on recurrent and chronic HSV.
Routine supportive measures include aspirin or aceta-
minophen for fever and uids to maintain proper hydration
and electrolyte balance. If the patient has difculty eating and
drinking, a topical anesthetic may be administered prior to
meals. Dyclonine hydrochloride 0.5% has been shown to be an
excellent topical anesthetic for the oral mucosa. If this med-
ication is not available, a solution of diphenhydramine
hydrochloride 5 mg/mL mixed with an equal amount of milk
of magnesia also has satisfactory topical anesthetic properties.
Infants who are not drinking because of severe oral pain
should be referred to a pediatrician for maintenance of proper
uid and electrolyte balance.
Antibiotics are of no help in the treatment of primary her-
pes infection, and use of corticosteroids is contraindicated.
Future therapy may include prevention of the infection with
use of a genetically disabled HSV vaccine.
Coxsackievirus Infections
Coxsackieviruses are ribonucleic acid (RNA) enteroviruses
and are named for the town in upper New York State where
they were rst discovered. Coxsackieviruses have been sepa-
rated into two groups, A and B. There are 24 known types of
coxsackievirus group A and 6 types of coxsackievirus group B.
These viruses cause hepatitis, meningitis, myocarditis, peri-
carditis, and acute respiratory disease. Three clinical types of
infection of the oral region that have been described are usu-
ally caused by group A coxsackieviruses: herpangina, hand-
foot-and-mouth disease, and acute lymphonodular pharyngi-
tis. Types of coxsackievirus A have also been described as
causing a rare mumpslike form of parotitis.
HERPANGINA
Coxsackievirus A4 has been shown to cause a majority of
cases of herpangina, but types A1 to A10 as well as types A16
to A22 have also been implicated. Because many antigenic
strains of coxsackievirus exist, herpangina may be seen more
than once in the same patient. Unlike herpes simplex infec-
tions, which occur at a constant rate, herpangina frequently
occurs in epidemics that have their highest incidence from
June to October. The majority of cases affect young children
ages 3 through 10, but infection of adolescents and adults is
not uncommon.
Clinical Manifestations. After a 2- to 10-day incubation
period, the infection begins with generalized symptoms of
fever, chills, and anorexia. The fever and other symptoms are
generally milder than those experienced with primary HSV
infection. The patient complains of sore throat, dysphagia,
and occasionally sore mouth. Lesions start as punctate mac-
ules, which quickly evolve into papules and vesicles involving
the posterior pharynx, tonsils, faucial pillars, and soft palate.
Lesions are found less frequently on the buccal mucosa,
tongue, and hard palate (Figure 4-6). Within 24 to 48 hours,
the vesicles rupture, forming small 1 to 2 mm ulcers. The dis-
ease is usually mild and heals without treatment in 1 week.
Herpangina may be clinically distinguished from primary
HSV infection by several criteria:
1. Herpangina occurs in epidemics; HSV infections do
not.
2. Herpangina tends to be milder than HSV infection.
3. Lesions of herpangina occur on the pharynx and pos-
terior portions of the oral mucosa, whereas HSV pri-
marily affects the anterior portion of the mouth.
4. Herpangina does not cause a generalized acute gin-
givitis like that associated with primary HSV infection.
5. Lesions of herpangina tend to be smaller than those of
HSV.
FIGURE 4-5 Cytology smear stained with Giemsa, demonstrating
multinucleated giant cells.
Laboratory Studies. A smear taken from the base of a fresh
vesicle and stained with Giemsa will not show ballooning
degeneration or multinucleated giant cells. This helps to dis-
tinguish herpangina from herpes simplex and herpes zoster,
which do show these changes.
Treatment. Herpangina is a self-limiting disease, and treat-
ment is supportive, including proper hydration and topical
anesthesia when eating or swallowing is difficult. Specific
antiviral therapy is not available.
ACUTE LYMPHONODULAR PHARYNGITIS
This is a variant of herpangina caused by coxsackievirus A10.
The distribution of the lesions is the same as in herpangina,
but yellow-white nodules appear that do not progress to vesi-
cles or ulcers. The disease is self-limiting, and only support-
ive care is indicated.
HAND-FOOT-AND-MOUTH DISEASE
Hand-foot-and-mouth disease is caused by infection with
coxsackievirus A16 in a majority of cases, although instances
have been described in which A5, A7, A9, A10, B2, or B5 or
enterovirus 71 has been isolated. The disease is characterized
by low-grade fever, oral vesicles and ulcers, and nonpruritic
macules, papules, and vesicles, particularly on the extensor
surfaces of the hands and feet. The oral lesions are more
extensive than are those described for herpangina, and lesions
of the hard palate, tongue, and buccal mucosa are common.
Severe cases with central nervous system involvement,
myocarditis, and pulmonary edema have been reported in
epidemics caused by enterovirus 71.
27
Adler and colleagues
28
studied 20 cases of hand-foot-and-
mouth disease. The patients ranged in age from 8 months to
33 years, with 75% of cases occurring below 4 years of age. The
clinical manifestations lasted 3 to 7 days. The most common
complaint of the 20 patients was a sore mouth, and, clinically,
all 20 patients had lesions involving the oral mucosa. Because
of the frequent oral involvement, dentists are more likely to see
patients with this disease than with herpangina, and they
should remember to examine the hands and feet for macu-
lopapular and vesicular lesions when patients present with an
acute stomatitis and fever. Treatment is supportive.
Varicella-Zoster Virus Infection
Varicella zoster (VZV) is a herpesvirus, and, like other her-
pesviruses, it causes both primary and recurrent infection and
remains latent in neurons present in sensory ganglia.
29
VZV is
responsible for two major clinical infections of humans: chick-
enpox (varicella) and shingles (herpes zoster [HZ]).
Chickenpox is a generalized primary infection that occurs the
rst time an individual contacts the virus. This is analogous to
the acute herpetic gingivostomatitis of herpes simplex virus.
After the primary disease is healed, VZV becomes latent in the
dorsal root ganglia of spinal nerves or extramedullary ganglia
of cranial nerves. A child without prior contact with VZV can
develop chickenpox after contact with an individual with HZ.
In 3 to 5 of every 1,000 individuals, VZV becomes reacti-
vated, causing lesions of localized herpes zoster. The inci-
dence of HZ increases with age or immunosuppression.
30
Patients who are immunocompromised due to HIV disease,
cancer chemotherapy, immunosuppressive drug therapy, or
hematologic malignancy have an increased susceptibility to
severe and potentially fatal HZ. These HZ infections may be
deep-seated and disseminated, causing pneumonia, menin-
goencephalitis, and hepatitis; however, otherwise normal
patients who develop HZ do not have a signicant incidence
of underlying malignancy.
CLINICAL MANIFESTATIONS
General Findings. Chickenpox is a childhood disease charac-
terized by mild systemic symptoms and a generalized intensely
pruritic eruption of maculopapular lesions that rapidly develop
into vesicles on an erythematous base. Oral vesicles that rapidly
change to ulcers may be seen, but the oral lesions are not an
important symptomatic, diagnostic, or management problem.
HZ commonly has a prodromal period of 2 to 4 days, when
shooting pain, paresthesia, burning, and tenderness appear
along the course of the affected nerve. Unilateral vesicles on an
erythematous base then appear in clusters, chiey along the
course of the nerve, giving the characteristic clinical picture of
single dermatome involvement. Some lesions spread by
viremia occur outside the dermatome. The vesicles turn to
scabs in 1 week, and healing takes place in 2 to 3 weeks. The
nerves most commonly affected with HZ are C3, T5, L1, L2,
and the rst division of the trigeminal nerve.
When the full clinical picture of HZ is present with pain
and unilateral vesicles, the diagnosis is not difcult. Diagnostic
problems arise during the prodromal period, when pain is
present without lesions. Unnecessary surgery has been per-
formed because of the diagnosis of acute appendicitis, chole-
cystitis, or dental pulpitis.
31
A more difcult diagnostic prob-
lem is pain caused by VZ virus without lesions developing
along the course of the nerve (zoster sine herpete; zoster sine
FIGURE 4-6 A cluster of vesicles on the tongue in a patient with herpan-
gina. The patient had lesions of the posterior pharyngeal wall and tonsils, but
there was no gingivitis. Coxsackievirus A4 was isolated in tissue culture.
eruptione). Diagnosis in these cases is based on clinical symp-
toms and serologic evidence of a rising antibody titer.
HZ may also occasionally affect motor nerves. HZ of the
sacral region may cause paralysis of the bladder. The extrem-
ities and diaphragm have also been paralyzed during episodes
of HZ.
The most common complication of HZ is postherpetic
neuralgia, which is dened as pain remaining for over a month
after the mucocutaneous lesions have healed, although some
clinicians do not use the term postherpetic neuralgia unless the
pain has lasted for at least 3 months after the healing of the
lesions. The overall incidence of postherpetic neuralgia is 12
to 14%, but the risk increases signicantly after the age of 60
years, most likely due to the decline in cell-mediated immu-
nity.
3234
Immunosuppression does not increase the risk of
postherpetic neuralgia.
35
Oral Findings. Herpes zoster involves one of the divisions of
the trigeminal nerve in 18 to 20% of cases, but the ophthalmic
branch is affected several times more frequently than are the
second or third divisions. HZ of the rst division can lead to
blindness secondary to corneal scarring and should be man-
aged by an ophthalmologist. Facial and intraoral lesions are
characteristic of HZ involving the second and third divisions
of the trigeminal nerve.
Each individual oral lesion of HZ resembles lesions seen
in herpes simplex infections. The diagnosis is based on a his-
tory of pain and the unilateral nature and segmental distrib-
ution of the lesions (Figures 4-7 and 4-8). When the clinical
appearance is typical and vesicles are present, oral HZ can be
distinguished clinically from other acute multiple lesions of
the mouth, which are bilateral and are not preceded or accom-
panied by pain along the course of one trigeminal nerve
branch
36
(Figure 4-9).
HZ has been associated with dental anomalies and severe
scarring of the facial skin when trigeminal HZ occurs during
tooth formation. Pulpal necrosis and internal root resorption
have also been related to HZ.
37
In immunocompromised
patients, large chronic HZ lesions have been described that have
led to necrosis of underlying bone and exfoliation of teeth.
38
HZ of the geniculate ganglion, Ramsay Hunt syndrome, is
a rare form of the disease characterized by Bells palsy, unilat-
eral vesicles of the external ear, and vesicles of the oral mucosa.
Because oral lesions occurring without facial lesions are
rare, isolated oral HZ can be misdiagnosed, particularly when
erythema, edema, and nonspecific ulceration are seen with-
out the presence of intact vesicles. In these cases, a cytology
smear or viral culture is often necessary for diagnosis. An
incorrect diagnosis can be made when prodromal pain is
present prior to the appearance of the characteristic lesions.
During this period, endodontic therapy, extractions, or other
surgery may be performed unnecessarily. Similar problems
occur in zoster sine eruptione.
FIGURE 4-7 Facial lesions of herpes zoster involving the second divi-
sion of trigeminal nerve.
FIGURE 4-8 Herpes zoster of the third division of fth nerve, right side.
FIGURE 4-9 Unilateral palatal lesions of herpes zoster of the second
division of trigeminal nerve.
microvasculature of skin and mucosa, or cell-mediated immu-
nity. Kazmierowski and Wuepper studied specimens of lesions
less than 24 hours old from 17 patients with EM; 13 of the 17
had deposition of immunoglobulin (Ig) M and complement
(C) 3 in the supercial vessels.
42
Other health care workers
have detected elevated levels of immune complexes and
decreased complement in uid samples taken from vesicles.
Although the histopathology is not specic, two major his-
tologic patterns have been described: an epidermal pattern
characterized by lichenoid vasculitis and intraepidermal vesi-
cles, and a dermal pattern characterized by lymphocytic vas-
culitis and subepidermal vesiculation.
43
The most common triggers for episodes of EM are herpes
simplex virus and drug reactions. The drugs most frequently
associated with EM reactions are oxycam nonsteroidal anti-
inammatory drugs (NSAIDs); sulfonamides; anticonvulsants
such as carbamazepine, phenobarbital, and phenytoin;
trimethoprim-sulfonamide combinations, allopurinol, and
penicillin.
44
A majority of the severe cases of Stevens-Johnson
syndrome or TEN are caused by drug reactions.
The relationship of HSV to episodes of EM has been
known for over 50 years, but improved diagnostic techniques,
including polymerase chain reaction (PCR) and in situ
hybridization have demonstrated that herpes-associated EM is
a common form of the disease, accounting for at least 20 to
40% of the cases of single episodes of EM and approximately
80% of recurrent EM
45
(Figures 4-10 and 4-11). Herpes anti-
gens have been demonstrated in the skin and immunocom-
plexes obtained from patients with EM. Many investigators
now believe that the major cause of EM is a cellular immune
response to HSV antigens deposited in keratinocytes of the
skin and mucosa.
46
The tendency to develop mucous mem-
brane lesions during episodes of herpes-associated EM appears
to be genetically determined and related to specic human
leukocyte antigen (HLA) types.
47
Oral mucosal lesions were
detected in 8 of 12 children with HSV-associated EM.
48
Other
triggers for EM include progesterone, Mycoplasma benign and
malignant tumors, radiotherapy, Crohns disease, sarcoidosis,
histoplasmosis, and infectious mononucleosis.
4951
LABORATORY FINDINGS
Cytology is a rapid method of evaluation that can be used in
cases in which the diagnosis is uncertain. Fluorescent-anti-
body stained smears using uorescein conjugated monoclonal
antibodies is more reliable than is routine cytology and is pos-
itive in over 80% of cases. The most accurate method of diag-
nosis is viral isolation in tissue culture, but this test is more
expensive and the results take days rather than hours.
Demonstration of a rising antibody titer is rarely necessary for
diagnosis except in cases of zoster sine eruptione, when it is the
only means of conrming suspected cases.
TREATMENT
Management should be directed toward shortening the course
of the disease, preventing postherpetic neuralgia in patients
over 50 years of age, and preventing dissemination in
immunocompromised patients. Acyclovir or the newer anti-
herpes drugs valacyclovir or famciclovir accelerate healing and
reduce acute pain, but they do not reduce the incidence of
postherpetic neuralgia.
35
The newer drugs have greater
bioavailability and are more effective in the treatment of HZ.
39
The use of systemic corticosteroids to prevent postherpetic
neuralgia in patients over 50 years of age is controversial; a recent
review of the data indicated a reduction of pain and disability dur-
ing the rst 2 weeks but no effect on the incidence or severity of
post-herpetic neuralgia.
33,34
Some clinicians advocate the use of
a combination of intralesional steroids and local anesthetics to
decrease healing time and prevent postherpetic neuralgia, but a
controlled study of this therapy has not been performed.
Effective therapy for postherpetic neuralgia includes appli-
cation of capsaicin, a substance extracted from hot chili pep-
pers.
40
Topical capsaicin is safe but must be used for a prolonged
period to be effective and may cause a burning sensation of the
skin. When topical capsaicin therapy is ineffective, use of a tri-
cyclic antidepressant or gabapentin is indicated.
41
Chemical or
surgical neurolysis may be necessary in refractory cases (see
Chapter 11, Orofacial Pain).
Erythema Multiforme
Erythema multiforme (EM) is an acute inammatory disease
of the skin and mucous membranes that causes a variety of
skin lesionshence the name multiforme. The oral lesions,
typically inflammation accompanied by rapidly rupturing
vesicles and bullae, are often an important component of the
clinical picture and are occasionally the only component.
Erythema multiforme may occur once or recur, and it should
be considered in the diagnosis of multiple acute oral ulcers
whether or not there is a history of similar lesions. There is also
a rare chronic form of EM. EM has several clinical presenta-
tions: a milder self-limiting form and severe life-threatening
forms that may present as either Stevens-Johnson syndrome or
toxic epidermal necrolysis (TEN).
ETIOLOGY
EM is an immune-mediated disease that may be initiated
either by deposition of immune complexes in the supercial
FIGURE 4-10 Early vesicular lesions in a patient who develops ery-
thema multiforme after each episode of recurrent herpes labialis.
Many cases of EM continue to have no obvious detectable
cause after extensive testing for underlying systemic disease
and allergy and are labeled idiopathic.
General Findings. EM is seen most frequently in children
and young adults and is rare after age 50 years. It has an acute
or even an explosive onset; generalized symptoms such as fever
and malaise appear in severe cases. A patient may be asymp-
tomatic and in less than 24 hours have extensive lesions of the
skin and mucosa. EM simplex is a self-limiting form of the dis-
ease and is characterized by macules and papules 0.5 to 2 cm
in diameter, appearing in a symmetric distribution.
The most common cutaneous areas involved are the hands,
feet, and extensor surfaces of the elbows and knees. The face
and neck are commonly involved, but only severe cases affect
the trunk. Typical skin lesions of EM may be nonspecic mac-
ules, papules, and vesicles. More typical skin lesions contain
petechiae in the center of the lesion. The pathognomonic
lesion is the target or iris lesion, which consists of a central
bulla or pale clearing area surrounded by edema and bands of
erythema (Figure 4-12).
The more severe vesiculobullous forms of the disease,
Stevens-Johnson syndrome and TEN, have a signicant mor-
tality rate.
52
EM is classified as Stevens-Johnson syndrome
when the generalized vesicles and bullae involve the skin,
mouth, eyes, and genitals
53
(Figure 4-13).
The most severe form of the disease is TEN, (tone epider-
mal neurolysis), which is usually secondary to a drug reaction
and results in sloughing of skin and mucosa in large sheets.
Morbidity, which occurs in 30 to 40% of patients, results from
secondary infection, uid and electrolyte imbalance, or involve-
ment of the lung, liver, or kidneys.
54
Patients with this form of
the disease are most successfully managed in burn centers,
where necrotic skin is removed under general anesthesia and
healing takes place under sheets of porcine xenografts.
Oral Findings. Oral lesions commonly appear along with
skin lesions in approximately 70% of EM patients
55
(Figure
4-14). In some cases, oral lesions are the predominant or sin-
gle site of disease. When the oral lesions predominate and no
target lesions are present on the skin, EM must be differenti-
ated from other causes of acute multiple ulcers, especially pri-
mary herpes simplex infection. This distinction is important
because corticosteroids may be the treatment of choice in
EM, but they are specically contraindicated in primary her-
pes simplex infections. When there are no skin lesions and the
oral lesions are mild, diagnosis may be difcult and is usually
made by exclusion of other diseases. Cytologic smears and
virus isolation may be done to eliminate the possibility of
primary herpes infection. Biopsy may be performed when
acute pemphigus is suspected. The histologic picture of oral
EM is not considered specic, but the nding of a perivascu-
lar lymphocytic inltrate and epithelial edema and hyperpla-
sia is considered suggestive of EM.
The diagnosis is made on the basis of the total clinical pic-
ture, including the rapid onset of lesions. The oral lesions start
as bullae on an erythematous base, but intact bullae are rarely
seen by the clinician because they break rapidly into irregular
ulcers. Viral lesions are small, round, symmetric, and shallow,
but EM lesions are larger, irregular, deeper, and often bleed.
Lesions may occur anywhere on the oral mucosa with EM,
but involvement of the lips is especially prominent, and gin-
gival involvement is rare. This is an important criterion for dis-
tinguishing EM from primary herpes simplex infection, in
which generalized gingival involvement is characteristic.
In full-blown clinical cases, the lips are extensively eroded,
and large portions of the oral mucosa are denuded of epithe-
lium. The patient cannot eat or even swallow and drools
blood-tinged saliva. Within 2 or 3 days the labial lesions begin
to crust. Healing occurs within 2 weeks in a majority of cases,
but, in some severe cases, extensive disease may continue for
several weeks.
TREATMENT
Mild cases of oral EM may be treated with supportive measures
only, including topical anesthetic mouthwashes and a soft or
liquid diet. Moderate to severe oral EM may be treated with a
FIGURE 4-11 Target lesion on the arm of the patient with erythema multi-
forme shown in Figure 4-10.
FIGURE 4-12 Target lesions in a patient with erythema multiforme.
short course of systemic corticosteroids in patients without sig-
nicant contraindications to their use. Systemic corticosteroids
should only be used by clinicians familiar with the side effects,
and, in each case, potential benets should be carefully weighed
against potential risks. Young children treated with systemic
steroids for EM appear to have a higher rate of complications
than do adults, particularly gastrointestinal bleeding and sec-
ondary infections. Adults treated with short-term systemic
steroids have a low rate of complications and a shorter course
of EM.
56
The protein-wasting and adrenal-suppressive effects
of systemic steroids are not signicant when used short-term,
and the clinical course of the disease may be shortened. An ini-
tial dose of 30 mg/d to 50 mg/d of prednisone or methylpred-
nisolone for several days, which is then tapered, is helpful in
shortening the healing time of EM, particularly when therapy
is started early in the course of the disease. It should be noted
that the efcacy of this treatment has not been proven by con-
trolled clinical trials and is controversial.
Patients with severe cases of recurrent EM have been
treated with dapsone, azathioprine, levamisole, or thalido-
mide. EM triggered by progesterone, also referred to as
autoimmune progesterone dermatitis and stomatitis, has been
treated successfully with tamoxifen. In resistant cases,
oophorectomy has been necessary to cure the disorder.
57
Antiherpes drugs such as acyclovir or valacyclovir can be effec-
tive in preventing susceptible patients from developing herpes-
FIGURE 4-13 Labial (A), skin (B), and penile (C) lesions in a
17-year-old male with Stevens-Johnson form of erythema multiforme.
The lesions began to arise less than 12 hours before the pictures were
taken.
FIGURE 4-14 Intraoral lesions of erythema multiforme in an 18-year-
old male.
A
B C
associated EM, if the drug is administered at the onset of the
recurrent HSV lesion. Prophylactic use of antiherpes drugs is
effective in preventing frequent recurrent episodes of HSV-
associated EM.
56,58
Systemic steroids are recommended for
management of Stevens-Johnson syndrome and are consid-
ered life saving in severe cases.
59,60
Contact Allergic Stomatitis
Contact allergy results from a delayed hypersensitivity reac-
tion that occurs when antigens of low molecular weight pen-
etrate the skin or mucosa of susceptible individuals. These
antigens combine with epithelial-derived proteins to form
haptens that bind to Langerhans cells in the epithelium.
The Langerhans cells migrate to the regional lymph nodes
and present the antigen to T lymphocytes, which become
sensitized and undergo clonal expansion. After re-exposure
to the antigen, sensitized individuals develop an inflamma-
tory reaction confined to the site of contact. Since the reac-
tion resulting from contact allergy appears as nonspecific
inflammation, contact dermatitis or stomatitis may be dif-
ficult to distinguish from chronic physical irritation. The
incidence of contact stomatitis is unknown, but it is believed
to be significantly less common than contact dermatitis for
the following reasons:
1. Saliva quickly dilutes potential antigens and physically
washes them away and digests them before they can
penetrate the oral mucosa.
2. Since the oral mucosa is more vascular than the skin,
potential antigens that do penetrate the mucosa are
rapidly removed before an allergic reaction can be
established.
3. The oral mucosa has less keratin than does the skin,
decreasing the possibility that haptens will be formed.
Contact stomatitis may result from contact with dental
materials, oral hygiene products, or foods. Common causes
of contact oral reactions are cinnamon or peppermint,
which are frequently used flavoring agents in food, candy,
and chewing gum, as well as oral hygiene products such as
toothpaste, mouthwash and dental floss
61
(Figure 4-15).
Dental materials that have been reported to cause cases of
contact allergic stomatitis include mercury in amalgam, gold
in crowns, free monomer in acrylic, and nickel in ortho-
dontic wire.
6264
Pyrophosphates and zinc citrate, which are
components of tartar control toothpaste, cause superficial
peeling of the mucosa in some users, but this reaction is
believed to be caused by physical irritation rather than an
allergic reaction.
65
The clinical signs and symptoms of contact oral allergy are
nonspecic and are frequently difcult to distinguish from
physical irritation. The reaction occurs only at the site of con-
tact and includes a burning sensation or soreness accompanied
by erythema, and occasionally the formation of vesicles and
ulcers. Burning sensations without the presence of lesions is
not a result of contact allergy, and obtaining allergy tests for
patients with burning mouth syndrome with normal-appear-
ing mucosa is not indicated.
Lesions that appear lichenoid both clinically and histolog-
ically may also be a result of contact allergy when the lichenoid
lesion is in direct contact with the potential allergen. These
lesions occur most frequently as a result of mercury in amal-
gam, and appear on the buccal mucosa and lateral border of
the tongue in direct contact with the restoration. These lesions
disappear when the amalgam is removed. It should be empha-
sized that there is no evidence that generalized lesions of oral
lichen planus not in direct contact with restorations heal when
amalgam restorations are removed.
Another oral manifestation of contact allergy is plasma
cell gingivitis, which is characterized by generalized erythema
and edema of the attached gingiva, occasionally accompanied
by cheilitis and glossitis
66
(Figure 4-16). The histopathology
is described as sheets of plasma cells that replace normal
connective tissue. Some cases have been related to an aller-
gen present in toothpaste, chewing gum, or candy, whereas
other cases remain of unknown etiology even after extensive
allergy testing. Plasma cell gingivitis must be distinguished
from neoplastic plasma cell diseases such as plasmacytoma or
multiple myeloma.
FIGURE 4-15 Contact allergy of the labial mucosa, due to peppermint. FIGURE 4-16 Plasma cell gingivitis of unknown etiology.
DIAGNOSIS
Contact allergy is most accurately diagnosed by the use of a
patch test.
67
This test is performed by placing the suspected
allergens in small aluminum disks, called Finn chambers,
which are taped onto hairless portions of the skin. The disks
remain in place for 48 hours. A positive response to a contact
allergen is identied by inammation at the site of the test,
which is graded on a scale of 0 to 3. Patch tests should be per-
formed by clinicians trained and experienced in using the test,
so the results are interpreted accurately.
TREATMENT
Management of oral contact allergy depends on the severity of
the lesions. In mild cases, removal of the allergen sufces. In
more severe symptomatic cases, application of a topical corti-
costeroid is helpful to speed healing of painful lesions.
Oral Ulcers Secondary to Cancer Chemotherapy
Chemotherapeutic drugs are frequently used to effect remis-
sion of both solid tumors, hematologic malignancies, and bone
marrow transplantation. Similar drugs are used for patients
with bone marrow transplants. One of the common side
effects of the anticancer drugs is multiple oral ulcers. Dentists
who practice in hospitals where these drugs are used exten-
sively may see oral ulcers secondary to such drug therapy more
frequently than any other lesion described in this chapter.
68,69
Anticancer drugs may cause oral ulcers directly or indi-
rectly. Drugs that cause stomatitis indirectly depress the bone
marrow and immune response, leading to bacterial, viral, or
fungal infections of the oral mucosa. Others, such as
methotrexate, cause oral ulcers via direct effect on the replica-
tion and growth of oral epithelial cells by interfering with
nucleic acid and protein synthesis, leading to thinning and
ulceration of the oral mucosa.
A recent publication by Sonis describes a new hypothesis
that explains the severe stomatitis observed in patients receiv-
ing cytotoxic drugs for stem cell transplantation.
70
It is noted
that an inammatory reaction precedes ulceration and that
anti-inammatory drugs may be useful in minimizing bone
marrowrelated ulceration.
Details of the diagnosis and management of these lesions
are discussed in Chapters 19, Transplantation Medicine, and
16, Hematologic Disease.
Acute Necrotizing Ulcerative Gingivitis
Acute necrotizing ulcerative gingivitis (ANUG) is an
endogenous oral infection that is characterized by necrosis
of the gingiva. Occasionally, ulcers of the oral mucosa also
occur in patients with hematologic disease or severe nutri-
tional deficiencies (see Chapter 16).
ANUG became known notoriously as trench mouthdur-
ing World War I because of its prevalence in the combat
trenches, and it was incorrectly considered a highly contagious
disease. Since then, studies have shown that the disease is
accompanied by an overgrowth of organisms prevalent in nor-
mal oral ora and is not transmissible. The organisms most
frequently mentioned as working symbiotically to cause the
lesions are the fusiform bacillus and spirochetes.
Plaque samples taken from ANUG patients demonstrate a
constant anaerobic ora of Treponema spp, Selenomonas spp,
Fusobacterium spp, and Bacteroides intermedius.
71
The tissue
destruction is thought to be caused by endotoxins that act
either directly on the tissues or indirectly by triggering
immunologic and inammatory reactions.
Classic ANUG in patients without an underlying medical
disorder is found most often in those between the ages of 16
and 30 years, and it is associated with three major factors:
1. Poor oral hygiene with pre-existing marginal gingivitis
or faulty dental restorations
2. Smoking
3. Emotional stress
Systemic disorders associated with ANUG are diseases
affecting neutrophils (such as leukemia or aplastic anemia),
marked malnutrition, and HIV infection. Malnutrition-asso-
ciated cases are reported from emergent countries where the
untreated disease may progress to noma, a large necrotic ulcer
extending from the oral mucosa through the facial soft tissues.
The prevalence of the disease was reported by Giddon and
colleagues,
72
who studied the prevalence of ANUG in 12,500
students served by the Harvard University Dental Health
Service. About 0.9% of the total sample developed ANUG dur-
ing the period of study. A 4% prevalence in those students
who made use of the dental clinic was observed. Members of
the junior class were most often affected. A relation to stress
was noted by an increased frequency during examination and
vacation periods. Studies of military trainees or college stu-
dents demonstrated a prevalence of 5 to 7%.
There are three forms of periodontal diseases observed
in patients with acquired immunodeficiency syndrome
(AIDS): linear gingival erythema (LGE), necrotizing ulcer-
ative gingivitis (NUG), and necrotizing ulcerative peri-
odontitis (NUP).
LGE is an intense red band involving the marginal gingiva
that does not resolve with standard oral hygiene procedures.
Some cases are believed to be caused by candidal overgrowth,
and these cases resolve with antifungal therapy. NUG and NUP
are clinically similar to ANUG; the term NUG is used when
the disease involves only the gingiva, and NUPinvolves a loss
of periodontal attachment.
73,74
There is evidence that, in
patients with AIDS, the host response in the gingival crevice is
altered. Levels of proinammatory cytokines such as inter-
leukin-1 are increased in the gingival crevice of patients with
human immunodeciency virus (HIV), which alters the reg-
ulation of neutrophils. This alteration in neutrophil function
may explain the increase in NUP-related organisms including
fusobacteria and Candida, which results in the rapid necrosis
of gingival tissues.
75
A fulminating form of ulcerative stomatitis related to
ANUG is noma (cancrum oris), which predominantly affects
children in sub-Saharan Africa. This disease is characterized by
extensive necrosis that begins on the gingiva and then pro-
gresses from the mouth through the cheek to the facial skin,
causing extensive disgurement (Figure 4-17). The major risk
factors associated with noma include malnutrition, poor oral
hygiene, and concomitant infectious diseases such as
measles.
76
Living in close proximity to livestock is also believed
to play a role, and Fusobacterium necrophorum, a pathogen
associated with disease in livestock, has been isolated from
over 85% of noma lesions.
77
The mortality rate without appro-
priate therapy exceeds 70%.
The onset of acute forms of ANUG is usually sudden, with
pain, tenderness, profuse salivation, a peculiar metallic taste,
and spontaneous bleeding from the gingival tissues. The
patient commonly experiences a loss of the sense of taste and
a diminished pleasure from smoking. The teeth are frequently
thought to be slightly extruded, sensitive to pressure, or to
have a woody sensation. At times they are slightly movable.
The signs noted most frequently are gingival bleeding and
blunting of the interdental papillae (Figure 4-18).
The typical lesions of ANUG consist of necrotic punched-
out ulcerations, developing most commonly on the interden-
tal papillae and the marginal gingivae. These ulcerations can be
observed most easily on the interdental papillae, but ulceration
may develop on the cheeks, the lips, and the tongue, where
these tissues come in contact with the gingival lesions or fol-
lowing trauma. Ulcerations also may be found on the palate and
in the pharyngeal area (Figure 4-19). When the lesions have
spread beyond the gingivae, blood dyscrasias and immunode-
ciency should be ruled out by ordering appropriate laboratory
tests, depending upon associated signs and symptoms.
The ulcerative lesions may progress to involve the alveolar
process, with sequestration of the teeth and bone. When gin-
gival hemorrhage is a prominent symptom, the teeth may
become supercially stained a brown color, and the mouth
odor is extremely offensive.
The tonsils should always be examined since these organs
may be affected. The regional lymph nodes usually are slightly
enlarged, but occasionally the lymphadenopathy may be
marked, particularly in children.
The constitutional symptoms in primary ANUG are usually
of minor signicance when compared with the severity of the
oral lesions. Signicant temperature elevation is unusual, even
in severe cases, and, when it exists, other accompanying or
underlying diseases should be ruled out, particularly blood
dyscrasias and AIDS. HIV-infected patients with NUG have
rapidly progressing necrosis and ulceration rst involving the
gingiva alone, and then NUP with the periodontal attachment
and involved alveolar bone. The ulcerated areas may be localized
or generalized and often are very painful. In severe cases, the
underlying bone is denuded and may become sequestrated, and
the necrosis may spread from the gingiva to other oral tissues.
TREATMENT
The therapy of ANUG uncomplicated by other oral lesions or
systemic disease is local dbridement. At the initial visit, the
gingivae should be dbrided with both irrigation and peri-
odontal curettage. The extent of the dbridement depends on
the soreness of the gingivae. The clinician should remember
that the more quickly the local factors are removed, the faster
is the resolution of the lesions. Special care should be taken by
the clinician to dbride the area just below the marginal gin-
FIGURE 4-17 Cancrum oris or noma. (Courtesy of Dr. Gustavo Berger,
Guatemala City, Guatemala).
FIGURE 4-18 Extensive necrosis of the interdental papillae, and mar-
ginal and attached gingivae caused by acute necrotizing ulcerative gingivitis.
FIGURE 4-19 Palatal ulceration in a 21-year-old male with fusospiro-
chetal stomatitis, which began as a necrotizing lesion of a pericoronal ap.
givae. Complete dbridement may not be possible on the rst
visit because of soreness. The patient must return, even though
the pain and other symptoms have disappeared, to remove all
remaining local factors.
Treatment of ANUG is not nished until there has been a
complete gingival curettage and root planing, including removal
of overhanging margins and other predisposing local factors.
After the rst visit, careful home care instruction must be given
to the patient regarding vigorous rinsing and gentle brushing
with a soft brush. Patients should be made aware of the signi-
cance of such factors as poor oral hygiene, smoking, and stress.
Antibiotics are usually not necessary for routine cases of
ANUG confined to the marginal and interdental gingivae.
These cases can be successfully treated with local dbridement,
irrigation, curettage, and home care instruction including
hydrogen peroxide (approximately 1.5 to 2% in water) mouth
rinses three times a day and chlorhexidine 12% rinses.
Antibiotics should be prescribed for patients with extensive
gingival involvement, lymphadenopathy, or other systemic
signs, and in cases in which mucosa other than the gingivae is
involved. Metronidazole and penicillin are the drugs of choice
in patients with no history of sensitivity to these drugs. Patients
whose lesions have extended from the gingivae to the buccal
mucosa, tongue, palate, or pharynx should be placed on antibi-
otics and should have appropriate studies to rule out blood
dyscrasias or AIDS. After the disease is resolved, the patient
should return for a complete periodontal evaluation.
Periodontal treatment should be instituted as necessary. The
patient must be made aware that, unless the local etiologic
factors of the disease are removed, ANUG may return or
become chronic and lead to periodontal disease.
THE PATIENT WITH RECURRING
ORAL ULCERS
Recurring oral ulcers are among the most common problems
seen by clinicians who manage diseases of the oral mucosa.
There are several diseases that should be included in the dif-
ferential diagnosis of a patient who presents with a history of
recurring ulcers of the mouth, including recurrent aphthous
stomatitis (RAS), Behets syndrome, recurrent HSV infec-
tion, recurrent erythema multiforme, and cyclic neutropenia.
Recurrent Aphthous Stomatitis
RAS is a disorder characterized by recurring ulcers conned to
the oral mucosa in patients with no other signs of disease.
Many specialists and investigators in oral medicine no longer
consider RAS to be a single disease but, rather, several patho-
logic states with similar clinical manifestations. Immunologic
disorders, hematologic deciencies, and allergic or psycholog-
ical abnormalities have all been implicated in cases of RAS.
RAS affects approximately 20% of the general population,
but when specic ethnic or socioeconomic groups are studied,
the incidence ranges from 5 to 50%.
78
RAS is classied accord-
ing to clinical characteristics: minor ulcers, major ulcers
(Suttons disease, periadenitis mucosa necrotica recurrens),
and herpetiform ulcers. Minor ulcers, which comprise over
80% of RAS cases, are less than 1 cm in diameter and heal
without scars. Major ulcers, are over 1 cm in diameter and
take longer to heal and often scar. Herpetiform ulcers are con-
sidered a distinct clinical entity that manifests as recurrent
crops of dozens of small ulcers throughout the oral mucosa.
ETIOLOGY
It was once assumed that RAS was a form of recurrent HSV
infection, and there are still clinicians who mistakenly call RAS
herpes. Many studies done during the past 40 years have
conrmed that RAS is not caused by HSV.
79,80
This distinction
is particularly important at a time when there is specic effec-
tive antiviral therapy available for HSV that is useless for RAS.
Herpes is an anxiety-producing word, suggesting a sexually
transmitted disease among many laypersons, and its use
should be avoided when it does not apply. There continue to
be investigations studying the relationship of RAS to other
herpesviruses such as varicella-zoster virus or Cytomegalovirus,
but the results of these studies continue to be inconclusive.
81,82
The current concept is that RAS is a clinical syndrome with
several possible causes. The major factors identied include
heredity, hematologic deciencies, and immunologic abnor-
malities.
83,84
The best documented factor is heredity.
85
Miller
and colleagues studied 1,303 children from 530 families and
demonstrated an increased susceptibility to RAS among chil-
dren of RAS-positive parents.
86
A study by Ship and associates
showed that patients with RAS-positive parents had a 90%
chance of developing RAS, whereas patients with no RAS-pos-
itive parents had a 20% chance of developing the lesions.
85
Further evidence for the inherited nature of this disorder
results from studies in which genetically specic HLAs have
been identied in patients with RAS, particularly in certain
ethnic groups.
87,88
Hematologic deciency, particularly of serum iron, folate,
or vitamin B
12
, appears to be an etiologic factor in a subset of
patients with RAS.
84
The size of the subset is controversial, but
most estimates range from 5 to 15%. A study by Rogers and
Hutton reported clinical improvement in 75% of patients with
RAS when a specic hematologic deciency was detected and
corrected with specic replacement therapy.
89
Some cases of
nutritional deciency, such as celiac disease, are reported to be
secondary to malabsorption syndrome.
90
Most of the research into the etiology of RAS centers on
immunologic abnormalities. Early work suggested either an
autoimmune disorder or hypersensitivity to oral organisms such
as Streptococcus sanguis.
91
Investigations using more sophisti-
cated immune assays have not supported the early work and
suggest a role of lymphocytotoxicity,
92
antibody-dependent cell-
mediated cytotoxicity, and defects in lymphocyte cell subpopu-
lations.
9395
Burnett and Wray showed that sera and monocytes
induced signicantly more cytolysis in patients with RAS than
in control patients.
96
Thomas and colleagues showed that T
lymphocytes from patients with RAS had increased cytotoxic-
ity to oral epithelial cells.
92
Work by Pedersen and colleagues and
other studies demonstrated an alteration in CD4:CD8 lympho-
cyte ratio, or a dysfunction of the mucocutaneous cytokine net-
work.
9799
Further work is needed to determine if these are spe-
cic or nonspecic responses.
Other factors that have been suggested as being etiologic in
RAS include trauma, psychological stress, anxiety, and allergy
to foods.
100
It is well documented that cessation of smoking
increases the frequency and severity of RAS.
101
In cases of
refractory disease, Hay and Reade reported the benet of an
elimination diet in some patients with suspected or proven
allergy to foods such as milk, cheese, wheat, and our.
102
A detergent present in toothpaste, sodium lauryl sulfate
(SLS), was suspected as an etiologic factor in RAS develop-
ment,
103
but a recent double-blind crossover study showed
that use of an SLS-free toothpaste had no signicant effect on
ulcer development.
104
The rst episodes of RAS most frequently begin during the sec-
ond decade of life and may be precipitated by minor trauma,
menstruation, upper respiratory infections, or contact with
certain foods. The lesions are conned to the oral mucosa and
begin with prodromal burning any time from 2 to 48 hours
before an ulcer appears. During this initial period, a localized
area of erythema develops. Within hours, a small white papule
forms, ulcerates, and gradually enlarges over the next 48 to 72
hours. The individual lesions are round, symmetric, and shal-
low (similar to viral ulcers), but no tissue tags are present from
ruptured vesicles (this helps to distinguish RAS from disease
with irregular ulcers such as EM, pemphigus, and pem-
phigoid). Multiple lesions are often present, but the number,
size, and frequency of them vary considerably (Figure 4-20).
The buccal and labial mucosae are most commonly involved.
Lesions are less common on the heavily keratinized palate or
gingiva. In mild RAS, the lesions reach a size of 0.3 to 1.0 cm
and begin healing within a week. Healing without scarring is
usually complete in 10 to 14 days.
Most patients with RAS have between two and six lesions at
each episode and experience several episodes a year. The disease
is an annoyance for the majority of patients with mild RAS, but
it can be disabling for patients with severe frequent lesions,
especially those classied as major aphthous ulcers. Patients
with major ulcers develop deep lesions that are larger than 1 cm
in diameter and may reach 5 cm (Figure 4-21, A and B). Large
portions of the oral mucosa may be covered with large deep
ulcers that can become conuent. The lesions are extremely
painful and interfere with speech and eating. Many of these
patients continually go from one clinician to another, looking
for a cure.The lesions may last for months and sometimes be
misdiagnosed as squamous cell carcinoma, chronic granulo-
matous disease, or pemphigoid. The lesions heal slowly and
leave scars that may result in decreased mobility of the uvula
and tongue and destruction of portions of the oral mucosa. The
least common variant of RAS is the herpetiform type, which
tends to occur in adults. The patient presents with small punc-
tate ulcers scattered over large portions of the oral mucosa.
DIAGNOSIS
RAS is the most common cause of recurring oral ulcers and is
essentially diagnosed by exclusion of other diseases. A detailed
history and examination by a knowledgeable clinician should dis-
tinguish RAS from primary acute lesions such as viral stomati-
tis or from chronic multiple lesions such as pemphigoid, as well
as from other possible causes of recurring ulcers, such as con-
nective tissue disease, drug reactions, and dermatologic disorders.
The history should emphasize symptoms of blood dyscrasias, sys-
temic complaints, and associated skin, eye, genital, or rectal
lesions. Laboratory investigation should be used when ulcers
worsen or begin past the age of 25 years. Biopsies are only indi-
cated when it is necessary to exclude other diseases, particularly
granulomatous diseases such as Crohns disease or sarcoidosis.
Patients with severe minor aphthae or major aphthous
ulcers should have known associated factors investigated,
including connective-tissue diseases and abnormal levels of
serum iron, folate, vitamin B
12
, and ferritin (Figure 4-22).
Patients with abnormalities in these values should be referred
to an internist to rule out malabsorption syndromes and to ini-
tiate proper replacement therapy. The clinician may also
choose to have food allergy or gluten sensitivity investigated in
severe cases resistant to other forms of treatment.
102
HIV-
infected patients, particularly those with CD4 counts below
100/mm
3
, may develop major aphthous ulcers (Figure 4-23).
TREATMENT
Medication prescribed should relate to the severity of the dis-
ease. In mild cases with two or three small lesions, use of a pro-
tective emollient such as Orabase (Bristol-Myers Squibb,
Princeton, NJ) or Zilactin (Zila Pharmaceutions, Phoenix, AZ)
is all that is necessary. Pain relief of minor lesions can be
obtained with use of a topical anesthetic agent or topical
diclofenac, an NSAID frequently used topically after eye
surgery.
105
In more severe cases, the use of a high-potency top-
ical steroid preparation, such as uocinonide, betamethasone
or clobetasol, placed directly on the lesion shortens healing
time and reduces the size of the ulcers. The effectiveness of the
topical steroid is partially based upon good instruction and
FIGURE 4-20 Recurrent aphthous stomatitis of the tongue and oor of
the mouth.
patient compliance regarding proper use. The gel can be care-
fully applied directly to the lesion after meals and at bedtime
two to three times a day, or mixed with an adhesive such as
Orabase prior to application. Larger lesions can be treated by
placing a gauze sponge containing the topical steroid on the
ulcer and leaving it in place for 15 to 30 minutes to allow for
longer contact of the medication. Other topical preparations
that have been shown to decrease the healing time of RAS
lesions include amlexanox paste and topical tetracycline, which
can be used either as a mouth rinse or applied on gauze
sponges. Intralesional steroids can be used to treat large indo-
lent major RAS lesions. It should be emphasized that no avail-
able topical therapy decreases the onset of new lesions. In
patients with major aphthae or severe cases of multiple minor
aphthae not responsive to topical therapy, use of systemic ther-
apy should be considered. Drugs that have been reported to
reduce the number of ulcers in selected cases of major aphthae
include colchicine, pentoxifylline, dapsone, short bursts of sys-
temic steroids, and thalidomide.
106108
Each of these drugs has
the potential for side effects, and the clinician must weigh the
potential benets versus the risks. Thalidomide has been shown
to reduce both the incidence and severity of major RAS in both
HIV-positive and HIV-negative patients, but this drug must be
used with extreme caution in women during childbearing years
owing to the potential for severe life-threatening and deform-
ing birth defects.
109
All clinicians prescribing thalidomide in the
United States must be registered in the STEPS (System for
Thalidomide Education and Prescribing Safety) program, and
patients receiving the drug must be thoroughly counseled
regarding effective birth control methods that must be used
whenever thalidomide is prescribed. For example, two methods
of birth control must be used, and the patient must have a
pregnancy test monthly. Other side effects of thalidomide
include peripheral neuropathy, gastrointestinal complaints, and
drowsiness.
Behets Syndrome
Behets syndrome, described by the Turkish dermatologist
Hulsi Behet, was classically described as a triad of symptoms
including recurring oral ulcers, recurring genital ulcers, and
FIGURE 4-21 Major aphthous ulcers of the labial mucosa (A) and alveolar mucosa (B).
FIGURE 4-22 A 42-year-old woman with a recent increase in severity
of recurrent aphthous ulcers. An iron deficiency was detected, and the
ulcers resolved when this deciency was corrected. FIGURE 4-23 Major aphthous ulcer in an HIV-infected patient.
A B
eye lesions. The concept of the disease has changed from a
triad of signs and symptoms to a multisystem disorder.
110
The
highest incidence of Behets syndrome has been reported in
eastern Asia, where 1 in 10,000 is affected, and the eastern
Mediterranean, where it is a leading cause of blindness in
young men; however, cases have been reported worldwide,
including in North America, where it is estimated that 1 in
500,000 persons is affected. The highest incidence of Behets
syndrome is in young adults, but cases of Behets syndrome
in children are being reported with increasing frequency.
111
ETIOLOGY
Behets syndrome is caused by immunocomplexes that lead to
vasculitis of small and medium-sized blood vessels and inam-
mation of epithelium caused by immunocompetent T lym-
phocytes and plasma cells.
112,113
Increased neutrophil activity
has also been noted.
114
There is a genetic component to the
disease, with a strong association with HLA-B51. Studies of the
immune abnormalities associated with Behets syndrome
have included ndings described above for patients with RAS.
This has led some investigators to believe that Behets syn-
drome and RAS are both manifestations of a similar disorder
of the immune response.
The most common single site of involvement of Behets syn-
drome is the oral mucosa. Recurring oral ulcers appear in over
90% of patients; these lesions cannot be distinguished from
RAS (Figure 4-24). Some patients experience mild recurring
oral lesions; others have the deep large scarring lesions char-
acteristic of major RAS. These lesions may appear anywhere on
the oral or pharyngeal mucosa. The genital area is the second
most common site of involvement and involves ulcers of the
scrotum and penis in males and ulcers of the labia in females.
The eye lesions consist of uveitis, retinal inltrates, edema and
vascular occlusion, optic atrophy, conjunctivitis, and keratitis.
Generalized involvement occurs in over half of patients
with Behets syndrome. Skin lesions are common and usually
manifest as large pustular lesions. These lesions may be pre-
cipitated by trauma, and it is common for patients with Behets
syndrome to have a cutaneous hyper-reactivity to intracuta-
neous injection or a needlestick (pathergy). Positive pathergy
is dened as an inammatory reaction forming within 24 hours
of a needle puncture, scratch, or saline injection.
Arthritis occurs in greater than 50% of patients and most
frequently affects the knees and ankles.
115
The affected joint
may be red and swollen as in rheumatoid arthritis, but
involvement of small joints of the hand does not occur, and
permanent disability does not result.
In some patients, central nervous system involvement is the
most distressing component of the disease. This may include
brainstem syndrome, involvement of the cranial nerves, or neu-
rologic degeneration resembling multiple sclerosis that can be
visualized by magnetic resonance imaging of the brain. Other
reported signs of Behets syndrome include thrombophlebitis,
intestinal ulceration, venous thrombosis, and renal and pul-
monary disease. Involvement of large vessels is life threatening
because of the risk of arterial occlusion or aneurysms.
Behets syndrome in children, which most frequently
presents between the ages of 9 and 10 years, has similar man-
ifestations as does the adult form of the disease, but oral
ulcers are a more common presenting sign in children, and
uveitis is less common.
116
Oral lesions are the presenting
symptom in over 95% of children with Behets syndrome. A
variant of Behets syndrome, MAGIC syndrome, has been
described. It is characterized by Mouth And Genital ulcers
with Inflammed Cartilage.
117
DIAGNOSIS
Because the signs and symptoms of Behets syndrome over-
lap with those of several other diseases, particularly the con-
nective-tissue diseases, it has been difcult to develop criteria
that meet with universal agreement. Five different sets of diag-
nostic criteria have been in use during the past 20 years. In
1990, an international study group reviewed data from 914
patients from seven countries.
118
A new set of diagnostic cri-
teria was developed that includes recurrent oral ulceration
occurring at least three times in one 12-month period plus two
of the following four manifestations:
1. Recurrent genital ulceration
2. Eye lesions including uveitis or retinal vasculitis
3. Skin lesions including erythema nodosum, pseudofol-
liculitis, papulopustular lesions, or acneiform nodules
in postadolescent patients not receiving corticosteroids
4. A positive pathergy test
TREATMENT
The management of Behets syndrome depends on the sever-
ity and the sites of involvement. Patients with sight-threatening
eye involvement or central nervous system lesions require more
aggressive therapy with drugs with a higher potential for serious
side effects.
119
Azathioprine combined with prednisone has been
shown to reduce ocular disease as well as oral and genital
involvement.
120
Pentoxifylline, which has fewer side effects than
do immunosuppressive drugs or systemic steroids, has also been
reported to be effective in decreasing disease activity, particularly
FIGURE 4-24 Aphthous-like lesion in a patient with Behets syndrome.
stress. The lesions are preceded by a prodromal period of tingling
or burning. This is accompanied by edema at the site of the
lesion, followed by formation of a cluster of small vesicles (Figure
4-25). Each vesicle is 1 to 3 mm in diameter, with the size of the
cluster ranging from 1 to 2 cm. Occasionally, the lesions may be
several centimeters in diameter, causing discomfort and disg-
urement. These larger lesions are more common in immuno-
suppressed individuals. The frequency of recurrences varies.
RIH lesions in otherwise normal patients are similar in
appearance to RHL lesions, but the vesicles break rapidly to
form ulcers. The lesions are typically a cluster of small vesicles
or ulcers, 1 to 2 mm in diameter, clustered on a small portion
of the heavily keratinized mucosa of the gingiva, palate, and
alveolar ridges, although RIH lesions can occasionally involve
other mucosal surfaces
139
(Figure 4-26). In contrast, lesions of
RAS tend to be larger, to spread over a larger area of mucosa,
and to have a predilection for the less heavily keratinized buc-
cal mucosa, labial mucosa, or oor of the mouth.
131
DIAGNOSIS
If laboratory tests are desired, RIH can be distinguished from
RAS by cytology smears taken from the base of a fresh lesion.
Smears from herpetic lesions show cells with ballooning
degeneration and multinucleated giant cells; those from RAS
lesions do not. For more accurate results, cytology smears may
also be tested for HSV using uorescein-labeled HSV antigen.
Viral cultures also are used to distinguish herpes simplex from
other viral lesions, particularly varicella-zoster infections.
TREATMENT
Recurrent herpes infections of the lips and mouth are seldom
more than a temporary annoyance in otherwise normal individ-
uals and should be treated symptomatically. Patients who expe-
rience frequent, large, painful, or disguring lesions may request
professional consultation. The clinician should rst attempt to
minimize obvious triggers. Some recurrences can be eliminated
by the wearing of sunblock during intense sun exposure.
eye involvement.
121
Cyclosporine or colchicine in combination
with corticosteroids has also been shown to be useful in severe
disease.
122,123
Colchicine
124
and thalidomide
125
have been
shown to be useful in mucocutaneous and gastrointestinal man-
ifestations. Systemic corticosteroids remain a mainstay of treat-
ment and are particularly useful in rapidly controlling the dis-
ease until immunosuppressive agents begin to work.
Plasmapheresis has also been used successfully in emergencies.
Oral mucosal lesions not adequately controlled by systemic
therapy may be treated with topical or intralesional steroids in
regimens described in the section on RAS.
Recurrent Herpes Simplex Virus Infection
Recurrent herpes infection of the mouth (recurrent herpes
labialis [RHL]; recurrent intraoral herpes simplex infection
[RIH]) occurs in patients who have experienced a previous
herpes simplex infection and who have serum-antibody pro-
tection against another exogenous primary infection. In oth-
erwise healthy individuals, the recurrent infection is conned
to a localized portion of the skin or mucous membranes.
Recurrent herpes is not a re-infection but a reactivation of virus
that remains latent in nerve tissue between episodes in a non-
replicating state.
126,127
Herpes simplex has been cultured from
the trigeminal ganglion of human cadavers, and recurrent her-
pes lesions commonly appear after surgery involving the gan-
glion.
128,129
Recurrent herpes may also be activated by trauma
to the lips, fever, sunburn, immunosuppression, and menstru-
ation.
130
The virus travels down the nerve trunk to infect
epithelial cells, spreading from cell to cell to cause a lesion.
The published evidence demonstrating that RAS is not
caused by herpesvirus induced many to believe that recurrent
herpes infection of the oral region occurred only on the lips
and not on the oral mucosa; this has been shown to be false.
RAS and herpes lesions can both exist intraorally and are two
separate and distinct disease processes.
131133
All patients who experience primary herpes infection do
not experience recurrent herpes. The number of patients with
a history of primary genital infection with HSV1 who subse-
quently experience recurrent HSV infections is approximately
15%.
134
The recurrence rate for oral HSV1 infections is esti-
mated to be between 20 and 40%.
Studies have suggested several mechanisms for reactivation
of latent HSV, including low serum IgA,
135
decreased cell-
mediated immunity, decreased salivary antiherpes activity,
136
and depression of ADCC (antibody-dependent cell-mediated
cytotoxicity)
137
and interleukin-2 caused by prostaglandin
release in the skin.
Individuals with T-lymphocyte deficiencies owing to
AIDS or transplant or cancer chemotherapy may develop
large chronic lesions
138
(see Herpes Simplex Virus Infection
in Immunosuppressed Patients, below) or, rarely, dissemi-
nated HSV infection.
RHL, the common cold sore or fever blister, may be precipitated
by fever, menstruation, ultraviolet light, and perhaps emotional FIGURE 4-25 Crusted lesions of recurrent herpes labialis.
Drugs are available that suppress the formation and
shorten the healing time of new recurrent lesions. Acyclovir,
the original antiherpes drug, has been shown to be both safe
and effective. The newer antiviral drugs such as valacyclovir,
a prodrug of acyclovir, and famciclovir, a prodrug of penci-
clovir, have greater bioavailability than does acyclovir, but
they do not eliminate established latent HSV. However, in the
mouse model, famciclovir appeared to decrease the rate of
HSV latency.
140,141
The clinical importance of this finding in
human HSV infection is not known. The effectiveness of
these antiherpes drugs to prevent recurrences of genital HSV
has been studied extensively. Acyclovir 400 mg twice daily,
valacyclovir 250 mg twice daily, and famciclovir 250 mg were
each highly effective in preventing genital recurrences.
142,143
The use of antiherpes nucleoside analogues to prevent and
treat RHL in otherwise normal individuals is controversial.
Systemic therapy should not be used to treat occasional or
trivial RHL in otherwise healthy individuals, but episodic
use to prevent lesions in susceptible patients before high-
risk activities such as skiing at high altitudes or before under-
going procedures such as dermabrasion or surgery involving
the trigeminal nerve is justifiable. Some clinicians advocate
the use of suppressive antiherpes therapy for the small per-
centage of RHL patients who experience frequent deforming
episodes of RHL. Acyclovir 400 mg twice daily has been
shown to reduce the frequency and severity of RHL in this
group of patients.
144
Both acyclovir and penciclovir are avail-
able in topical formulations, but use of these preparations
shortens the healing time of RHL by less than 2 days.
THE PATIENT WITH CHRONIC
MULTIPLE LESIONS
Patients with chronic multiple lesions are frequently misdiag-
nosed for weeks to months since their lesions may be confused
with recurring oral mucosal disorders. The clinician can avoid
misdiagnosis by carefully questioning the patient on the initial
visit regarding the natural history of the lesions. In recurring
disorders such as severe aphthous stomatitis, the patient may
experience continual ulceration of the oral mucosa, but indi-
vidual lesions heal and new ones form. In the category of dis-
ease described in this section, the same lesions are present for
weeks to months. The major diseases in this group are pem-
phigus vulgaris, pemphigus vegetans, bullous pemphigoid,
mucous membrane pemphigoid, linear IgA disease, and erosive
lichen planus. Herpes simplex infections may cause chronic
lesions in patients immunocompromised by cancer chemother-
apy, immunosuppressive drugs, or HIV infection.
Pemphigus
Pemphigus is a potentially life-threatening disease that causes
blisters and erosions of the skin and mucous membranes.
These epithelial lesions are a result of autoantibodies that react
with desmosomal glycoproteins that are present on the cell
surface of the keratinocyte. The immune reaction against these
glycoproteins causes a loss of cell-to-cell adhesion, resulting in
the formation of intraepithelial bullae.
145,146
There are 0.5 to
3.2 cases reported each year per 100,000 population, with the
highest incidence occurring in the fth and sixth decades of
life, although rare cases have been reported in children and the
elderly.
147
Pemphigus occurs more frequently in the Jewish
population, particularly among Ashkenazi Jews, in whom
studies have shown a strong association with major histo-
compatibility complex (MHC) class II alleles HLA-DR4 and
DQW3. Familial pemphigus has also been reported.
The major variants of pemphigus are pemphigus vulgaris
(PV), pemphigus vegetans, pemphigus foliaceus, pemphigus
erythematosus, paraneoplastic pemphigus (PNPP), and drug-
related pemphigus. Pemphigus vegetans is a variant of pem-
phigus vulgaris, and pemphigus erythematosus is a variant of
pemphigus foliaceus. Each form of this disease has antibod-
ies directed against different target cell surface antigens,
resulting in a lesion forming in different layer of the epithe-
lium. In pemphigus foliaceus, the blister occurs in the super-
cial granular cell layer, whereas, in pemphigus vulgaris, the
lesion is deeper, just above the basal cell layer. Mucosal
involvement is not a feature of the foliaceus and erythematous
forms of the disease.
PEMPHIGUS VULGARIS
PV is the most common form of pemphigus, accounting for
over 80% of cases. The underlying mechanism responsible for
causing the intraepithelial lesion of PV is the binding of IgG
autoantibodies to desmoglein 3, a transmembrane glycopro-
tein adhesion molecule present on desmosomes. The presence
of desmoglein 1 autoantibodies is a characteristic of pemphi-
FIGURE 4-26 Typical lesions of recurrent intraoral herpes simplex virus
infection in patients with normal immunity are clusters of small vesicles and
ulcers on the heavily keratinized oral mucosa.
gus foliaceus, but these antibodies are also detected in patients
with long-standing PV. Evidence for the relationship of the IgG
autoantibodies to PV lesion formation includes studies
demonstrating the formation of blisters on the skin of mice
after passive transfer of IgG from patients with PV.
148
The
mechanism by which antidesmoglein antibodies cause the loss
of cell-to-cell adhesion is controversial. Some investigators
believe that binding of the PV antibody activates proteases,
whereas more recent evidence supports the theory that the
PV antibodies directly block the adhesion function of the
desmogleins.
146,149,150
The separation of cells, called acantholysis, takes place in
the lower layers of the stratum spinosum (Figure 4-27).
Electron microscopic observations show the earliest epithelial
changes as a loss of intercellular cement substance; this is fol-
lowed by a widening of intercellular spaces, destruction of
desmosomes, and nally cellular degeneration. This progres-
sive acantholysis results in the classic suprabasilar bulla, which
involves increasingly greater areas of epithelium, resulting in
loss of large areas of skin and mucosa.
Pemphigus has been reported coexisting with other
autoimmune diseases, particularly myasthenia gravis.
147
Patients with thymoma also have a higher incidence of pem-
phigus. Several cases of pemphigus have been reported in
patients with multiple autoimmune disorders or those with
neoplasms such as lymphoma. Death occurs most frequently
in elderly patients and in patients requiring high doses of cor-
ticosteroids who develop infections and bacterial septicemia,
most notably from Staphylococcus aureus.
151,152
Clinical Manifestations. The classical lesion of pemphigus is
a thin-walled bulla arising on otherwise normal skin or mucosa.
The bulla rapidly breaks but continues to extend peripherally,
eventually leaving large areas denuded of skin (Figure 4-28). A
characteristic sign of the disease may be obtained by applica-
tion of pressure to an intact bulla. In patients with PV, the bulla
enlarges by extension to an apparently normal surface. Another
characteristic sign of the disease is that pressure to an appar-
ently normal area results in the formation of a new lesion. This
phenomenon, called the Nikolsky sign, results from the upper
layer of the skin pulling away from the basal layer. The Nikolsky
sign is most frequently associated with pemphigus but may
also occur in epidermolysis bullosa.
Some patients with pemphigus develop acute fulminating
disease, but, in most cases, the disease develops more slowly,
usually taking months to develop to its fullest extent.
Oral Manifestations. Eighty to ninety percent of patients with
pemphigus vulgaris develop oral lesions sometime during the
course of the disease, and, in 60% of cases, the oral lesions are the
rst sign.
153
The oral lesions may begin as the classic bulla on a
noninamed base; more frequently, the clinician sees shallow
irregular ulcers because the bullae rapidly break. A thin layer of
epithelium peels away in an irregular pattern, leaving a denuded
base. The edges of the lesion continue to extend peripherally
over a period of weeks until they involve large portions of the oral
mucosa. Most commonly the lesions start on the buccal mucosa,
often in areas of trauma along the occlusal plane. The palate and
gingiva are other common sites of involvement.
154
It is common for the oral lesions to be present up to 4
months before the skin lesions appear. If treatment is instituted
during this time, the disease is easier to control, and the chance
for an early remission of the disorder is enhanced. Frequently,
however, the initial diagnosis is missed, and the lesions are mis-
diagnosed as herpes infection or candidiasis. Zegarelli and
Zegarelli studied 26 cases of intraoral PV. The average time from
onset of the disease to diagnosis was 6.8 months.
155
They also
noted that several patients had coexisting candidiasis, which
sometimes masked the typical clinical picture of the pemphigus
lesions. There is also a subgroup of pemphigus patients whose
disease remains conned to the oral mucosa. These patients
often have negative results on direct immunouorescence (DIF).
If a proper history is taken, the clinician should be able to
distinguish the lesions of pemphigus from those caused by
acute viral infections or erythema multiforme because of the
acute nature of the latter diseases. It is also important for the
clinician to distinguish pemphigus lesions from those in the
RAS category. RAS lesions may be severe, but individual lesions
heal and recur. In pemphigus, the same lesions continue to
extend peripherally over a period of weeks to months. Lesions
of pemphigus are not round and symmetric like RAS lesions
but are shallow and irregular and often have detached epithe-
lium at the periphery (see Figure 4-27). In early stages of the
disease, the sliding away of the oral epithelium resembles skin
peeling after a severe sunburn. In some cases, the lesions may
start on the gingiva and be called desquamative gingivitis. It
should be remembered that desquamative gingivitis is not a
diagnosis in itself; these lesions must be biopsied to rule out the
possibility of PV as well as bullous pemphigoid, mucous mem-
brane pemphigoid, and erosive lichen planus.
Laboratory Tests. PV is diagnosed by biopsy. Biopsies are best
done on intact vesicles and bullae less than 24 hours old; how-
ever, because these lesions are rare on the oral mucosa, the
FIGURE 4-27 Histologic picture of pemphigus vulgaris. The bulla is
intraepithelial because of acantholysis (32 original magnification).
(Courtesy of Margaret Wood, MD)
biopsy specimen should be taken from the advancing edge of the
lesion, where areas of characteristic suprabasilar acantholysis
may be observed by the pathologist. Specimens taken from the
center of a denuded area are nonspecic histologically as well as
clinically. Sometimes several biopsies are necessary before the
correct diagnosis can be made. If the patient shows a positive
Nikolsky sign, pressure can be placed on the mucosa to produce
a new lesion; biopsy may be done on this fresh lesion.
A second biopsy, to be studied by DIF, should be performed
whenever pemphigus is included in the differential diagnosis.
This study is best performed on a biopsy specimen that is
obtained from clinically normal-appearing perilesional mucosa
or skin. In this technique for DIF, uorescein-labeled antihuman
immunoglobulins are placed over the patients tissue specimen.
In cases of PV, the technique will detect antibodies, usually IgG
and complement, bound to the surface of the keratinocytes.
Indirect immunofluorescent antibody tests have been
described that are helpful in distinguishing pemphigus from
pemphigoid and other chronic oral lesions and in following the
progress of patients treated for pemphigus. In this technique,
serum from a patient with bullous disease is placed over a pre-
pared slide of an epidermal structure (usually monkey esoph-
agus). The slide is then overlaid with uorescein-tagged anti-
human gamma globulin. Patients with pemphigus vulgaris have
antikeratinocyte antibodies against intercellular substances that
show up under a uorescent microscope. The titer of the anti-
body has been directly related to the level of clinical disease. An
ELISA (enzyme-linked immunosorbent assay) has been devel-
oped that can detect desmoglein 1 and 3 in serum samples of
patients with PV. These laboratory tests should provide a new
tool for the accurate diagnosis of PV and may also prove use-
ful in monitoring the progress of the disease.
156,157
Treatment . An important aspect of patient management is
early diagnosis, when lower doses of medication can be used
for shorter periods of time to control the disease. The main-
stay of treatment remains high doses of systemic cortico-
steroids, usually given in dosages of 1 to 2 mg/kg/d. When
steroids must be used for long periods of time, adjuvants such
as azathioprine or cyclophosphamide are added to the regi-
men to reduce the complications of long-term cortico-
steroid therapy. Prednisone is used initially to bring the dis-
ease under control, and, once this is achieved, the dose of
prednisone is decreased to the lowest possible maintenance
levels. Patients with only oral involvement also may need
lower doses of prednisone for shorter periods of time, so the
clinician should weigh the potential benets of adding adju-
vant therapy against the risks of additional complications
such as blood dyscrasias, hepatitis, and an increased risk of
malignancy later in life. There is no one accepted treatment
for pemphigus conned to the mouth, but one 5-year follow
-up study of the treatment of oral pemphigus showed no
additional benefit of adding cyclophosphamide or
cyclosporine to prednisone versus prednisone alone, and it
showed a higher rate of complications in the group taking the
immunosuppressive drug.
158
Most studies of pemphigus of
the skin show a decreased mortality rate when adjuvant ther-
apy is given along with prednisone.
159
One new immuno-
suppressive drug, mycophenolate, has been effective when
managing patients resistant to other adjuvants.
160
The need
for systemic steroids may be lowered further in cases of oral
pemphigus by combining topical with systemic steroid ther-
apy, either by allowing the prednisone tablets to dissolve
slowly in the mouth before swallowing or by using potent
topical steroid creams. Other therapies that have been
reported as benecial are parenteral gold therapy, dapsone,
tetracycline, and plasmapheresis.
161
Plasmapheresis is partic-
ularly useful in patients refractory to corticosteroids. A ther-
apy described by Rook and colleagues involves administration
of 8-methoxypsoralen followed by exposure of peripheral
blood to ultraviolet radiation.
162
PARANEOPLASTIC PEMPHIGUS
PNPP is a severe variant of pemphigus that is associated with
an underlying neoplasmmost frequently non-Hodgkins
lymphoma, chronic lymphocytic leukemia, or thymoma.
FIGURE 4-28 A, Shallow irregular erosions on the buccal mucosa and ventral surface of the tongue caused by pemphigus. B, Bullae between the n-
gers of the same patient.
A B
and bullous lichen planus. There is signicant overlap among
these diseases, and the diagnosis often depends on whether the
disease is categorized by clinical manifestations combined with
routine histopathology or the newer techniques of molecular
biology. Recent research into pathologic mechanisms is den-
ing the specic antigens in the basement membrane complex
involved in triggering the autoantibody response.
BULLOUS PEMPHIGOID
BP, which is the most common of the subepithelial blistering
diseases, occurs chiefly in adults over the age of 60 years; it is
self-limited and may last from a few months to 5 years. BP
may be a cause of death in older debilitated individuals.
168
BP
has occasionally been reported in conjunction with other
diseases, particularly multiple sclerosis and malignancy, or
drug therapy, particularly diuretics.
169
In pemphigoid, the
initial defect is not intraepithelial as in PV, but it is subep-
ithelial in the lamina lucida region of the basement mem-
brane
170
(Figure 4-30). There is no acantholysis, but the split
in the basement membrane is accompanied by an inflam-
matory infiltrate that is characteristically rich in eosinophils.
Castlemans disease and Waldenstrms macroglobulinemia
are also associated with cases of PNPP. Patients with this
form of pemphigus develop severe blistering and erosions of
the mucous membranes and skin. Treatment of this disease
is difficult, and most patients die from the effects of the
underlying tumor, respiratory failure due to acantholysis of
respiratory epithelium, or the severe lesions that do not
respond to the therapy successful in managing other forms
of pemphigus.
163,164
Histopathology of lesions of PNPP includes inammation
at the dermal-epidermal junction and keratinocyte necrosis in
addition to the characteristic acantholysis seen in PV. The
results of direct and indirect immunouorescence also differ
from those in PV. DIF shows deposition of IgG and comple-
ment along the basement membrane as well as on the ker-
atinocyte surface. Indirect immunouorescence demonstrates
antibodies that not only bind to epithelium but to liver, heart,
and bladder tissue as well.
PEMPHIGUS VEGETANS
Pemphigus vegetans, which accounts for 1 to 2% of pemphi-
gus cases, is a relatively benign variant of pemphigus vulgaris
because the patient demonstrates the ability to heal the
denuded areas. Two forms of pemphigus vegetans are recog-
nized: the Neumann type and the Hallopeau type. The
Neumann type is more common, and the early lesions are
similar to those seen in pemphigus vulgaris, with large bullae
and denuded areas. These areas attempt healing by developing
vegetations of hyperplastic granulation tissue. In the
Hallopeau type, which is less aggressive, pustules, not bullae,
are the initial lesions. These pustules are followed by verrucous
hyperkeratotic vegetations.
Biopsy results of the early lesions of pemphigus vegetans
show suprabasilar acantholysis.
165
In older lesions, hyperker-
atosis and pseudoepitheliomatous hyperplasia become promi-
nent. Immunouorescent study shows changes identical to
those seen in PV.
Oral Manifestations. Oral lesions are common in both forms
of pemphigus vegetans and may be the initial sign of dis-
ease.
166
Gingival lesions may be lace-like ulcers with a puru-
lent surface on a red base or have a granular or cobblestone
appearance (Figure 4-29). Oral lesions that are associated with
inammatory bowel disease and resemble pemphigus vegetans
both clinically and histologically are referred to by some
authors as pyostomatitis vegetans.
167
Treatment. Treatment is the same as that for PV.
Subepithelial Bullous Dermatoses
Subepithelial bullous dermatoses are a group of mucocuta-
neous autoimmune blistering diseases that are characterized by
a lesion in the basement membrane zone. The diseases in this
group include bullous pemphigoid (BP), mucous membrane
(cicatricial) pemphigoid (MMP), linear IgA disease (LAD),
chronic bullous dermatosis of childhood (CBDC), and erosive
FIGURE 4-29 Chronic palatal lesions of pemphigus vegetans.
FIGURE 4-30 Histologic picture of bullous pemphigoid. The bulla is
subepithelial.(Courtesy of Margaret Wood, MD)
Direct immunofluorescent study of a biopsy specimen
demonstrates deposition of IgG bound to the basement
membrane. Indirect immunoflourescent study of serum
obtained from patients with BP demonstrates IgG antibod-
ies bound to the epidermal side of salt-split skin onto anti-
gens that have been named BP antigens 1 and 2. This latter
test is particularly useful in distinguishing BP from another
subepithelial bullous disease, epidermolysis bullosa aquisita,
which has IgG antibodies localized to the dermal side of the
salt-split skin.
Clinical Manifestations. The characteristic skin lesion of
BP is a blister on an inflamed base that chiefly involves the
scalp, arms, legs, axilla, and groin (Figure 4-31). Pruritic mac-
ules and papules may also be a presenting sign. The disease
is self-limiting but can last for months to years without ther-
apy. Patients with BP may experience one episode or recur-
rent bouts of lesions. Unlike pemphigus, BP is rarely life
threatening since the bullae do not continue to extend at the
periphery to form large denuded areas, although death from
sepsis or cardiovascular disease secondary to long-term
steroid use has been reported to be high in groups of sick
elderly patients.
171
Oral Manifestations. Oral involvement is common in BP.
Lever reported 33 patients with bullous pemphigoid. Oral
lesions were present in 11.
172
In 3 of the cases, the oral lesions
preceded the skin lesions, most frequently on the buccal
mucosa. Venning and colleagues reported oral lesions in 50%
(18 of 36) of BP patients studied.
170
The oral lesions of pemphigoid are smaller, form more
slowly, and are less painful than those seen in pemphigus
vulgaris, and the extensive labial involvement seen in pem-
phigus is not present. Desquamative gingivitis has also been
reported as a manifestation of BP. The gingival lesions con-
sist of generalized edema, inflammation, and desquamation
with localized areas of discrete vesicle formation. The oral
lesions are clinically and histologically indistinguishable from
oral lesions of mucous membrane pemphigoid, but early
remission of BP is more common.
Treatment. Patients with localized lesions of BP may be
treated with high-potency topical steroids,
168
whereas patients
with severe disease require use of systemic corticosteroids
alone or combined with immunosuppressive drugs such as
azathioprine, cyclophosphamide, or mycophenolate. Patients
with moderate levels of disease may avoid use of systemic
steroids by use of dapsone or a combination of tetracycline
and nicotinamide.
MUCOUS MEMBRANE PEMPHIGOID (CICATRICIAL PEMPHIGOID)
MMP is a chronic autoimmune subepithelial disease that
primarily affects the mucous membranes of patients over the
age of 50 years, resulting in mucosal ulceration and subse-
quent scarring. The primary lesion of MMP occurs when
autoantibodies directed against proteins in the basement
membrane zone, acting with complement (C3) and neu-
trophils, cause a subepithelial split and subsequent vesicle
formation (Figure 4-32). The antigens associated with MMP
are most frequently present in the lamina lucida portion of
the basement membrane, but recent research has demon-
strated that the identical antigen is not involved in all cases,
and the lamina densa may be the primary site of involve-
ment in some cases. The circulating autoantibodies are not
the same in all cases, and subsets of MMP have been identi-
fied by the technique of immunofluorescent staining of skin
that has been split at the basement membrane zone with
the use of sodium chloride.
173
The majority of cases of MMP
demonstrate IgG directed against antigens on the epidermal
side of the salt-split skin, which have been identified as BP
180 (also called type XVII collagen); however, cases of MMP
have also been identified where the antigen is present on the
dermal side of the split. This latter antigen has been identi-
fied as epiligrin (laminin 5), an adhesion molecule that is a
component of the anchoring filaments of the basement
membrane.
174,175
Figure 4-31 Bullous pemphigoid lesion of the scalp.
FIGURE 4-32 Histopathology of mucous membrane pemphigoid,
demonstrating subepithelial separation at the basement membrane.
Clinical Manifestations. The subepithelial lesions of MMP
may involve any mucosal surface, but they most frequently
involve the oral mucosa. The conjunctiva is the second most
common site of involvement and can lead to scarring and adhe-
sions developing between the bulbar and palpebral conjunctiva
called symblepharon (Figure 4-33, A and B). Corneal damage
is common, and progressive scarring leads to blindness in close
to 15% of patients. Lesions may also affect the genital mucosa,
causing pain and sexual dysfunction. Laryngeal involvement
causes pain, hoarseness, and difficulty breathing, whereas
esophageal involvement may cause dysphagia, which can lead
to debilitation and death in severe cases. Skin lesions, usually of
the head and neck region, are present in 20 to 30% of patients.
Oral Manifestations. Oral lesions occur in over 90% of
patients with MMP. Desquamative gingivitis is the most com-
mon manifestation and may be the only manifestation of the
disease (Figure 4-34). Since these desquamative lesions resem-
ble the lesions of erosive lichen planus and pemphigus, all
cases of desquamative gingivitis should be biopsied and stud-
ied with both routine histology and direct immunouores-
cence to determine the correct diagnosis. Lesions may present
as intact vesicles of the gingival or other mucosal surfaces, but
more frequently they appear as nonspecic-appearing ero-
sions (Figure 4-35). The erosions typically spread more slowly
than pemphigus lesions and are more self-limiting.
Diagnosis. Patients with MMP included in the differential
diagnosis must have a biopsy done for both routine and direct
immunouorescent study. Routine histopathology shows sub-
basilar cleavage. Using the direct immunofluorescent tech-
nique (see Laboratory Tests under Pemphigus Vulgaris
for description), biopsy specimens taken from MMP patients
demonstrate positive uorescence for immunoglobulin and
complement in the basement membrane zone in 50 to 80% of
patients. Splitting the biopsy specimen at the basement mem-
brane zone with 1 M NaCl prior to direct immunouores-
cence increases the sensitivity of the test. The direct immuno-
fluorescent technique is excellent for distinguishing MMP
from pemphigus, and specimens obtained show
immunoglobulin and complement deposition in the inter-
cellular substance of the prickle cell layer of the epithelium.
Only 10% of MMP patients demonstrate positive indirect
immunofluorescence for circulating antibasement mem-
brane-zone antibodies; however, use of salt-split skin as a sub-
strate increases the sensitivity of this test.
Treatment. Management of MMP depends on the severity of
symptoms. When the lesions are conned to the oral mucosa,
systemic corticosteroids will suppress their formation, but the
clinician must weigh the benets against the hazards from side
effects of the drug.
176
Unlike pemphigus, MMP is not a fatal
disease, and long-term use of steroids for this purpose must be
carefully evaluated, particularly because most cases are
chronic, most patients are elderly, and treatment is required for
a long period of time.
Patients with mild oral disease should be treated with top-
ical and intralesional steroids. Desquamative gingivitis can
often be managed with topical steroids in a soft dental splint
that covers the gingiva, although the clinician using topical
steroids over large areas of mucosa must closely monitor the
patient for side effects such as candidiasis and effects of sys-
temic absorption. When topical or intralesional therapy is not
successful, dapsone therapy may be attempted. Rogers and
Mehregan have developed a protocol for use of dapsone in
patients with MMP.
177
The effectiveness of this protocol for the
management of MMP was recently conrmed by Ciarrocca
and Greenberg.
178
Since dapsone causes hemolysis and methe-
moglobinemia, glucose-6-phosphate dehydrogenase deciency
must be ruled out, and the patients hemoglobin must be
closely monitored. Methemoglobinemia can be reduced with
the use of cimetidine and vitamin E.
151
Another rare side effect
of dapsone is dapsone hypersensitivity syndrome, an idiosyn-
cratic disorder characterized by fever, lymphadenopathy, skin
eruptions, and occasional liver involvement. Patients resistant
to dapsone should be treated with a combination of systemic
corticosteroids and immunosuppressive drugs,
152
particularly
when there is risk of blindness from conjunctival involvement,
FIGURE 4-33 Mucous membrane pemphigoid; early (A) and advanced (B) cicatricial pemphigoid of the conjunctiva with symblepharon formation.
A B
or signicant laryngeal or esophageal damage. Reports suggest
that tetracycline and nicotinamide may also be helpful in con-
trolling the lesions of MMP.
179,180
LINEAR IGA DISEASE
LAD is characterized by the deposition of IgA rather than IgG
at the basement membrane zone, and the clinical manifesta-
tions may resemble either dermatitis herpetiformis or pem-
phigoid. The cause of the majority of cases is unknown, but a
minority of cases have been drug induced.
181
As in MMP, the
antigens associated with LAD are heterogeneous and may be
found in either the lamina lucida or lamina densa portions of
the basement membrane.
182,183
The skin lesions of LAD may resemble those observed in
patients with dermatitis herpetiformis, which are characterized
by pruritic papules and blisters at sites of trauma such as the
knees and elbows. Other patients have bullous skin lesions
similar to those seen in patients with bullous pemphigoid.
Oral lesions are common in LAD and may be seen in up to
70% of patients. These lesions are clinically indistinguishable
from the oral lesions of MMP, with blisters and erosions of the
mucosa frequently accompanied by desquamative gingivitis.
The oral lesions of LAD may be managed with the use of top-
ical steroids, but dapsone is effective therapy for more severe
cases. Resistant cases may require systemic corticosteroids.
CHRONIC BULLOUS DISEASE OF CHILDHOOD
CBDC is another blistering disorder, which chiey affects chil-
dren below the age of 5 years. It is characterized by the depo-
sition of IgA antibodies in the basement membrane zone,
184
which are detected by direct immunouorescence on the epi-
dermal side of salt-split skin or mucosa. The onset of the dis-
ease may be precipitated by an upper respiratory infection or
drug therapy.
185
The characteristic lesion of CBDC is a cluster
of vesicles and bullae on an inamed base. The genital region
is involved; conjunctival, rectal, and oral lesions may also be
present. Oral mucosal involvement is present in up to 50% of
cases, and the oral lesions are similar to those observed in
patients with MMP.
Diagnosis is made by biopsy demonstrating a subepithelial
lesion on routine histology and by deposition of IgA in the
basement membrane zone on direct immunofluorescence.
Indirect immunouorescence demonstrates circulating IgA in
80% of cases.
186
This disease is self-limiting, and the lesions
characteristically heal within 2 years. As with LAD, the lesions
are responsive to sulfapyridine or dapsone therapy.
Corticosteroids may be required for severe cases.
EROSIVE LICHEN PLANUS
The majority of cases of lichen planus present as white lesions
(discussed in detail in Chapter 5). An erosive and bullous form
of this disease presents as chronic multiple oral mucosal ulcers.
Erosive and bullous lesions of lichen planus occur in the severe
form of the disease when extensive degeneration of the basal
layer of epithelium causes a separation of the epithelium from
the underlying connective tissue.
187,188
In some cases, the
lesions start as vesicles or bullaethis has been classied as
bullous lichen planus; in a majority of cases, the disease is
characterized by ulcers and is called erosive lichen planus.
Both of these disorders are variations of the same process and
should be considered together. The erosive form of lichen
planus has been associated with drug therapy, underlying med-
ical disorders, and reactions to dental restorations.
189
The
drugs most commonly associated with severe lichenoid reac-
tions include NSAIDs, hydrochlorothiazide, penicillamine, and
angiotensin-converting enzyme inhibitors. The most fre-
quently reported underlying disease associated with oral
lichenoid reactions is chronic hepatitis caused by hepatitis C,
particularly in Japan and the Mediterranean region.
190,191
Contact allergic reactions to avoring agents such as cinnamon
and peppermint and to dental materials such as mercury in
amalgam may also result in lichenoid reactions of the oral
mucosa.
192,193
Lichen planus lesions suspected of being caused
by contact allergy should be in direct contact with the sus-
pected allergen. Graft-versus-host disease due to bone marrow
transplantation also causes oral lichenoid lesions.
194
The association between erosive lichen planus and squa-
mous cell carcinoma remains controversial. There have been
FIGURE 4-34 Chronic desquamative gingival lesions of mucous mem-
brane pemphigoid.
FIGURE 4-35 Mucous membrane pemphigoid causing scarring of the
soft palate.
many case reports of carcinoma developing in areas of lichen
planus.
195198
A case by Massa and colleagues shows histologic
progression from lichen planus, lichen planus with epithelial
atypia, and frank squamous cell carcinoma.
199
Reviews of large
numbers of patients with lichen planus by Silverman and col-
leagues and Murti and associates show an association between
the two diseases of between 0.4 and 1.2%.
200,201
Affected
patients were frequently tobacco users; this leads to speculation
that lichen planus is a cofactor in malignant transformation.
Clinical Manifestations. Erosive lichen planus is character-
ized by the presence of vesicles, bullae, or irregular shallow
ulcers of the oral mucosa
187
(Figures 4-36 and 4-37). The
lesions are usually present for weeks to months and thus can
be distinguished from those of aphthous stomatitis, which
form and heal in a period of 10 days to 2 weeks. A signicant
number of cases of erosive lichen planus present with a picture
of desquamative gingivitis
202
(Figure 4-38). It is important to
remember that desquamative gingivitis is not a disease entity
but a sign of disease that can be caused by erosive lichen
planus, pemphigus vulgaris, or cicatricial pemphigoid.
Desquamative gingivitis caused by lichen planus may be
accompanied by characteristic Wickhams striae, simplifying
the diagnosis, or they may be present without other lesions.
Diagnosis. A diagnosis of erosive lichen planus should be
suspected when erosive or bullous lesions are accompanied by
typical lichenoid white lesions. Biopsy is necessary for deni-
tive diagnosis. Biopsy of the erosive lesions shows hydropic
degeneration of the basal layer of epithelium. This can help to
distinguish it from mucous membrane pemphigoid, which is
also a subepithelial lesion but which shows an intact basal layer,
or from pemphigus vulgaris, in which acantholysis is demon-
strated. Direct immunouorescence should be performed on
biopsy specimens when pemphigus, pemphigoid, or discoid
lupus erythematosus is included in the differential diagnosis.
Management. Patients with severe lichen planus should have
drug therapy and underlying disease ruled out as possible
causes. The bullous and erosive forms of lichen planus can be
distressingly painful. The treatment of choice is topical corti-
costeroids (Figure 4-39). Intralesional steroids can be used for
indolent lesions, and, in cases of severe exacerbation, systemic
steroids may be considered for short periods of time.
Cyclosporine rinses may be effective for patients with severe
erosions resistant to topical steroids, although the expense may
be a limiting factor.
203,204
Tacrolimus, another immunosup-
pressive drug, has recently been marketed in a topical form and
has been reported useful in the management of oral erosive
lichen planus. Systemic etretinate, dapsone, or pho-
tochemotherapy have also been reported to be effective in severe
resistant cases.
205207
Because patients with oral lichen planus
appear to be in a higher risk group for development of squa-
mous cell carcinoma, it is prudent to periodically evaluate all
patients with erosive and bullous forms of lichen planus for the
presence of suspicious lesions requiring biopsy (Figure 4-40).
Herpes Simplex Virus Infection in
Immunosuppressed Patients
Immunosuppressed patients may develop an aggressive or
chronic form of herpes infection; therefore, herpes simplex
infection should be included in the differential diagnosis
when immunosuppressed patients develop chronic oral
FIGURE 4-36 Erosive lichen planus of the labial mucosa.
FIGURE 4-38 Desquamative gingival lesions in a patient with erosive
lichen planus.
FIGURE 4-37 Palatal lesions of erosive lichen planus.
ulcers. The chronic form of herpes is a variation of recurrent
herpes simplex infection rather than a primary infec-
tion.
208,209
AIDS patients, transplant patients taking immuno-
suppressed drug therapy, patients on high doses of cortico-
steroids, and patients with leukemia, lymphoma, or other dis-
orders that alter the T-lymphocyte response are those most
susceptible to aggressive HSV lesions.
Lesions appear on the skin or the mucosa of the mouth, rec-
tal, or genital area. They begin as an ordinary recurrent herpes
infection but remain for weeks to months and develop into
large ulcers up to several centimeters in diameter (Figure 4-42).
Chronic herpes simplex infection has been reported with both
type 1 and type 2 herpesviruses. This disease causes signicant
local morbidity and occasional dissemination.
ORAL MANIFESTATIONS
Lesions of chronic or aggressive recurrent HSV may occur on
the lips or intraoral mucosa. Schneidman and colleagues
210
reviewed 18 cases of chronic herpes infection; 7 cases occurred
in renal transplant patients, and 8 occurred in patients with
hematologic malignancies. Fourteen of the 18 patients had
oral or perioral lesions. Greenberg and colleagues studied 98
immunosuppressed patients: 68 renal transplant patients and
30 acute leukemic patients receiving chemotherapy.
209
Fifty
percent of the leukemic patients and 15% of the transplant
patients developed aggressive or chronic recurrent HSV. HSV
was the most common cause of oral lesions in both groups,
producing lesions that were previously thought to be due to
the toxic effects of chemotherapy or bacterial infection. The
oral lesions may be small, round, symmetric, and associated
with recurrent herpes infection, or they may be large and
deep and often confused with lesions of other diseases (see
Figure 4-41, A and B) The lesions last from weeks to months
and may reach several centimeters in diameter. The larger
lesions often have raised white borders composed of small
vesicles (Figure 4-42).
DIAGNOSIS
HSV must be ruled out whenever oral mucosal vesicles or ulcers
occur in immunosuppressed or myelosuppressed patients. Both
a cytology for staining with uorescent HSV antibody and a
viral culture should be obtained. If these lesions occur in a
patient without an obvious known cause, they should be thor-
oughly evaluated for an immunologic deciency disease.
TREATMENT
Immunosuppressed patients with HSV infection respond well
to acyclovir administered orally or intravenously.
21
Occasional cases of acyclovir-resistant HSV have been
reported in AIDS patients. Foscarnet has been effective ther-
apy for these patients.
211
THE PATIENT WITH SINGLE
ULCERS
The most common cause of single ulcers on the oral mucosa
is trauma. Trauma may be caused by teeth, food, dental appli-
ances, dental treatment, heat, chemicals, or electricity (Figure
443). The diagnosis is usually not complicated and is based
on the history and physical ndings. The most important dif-
ferentiation is to distinguish trauma from squamous cell car-
cinoma. The dentist must examine all single ulcers for signif-
icant healing in 1 week; if healing is not evident in this time, a
biopsy should be done to rule out cancer. (Cancer of the
mouth is discussed in detail in Chapter 8.)
Infections that may cause a chronic oral ulcer include the
deep mycoses histoplasmosis, blastomycosis, mucormycosis,
aspergillosis, cryptococcosis, and coccidioidomycosis as well as
a chronic herpes simplex infection. Syphilis, another infection
that may cause a single oral ulcer in the primary and tertiary
stages, is described in Chapter 20.
The deep mycoses were rare causes of oral lesions prior to
HIV infection and immunosuppressive drug therapy. The den-
tist must consider this group of diseases in the differential
diagnosis whenever isolated ulcerative lesions develop in
known or suspected immunosuppressed patients. Biopsy of
FIGURE 4-39 Soft medication splint used to treat desquamative gin-
givitis secondary to erosive lichen planus.
FIGURE 4-40 Squamous cell carcinoma forming on the buccal mucosa
of a patient with erosive lichen planus.
suspected tissue, accompanied by a request for appropriate
stains, is necessary for early diagnosis (Figure 4-44). Deep
mycoses in immunosuppressed patients are discussed in
greater detail in Chapters 16 and 18.
Histoplasmosis
Histoplasmosis is caused by the fungus Histoplasma capsula-
tum, a dimorphic fungus that grows in the yeast form in
infected tissue. Infection results from inhaling dust contam-
inated with droppings, particularly from infected birds or
bats. An African form of this infection is caused by a larger
yeast, which is considered a variant of H. capsulatum and is
called H. duboisii.
Histoplasmosis is the most common systemic fungal infec-
tion in the United States; in endemic areas such as the
Mississippi and Ohio River valleys, serologic evidence of pre-
vious infection may be found in 75 to 80% of the population.
In most cases, particularly in otherwise normal children, pri-
mary infection is mild, manifesting as a self-limiting pulmonary
disease that heals to leave brosis and calcication similar to
tuberculosis. In a small percentage of cases, progressive disease
results in cavitation of the lung and dissemination of the organ-
ism to the liver, spleen, adrenal glands, and meninges. Patients
with the disseminated form of the disease may develop anemia
and leukopenia secondary to bone marrow involvement.
Immunosuppressed or myelosuppressed patients are more
likely to develop the severe disseminated form of the disease.
During the past decade, most reported cases of oral lesions of
histoplasmosis have been reported in HIV-infected individuals
who live in or have visited endemic areas.
ORAL MANIFESTATIONS
Oral involvement is usually secondary to pulmonary involve-
ment and occurs in a signicant percentage of patients with
disseminated histoplasmosis. Oral mucosal lesions may appear
as a papule, a nodule, an ulcer, or a vegetation. If a single lesion
is left untreated, it progresses from a rm papule to a nodule,
which ulcerates and slowly enlarges. The cervical lymph nodes
are enlarged and rm. The clinical appearance of the lesions,
as well as the accompanying lymphadenopathy, often resem-
bles that of squamous cell carcinoma, other chronic fungal
infections, or even Hodgkins disease.
FIGURE 4-41 A, This large ulcer of the buccal mucosa was caused by a chronic herpes simplex infection in a kidney transplant patient receiving
immunosuppressive drug therapy. B, A herpetic ulcer near the eye of the same patient.
FIGURE 4-42 Chronic herpes simplex infection of the palate in a
patient taking chemotherapy for acute leukemia.
FIGURE 4-43 Traumatic ulcer of the buccal mucosa secondary to cheek
biting.
A B
Cases of oral histoplasmosis have been reported as the ini-
tial sign of HIV infection. The most common oral lesion of
histoplasmosis in patients with HIV is an ulcer with an
indurated border, which is most commonly seen on the gin-
giva, palate, or tongue.
212
These oral histoplasmosis lesions
in patients with HIV may occur alone or as part of a dis-
seminated infection.
213,214
DIAGNOSIS
Denitive diagnosis of histoplasmosis is made by a culture of
infected tissues or exudates on Sabourauds dextrose agar or
other appropriate media. Biopsy of infected tissue shows small
oval yeasts within macrophages and reticuloendothelial cells as
well as chronic granulomas, epithelioid cells, giant cells, and
occasionally caseation necrosis. Skin tests and serology are not
denitive because of signicant numbers of false-negative and
false-positive reactions.
TREATMENT
Mild to moderate cases of histoplasmosis can be treated with
ketoconazole or itraconazole for 6 to 12 months. Immunosup-
pressed patients or patients with severe disease require intra-
venous amphotericin B for up to 10 weeks.
Blastomycosis
Blastomycosis is a fungal infection caused by Blastomyces der-
matitidis. This dimorphic organism can grow in either a yeast
or as a mycelial form. The organism is found as a normal
inhabitant of soil; therefore, the highest incidence of this infec-
tion is found in agricultural workers, particularly in the mid-
dle Atlantic and southeastern portions of the United States.
This geographic distribution of the infection has led to the des-
ignation by some as North American blastomycosis.
Infection by the same organism, however, has also been found
in Mexico and Central and South Americas.
Infection with Blastomyces begins in a vast majority of cases
by inhalation; this causes a primary pulmonary infection.
Although an acute self-limiting form of the disease exists, the
infection commonly follows a chronic course beginning with
mild symptoms such as malaise, low-grade fever, and mild
cough. If the infection goes untreated, the symptoms worsen
to include shortness of breath, weight loss, and production of
blood-tinged sputum. Infection of the skin, mucosa, and bone
may also occur, resulting from metastatic spread of organisms
from the pulmonary lesions through the lymphatic system.
The skin and mucosal lesions start as subcutaneous nodules
and progress to well-circumscribed indurated ulcers.
ORAL MANIFESTATIONS
Oral lesions are rarely the primary site of infection. When oral
lesions have been reported as a rst sign of blastomycosis, they
have occurred in patients with mild pulmonary symptoms
that have been overlooked by the patient or physician. Most
cases of oral involvement demonstrate concomitant pul-
monary lesions on chest radiographs.
The most common appearance of the oral lesions of blas-
tomycosis is a nonspecific painless verrucous ulcer with
indurated borders, often mistaken for squamous cell carci-
noma. Occasionally, this mistake is perpetuated by an inexpe-
rienced histopathologist who confuses the characteristic pseu-
doepitheliomatous hyperplasia with malignant changes.
Other oral lesions that have been reported include hard
nodules and radiolucent jaw lesions. Page and colleagues
reported two cases of painless oral mucosal ulcers as the rst
sign of blastomycosis; in both cases, a careful history taking
revealed mild respiratory symptoms.
215
Bell and colleagues
reported 7 cases of oral lesions occurring in patients with blas-
tomycosis; 4 presented as chronic oral ulcers and 3 as radiolu-
cent bone lesions.
216
Chest radiographs showed concomitant
pulmonary involvement in all cases.
Dentists should include the diagnosis of blastomycosis in
the differential diagnosis of a chronic oral ulcer. The diagno-
sis cannot be made on clinical grounds alone. The index of sus-
picion should increase when a chronic painless oral ulcer
appears in an agricultural worker or when the review of sys-
tems reveals pulmonary symptoms. Diagnosis is made on the
basis of biopsy and on culturing the organism from tissue.
217
The histologic appearance shows pseudoepitheliomatous
hyperplasia with a heavy inltrate of chronic inammatory
cells and microabscesses.
TREATMENT
Treatment for blastomycosis is similar to that described for
histoplasmosis.
Mucormycosis
Mucormycosis (phycomycosis) is caused by an infection with
a saprophytic fungus that normally occurs in soil or as a mold
on decaying food. The fungus is nonpathogenic for healthy
individuals and can be cultured regularly from the human
nose, throat, and oral cavity. (The organism represents an
opportunistic rather than a true pathogen.) Infection occurs
in individuals with decreased host resistance, such as those
with poorly controlled diabetes or hematologic malignancies,
FIGURE 4-44 Palatal ulcer can be the initial sign of Cryptococcus in an
AIDS patient.
or those undergoing cancer chemotherapy or immunosup-
pressive drug therapy.
218,219
In the debilitated patient,
mucormycosis may appear as a pulmonary, gastrointestinal,
disseminated, or rhinocerebral infection.
The rhinomaxillary form of the disease, a subdivision of
the rhinocerebral form, begins with the inhalation of the fun-
gus by a susceptible individual. The fungus invades arteries and
causes damage secondary to thrombosis and ischemia. The
fungus may spread from the oral and nasal region to the brain,
causing death in a high percentage of cases. Symptoms include
nasal discharge caused by necrosis of the nasal turbinates, pto-
sis, proptosis secondary to invasion of the orbit, fever, swelling
of the cheek, and paresthesia of the face.
ORAL MANIFESTATIONS
The most common oral sign of mucormycosis is ulceration of
the palate, which results from necrosis due to invasion of a
palatal vessel.
218,220
The lesion is characteristically large and
deep, causing denudation of underlying bone (Figure 4-45).
Ulcers from mucormycosis have also been reported on the
gingiva, lip, and alveolar ridge. The initial manifestation of the
disease may be confused with dental pain or bacterial maxil-
lary sinusitis caused by invasion of the maxillary sinus. The
clinician must include mucormycosis in the differential diag-
nosis of large oral ulcers occurring in patients debilitated from
diabetes, chemotherapy, or immunosuppressive drug therapy.
Early diagnosis is essential if the patient is to be cured of
this infection. Negative cultures do not rule out mucormyco-
sis because the fungus is frequently difcult to culture from
infected tissue; instead, a biopsy must be performed when
mucormycosis is suspected. The histopathologic specimen
shows necrosis and nonseptate hyphae, which are best demon-
strated by a periodic acidSchiff stain.
TREATMENT
When diagnosed early, mucormycosis may be cured by a com-
bination of surgical dbridement of the infected area and sys-
temic administration of amphotericin B for up to 3 months.
Proper management of the underlying disorder is an impor-
tant aspect affecting the final outcome of treatment. All
patients given amphotericin B must be closely observed for
renal toxicity by repeated measurements of the blood urea
nitrogen and creatinine.
REFERENCES
1. Scully C. Orofacial herpes simplex virus infections. Current
concepts in the epidemiology, pathogenesis and treatment.
Oral Surg 1989;68:70110.
2. Levy JA. Three new human herpesviruses (HHV-6, 7 and 8).
Lancet 1997;349:55862.
3. Greenberg MS, Glick M, Nghiem L, et al. Relationship of
cytomegalovirus to salivary gland dysfunction in HIV-infected
patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1997;83:3349.
4. Embil JA, Manuel R, McFarlane S. Concurrent oral and geni-
tal infection with an identical strain of herpes simplex type I.
Sex Transm Dis 1981;8:702.
5. Fife KH, Schmidt O, Remington M, Corely L. Primary and
recurrent concomitant genital infection with herpes simplex
virus types 1 and 2. J Infect Dis 1983;147:163.
6. Christenson B, Bottinger M, Svenson A, Jeansson S. A 15 year
surveillance study of antibodies to herpes simplex types 1 and
2 in a cohort of young girls. J Infect 1992;25:147.
7. Scott DA, Coulter WA, Lamey PJ. Oral shedding of herpes sim-
plex virus type 1: a review. J Oral Pathol Med 1997;26:4417.
8. Wheeler CE. The herpes simplex problem. J Am Acad
Dermatol 1988;18:1638.
9. Wald A. Herpes. Transmission and viral shedding. Dermatol
Clin 1998;16:7957.
10. Roizman B, Sears AE. An inquiry into the mechanisms of her-
pes simplex virus latency. Ann Rev Microbiol 1987;41:54357.
11. Riley LE. Herpes simplex virus. Semin Perinatol 1998;22:28492.
12. Miller CS, Danaher RJ, Jacob RJ. Molecular aspects of herpes
simplex virus I latency, reactivation, and recurrence. Crit Rev
Oral Biol Med 1998;9:54162.
13. McCormick DD. Herpes simplex virus as cause of Bells palsy.
Lancet 1972;1:9379.
14. Murakami S, Mizobuchi M, Nakashiro Y, et al. Bells palsy and
herpes simplex virus. Ann Intern Med 1996;124:2730.
15. Rodriguez AS, Martin Oterino JA, Ruiz VA. Arch Intern Med
1998;158:157778.
16. Rapp F, Duff R. Transformation of hamster embryo broblasts
by herpes simplex viruses type 1 and type 2. Cancer Res
1973;33:1527.
17. Scully C. Herpes simplex virus (HSV). In: Millard HD, Mason
DK, editor. 1988 World Workshop on Oral Medicine. Yearbook
Medical Publishers, 1988. Ann Arbor, MI. p. 160.
18. Brightman VJ, Guggenheimer JG. Herpetic paronychiapri-
mary herpes simplex infection of the nger. J Am Dent Assoc
1970;80:112.
19. Stone KM, Brooks CA, Guinan ME, Alexander ER. National
surveillance for neonatal herpes simplex infections. Sex
Transm Dis 1989;16:1526.
20. Nahmias AJ. Disseminated herpes simplex virus infections. N
Engl J Med 1970;282:684.
21. Whitley RJ, Kimberlin DW, Roizman B. Herpes simplex
viruses. Clin Infect Dis 1998;26:54153.
FIGURE 4-45 Mucormycosis of the palate in a kidney transplant patient
taking immunosuppressive drugs (azathioprine and prednisone).
22. Greenberg MS, Brightman VJ, Ship II. Clinical and laboratory
differentiation of recurrent intraoral herpes simplex infections
following fever. J Dent Res 1969;48:435.
23. Bagg J, Mannings A, Munso J, Walker DM. Rapid diagnosis of
oral herpes simplex or zoster virus infections by immunou-
orescence: comparison with Tzanck cell preparations and viral
culture. Br Dent J 1989;167:235.
24. Penna JJ, Eskinazi DP. Treatment of oro-facial herpes simplex
infections with acyclovir: a review. Oral Surg 1988;65:689.
25. Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes
simplex gingivostomatitis with acyclovir in children: a ran-
domized double blind placebo controlled study. J Pediatr
1998;132:185.
26. Balfour HH. Antiviral drugs. N Engl J Med 1999;340:125568.
27. Ho M, Chen ER, Hsu KH, et al. An epidemic of enterovirus 71
infection in Taiwan. N Engl J Med 1999;341:929.
28. Adler L, Epidemiologic investigation of hand-foot-and-mouth
disease. Am J Dis Child 1970;120:309.
29. Dueland AN. Latency and reactivation of varicella zoster virus
infections. Scand J Infect Dis 1996;100:4650.
30. Morgan R, King D. Shingles: a review of diagnosis and man-
agement. Hosp Med 1998;59:7706.
31. Lopes MA, de Souza Filho FJ, Jorge J Jr, de Almeida OP. Herpes
zoster infection as a differential diagnosis of acute pulpitis. J
Endod 1998;24:1434.
32. Petursson G, Helgason S, Gudmundsson S, Sigurdsson JA.
Herpes zoster in children and adolescents. Pediatr Infect Dis J
1998;17:9058.
33. MacFarlane LL, Simmons MM, Hunter MH. The use of corti-
costeroids in the management of herpes zoster. J Am Board
Fam Pract 1998;11:2248.
34. Kost RG, Straus SE. Postherpetic neuralgiapathogenesis,
treatment, and prevention. N Engl J Med 1996;335:3242.
35. Kost RG, Straus SE. Postherpetic neuralgia: predicting and
preventing risk. Arch Intern Med 1997;157:11667.
36. McKenzie CD, Gobetti JP. Diagnosis and treatment of orofa-
cial herpes zoster: report of cases. J Am Dent Assoc
1990;120:679.
37. Solomon CS, Cofner MO, Chaln HE. Herpes zoster revis-
ited: implicated in root resorption. J Endod 1986;12:210.
38. Schwartz O, Kvorning SA. Tooth exfoliation, osteonecrosis of
the jaw and neuralgia following herpes zoster of the trigemi-
nal nerve. Int J Oral Surg 1982;11:364.
39. Wood MJ, Shukla S, Fiddian PA, Crooks RJ. Treatment of acute
herpes zoster: effect of early (< 48 h) versus late (4872 h) ther-
apy with acyclovir and valacyclovir on prolonged pain. J Infect
Dis 1998;178 Suppl 1:S814.
40. Menke JJ, Heins JR. Treatment of postherpetic neuralgia. J Am
Pharm Assoc 1999;39:21721.
41. Robotham M, Harden N, Stacey B, et al. Gabapentin for the
treatment of postherpetic neuralgia: a randomized controlled
trial. J Am Med Assoc 1998;280:183742.
42. Kazmierowski JA, Wuepper KD. Erythema multiforme:
immune complex vasculitis of the superficial cutaneous
microvasculature. J Invest Dermatol 1978;71:366.
43. Reed RJ. Erythema multiforme: a clinical syndrome and a his-
tologic complex. Am J Dermatopathol 1985;7:143.
44. Roujeau J-C, Kelly JP, Naldi L, et al. Medication use and the risk
of Stevens-Johnson syndrome or toxic epidermal necrolysis. N
Engl J Med 1995;333:16007.
45. Huff JC. Erythema multiforme and latent herpes simplex
infection. Semin Dermatol 1992;11:20710.
46. Aurelian L, Kokuba H, Burnett JW. Understanding the patho-
genesis of HSV-associated erythema multiforme. Dermatology
1998;197:21922.
47. Malo A, Kampgen E, Wank R. Recurrent herpes simplex virus
induced erythema multiforme: different HLA-DQB1 alleles
associate with severe mucous membrane versus skin attacks.
Scand J Immunol 1998;47:40811.
48. Weston WL, Morelli JG. Herpes simplex virusassociated ery-
thema multiforme in prepubertal children. Arch Pediatr
Adolesc Med 1997;151:10146.
49. Wojnarowska F Progesterone induced erythema multiforme.
J R Soc Med 1985;78:407.
50. Kroonen LM. Erythema multiforme: case report and discus-
sion. J Am Board Fam Pract 1998;11:635.
51. Chan HL, Stern RS, Arndt KA, et al. The incidence of ery-
thema multiforme, Stevens-Johnson syndrome and toxic epi-
dermal necrolysis. A population based study with particular
reference to reactions caused by drugs among outpatients.
Arch Dermatol 1990;126:43.
52. Stevens AM, Johnson FC. A new eruptive fever associated with
stomatitis and ophthalmia. Am J Dis Child 1922;24:526.
53. Lever WF. My concept of erythema multiforme. Am J
Dermatolpathol 1985;7:141.
54. Patterson R, Dykewicz MS, Gonzales A, et al. Erythema mul-
tiforme and Stevens-Johnson syndrome. Descriptive and ther-
apeutic controversy. Chest 1990;98:331.
55. Pisanty S, Tzukert A, Sheskin J. Erythema multiforme: a clin-
ical study on ninety patients. Ann Dent 1986;45:23.
56. Fine JD. Drug therapy: management of acquired bullous skin
diseases. N Engl J Med 1995;333:147584.
57. Rodenas JM, Herranz MT, Tercedor J. Autoimmune proges-
terone dermatitis: treatment with oophorectomy. Br J
Dermatol 1998;139:50811.
58. Tatnall FM, Schoeld JK, Leight IM. A double-blind, placebo-
controlled trial of continuous acyclovir therapy in recurrent
erythema multiforme. Br J Dermatol 1995;132:26770.
59. Patterson R, Miller M, Kaplan M, et al. Effectiveness of early
therapy with corticosteroids in Stevens-Johnson syndrome:
experience with 41 cases and a hypothesis regarding patho-
genesis. Ann Allergy 1994;73:2734.
60. Cheriyan S, Patterson R, Greenberger PA, et al. The outcome
of Stevens-Johnson syndrome treated with corticosteroids.
Allergy Proc 1995;16:1515.
61. DeRossi SS, Greenberg MS. Intraoral contact allergy: a litera-
ture review and case reports. J Am Dent Assoc 1998;129:1435.
62. Pang BK, Freeman S. Oral lichenoid lesions caused by allergy to
mercury in amalgam llings. Contact Dermatitis 1995;33:4237.
63. Marcusson JA. Contact allergies to nickel sulfate, gold sodium
thiosulfate and palladium chloride in patients claiming side-
effects from dental alloy components. Contact Dermatitis
1996;34;3203.
64. Rasanen L, Laimo K, Laine J, et al. Contact allergy to gold in
dental patients. Br J Dermatol 1996;134:6737.
65. Kowitz G, Jacobson J, Meng Z, Lucatorto F. The effects of tar-
tar-control toothpaste on the oral soft tissue. Oral Surg Oral
Med Oral Pathol 1990;70:52936.
66. Sollecito TP, Greenberg MS. Plasma cell gingivitis: a report of
two cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1992;73:690.
67. Alanko K, Kanerva L, Jolanki R, et al. Oral mucosal diseases
investigated by patch testing with a dental screening series.
Contact Dermatitis 1996;34:2637.
68. Dreizen S, Bodey GP, Rodriquez V. Oral complications of can-
cer chemotherapy. Postgrad Med 1975;58:75.
69. Dreizen S, McCredie KB, Keating MJ. Chemotherapy induced
oral mucositis in adult leukemia. Postgrad Med 1981;69:103.
70. Sonis ST. Mucositis as a biological process: a new hypothesis
for the development of chemotherapy induced stomatotoxic-
ity. Oral Oncol 1998;34:39.
71. Loesche WJ, Syed SA, Laughon BE, Stoll J. The bacteriology of
acute necrotizing ulcerative gingivitis. J Periodontol
1982;53:223.
72. Giddon DB, Zackin SJ, Goldhaber P. Acute necrotizing ulcer-
ative gingivitis in college students. J Am Dent Assoc
1964;68:381.
73. Winkler JR, Grassi M, Murray PA. Clinical description and
etiology of HIV-associated periodontal diseases. In: Robertson
PB, Greenspan JS, editors. Perspectives on oral manifestations
of AIDS. Proceedings of First International Symposium on
Oral Manifestations of AIDS. Littleton (MA): PSG Publishing
Company; 1988. p. 49.
74. Holmstrup P, Westergaard J. HIV infection and periodontal
disease. Periodontol 2000 1998;18:37.
75. Lamster IB, Grbic JT, Mitchell-Lewis DA, et al. New concepts
regarding the pathogenesis of periodontal disease in HIV
infection. Ann Periodontol 1998;3:62.
76. Enwonwu CO, Falker WA, Idigbe EO, Savage KO. Noma (can-
crum oris) questions and answers. Oral Dis 1999;5:144.
77. Falker WA, Enwonwa CO, Idigbe EO. Microbiological under-
standings and mysteries of noma. Oral Dis 1999;5:150.
78. Roger RS. Recurrent aphthous stomatitis: clinical characteris-
tics and associated systemic disorders. Semin Cutan Med Surg
1997;16:27883.
79. Ship II, Ashe WK, Scherp HW. Recurrent fever blister and
canker sore tests for herpes simplex and other viruses with
mammalian cell cultures. Arch Oral Biol 1961;3:117.
80. Lennette EH, Magofn RL. Virologic and immunologic aspects
of major oral ulcerations. J Am Dent Assoc 1973;87:1055.
81. Peterson A, Hornsieth A. Recurrent aphthous ulceration: pos-
sible clinical manifestations of varicella zoster in
cytomegalovirus infection. J Oral Pathol Med 1993;22:648.
82. Ghodratnama F, Riggio MP, Wray D. Search for human her-
pesvirus 6, human cytomegalovirus and varicella zoster virus
DNA in current aphthous stomatitis tissue. J Oral Pathol Med
1997;26:1927.
83. Scully C, Porter S. Recurrent aphthous stomatitis current con-
cepts of etiology, pathogenesis and management. J Oral Pathol
Med 1989;18:21.
84. Challacombe SJ, Barkhan P, Lehner T. Hematologic features
and differentiation of recurrent oral ulcerations. Br J Oral Surg
1977;15:37.
85. Ship JJ. Epidemiologic aspects of recurrent aphthous ulcera-
tions. Oral Surg 1972;33:400.
86. Miller MF, Garfunkel AA, Ram CA, Ship II. The inheritance of
recurrent aphthous stomatitis observations on susceptibility.
Oral Surg 1980;49:409.
87. Savage NW, Seymour AJ, Kruger BJ. Expression of class I and
class II major histocompatibility complex antigens on epithe-
lial cells in recurrent aphthous stomatitis. J Oral Pathol
1986;15:191.
88. Eversole LR. Immunopathogenesis of oral lichen planus and
recurrent aphthous stomatitis. Semin Cutan Med Surg
1997;16:28494.
89. Rogers RS, Hutton KP. Screening for haematinic deciencies in
patients with recurrent aphthous stomatitis. Aust J Dermatol
1986;27:98.
90. Ferguson MM, Wray D, Carmichael HA, et al. Coeliac disease
associated with recurrent aphthae. Gut 1980;21:223.
91. Donatsky O, Bendixen G. In vitro demonstration of cellular
hypersensitivity to Strep 2A in recurrent aphthous stomatitis
by means of the leukocyte migration test. Acta Allergol
1972;27:137.
92. Thomas DW, Bagg J, Walker DM. Characterization of the effec-
tor cells responsible for the in vitro cytotoxicity of blood leu-
cocytes from aphthous ulcer patients for oral epithelial cells.
Gut 1990;31:294.
93. Hoover CI, Olson JA, Greenspan JA. Humoral responses and
cross-reactivity to viridians streptococci in recurrent aphthous
ulceration. J Dent Res 1986;65:1101.
94. Savage NW, Seymour GJ, Kruger BJ. T-lymphocyte subset
changes in recurrent aphthous stomatitis. Oral Surg
1985;60:175.
95. Greenspan JL, Gadol N, Olson JA, et al. Lymphocyte function
in recurrent aphthous ulceration. J Oral Pathol 1985;14:592.
96. Burnett PR, Wray D. Tyler effects of serum and mononuclear
leukocytes on oral epithelial cells in recurrent aphthous stom-
atitis. Clin Immunol Immunopathol 1985;34:197.
97. Pedersen A, Klausen B, Hougen HP, Stenvang JP. T-lymphocyte
subsets in recurrent aphthous ulceration. J Oral Pathol Med
1989;18:59.
98. Galliani EA, Infantolino D, Tarantello M, et al. Recurrent aph-
thous stomatitis: which role for viruses, food and dental mate-
rials? Ann Ital Med Int 1998;13:1526.
99. Buno IJ, Huff JC, Weston WL, et al. Elevated levels of interferon
gamma, tumor necrosis factor alpha, interleukins 2, 4, 5, but
not interleukin 10, are present in recurrent aphthous stomati-
tis. Arch Dermatol 1998;134:82731.
100. Rennu JS, Reade PC, Hay KD, Scully C. Recurrent aphthous
stomatitis. Br Dent J 1985;159:361.
101. Axell T, Henricsson V. Association between recurrent aph-
thous ulcers and tobacco habits. Scand J Dent Res 1985;93:239.
102. Hay KD, Reade PC. The use of elimination diet in the treat-
ment of recurrent aphthous ulceration in the oral cavity. Oral
Surg 1984;57:504.
103. Chahine L, Sempson N, Wagoner C. The effect of sodium lau-
ryl sulfate on recurrent aphthous ulcers: a clinical study. Comp
Continu Educ Dent 1997;18:123840.
104. Healy CM, Paterson M, Joyston-Bechal S, et al. The effect of
sodium lauryl sulfate-free dentifrice on patients with recurrent
oral ulceration. Oral Dis 1999;5:3943.
105. Saxen MA, Ambrosius WT, Rehemtula al-KF, Eckert GJ.
Sustained relief of oral aphthous ulcer pain from topical
diclofenac in hyaluronan: a randomized, double-blind clinical
trial. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1997;84:35661.
106. Wahba-Yahav AV. Pentoxifylline in intractable recurrent aph-
thous stomatitis: an open trial. J AM Acad Dermatol
1995;33:680.
107. Katz J, Langeritz P, Shemer J. Prevention of RAS with
colchicines: an open trial. J Am Acad Dermatol 1994;31:45961.
108. Tananis R, DeRossi S, Sollecito TP, Greenberg MS.
Management of recurrent aphthous stomatitis with colchicine
and pentoxifylline. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2000;89:449.
109. Jacobson JM, Greenspan J, Spritzler N, et al. Thalidomide for the
treatment of oral aphthous ulcers in patients with human immu-
nodeciency virus infection. N Engl J Med 1997;336:148793.
110. ODuffy JD. Behets syndrome. N Engl J Med 1990;322:326.
111. Kone-Paut I, Yurdakul S, Bahabri SA, et al. Clinical features of
Behets disease in children: an international collaborative
study of 86 cases. J Pediatr 1998;132:7215.
112. Matsumoto T, Vekusa T, Fukuda Y. Vasculo-Behets disease; a
pathologic study of eight cases. Hum Pathol 1991;22:45.
113. ODuffy JD. Vasculitis in Behets disease. Rheum Dis Clin
North Am 1990;16:423.
114. Yasui K, Ohta K, Kobayashi M, et al. Successful treatment
of Behet disease with pentoxifylline. Ann Intern Med 1996;
124:8913.
115. Benamour S, Zeroual B, Alaoui FZ. Joint manifestation in
Behets disease: a review of 340 cases. Rev Rhum 1998;
65:299-307.
116. Krause I, Uziel Y, Guedj D, et al. Mode of presentation and mul-
tisystem involvement in Behets disease: the inuence of sex
and age of disease onset. J Rheumatol 1998;25:15669.
117. Imai H, Motegi M, Mizuki N, et al. Mouth and genital ulcers
with inamed cartilage (MAGIC syndrome): a case report and
literature review. Am J Med Sci 1997;314:3302.
118. International Study Group. Criteria for diagnosis of Behets
disease. Lancet 1990;335:1078.
119. Bang D. Treatment of Behets disease. Yonsei Med J 1997;
38:40110.
120. Yazici H, Yurdakul S, Hamuryudan V. Behets syndrome. Curr
Opin Rhematol 1999;1:537.
121. Arici, M, Kiraz S, Ertenli I. Treatment of Behet disease with
pentoxifylline. Ann Intern Med 1997;126:4934.
122. Masuda K, Nakajima A, Urayama A. Double-masked trial of
cyclosporine versus colchicine and long term open study of
cyclosporine in Behets disease. Lancet 1989;1:1093.
123. ODuffy JD, Robertson DM, Goldstein NP. Chlorambucil in
the treatment of uveitis and meningoencephalitis of Behets
disease. Am J Med 1984;76:75.
124. Muzulu SI, Walton S, Keczkes K. Colchicine therapy in Behets
syndrome. A report of five cases. Clin Exp Dermatol
1989;14:298.
125. Eisenbud L, Horowitz I, Kay B. Recurrent aphthous stomatitis
of the Behets type: successful treatment with thalidomide.
Oral Surg 1987;64:289.
126. Blyth WA, Hill TJ. Establishment, maintenance and control of
herpes simplex virus (HSV-1) latency. In: Rouse BT, Lopez C,
editors. Immunobiology of herpes simplex virus infection.
Boca Raton: CRC Press; 1984. p. 9.
127. Roizman B, Sears AE. An inquiry into the mechanism of her-
pes simplex virus latency. Ann Rev Microbiol 1987;41:543.
128. Croen KD, Ostrove JM, Dragovic MD, et al. Latent herpes sim-
plex virus in human trigeminal ganglia: detection of an imme-
diate early gene antisensetranscript by in situ hybridization.
N Engl J Med 1987;317:1427.
129. Carton CA, Kilbourne ED. Activation of latent herpes sim-
plex by trigeminal sensory-root section. N Engl J Med
1952;246:172.
130. Halford WP, Gebhardt BM, Carr DJ. Mechanisms of herpes
simplex virus type 1 reactivation. J Virol 1996;70:505160.
131. Greenberg MS, Brightman VJ, Ship II. Clinical and laboratory
differentiation of recurrent intra-oral herpes simplex virus
infections following fever. J Dent Res 1969;48:435.
132. Grifn JW. Recurrent intraoral herpes simplex virus infection.
Oral Surg 1965;19:209.
133. Weathers DR, Grifn JW. Intraoral ulcerations of recurrent
herpes simplex and recurrent aphthaetwo distinct clinical
entities. J Am Dent Assoc 1970;81:81.
134. Reeves WC, Corey L, Adams HG. Risk of recurrence after rst
episodes of genital herpes: relation of HSV type and antibody
response. N Engl J Med 1981;305:315.
135. Greenberg MS, Brightman VJ. Serum immunoglobulins in
patients with recurrent intraoral herpes simplex infections. J
Dent Res 1971;50:781.
136. Heineman HS, Greenberg MS. Cell protective effect of human
saliva specic for herpes simplex virus. Arch Oral Biol 1980;
25:25761.
137. Greenberg MS, Friedman H, Cohen SG, et al. A comparative
study of herpes simplex infections in renal transplant and
leukemic patients. J Infect Dis 1987;156:280.
138. Greenberg MS, Cohen SG, Boosz B, Friedman H. Oral herpes
simplex infections in patients with leukemia. J Am Dent Assoc
1987;114:483.
139. Eisen D. The clinical characteristics of intraoral herpes simplex
virus infection in 52 immunocompetent patients. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 1998;86:432-7.
140. Thackray AM, Field HJ. Famciclovir and valacyclovir differ in
the prevention of herpes simplex virus type 1 latency in mice:
a quantitative study. Antimicrob Agents Chemother
1998;42:155562.
141. Thackray AM, Field HJ. Differential effects of famciclovir and
valacyclovir on the pathogenesis of herpes simplex virus in a
murine infection model including reactivation from latency. J
Infect Dis 1996;173:2919.
142. Reitano M, Tyring S, Lang W, et al. Valacyclovir for the sup-
pression of recurrent genital herpes simplex virus infection: a
large-scale dosage range-finding study. International
Valacyclovir HSV Study Group. J Infect Dis 1998;178:60310.
143. Diaz-Mitoma E, Sibbald RG, Shafran SD, et al. Oral famci-
clovir for the suppression of recurrent genital herpes: a ran-
domized controlled trial. Collaborative Famciclovir Genital
Herpes Research Group. JAMA 1998;280:88792.
144. Rooney JF, Straus SE, Mannix ML, et al. Oral acyclovir to sup-
press frequently recurrent herpes labialis: a double-blind,
placebo-controlled trial. Ann Intern Med 1993;118:26872.
145. Amagai M, Koch PJ, Nishikawa T, Stanley JR. Pemphigus vul-
garis antigen (desmoglein 3) is localized in the lower epider-
mis, the site of blister formation in patients. J Invest Dermatol
1996;106:3515.
146. Mahoney MG, Wang Z, Rothenberger K, et al. Explanations for
the clinical and microscopic localization of lesions in pem-
phigus foliaceus and vulgaris. J Clin Invest 1999;103:4618.
147. Williams DM. Vesiculobullous mucocutaneous disease: pem-
phigus vulgaris. J Oral Pathol Med 1989;18:544.
148. Anhalt GJ, Labib RS, Voorhees JJ, et al. Induction of pemphi-
gus in neonatal mice by passive transfer of IgG from patients
with the disease. N Engl J Med 1982;506:118996.
149. Jensen PJ, Baird J, Morioka S, et al. Epidermal plasminogen
activation is abnormal in cutaneous lesions. J Invest Dermatol
1988;90:777.
150. Stanley JR. Cell adhesion molecules as targets of autoantibod-
ies in pemphigus and pemphigoid, bullous diseases due to
defective epidermal cell adhesion. Adv Immunol 1993;
53:291325.
151. Coleman MD. Dapsone: modes of action, toxicity and possi-
ble strategies for increasing patient tolerance. Br J Dermatol
1993;129:50713.
152. Anhalt GJ. Pemphigoid: bullous and cicatricial. Dermatol Clin
1990;8:701.
153. Gilmore HK. Early detection of pemphigus vulgaris. Oral Surg
1978;46:641.
154. Lamey PJ, Rees TD, Binnie WH, et al. Oral presentation of
pemphigus vulgaris and its response to systemic steroid ther-
apy. Oral Surg 1992;74:54.
155. Zegarelli DJ, Zegarelli EV. Intraoral pemphigus vulgaris. Oral
Surg 1977;44:384.
156. Lenz P, Amagai M, Volc-Platzer B, et al. Desmoglein 3-ELISA:
a pemphigus vulgarisspecic diagnostic tool. Arch Dermatol
1999;135:143148.
157. Nishikawa T. Desmoglein ELISAs: a novel diagnostic test for
pemphigus. Arch Dermatol 1999;135:1956.
158. Chrysommlis F, Ioannides D, Teknetzis A, et al. Treatment of
oral pemphigus vulgaris. Int J Dermatol 1994;33:8037.
159. Stanley JR. Therapy of pemphigus vulgaris. Arch Dermatol
1999;135:767.
160. Enk AH. Mycophenolate is effective in the treatment pemphi-
gus vulgaris. Arch Dermatol 1999;135:546.
161. Calebotta A, Saenz AM, Gonzalez F, et al. Pemphigus vulgaris:
benets of tetracycline as adjuvant therapy in a series of thir-
teen patients. Int J Dermatol 1999;38:21721.
162. Rook AH, Jegasothy BV, Heald P, et al. Extracorporeal pho-
tochemotherapy for drug-resistant pemphigus vulgaris. Ann
Intern Med 1990;112:303.
163. Nousari HC, Deterding R, Wojtczak KH, et al. The mecha-
nism of respiratory failure in paraneoplastic pemphigus. N
Engl J Med 1999;340:140610.
164. Anhalt GJ. Paraneoplastic pemphigus. Adv Dermatol
1997;12:7796.
165. Virgils A, Trombelli L, Calura G. Sudden vegetation of the
mouth. Pemphigus vegetans of the mouth (Hallopeau type).
Arch Dermatol 1992;128:398.
166. Iwata M, Watanabe S, Tamaki K. Pemphigus vegetans present-
ing as scrotal tongue. J Dermatol 1989;16:159.
167. Thornhill MH, Zakrzewska JM, Gilkes JJ. Pyostomatitis vege-
tans. Report of three cases and review of the literature. J Oral
Pathol Med 1992;21:128.
168. Korman NJ. Bullous pemphigoid: the latest in diagnosis, prog-
nosis and therapy. Arch Dermatol 1998;134:113741.
169. Bastuji-Garin S, Joly P, Picard-Dahan C, et al. Drugs associated
with bullous pemphigoid: a case-control study. Arch Dermatol
1996;132:2726.
170. Venning VA, Frith PA, Bron AJ, et al. Mucosal involvement in
bullous and cicatricial pemphigoid. A clinical and
immunopathological study. Br J Dermatol 1988;118:7.
171. Roujeau JC, Lok C, Bastuji-Garin S, et al. High risk of death in
elderly patients with extensive bullous pemphigoid. Arch
Dermatol 1998;134:465.
172. Lever WF. Pemphigus and pemphigoid. J Am Acad Dermatol
1979;1:2.
173. Chan LS, Hammerberg C, Cooper KD. Cicatricial pemphigoid.
Identication of two distinct sets of epidermal antigens by IgA
and IgG class circulating autoantibodies. Arch Dermatol
1990;126:1466.
174. Albritton JI, Nousari HC, Anhalt GJ. Antiepiligrin (laminin-5)
cicatricial pemphigoid. Br J Dermatol 1997;137:9926.
175. Nousari HC, Rencic A, Hsu R, et al. Anti-epiligrin cicatricial
pemphigoid with antibodies against the gamma2 subunit of
laminin 5. Arch Dermatol 1999;135:1736.
176. Lamey PJ, Rees TD, Binnie WH, Rankin KV. Mucous mem-
brane pemphigoid. Treatment experience at two institutions.
Oral Surg 1992;74:50.
177. Rogers RS, Mehregan DA. Dapsone therapy of cicatricial pem-
phigoid. Semin Dermatol 1988;7:201.
178. Ciarrocca KN, Greenberg MS. A retrospective study of the
management of oral mucous membrane pemphigoid with
dapsone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1999;88:15963.
179. Berk MA, Lorincz AL. The treatment of bullous pemphigoid with
tetracycline and nicotinamide. Arch Dermatol 1986;122:670.
180. Korman NJ, Eyra RW, Zone J, Stanley JR. Drug-induced pem-
phigus. J Invest Dermatol 1991;96:273.
181. Wakelin SH, Allen J, Zhou S, Wojnarowska F. Drug-induced
linear IgA disease with antibodies to collagen vii. Br J Dermatol
1998;138:310.
182. Zhou S, Ferguson DJ, Allen J, Wojnarowska F. The localization
of target antigens and autoantibodies is variable. Br J Dermatol
1998;139:591.
183. Dabelsteen E. Molecular biological aspects of acquired bullous
diseases. Crit Rev Oral Biol Med 1998;9:162.
184. Marsden RA. Linear IgA disease of childhood. In:
Wojnarowska F, Briggaman RA, editors. Management of blis-
tering diseases. New York: Chapman & Hall; 1990. p. 11926.
185. Lear JT, Smith AG. Multiple blisters in a young boy. Arch
Dermatol 1998;134:625.
186. Marsden RA, Mckee PH, Bhogal B, et al. A study of chronic
bullous disease of childhood and comparison with dermati-
tis herpetiformis and bullous pemphigoid occurring in child-
hood. Clin Exp Dermatol 1980;5:159.
187. Greenspan JS, Yeoman CM, Harding SM. Oral lichen planus.
Br Dent J 1978;144:83.
188. Walsh LJ, Savage NW, Ishii T, Seymour GJ. Immunopathogenesis
of oral lichen planus. J Oral Pathol Med 1990;19:389.
189. Bolewska J, Hansen HJ, Holmstrup P, et al. Oral mucosal
lesions related to silver amalgam restorations. Oral Surg
1990;70:55.
190. Carrozzo M, Gandolpho S, Carbone M, et al. Hepatitis C virus
infection in Italian patients with oral lichen planus: a prospec-
tive case controlled study. J Oral Pathol Med 1997:26:36.
191. Bagan JV, Ramon C, Gonzalez L, et al. Preliminary investiga-
tion of the association of oral lichen planus and hepatitis C.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1998;85:532.
192. DeRossi S, Greenberg MS. Intraoral contact allergy: a literature
review and case reports. J Am Dent Assoc 1998;129:1435.
193. Yiannias JA, el Azhary RA, Hand JH, et al. Relevant contact sen-
sitivities in patients with the diagnosis of oral lichen planus. J
Am Acad of Dermatol 2000;42:177.
194. Schubert MM, Sullivan KM. Recognition, incidence and man-
agement of oral graft-versus-host disease. N C I Monogr
1990;9:135.
195. Fowler CB, Rees TD, Smith BR. Squamous cell carcinoma on
the dorsum of the tongue arising in a longstanding lesion of
erosive lichen planus. J Am Dent Assoc 1987;15:707.
196. Katz RW, Brahim JS, Travis WD. Oral squamous cell carci-
noma arising in a patient with longstanding lichen planus: a
case report. Oral Surg 1990;70:282.
209. Greenberg MS, Friedman H, Cohen SG, et al. A comparative
study of herpes simplex infections in renal transplant and
leukemic patients. J Infect Dis 1987;156:280.
210. Schneidman DW, Barr RJ, Graham JH. Chronic cutaneous
herpes simplex. JAMA 1979;241:542.
211. MacPhail LA, Greenspan D, Schiodt M, et al. Acyclovir-resis-
tant Foscarnet-sensitive oral herpes simplex type 2 lesion in a
patient with AIDS. Oral Surg 1989;67:427.
212. Economopoulou P, Laskaris G, Kittas C. Oral histoplasmosis
as an indicator of HIV infection. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1998;86:203.
213. Warnakulasuriya KAAS, Harrison JD, Johnson NW, et al.
Localized oral histoplasmosis associated with HIV infection. J
Oral Pathol Med 1997;26:294.
214. Chinn H, Chernoff DN, Migliorati CA, et al. Oral histoplas-
mosis in HIV infected patients: a report of two cases. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:710.
215. Page LR, Drummond JF, Daniels HT, et al. Blastomycosis with
oral lesions. Oral Surg 1979;47:157.
216. Bell WA, Gamble GE, Garrington GE. North American blas-
tomycosis with oral lesions. Oral Surg 1969;28:914.
217. Rose HD, Gingrass DJ. Localized oral blastomycosis mimick-
ing actinomycosis. Oral Surg 1982;54:12.
218. Cohen SG, Greenberg MS. Rhinomaxillary mucormycosis in
a kidney transplant patient. Oral Surg 1980;50:33.
219. Salisbury PL, Caloss R, Cruz JM, et al. Mucormycosis of the
mandible after dental extractions in a patient with acute myel-
ogenous leukemia. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1997;83:340.
220. Jones AC, Bentsen TY, Freedman PD. Mucormycosis of the
oral cavity. Oral Surg 1993;75:455.
197. Lind PO, Koppang HS, Eigil AAS. Malignant transformation in
oral lichen planus. Int J Oral Surg 1985;14:509.
198. Kaplan B, Barnes L. Oral lichen planus and squamous carci-
noma: case report and update of the literature. Arch
Otolaryngol 1985;111:543.
199. Massa MC, Greancy V, Kron T, Armin A. Malignant transfor-
mation of oral lichen planus: case report and review of the lit-
erature. Cutis 1990;45:45.
200. Silverman S, Gorsky M, Lozada-Nur F. A prospective follow-
up study of 570 patients with oral lichen planus: persistence,
remission and malignant association. Oral Surg 1985;60:30.
201. Murti PR, Daftary DK, Bhonsle RR, et al. Malignant potential
of oral lichen planus: observations in 722 patients from India.
J Oral Pathol 1986;15:71.
202. Jungell P. Oral lichen planus. A review. Int J Oral Maxillofac
Surg 1991;20:129.
203. Eisen D, Ellis CN, Duell EA, et al. Effect of topical cyclosporine
rinse on oral lichen planus. A double blind analysis. N Engl J
Med 1990;323:290.
204. Jungell P, Malmstrom M. Cyclosporin A mouthwash in the
treatment of oral lichen planus. Int J Oral Maxillofac Surg
1996;25:60.
205. Gorsky M, Raviv M. Efcacy of etretinate (Tigason) in symp-
tomatic oral lichen planus. Oral Surg 1992;73:52.
206. Lundquist G, Forsgren H, Gajecki M, et al. Photochemotherapy
of oral lichen planus. A controlled study. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 1995;79:554
207. McCreary CE, McCartan BE. Clinical management of oral
lichen planus. Br J Oral Maxillofac Surg 1999;37:338.
208. Greenberg MS, Cohen SG, Boosz B, Friedman H. Oral herpes
simplex infections in patients with leukemia. J Am Dent Assoc
1987;114:483.
525
20
INFECTIOUS DISEASES
JOHN A. MOLINARI, PHD
MICHAEL GLICK, DMD
In the early 1960s, Sir MacFarlane Burnet proclaimed, One
can think of the middle of the twentieth century as the end
of one of the most important social revolutions in history,
the virtual elimination of the infectious disease as a signifi-
cant factor in social life.
1
This was not an uncommon sen-
timent among the medical community and resulted in a
decrease in awareness, research, and funding to combat
emerging, re-emerging, and drug-resistant infections.
Consequently, the medical community was ill prepared
when diseases thought to be conquered, and new diseases,
started to emerge in the 1980s and 1990s. In a recent report
from the Institute of Medicine, six major factors were iden-
tified as contributors to the emergence and re-emergence of
infectious disease, as follows:
2
1. Changes in human demographics and behavior
2. Advances in technology and changes in industry prac-
tices
3. Economic development and changes in land use pat-
terns
4. Dramatic increases in volume and speed of interna-
tional travel and commerce
5. Microbial adaptation and change
6. Breakdown of public health capacity required to han-
dle infectious diseases
Although the number of deaths from infectious diseases
has decreased dramatically in the United States during the
twentieth century, there was a temporary increase between
1980 and 1995, mainly due to human immunodeciency virus
(HIV) disease.
3
HIV and other emerging and re-emerging
infectious diseases are recognized as signicant health hazards
and have become the focus of many federal and academic
health initiatives. Efforts in controling infectious diseases have
addressed sanitation and hygiene, vaccination, the use of
BACTERIAL INFECTIONS
Tuberculosis
Legionella
PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Microbial Characteristics
Epidemiology and Transmission
Clinical Syndrome
Treatment and Control
VIRAL INFECTIONS
Hepatitis C Virus
HIV Infection
antibiotics and other antimicrobial medications, and improved
technology in detection and monitoring. Oral health care
providers are not excluded from these efforts, as many of these
endeavors impact directly on dental care.
This chapter highlights a few infectious diseases that are of
importance to dentistry. Some of these diseases are well estab-
lished, whereas others are emerging and may become impor-
tant sources of both contamination and transmission in den-
tal settings. Oral health care providers need to be able to assess
and evaluate patients who are carriers of infectious diseases
with the purpose of providing appropriate and safe dental care.
BACTERIAL INFECTIONS
Tuberculosis
There is a well-known phrase that states, The more things
change, the more they stay the same. This expression contin-
ues to apply to tuberculosis (TB), a widespread infectious dis-
ease scourge traced back to the earliest of centuries. As a result
of a resurgence of TB cases in the United States during the
1980s, attention refocused on the factors associated with the
observed reversal of a previous declining disease trend; trans-
mission modes of Mycobacterium tuberculosis, occupational
infection risks associated with health care, and airborne-haz-
ard infection control precautions.
48
Despite dramatic
improvements in public health measures associated with M.
tuberculosis infection and disease, such as living conditions,
nutrition, and antimicrobial chemotherapy, that resulted in an
observed dramatic decline in the incidence of TB in the United
States and certain other countries during the past century, TB
remains a major public health concern for much of the worlds
population.
9,10
Evidence supporting this statement includes
the following:
1. TB is the most common cause of death from a single
microbial agent.
2. TB is responsible for almost 1 in 4 preventable deaths
in the world.
3. The World Health Organization estimates that world-
wide there are approximately 20 million active TB cases.
4. Approximately 3 million people die each year from
TB, with 80% of this total occurring in developing
countries.
In short, many problems associated with tuberculosis as a
signicant world health problem 100 years ago remain as this
debilitating illness continues to be an even greater infectious
disease concern at the end of the twentieth century.
The United States witnessed a dramatically different pattern
of TB incidence from much of the rest of the world, docu-
menting a three-decade decline through to 1984 (Table 20-1).
Based on that rate of decline, the Centers for Disease Control
and Prevention (CDC) projected that TB would be eliminated
within the United States by the year 2010. These optimistic pre-
dictions were quietened in 1985, when the number of reported
cases showed a smaller decrease compared to the previous 2
years. In 1986, the number of reported cases actually exceeded
526 Principles of Medicine
the 1985 gure. This trend continued until the peak year of
1992 (26,673 cases). With the development and institution of
appropriate infection control policies and procedures aimed at
minimizing airborne spread of M. tuberculosis, continued
decrease in new TB cases has been noted in each subsequent
year.
11,12
ETIOLOGY AND PATHOGENESIS
The genus Mycobacteriumcontains a variety of species, rang-
ing from human pathogens to relatively harmless organisms.
As the major cause of TB, a chronic communicable disease, M.
tuberculosis is by far the most historically prominent member
of this group of bacteria. In addition to their very slow growth
on special enriched media, these aerobic slender rods are char-
acterized by their acid-fast staining feature. The unusually
high lipid content of the cell wall confers the organisms with
an ability to strongly retain a red dye (carbolfuchsin) after
treatment with an acid-alcohol solution. This unique struc-
ture also allows the bacteria to survive outside a hosts body,
suspended in airborne microdroplet nuclei for extended peri-
ods of time.
Contrary to a perception believed through the ages, M.
tuberculosis is not a highly contagious bacterium. It does not
synthesize potent exotoxins or extracellular enzymes, and it is
not surrounded by an antiphagocytic capsule. Onset of infec-
tion appears to be related to the ability of tubercle bacilli to
multiply within host cells and tissues while at the same time
resisting host defenses. Infection with M. tuberculosis typically
requires prolonged close contact of a susceptible host with an
infectious source. The closeness of the contact with
aerosolized bacilli and the degree of infectivity of the
TABLE 20-1 Summary of Reported Cases of Tuberculosis in the
United States by Year
Year Total Number of Cases
1954 79,775
1967 45,647
1970 37,137
1975 33,989
1980 27,749
1985 22,201
1986 22,768
1990 25,701
1992 26,673
1993 25,313
1994 24,361
1995 22,860
1996 21,337
1997 19,851
1998 18,361
1999 16,607
2000 12,942
CDC. Reported tuberculosis in the United States, 2000. Surveillance Reports; 2001.
Infectious Diseases 527
mycobacterial source are the most important considerations
for infection. The overwhelming majority of primary human
infections involve inhalation of mycobacteria-laden respira-
tory microdroplets.
13,14
The diameter of these aerosolized
droplets ranges from 1 to 5 microns. Dispersal of M. tubercu-
losis occurs via these droplets as a result of coughing, sneez-
ing, or even speaking. Microdroplet nuclei are small enough
to bypass protective host bronchial mucocilliary defenses,
leading to mycobacteria subsequently replicating in both free
alveolar spaces and within phagocytic cells (Figure 20-1).
Repeated prolonged exposure to air that has been contami-
nated by droplets from a person with TB predisposes others
to infection. This rationale is illustrated by the fact that peo-
ple who live in the same home with an infected individual, or
close friends or co-workers who routinely breathe the same
mycobacteria-contaminated air from an undiagnosed or
untreated person with pulmonary TB, have a high risk of
acquiring infection. The organisms oxygen requirement pre-
disposes the lungs as primary infection sites, with the poten-
tial for subsequent dissemination to other tissues. Cross-infec-
tion or spread of tubercle bacilli does not result from casual
or sporadic exposure.
Onset of clinical disease is characterized by gradual inl-
tration of neutrophils, macrophages, and T lymphocytes.
Distinctive granulomatous TB lesions called tubercles may
appear anywhere in the lung parenchyma; however, they are
most evident in the periphery (Figure 20-2). Because TB is the
prototype microbial infection for inducing protective cellular
immunity, the immunocompetence of the affected host plays
a signicant role in controlling the extent and severity of resul-
tant disease.
15,16
It is important to remember that most peo-
ple infected with M. tuberculosis develop a positive type IV
hypersensitive skin test reaction when challenged (Figure 20-
3) but do not progress to clinical disease. For those infected
individuals who develop clinical symptoms, fatigue, malaise,
weight loss, night sweats, and fever are most commonly noted
in addition to positive chest radiograph manifestations.
Pulmonary manifestations most frequently are chest pain,
bloody sputum, and the presence of a prolonged productive
cough of greater than 3 weeks duration.
Initial mycobacterial infection may progress to several dif-
ferent states depending on the extent of M. tuberculosis expo-
sure and resistance of the patient. These include (1) asympto-
matic primary tuberculosis, (2) symptomatic primary
tuberculosis, (3) progressive primary tuberculosis, and (4)
reactivation tuberculosis. A major risk factor for progression
of initial infection with tubercle bacilli to more severe disease
stages is the absence of an adequate host acquired cellular
immune response to mycobacterial antigens. The ability of an
infected individual to develop dual cellular and humoral
immune responses against M. tuberculosis antigens thus greatly
inuences disease onset and progression.
FIGURE 20-1 Sequence of infection from a Mycobaterium tuberculo-
sisladen microdroplet in a susceptible person.
FIGURE 20-2 Chest radiograph of lungs in a patient with primary
symptomatic tuberculosis. Multiple areas of disease are visible, with radi-
ographic evidence of chronic granulomatous tubercles.
FIGURE 20-3 Positive 48-hour skin test following puried protein deriv-
ative intradermal challenge of a person with primary asymptomatic tuber-
culosis. No evidence of clinical disease was present, and the patient
remained asymptomatic following a prolonged course of isoniazid
chemotherapy.
Asymptomatic Primary Tuberculosis. Individuals may be
infected with M. tuberculosis without apparent clinical mani-
festations. When skin tested, individuals with asymptomatic
primary tuberculosis display a positive tuberculin reaction
indicating that they have been infected and have developed
cell-mediated immunity against the bacteria. This protective
immune response prevents the continued multiplication and
dissemination of the bacteria, but it does not destroy all of the
bacteria present. The remaining bacteria are sequestered
within tubercles in the affected tissues and may be the source
of bacteria that initiate reactivation tuberculosis.
Symptomatic Primary Tuberculosis. In symptomatic pri-
mary tuberculosis, M. tuberculosis is spread via the lymphat-
ics to cause granulomatous inammation in both the lung
periphery and hilar nodes, and it is accompanied by respira-
tory symptoms. The usual result is one of healing and devel-
opment of cell-mediated immunity. The Ghon complex, a
remnant of this infection, most often occurs in infants and
children and is comprised of small calcied lung nodules and
lymphadenopathy of the hilar lymph nodes.
Progressive Primary Tuberculosis. A much more serious dis-
ease may develop in those individuals who are less resistant to
tubercle bacilli. In these patients, microorganisms may spread
throughout the body either (1) by means of the blood, result-
ing in miliary tuberculosis; (2) via the respiratory tissues,
inducing a bronchopneumonia; or (3) through the gastroin-
testinal tract as a result of the organisms being coughed up. In
miliary tuberculosis, foci of infection occur in distant organs
and tissues but most frequently develop in the meninges, lungs,
liver, and renal cortex. Although cell-mediated immunity may
develop in some patients, others may not react (anergy) when
skin tested with tuberculin protein preparations. Anergic
patients have a poor prognosis for recovery and often die with-
out rapid treatment.
Reactivation Tuberculosis. Reactivation tuberculosis occurs
in individuals who have developed primary tuberculosis and
who are asymptomatic, but who still carry the bacteria within
tubercles. These patients exhibit positive tuberculin skin tests
and thus demonstrate cellular immunity. Reactivation of dis-
ease is thought to be due to the activation of persistent bacte-
ria in the tubercles of a previous infection, which become acti-
vated by some alteration in host resistance. Infection is
characterized by tubercle formation, caseation, brosis, and
further extension of the lesion. Progression may advance into
a bronchus, leading to cavitation of the lung and secretion of
an infectious sputum.
ORAL MANIFESTATIONS
Oral manifestations of tuberculosis occur in approximately
3% of cases involving long-standing pulmonary and/or sys-
temic infection.
17,18
The bacteria can infect oral tissues and
lymph nodes (scrofula) (Figure 20-4). Within the oral cavity,
lesions can occur in the soft tissues and supporting bone
(Figure 20-5) and in tooth extraction sites, and may even affect
the tongue and oor of the mouth (Figure 20-6).
When reviewing this information, it becomes apparent
that progression of infection with tubercle bacilli to more
severe disseminated stages occurs in the absence of adequate
cellular immunity to infection. Thus, the ability of an
infected individual to develop a dual immune response
against M. tuberculosis antigens greatly influences disease
onset and progression. These crucial protective responses are
(1) acquired immunity to infection and (2) development of
tuberculin hypersensitivity.
DIAGNOSIS
A diagnosis of infection with M. tuberculosis relies on (1) devel-
opment of a positive delayed hypersensitivity (tuberculin) skin
reaction to puried protein derivative (PPD), a mycobacterial
antigen isolated from bacterial cultures, and (2) demonstration
of acid-fast mycobacteria in clinical specimens. Information
obtained while collecting a patients medical history can pro-
vide evidence for suspicion of TB (Table 20-2).
RISK FACTORS
The re-emergence of M. tuberculosis infection as a signicant
US public health problem appears to be the result of a com-
bination of changing host susceptibility factors and declining
societal conditions for particular population groups. Among
FIGURE 20-4 Cervical tuberculosis lymphadenitis (scrofula) secondary
to pulmonary tuberculosis in a 16-year-old male.
TABLE 20-2 Patient History Prompting Suspicion of Active
Tuberculosis
1. Productive cough (> 3 wk) pulmonary tuberculosis
2. Other symptoms (eg, fever, chills, night sweats, fatigue)
3. Extrapulmonary tuberculosis (occurs in 15% of cases)
4. Patients with tuberculosis and HIV infection4075% have extrapulmonary
tuberculosis and pulmonary tuberculosis
5. History of tuberculosis exposure and/or previous tuberculosis infection
(active disease)
the most frequently noted risk factors is infection with
HIV.
1923
The suppressive effect of HIV infection on cell-
mediated immunity increases host susceptibility to a variety
of microbial pathogens that are normally controlled by these
defense mechanisms. It should be noted, however, that current
information does not suggest HIV-infected persons are more
susceptible to M. tuberculosis infection, but they can present
with earlier clinical manifestations of the disease. Increased
immigration of people to the United States from countries
with high TB prevalence rates adds to the reservoir for
mycobacterial transmission.
24
Unfortunately, funding for TB
research, screening programs, and epidemiologic tracking
lagged in the 1980s as attention focused on other infectious
diseases, such as those caused by herpesviruses, hepatitis B,
and HIV/acquired immunodeficiency syndrome (AIDS).
These factors, together with documented societal tragedies
such as increased parenteral drug abuse, homelessness, mal-
nutrition, and crowding, especially in larger US cities, have
exacerbated the potential for the spread of TB (Table 20-3).
13
TREATMENT
Prior to the advent of antimicrobial chemotherapy, approxi-
mately 50% of persons with active TB died within 2 years after
onset of symptoms.
24
Regimens of multiple antibiotics are
currently used to treat patients with active TB to ensure tissue
penetration and minimize emergence of resistant organisms.
General guidelines for appropriate TB chemotherapy include
necessity for long-term treatment interval (up to 2 years), ini-
tiation of treatment if sputum smear is positive for acid-fast
bacilli, and patient compliance (a major factor in determining
chemotherapy success).
Isoniazid (INH) is the antimycobacterial therapy corner-
stone and is included in all routine drug regimens. People who
develop a positive tuberculin skin reaction but do not have
active disease, as well as close contacts of patients who develop
TB, are placed on INH for 6 months to 1 year.
For treatment of patients with active TB, combinations of
three or more drugs are chosen based on the nature and site
of disease (Table 20-4). In addition to INH, rifampin, pyra-
zinamide, and ethambutol are the most frequently applied
drug combinations unless a specific instance of mycobacte-
rial resistance is noted.
25,26
Hepatotoxicity is a frequent
adverse effect noted with prolonged administration of
antimycobacterial chemotherapy.
Unfortunately, a major complication preventing success-
ful elimination of acid-fast organisms in TB patients is non-
compliance to the prolonged drug regimens. Patients often
notice a substantial decline in symptoms within a few weeks
of therapy and prematurely discontinue their medications.
Consequently, bacterial strains causing multidrug-resistant
tuberculosis (MDR-TB) have emerged and spread through-
out the world.
2730
FIGURE 20-5 Partially calcied oral tuberculosis localized in the soft
tissue at the angle of the mandible.
FIGURE 20-6 Oral tuberculosis in the soft tissue of mandible.
TABLE 20-3 Persons at High Risk for Contracting Tuberculosis
1. Persons with HIV infection
2. Persons with close contacts with infectious patients
3. Persons with medical conditions that increase risk of contracting TB
4. Persons from countries with high rates of TB
5. Persons in low-income populations
6. Alcoholics
7. Intravenous drug abusers
8. Prisoners
9. Nursing home residents
10. Health care workers in certain work settings (local risk)
TB = tuberculosis
TABLE 20-4 Chemotherapy for Tuberculosis
Combination therapy: usually 34 drugs to prevent resistance, chosen from the
following: isoniazid, rifampin, ethambutol, rifabutin, streptomycin, pyrazinamide
Prolonged therapy6 mo minimum indicated for slow growth rate of bacteria,
increasing incidence of Mycobacterium tuberculosis drug resistance
TUBERCULOSIS VACCINES
Bacille Calmette-Gurin (BCG), an attenuated strain of
Mycobacterium bovis, has been used for more than 80 years to
protect humans against TB. The original mycobacterial iso-
lates were responsible for causing TB in cattle. Calmette and
Guerin attenuated these bacteria by culturing, passaging, and
maintaining them in specialized growth media for more than
10 years. Humans began receiving the BCG preparations in
1921, with resultant protection observed in vaccinated chil-
dren. Most countries currently vaccinate children against TB,
and this preventive approach has been shown to result in a 60
to 80% reduction in disease in treated individuals.
31
Unfortunately, the vaccine is much less effective in adults, for
reasons that are still unexplained. With adults comprising the
major sources of infection, the expected worldwide success of
the BCG vaccine has not been accomplished. The successful
sequencing of the complete M. tuberculosis genome has pro-
vided new opportunities for vaccine development. Ongoing
efforts are being directed at using combinations of established
approaches to vaccine composition, with newer deoxyri-
bonucleic acid (DNA) technologies that look at the roles of
host and mycobacterial genetic factors, to better ascertain the
development of protective immune responses.
32
ORAL HEALTH CONSIDERATIONS
The risk of TB transmission from patients to dental care
providers is considered to be minimal.
33
Responding to reports
and conrmation of M. tuberculosis transmission in institu-
tional settings occurring the 1980s, the CDC developed a series
of guidelines for prevention of the spread of TB in health care
environments. Special emphasis within the document was
directed at the heightened TB risks for those persons living
with HIV infection or AIDS as a result of virus-induced sup-
pression of cellular immune defenses. As more clinical data
and scientic input were obtained from health care and pub-
lic sources, the CDC incorporated that information in updated
draft recommendations. The nalized document released in
1994 provided the following:
1. Guidance for assessing potential TB risks in a variety of
health care facilities
2. Detailed description of administrative procedures,
infection control practices, engineering controls, and
respiratory personal equipment appropriate for mini-
mizing airborne microbial transmission
3. Suggestions for ongoing health care worker (HCW)
training and education.
34
Specific considerations for dentistry were delineated
within this document and provided wellthought out admin-
istrative and infection control practice for the range of possi-
ble dental exposure categories.
The efforts of the CDC have been very effective, yet they
represent only one component of the governmental response
to the public health threat posed by mycobacterial infection
and TB. The Labor Coalition to ght TB in the Workplace
submitted a request to Occupational Safety and Health
Administration (OSHA) in December 1992 to issue national
enforcement guidelines to protect workers against M. tuber-
culosis exposure. This was followed by the coalition of labor
unions petitioning OSHA in 1993 to develop a permanent set
of rules to protect workers (mostly in patient care facilities)
from occupational TB transmission. Serious concern was
expressed by these groups about the emergence of cases of
MDR-TB, along with the contention that nonmandatory rec-
ommendations and guidelines would not be fully imple-
mented or enforced appropriately in many workplaces. The
nal OSHA-proposed rule incorporated many of the compo-
nents of the 1994 CDC guidelines but also added a number of
mandatory regulations that have stirred considerable contro-
versy within the CDC, among numerous hospital-based infec-
tion-control professionals, and infection-control groups. A
few of the areas of contention include (1) overstatement of the
current TB risk to HCWs in lieu of the effectiveness of the 1994
CDC TB control guidelines; (2) elimination of the CDC-rec-
ommended facility TB risk assessment protocol; (3) additional
respirator t-testing requirements; (4) more frequent skin-
testing requirements for employees, including TB skin testing
within 30 days of job termination; and (5) increased facility
costs to implement new regulations.
OSHAs rationale for mandatory TB controls stemmed
from the assessment that TB is still endemic in certain popu-
lation groups, and HCWs and other employees who come into
contact with persons manifesting active TB may have signi-
cantly increased infection risks above that of the general pop-
ulation. The agency also made a preliminary determination
that the portions of the standard directing engineering, work
practice, and administrative controls, respiratory protection,
training, and medical surveillance are technologically and eco-
nomically feasible for affected workplaces. Few OSHA pro-
posals for worker protection in any American workplace have
sparked as much debate and resistance as the proposed rules
regarding tuberculosis. The issue may have been resolved in
favor of continuing the successful adherence to the 1994 CDC
guidelines in early 2001, but the Institute of Medicine then
published a report that critically reviewed the proposed stan-
dard and found numerous problems with some of mandatory
aspects of the legislation.
35
Legionella
Scientists, clinicians, and the public officially became
acquainted with Legionella pneumophila as a result of the out-
break of legionnaires disease in a Philadelphia hotel hous-
ing the 1976 American Legion convention. As a result of the
first reports of sudden severe pneumonia among conven-
tioneers, multiple epidemiologic groups were rapidly mobi-
lized in an effort to determine both the cause(s) and contrib-
utory factors responsible for the 221 total cases and 34
illness-associated deaths.
36
MICROBIAL CHARACTERISTICS
When the elusive etiologic bacterium was eventually iso-
lated in 1977, using lung tissue from patients in the
Philadelphia epidemic, it became apparent that the aerobic
gram-negative bacillus represented a previously unrecog-
nized species. Table 20-5 summarizes representative bacte-
riologic features of this organism.
3739
One of the early surprises stemming from these studies
was that L. pneumophila had actually rst been isolated from
the blood of a patient with respiratory illness in 1947.
40
Improved more-sensitive research technologies provided bet-
ter cultural and serologic methodologies for isolation and
characterization. As a result, scientists began to appreciate (1)
the ubiquity of L. pneumophila and related species in man-
made waterborne environments, (2) the role of this bacterial
species as one of the three most common microbial etiologies
of community-acquired pneumonia, and (3) the multiple
forms of disease that can develop in immunocompetent and
immunocompromised individuals. L. pneumophila serogroup
1 is still the most clinically important pathogenic species, caus-
ing the overwhelming majority of illnesses after exposure to
contaminated water.
MAJOR HABITATS
Legionella species are found extensively in natural bodies of
water. Most samples from colonized rivers, lakes, and other
sources typically contain only low concentrations of L. pneu-
mophila. However, the species is remarkably chlorine toler-
ant. This feature appears to allow for microbial survival dur-
ing treatment procedures, leading to subsequent entrance and
proliferation in water distribution systems.
Multiple studies have shown that the presence of amebae
and other waterborne microbes offers L. pneumophila a unique
opportunity for initial parasitism, leading to ultimate survival
and proliferation. Amebae appear to serve as primary natural
hosts for the bacteria in man-made water environments such
as water distribution systems.
4143
This intracellular parasitic
characteristic allows the legionellae to thrive and replicate,
protected from adverse external surroundings. When the
infected amebae die and lyse, both the water source and other
susceptible single-cell organisms are then exposed to a much
higher concentration of Legionella.
CLINICAL SYNDROME
Clinical conditions caused by L. pneumophila and other
Legionella species are grouped under the term legionellosis.
With regard to virulence factors, neither exotoxins nor destruc-
tive enzymes have been associated with the pneumonia caused
by L. pneumophila. The acute inammatory inltration and
febrile nature of clinical illness appear to be consistent with the
biologic manifestations of released endotoxin in tissues.
MODES OF TRANSMISSION
Legionella infections differ from other kinds of pneumonia-
inducing conditions in that the bacteria are not transmitted
from person to person but from contaminated environmen-
tal reservoirs. Evidence accumulated from outbreaks of the
disease and experimental investigations suggests that
Legionella species may be passed to susceptible hosts via mul-
tiple routes: aspiration, aerosolization, and instillation into
the lungs. Aspiration of contaminated water appears to be the
major means of human infection.
44
In one study, passage of
microorganisms via this mechanism appeared to be excep-
tionally serious in patients after surgery for head and neck
cancer because of the patients frequency of aspiration of
fluids.
45
Aerosolization of contaminated water occurs from
such sources as humidifiers, nebulizers, and cooling tower air
conditioners. Because the organisms are resistant to destruc-
tion in moist environments, it is believed that exposure to
legionellae is common. Reports in the literature in recent
years have implicated potable water harboring L. pneu-
mophila as an important source of community-acquired
pneumonia. As a result, investigation of legionellosis cases
now includes examination of water supplies in patients
rooms, homes, and workplaces.
4648
CLINICAL FEATURES
Two disparate forms of clinical disease can develop after
Legionella infection. The most common manifestation,
known as Pontiac fever, presents as an acute influenza-like
illness without any evidence of pneumonia. There is a 24- to
48-hour incubation period, and many patients experience
fever, chills, malaise, and headaches. Patients typically
recover from this self-limiting illness within 7 to 10 days.
49
Although the attack rate for Pontiac fever among exposed
persons is high (Tables 20-6 and 20-7), many cases of
legionellosis are never diagnosed because symptoms are
either absent or mild.
Published reports suggest that dental professionals may
have a signicant occupational exposure to Legionella from
aerosolization of contaminated dental-unit water, resulting in
the formation of anti-Legionella antibodies.
50,51
Individuals
similarly exposed in a variety of environments may have sub-
sequently developed Pontiac fever and not been aware of it.
The second, more publicized, type of legionellosis is a
potentially life-threatening illness termed legionnaires dis-
ease. The incubation period (2 to 10 days) is longer than that
for Pontiac fever. An individual may abruptly exhibit fever,
chills, headache, and other nonspecic signs of acute infec-
tion. Subsequently, multisystem involvement becomes evi-
dent with pneumonia as the pathognomonic feature.
52
If
untreated, this form of severe pneumonia can result in a 15%
TABLE 20-5 Bacteriologic Characteristics of Legionella
pneumophila
Family: Legionellaceae
Morphology: gram-negative non-spore-forming motile unencapsulated bacilli
Physiology: aerobic and nutritionally fastidious; does not grow on standard
bacteriologic media; requires charcoal yeast extract at pH 6.9; L-cysteine
is essential nutrient
Ecology: natural habitat: rivers, lakes, streams, thermally polluted waters; can
survive water treatment processes; chlorine tolerant; proliferates in man-made
water habitats (cooling towers, water distribution systems)
or higher patient mortality rate (see Tables 20-6 and 20-8).
Legionnaires disease in healthy immunocompetent persons
appears infrequently because of efcient innate and specic
host defenses. Most patients diagnosed with legionnaires dis-
ease present with previous immunosuppressive disorders.
Investigation of nosocomially acquired legionnaires disease
suggests that patients recovering from surgery may be at
greatest risk of contraction.
5355
Other conditions identied
as legionellosis risk factors include advanced age, cigarette
smoking, chronic obstructive pulmonary disease, neoplasia,
and immunosuppressive therapy.
TREATMENT
Erythromycin was the historic antibiotic of choice for treat-
ment of legionnaires disease. Timely appropriate chemother-
apy can dramatically reduce the mortality rate of legionnaires
disease, with many patients showing signs of recovery within
3 to 5 days. With the advent of later-generation macrolides,
azithromycin has replaced erythromycin because of
azithromycins lower toxicity potential in a range of infected
patients.
52
Quinolones also have been shown to be effective
antimicrobial agents in studies of patients with community-
acquired pneumonia who are suspected of having L. pneu-
mophila legionnaires disease.
56,57
Antibiotic therapy is not
indicated for patients diagnosed with Pontiac fever because of
the self-limiting nature of the infection.
PROTOZOAL INFECTION:
CRYPTOSPORIDIUM
Although rst isolated and identied in 1907,
58
the protozoan
genus Cryptosporidiumwas not associated with human disease
until 1976.
59
Only a few cases of cryptosporidiosis were
reported over the next few years, with those occurring in per-
sons having severely compromised immune defenses. Since
the early 1980s, however, Cryptosporidium parvum has
emerged as a major etiology of persistent diarrhea in people of
developing countries, of severe life-threatening diarrhea in
persons with AIDS and other immunosuppressive conditions,
and in previously healthy individuals, as well as an increasingly
serious threat to the safety of the US water supply.
Microbial Characteristics
Among the most common of human pathogens, the diversity
of members within the protozoa has required their classica-
tion to be accomplished via disparate criteria, including phy-
logeny, epidemiology, and clinical manifestations. Protozoa
such as Plasmodium, Entamoeba, and Trypanosoma have long
been recognized as leading causes of human disease and mor-
tality in many parts of the world. The dramatic increase in
numbers of individuals with less-than-adequate immune
defenses throughout the world, in part related to HIV infec-
tion with subsequent progression to AIDS, has also been
related to signicant increases in other protozoan infections,
such as those caused by Cryptosporidium species.
6065
TABLE 20-6 Clinical Conditions Caused by Legionella
Conditions
Characteristic Legionnaires Disease Pontiac Fever
Epidemiology
Attack rate < 5% > 90%
Person-to-person spread No No
Clinical manifestations
Incubation period 210 d 12 d
Clinical features Pneumonia is dominant feature; spectrum from mild Acute self-limiting inuenza-like illness; no pneumonia;
cough to stupor with multisystem failure; cough fever, malaise, myalgia, chills, and headache are
initially mild; only slightly productive predominant symptoms
Course Requires antibiotic therapy (eg, erythromycin) Self-limiting
Mortality 1520%; higher if diagnosis is delayed < 1%
TABLE 20-7 Characteristics of Pontiac Fever
Acute self-limiting inuenza-like illness
24- to 48-hour incubation period
Malaise, myalgia, fever, chills, headache
> 90% of those exposed develop symptoms
Only symptomatic treatment necessary
Complete recovery within 1 wk
Most cases undiagnosed
TABLE 20-8 Characteristics of Legionnaires Disease
Early inuenza-like symptomsinitial cough
2- to 10-day incubation period
Chest pain may be prominent
Pneumonia is dominant nding
Spectrum from mild cough to stupor with multisystem failure
Treatment: erythromycin and other macrolides
The type-species of this genus is C. parvum, which mea-
sures approximately 2.5 m in diameter, about the same size
and shape as yeast cells. It is capable of infecting and causing
disease in both humans and mammals. The infectious form of
C. parvum is a thick-walled oocyst that is excreted in feces
from infected hosts. Oocysts are resistant to standard munic-
ipal chlorination procedures, and this feature is important in
distinguishing cryptosporidia from many other unicellular
waterborne organisms. Because the oocysts can be found in
numerous natural water sources, they can readily cause large
cryptosporidiosis outbreaks when water treatment is less than
optimal and community supplies become contaminated.
Cryptosporidia are also unlike many other single-celled water-
borne organisms in that they are highly resistant to the chlo-
rine treatments used in municipal water facilities. In addition,
they are difcult to lter out because of their small size, and
thus they can escape the standard water treatment processes.
Epidemiology and Transmission
As awareness of the potential threat of cryptosporidiosis has
increased, so have efforts to investigate water sources for evi-
dence of contamination. Unfortunately, accumulated data
suggest that Cryptosporidium is found in numerous munici-
pal water supplies, public pools, nursing homes, and hospitals.
It is also highly infectious, with an inoculum of 30 to 100
oocysts capable of initiating infection.
66,67
Numerous out-
breaks have been demonstrated over the past 20 years. With
the development of better detection techniques, some impor-
tant epidemiologic features have become apparent (Table 20-
9). Most cases in the United States have occurred as a result
of environmental water contamination related to treatment
facility failures.
6871
As reports of the wide distribution of this pathogen accu-
mulate, so have the number of cryptosporidiosis cases with
life-threatening acute diarrhea, mostly seen in immunocom-
promised persons but also in previously healthy individuals. A
dramatic rise in the number of large outbreaks and individual
cases has been noted since 1982, corresponding to the early
days of the AIDS epidemic. Multiple reports have shown per-
sons with AIDS to be among the most susceptible immuno-
compromised groups.
6365
The largest documented outbreak occurred in 1993,
involving the entire city of Milwaukee, in which over 400,000
people became ill after drinking parasite-contaminated water.
Defective ltration of the citys water supply was determined
to be the prime factor responsible for the epidemic, which
resulted in the death of a number of severely immunocom-
promised patients.
68
Other instances of waterborne
C. parvum infection have been traced back to ingestion of
water from oocyst-contaminated swimming pools and
amusement park wave pools.
70
A second mode of parasite infection is person-to-person
spread. Fecal-oral transmission of oocysts within day care cen-
ters, hospitals, and households is probably much more com-
mon than accumulated statistics suggest.
7274
The route of
microbial passage can place child care workers, children in day
care facilities, and other health care providers, who come into
direct contact with feces while attending to cryptosporidiosis
patients, at increased risk for acquiring the infection.
The ability of C. parvumto infect and colonize a variety of
mammals has also led to investigation of suggested animal-to-
person cryptosporidiosis. Multiple investigations have shown
protozoal transmission from calves to humans, and these have
triggered intense study of potential risks for those persons
who have constant close contact on dairy farms.
75
The least proven risk factor for cryptosporidiosis involves
food. Although the CDC conrmed an outbreak in children in
1994 traced to fresh-pressed apple cider unknowingly contam-
inated with animal feces, contaminated hands were also thought
to have substantially contributed to oocyst cross-infection.
76
Clinical Syndrome
The complex C. parvumlife cycle occurs within a single host.
77
Symptoms of cryptosporidiosis may develop within 2 to 10
days after a person has swallowed environmentally contami-
nated water. The most common manifestations of C. parvum
infection are a profuse watery diarrhea, accompanied by fever,
severe abdominal cramping, and pain. Rapid dehydration of
patients is a major concern for physicians, as onset of diarrhea
can be quite sudden and can last for over 2 weeks.
Gastrointestinal symptoms abate in many patients with healthy
immune systems in about 2 weeks, although some may suffer
a relapse of the syndrome.
78
The infection is typically more pro-
tracted and severe in immunocompromised hosts, however, as
extensive dehydration and weight loss may occur over a pro-
longed period of longer than 2 weeks. In some cases, multiple
intravenous infusions of uids are required to replace body
uids lost owing to diarrhea. Even after symptoms of cryp-
tosporidiosis diminish or disappear, the patient can still trans-
mit infectious parasites to others for months via contaminated
stools (fecal-oral transmission). Infected individuals with debil-
itated immune systems can remain infectious much longer.
Treatment and Control
Currently, there is no generally accepted antimicrobial agent
available to treat cryptosporidiosis, and thus, supportive care
of patients remains the treatment of choice.
77
As expected,
this problem is a major area of research, with certain experi-
mental antibiotic regimens showing some promise. Because
the thick-walled oocyst portion of the C. parvum life cycle is
so resistant to chlorine, new approaches to control the spread
of these infectious particles are also being pursued. Reverse
osmosis, better ltration techniques, and other efcient pro-
cedures are under investigation.
TABLE 20-9 Epidemiology of Cryptosporidium Infection
C. parvum is a highly infectious enteric pathogen.
The protozoa are ubiquitous in many mammals.
Infections can occur worldwide.
It is the leading cause of persistent diarrhea in developing countries.
VIRAL INFECTIONS
Hepatitis C Virus
Traditional health care concerns about viral hepatitis focused
primarily on hepatitis B virus (HBV) from the late 1940s to the
early 1980s. Yet, despite accumulated evidence for the docu-
mented occupational risks for HBV over a three-decade
period, signicant voids from other potentially serious hepati-
tis challenges continue to require denition. Although the rou-
tine application of specific serologic tests was valuable in
screening and diagnosing infections caused by hepatitis A virus
(HAV) and HBV, a number of reports, written beginning in
1975, described a form of bloodborne post-transfusion hepati-
tis that could not be attributed to any known microorgan-
ism.
79,80
Since diagnosis of this type of hepatitis was based on
abnormal liver function in the absence of positive blood mark-
ers for HAV, HBV, and other viruses known to cause hepatitis,
the term non-A, non-B hepatitis(NANBH) was introduced.
Most of the risk factors associated with NANBH transmission
were identied prior to recognition and characterization of its
viral etiology. These included blood transfusion, parenteral
drug use, health care worker exposure in clinical settings, sex-
ual transmission from a person with a history of hepatitis, and
low socioeconomic status. Signicant advances in recombinant
DNA technology were instrumental in the later isolation and
cloning of the responsible microorganism in 1989the
hepatitis C virus (HCV).
81
A initial diagnostic serologic assay
was also developed for detection of antibodies to HCV (anti-
HCV) produced by infected persons against a recombinant
viral antigen c100-3.
82
Later generations of more sensitive
immunoassays have been implemented since 1990. Currently,
at least six viral agents appear to account for the majority of
viral hepatitis cases (Table 20-10), with new information
emerging to expand this list.
VIROLOGY
HCV is a single-stranded positive-sense ribonucleic acid
(RNA) virus whose structure appears closely related to the
genera Flavivirus and Pestivirus. Because of the similarities to
these viral types, HCV is currently classied as a separate genus
in the family Flaviviridae. Detailed molecular biologic studies
have shown that different HCV strains can have substantial
differences in genome sequencing. These are due to the abil-
ity of the virus to mutate and modify surface components
during replication within an infected host. As a result, several
genotypes, or quasi-species, have been described that can
exhibit significant differences throughout the RNA
genome
8385
and contribute to the observed alarming high
rate of chronic infection.
EPIDEMIOLOGY AND TRANSMISSION
HCV has a primary bloodborne mode of transmission and is
a dominant cause of chronic liver disease throughout the world.
Data using anti-HCV as a marker have been used to approxi-
mate both worldwide infection prevalence and HCV incidence
in various geographic areas, in an attempt to better dene infec-
tion and disease patterns.
86
Infection with HCV is also the most
common chronic bloodborne infection in the United States.
Current estimates range from 2.7 (1.3%) to 3.9 (1.8%) million
HCV-infected persons in the United States (Table 20-11).
87,88
Approximately 2.7 million people are thought to have per-
sistent chronic hepatitis C infection, and thus are classied as
potentially infectious viral carriers. Mortality in the United
States from all forms of hepatitis C infection is believed to
occur in 8,000 to 10,000 people each year. With the advent of
widespread use of anti-HCV assays and increased awareness of
documented risks and changing viral transmission patterns,
the incidence of new cases of acute hepatitis C has declined by
greater than 80% since 1989.
Statistics acquired during the 1970s and 1980s indicated
that parenteral NANBH was responsible for nearly 90% of
the reported US transfusion-associated hepatitis cases.
Accumulated data suggested that approximately 150,000 per-
sons (5 to 10%) of 3,000,000 who received transfusions devel-
oped acute NANBH.
89,90
With the advent of routine testing
using sensitive anti-HCV tests, however, the current risk for
acquiring transfusion-associated hepatitis C is 1/100,000 per
unit transfused.
91
According to CDC national surveillance
data, parenteral drug use was the most common risk factor
reported by patients with NANBH between 1990 and 1992.
Injection-drug use remains the primary risk factor for new
cases of HCV infection. In addition, persons with hemophilia
who routinely received factor VIII or IX before 1987 and
chronic hemodialysis patients have also been considered at
risk. Occasionally, health care workers who have frequent con-
tact with blood and personal contact with others who may be
infected have been documented to have an increased incidence
for hepatitis C compared with that of the general popula-
tion.
91,92
A summary of these and other epidemiologic esti-
mates is presented in Table 20-12. In recent years, other sero-
logic surveys have revealed a large previously undetected group
of persons at risk for HCV: military veterans, especially
Vietnam-era veterans. Testing at multiple Veterans
Administration (VA) hospitals found an 8 to 10% HCV preva-
lence rate, which is over four times that of the general popu-
lation. Other reports indicate that more than half of the
patients receiving liver transplants in VA medical centers were
diagnosed with HCV infections.
9395
Unfortunately, even with
improved epidemiologic tracking, published studies continue
to report that greater than 40% of the hepatitis C patients do
not have any identifiable risk factors.
91
Evidence of sexual
transmission and of perinatal passage from HCV-infected
mothers to their offspring suggest possible, but not efcient,
modes of viral exposure. In summary, transmission data still
strongly implicate parenteral exposure as the primary mech-
anism for HCV transmission.
SEROLOGY
In May 1990, the US Food and Drug Administration (FDA)
licensed two anti-HCV screening tests.
96
Almost immedi-
ately, blood donation centers began testing for HCV infection
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as a component of their routine donor screening. In a note-
worthy positive outcome, the use of this radioimmunoassay
was found to yield positive anti-HCV results in 80 to 90% of
specimens from potential donors thought to be infectious for
HCV.
97
Unfortunately, false-negative results are possible at
early stages of HCV infection since development of
detectable antibody could be delayed for months post viral
infection. This prolonged delay in seroconversion suggests
that some potentially infectious donors could pass unde-
tected through screening, and their blood subsequently
administered to patients. In addition, false-positive test
results are possible for those donors with certain
immunopathologic conditions, such as hypergammaglobu-
linemia, liver disease, or autoimmune connective-tissue dis-
orders.
98
More recently, blood tests have used other recom-
binant HCV synthetic peptide antigens, and these assays have
increased sensitivity and specificity (Table 20-13).
91
As a
result, the incidence of transfusion-associated hepatitis C
has become increasingly uncommon.
PATHOGENESIS
Presentation of viral hepatitis in patients ranges from asymp-
tomatic illness to a fulminant chronic form in which severe
sequelae and high mortality rates are seen. Many chronic
hepatitis carriers are also at increased risk for hepatocellular
carcinoma. For those individuals who develop icteric mani-
festations of acute viral hepatitis, symptomatologies may vary
in intensity; yet they can be strikingly similar in their spec-
trum, regardless of the etiology. Disease presentations may
include jaundice, malaise, fever, anorexia, nausea, abdominal
pain, dark (stormy,foamy) urine, chalky gray stools, rash,
and arthritis.
The clinical features of HCV infection can be variable, in
patterns reminiscent of those observed for other hepatitis
viruses. Less than one-third of HCV-infected individuals
TABLE 20-11 Hepatitis C Incidence in the United States
Approximately 3.9 million HCV-infected persons (1.8% of population)
4 times HIV infection incidence
2.7 million chronic potentially infectious carriers
10,000 HCV-related deaths/yr
80% decline in new cases since 1989
> 50% new cases related to IV-drug users
Incidence of transfusion cases is declining rapidly.
Most cases are mild to asymptomatic.
Many cases still have no risk factors.
HCV = hepatitis C virus; HIV = human immunodeciency virus; IV = intravenous.
TABLE 20-12 Estimated Average Prevalence of Hepatitis C Virus Infection in the United States*
Infection
Prevalence of
Prevalence
Persons with
Characteristic % Range % Characteristic (%)
Persons with hemophilia treated with products made before 1987 87 7490 < 0.01
Injection-drug users
Current 79 7286 0.5
History of prior use No data 5
Persons with abnormal alanine aminotransferase levels 15 1018 5
Chronic hemodialysis patients 10 064 0.1
Persons with multiple sex partners (lifetime)
50 9 616 4
1049 3 34 22
29 2 12 52
Persons reporting a history of sexually transmitted diseases 6 110 17
Persons receiving blood transfusions before 1990 6 59 6
Infants born to infected mothers 5 025 0.1
Men who have sex with men 4 218 5
General population 1.8 1.52.3 NA
Health care workers 1 12 9
Pregnant women 1 1.5
Military personnel 0.3 0.20.4 0.5
Volunteer blood donors 0.16 5
NA = not applicable.
*By various characteristics and estimated prevalence of persons with these characteristics in the population.
manifest jaundice after receiving contaminated units of
blood.
99,100
They may appear healthy with normal liver
function and no pathologic sequelae, or develop acute
and/or chronic disease manifestations. Although acute
hepatitis C can resemble hepatitis A and hepatitis B clini-
cally, HCV infection often induces less hepatic inflammatory
reactions and thus usually manifests milder symptoms.
Serologic demonstration of anti-HCV often does not occur
for weeks to months after viral infection, thereby providing
a prolonged undetected period during which the patient
continues to be infectious. As occurs with HBV infection,
pathologic sequelae can occur in persons who have chronic
HCV infection, often with life-threatening ramifications.
Unfortunately, as many as 50% of long-term chronic hepati-
tis C cases may progress to chronic hepatitis C liver disease.
This develops far more often than the 5 to 10% carrier rate
observed with HBV infection. Persons with chronic hepati-
tis C can present with few initial clinical manifestations of
liver disease and remain so as inactive viral carriers, or per-
sistent viral infection can predispose a person later to
increased risk for hepatic failure and hepatocellular carci-
noma.
101
Patients with pre-existent immunosuppressive
conditions, such as those with HIV infection and others
undergoing kidney or liver transplantation, also have been
found to have higher hepatitis C morbidity. Transmission
here is most probably due to the patients potential to expe-
rience frequent parenteral exposure to HCV via blood trans-
fusion or intravenous drug use. High-risk sexual activity
may also be a factor.
At the present time, the demonstration and characteriza-
tion of a protective host immune response against HCV have
not been accomplished. Presence of anti-HCV in a persons
blood does not distinguish between cases of acute or chronic
hepatitis C, nor can a positive test for this immunoglobulin
discriminate between a person who has recovered from infec-
tion with natural active immunity from one who has devel-
oped chronic hepatitis C.
OCCUPATIONAL RISKS TO HEALTH CARE PROFESSIONALS
Health care workers are at risk for exposure to patient blood
and possible subsequent infection from bloodborne diseases,
such as those caused by members of the hepatitis virus group.
Early observation that a form of NANBH has a bloodborne eti-
ology spurred intense occupational-risk investigations by clin-
ical scientists. Accidental injuries from contaminated sharps
have been associated with resulting onset of both hepatitis B
and hepatitis C. Information describing occupational HCV
transmission in hospital settings was investigated and pub-
lished even before cloning of the virus was accomplished.
Multiple investigations documented HCV transmission to
health care workers and to other patients following percuta-
neous accidents involving blood (Table 20-14).
102106
TABLE 20-13 Tests for Hepatitis C Virus Infection
Test/Type Applications Comments
Hepatitis C virus antibody (anti-HCV) Indicates past or present infection but does Sensitivity 97%
EIA (enzyme immunoassay); not differentiate between acute, chronic, EIA alone has low positive-predictive value in low-
supplemental assay (ie, recombinant or resolved infection prevalence populations
immunoblot assay [RIBA]) All positive EIA results should be veried
with supplemental assay
HCV RNA (hepatitis C virus ribonucleic acid) Detect presence of circulating HCV RNA Detect virus as early as 12 wk after exposure
Qualitative tests *
: reverse transcriptase Monitor patients on antiviral therapy Detection of HCV RNA during course of infection might
polymerase chain reaction (RT-PCR) be intermittent; single negative RT-PCR is not conclusive
amplication of HCV RNA by in-house False-positive and false-negative results might occur
or commercial assays (eg, Amplicor HCV)
Quantitative tests *
:
RT-PCR amplication Determine concentration of HCV RNA Less sensitive than qualitative RT-PCR
of HCV RNA by in-house or commercial Might be useful for assessing the likelihood of Should not be used to exclude the diagnosis of HCV
assays (eg, Amplicor HCV Monitor) response to antiviral therapy infection or to determine treatment end point
Branched-chain DNA (bDNA) assays
(eg, Quantiplex HCV RNA Assay)
Genotype *
: several methodologies available Group isolates of HCV on the basis ofgenetic Genotype 1 (subtypes 1a and 1b) most common in United
(eg, hybridization, sequencing) differences into 6 genotypes and > 90 subtypes States and associated with lower response to
With new therapies, length of treatment antiviral therapy
might vary based on genotype
Serotype*: EIA based on immunoreactivity No clinical utility Cannot distinguish between subtypes
to synthetic peptides (eg, Murex HCV Dual infections often observed
Serotyping 16 Assay)
DNA = deoxyribonucleic acid; HCV = hepatitis C virus.
*Currently not approved by US Food and Drug Administration; lack standardization.
Samples require special handling (eg, serum must be separated within 24 h of collection and stored frozen [-20
C or -70
C]; frozen samples should be shipped on dry ice).

Relatively few studies have looked at HCV transmission in
dental treatment facilities. Initial reports showed oral surgeons
had a significantly higher incidence of positive anti-HCV
results than did general dentists and the general population,
owing to greater potential exposures to blood.
107
These and
other data have been summarized by Cleveland and col-
leagues.
108
When taken together, accumulated ndings suggest
that although hepatitis C remains a bloodborne infection of
occupational concern, the long-term application of universal
infection-control precautions targeting HBV as the most infec-
tious bloodborne pathogen has signicantly lowered the den-
tal providers risks for contracting HCV infection.
The most hazardous type of exposure that can increase the
possibility of HCV acquisition is an on-the-job needlestick
injury. A second primary characteristic of HCV risks to health
care workers is related to the virus life cycle and the titers of
infectious particles in blood. HCV is present in concentra-
tions ranging from only a few virions to 100,000 or more par-
ticles per milliliter of a patients blood. Although this re-
inforces HCVs position as being a greater occupational
infectious risk than HIV, the concentrations fall far below those
routinely seen in HBV-infected persons. Thus, the substantially
lower HCV titer in blood offers less opportunity for occupa-
tional transmission per exposure incident. Table 20-15 puts
this into perspective by summarizing potential transmission
risks to health care workers for HBV, HIV, and HCV, by com-
paring viral concentrations found in blood and calculated
infection rates following needlestick accidents.
109
Infection control precautions against bloodborne disease
have correctly focused on prevention of hepatitis B transmis-
sion in health care facilities, in large part because of the high
HBV concentrations that can be reached in the blood of
infected patients and the high potential of infection after expo-
sure to certain contaminated body fluids. With regard to
hepatitis C, sizable volumes of HCV-contaminated blood, such
as those used for blood transfusion, can readily cause infection.
Despite apparent lower risks from sharps, however, HCV infec-
tion carries with it the increased possibility of chronic liver dis-
ease. The progression from persistent viral infection to either
hepatic cirrhosis in about one-quarter of infected persons or
to hepatocellular carcinoma in others presents real challenges
to infection control for care providers.
HCV THERAPY AND PREVENTIVE APPROACHES
Preliminary studies began appearing in the literature in the mid-
1980s that suggested that a prolonged course of therapy with
interferon- could have beneficial effects for persons with
chronic hepatitis C.
110,111
These beneficial effects occurred
rapidly during therapy, with alanine aminotransferase (ALT) lev-
els eventually falling to within the normal range. Follow-up test-
ing after completion of the regimen unfortunately found the
ALT decline to be transient in most of the patients. Later inves-
tigations involving larger numbers of HCV-infected persons led
to FDA approval of a recombinant form of this antiviral agent for
treatment of chronic hepatitis C in 1991.
112
Additional studies
have attempted to further rene therapeutic dosages and drug
regimen intervals.
113
Combination of chemotherapeutic agents has shown
promising results in recent years. Currently, a daily regimen of
interferon -2b plus ribavirin for 6 to 12 months has demon-
strated a signicant improvement in patient biochemical and
virologic responses when compared with interferon monother-
apy. Approximately 50% of treated patients have a sustained
benecial response, compared with response rates of 15 to 25%
using interferon alone.
114
Future therapies will probably
include additional multidrug approaches, such as other forms
of interferon and specic HCV enzyme inhibitors.
115
An effective vaccine for hepatitis C is not yet commercially
available. Multiple factors have hindered research efforts
directed at prophylactic strategies. Two principal factors are the
failure to dene a protective host immune response against
HCV infection, and the antigenic heterogeneity described for
different viral strains. Until scientists ascertain how host resis-
tance develops during recovery from hepatitis C, and against
what antigen(s) the immunity is directed, vaccine studies will
continue to be limited. At present, routine use of universal
precautions during patient care and anti-HCV screening of
potential blood donors appears to be successful in reducing
health care provider, patient, and public exposures.
HIV Infection
Since the early 1980s, HIV has been recognized as one of the
most devastating infectious diseases of the twentieth cen-
tury. By the end of the century, almost 60 million people
TABLE 20-14 Modes of Transmission of Hepatitis C Virus in
Health Care Settings
Accidental needlesticks
Blood splashes into eyes
Blood transfusion (incidence declining rapidly)
Association with contaminated immune globin
Organ/tissue transplantation
Infected cardiac surgeon to patients
Infected patient to anesthesia assistant to other patients
Patient to patient via colonoscope
TABLE 20-15 Risks of Transmission to Health Care Workers
Concentration/mL
Pathogen of Serum/Plasma Transmission Rate (%)*
HBV 1,000,000100,000,000 6.030.0
HCV 101,000,000 2.76.0
HIV 101,000 0.30
Adapted from Lanphear BP.
109
HBV = hepatitis B virus, HCV=hepatitis C virus; HIV = human immunodeciency
virus.
*As a result of a needlestick accident.
worldwide had been infected with the virus, and the rate of
infection continued unabated.
116
The vast majority of
exposed and at-risk individuals had no access to effective
medications to combat the virus or its associated oppor-
tunistic infections. Even in the early stage of the twenty-first
century, there are few indications that there soon will be any
effective and affordable vaccines or anti-HIV medications
available for most people afflicted by this disease. This chap-
ter explores many different aspects of HIV disease and
emphasizes oral health considerations, which impact on the
overall health of HIV-infected individuals.
EPIDEMIOLOGY
In June and July of 1981, the Centers for Disease Control pub-
lished two reports on several clusters of young homosexual
men who developed opportunistic infections that were chiey
detected in severely immunodecient individuals.
117,118
It was
not clear what caused this apparent immunodeciency, and
the disease was initially referred to as gay-related immune
deciency,or GRID.Several theories focusing on the lifestyle
of homosexual and bisexual men were put forth to explain the
cause of this illness. However, soon after, it became clear that
there were other groups in society who also developed this
rapidly evolving disease and that the cause was most probably
an infectious pathogen and not sexual preference.
119125
It became evident that nding a causative agent, develop-
ing an accurate test to detect this pathogen, and elucidating the
modes of transmission were imperative to slow down the
quickly expanding epidemic. The etiologic agent of this disease,
now termed human immunodeciency virus,was recognized
within 2 years of the rst reported cases.
126,127
Due to the severe
immunosuppression observed in affected individuals, this dis-
ease was eventually given the name acquired immunode-
ciency syndrome. The CDC quickly put a surveillance system
in place. This surveillance system was based on standard case
denitions. Due to the changing nature of this disease, the orig-
inal case denition from 1985 was expanded in 1987 and again
in 1993 to better incorporate specic illnesses in different pop-
ulations as well as reflect changes in infected individuals
immune status
128
(Table 20-16). AIDS, the stage of HIV disease
when individuals start to develop opportunistic infections or
have severe immunosuppression, is a reportable condition in all
50 states, the District of Columbia, and the US territories. At the
time of this writing, HIV infection is not a reportable condition
in all states. The number of total accumulated cases of AIDS
and the rate of AIDS in the United States are reported by the
CDC on a biannual basis
129
(Table 20-17). Although the num-
ber of total accumulated cases of AIDS changes over time, the
ranking of states and metropolitan areas remains fairly stable.
More important than the actual number of cases and rates is the
trend of change. The directions of these trends reect the course
of the HIV epidemic. Between June 1999 and June 2000, there
were an additional 42,563 persons who developed AIDS in the
United States. However, this represented a decrease of 7.6% of
new cases from 1998 to 1999. Also, the rate of AIDS per 100,000
population decreased by 8.2%. A decrease of 8.6% in new cases
among males and a decrease of 3.4% in new cases among
females were noted for the same period. Thus, even though
new cases were reported, there was a marked decrease in the rate
of new AIDS cases. Taking into consideration that there are
between 40,000 to 50,000 new HIV infections annually in the
United States, the decreasing number of AIDS cases suggests
that infected individuals are remaining healthier and that the
disease is progressing more slowly over time. Since the intro-
duction of more potent anti-HIV medications in the middle
1990s, an initial dramatic decrease in the rate of death of per-
sons with AIDS has been observed (Table 20-18).
129
However,
this trend has tapered off due to factors such as increased resis-
tance to medications and patients reaching the limits of extend-
ing survival with these medications. By the end of the 1990s, it
was estimated that there were 650,000 to 900,000 HIV-infected
persons in the United States; approximately 500,000 of these
persons were aware of their HIV infection, and an estimated
335,000 of these received medical care.
130
There are two different types of HIV: HIV-1 and HIV-2.
Both viruses cause immune deterioration and AIDS, but
HIV-2 has been associated with a more indolent course and
a less efficient transmission. The median time from infection
to AIDS has been reported to be approximately 10 years for
those infected with HIV-1 but almost 20 years for those with
HIV-2. The vast majority of HIV infections are caused by
HIV-1, except in particular geographic areas, such as the
western parts of Africa. Unless specified, HIV in this chap-
ter refers to HIV-1.
Mainly through phylogenic analyses, it has been possible
to extrapolate that HIV-1, HIV-2, and the simian immuno-
deficiency virus (SIV) may have originated from the same
source in Africa and started to separate into different viruses
in the beginning of 1900s. It is not clear when HIV was intro-
duced into the human host, but it likely happened in the 1920s
or 1930s, with a more rapid sustained spread around the mid-
1940s. The prevailing theory suggests that the human variant
of this immunodeficiency virus originated from different
types of primates. It is assumed that SIV from chimpanzees
(SIV
CPZ
) is the source of HIV-1, whereas HIV-2 originated
from monkeys, predominantly sooty mangabeys
(SIV
SM
).
131,132
The earliest reported cases of AIDS in Europe
were observed in the 1950s; approximately 10 years later, AIDS
was reported in the United States. HIV is transmitted sexually
through contaminated blood and products, and vertically
from mother to child. It is important to realize that since the
recognition of HIV disease, the modes of transmission have
not changed and are not likely to change in the future.
Although extraordinary cases of HIV transmission by other
means have been reported, they are extremely rare or are
based on faulty documentation. There has never been any
documented case of occupational transmission of HIV from
patients to dental health care workers. In one celebrated case
from 1990, an HIV-infected dentist was implicated in trans-
mitting the virus to several of his patients. Although this case
was thoroughly investigated by CDC and other agencies, how
the transmission occurred was never fully elucidated.
133
TABLE 20-16 1993 Revised Classication System for HIV Infection and Expanded Surveillance Case Denition for AIDS among
Adolescents and Adults
CD4+ T-Lymphocyte Categories
The lowest accurate CD4+ T-lymphocyte count should be used for classication purposes, even though more recent and possibly different counts may be available.
Clinical Categories
Clinical category A
Conditions:
Asymptomatic human immunodeciency virus (HIV) infection
Persistent generalized lymphadenopathy (PGL)
Acute HIV infection with accompanying illness or history of acute HIV infection
Conditions listed in category B and category C must not have occurred.
Clinical category B
Symptomatic conditions in HIV-infected adolescents or adults that are not included in clinical category C and meet at least one of the following criteria: (a) the conditions
are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; (b) the conditions are considered by physicians to have a clinical course or to
require management that is complicated by HIV infection.
Examples of, but not limited to, the following conditions:
Bacillary angiomatosis
Candidiasis, oropharyngeal (thrush)
Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Constitutional symptoms, such as fever (38.5
C) or diarrhea lasting > 1 mo

Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome
Idiopathic thrombocytopenia purpura
Listeriosis
Oral hairy leukoplakia
Pelvic inammatory disease, particular if complicated by tubo-ovarian abscess
Peripheral neuropathy
Clinical category C
Conditions:
Candidiasis of bronchi, trachea, or lung
Candidiasis, esophageal
Cervical cancer, invasive
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (> 1 mo duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy, HIV related
Herpes simplex: chronic ulcer(s) (> 1 mo duration); or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal ( > 1 mo duration)
Kaposis sarcoma
Lymphoma, Burkitts (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium-intracellulare complex or Mycobacterium kansasii, disseminated or extrapulmonary
Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
Mycobacterium, other species or unidentied species, disseminated or extrapulmonary
Pneumocystis carinii pneumonia
Pneumonia, recurrent
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis
Wasting syndrome due to HIV infection
CD4+ T Cells/mm
3
or
Clinical Categories
CD4+ Percentage A: Asymptomatic Acute HIV or PGL B: Symptomatic, no A or C Conditions C: AIDS-Indicator Conditions
500 or 29% A1 B1 C1*
200499 or 1428% A2 B2 C2*
< 200 or < 14% A3* B3* C3*
Adapted from Centers for Disease Control and Prevention.
128
* Expanded acquired immunodeciency syndrome (AIDS) surveillance case denition.
PATHOGENESIS
Early in the HIV epidemic, it was recognized that this disease
was caused by a virus that gradually destroyed a hosts immune
defenses, making virtually all infected individuals susceptible
to opportunistic infections. The particular immunodeciency
in HIV disease was attributed to CD4+ lymphocyte depletion,
enabling the development of specic opportunistic infections
that were associated with a high degree of morbidity and mor-
tality. More than 20 years after the recognition of this disease
and its causative agents, it has been possible, with the help of
improved and new molecular biologic tools and methods, to
explain in more detail the pathogenesis of HIV disease.
HIV is a retrovirus harboring its genetic information in
two copies of a single-stranded RNA. The viral genome is con-
tained within a protein core, which also contains the enzyme
reverse transcriptase. Surrounding the core particle is a lipid
membrane. Embedded within this membrane are two enve-
lope glycoproteins, gp 41 and gp 120, both essential for the
recognition and binding of target cells. These two glycopro-
teins are subunits generated by the cleavage of the gp 160 pre-
cursor. HIV targets cells expressing CD4 molecules, particu-
larly CD4+ T lymphocytes, monocytes, and macrophages,
taking advantage of the afnity between the viral gp 120 and
the cellular CD4 receptor. The binding of gp 120 to CD4 recep-
tors causes a conformational change in gp 120, which exposes
and stabilizes a cellular chemokine receptor called CCR5.
These interactions activate gp 41, resulting in fusion of the
viral membrane with the cellular membrane, which allows the
viral RNA and reverse transcriptase to enter into the target cell.
The reverse transcriptase transcribes the viral RNA into DNA,
which integrates into the target cells genome. With the suc-
cessful integration of viral DNA into the cellular genetic mate-
rial, an infection has occurred.
HIV gains entry into the body directly through the blood
or at mucosal surfaces. The virus establishes itself within lym-
phoid tissues, where it replicates, makes itself available to the
cells of the immune system (such as T lymphocytes, mono-
cytes, and macrophages), and slowly brings about destruction
of the lymphoid tissue. Mucosal surfaces have an abundance
of dendritic cells, such as Langerhans cells, that trap the virus
and enable the uptake of the virus into lymphoid aggregates
below the surface. Contact between mucosal surfaces and HIV
can result in infection of Langerhans cells after only a couple
of hours. Within a few days, the virus can be detected in
regional lymph nodes.
The rapid replication of HIV results in an initial viremia
causing seeding of the virus to lymphoid tissue throughout
the body. It is estimated that more than 10 billion virions, with
a half-life of approximately 1.6 days, are produced daily in
infected individuals.
134,135
This continuous turnover of
viruses results in one-half of the circulating viruses being
replaced with newly formed virions every day. Furthermore,
almost 2 billion CD4+ lymphocytes are destroyed and
replaced every day.
Activated CD4+ lymphocytes express high levels of
chemokine receptors and are primary targets of HIV. However,
although these activated cells usually die within a few days, a
latent reservoir of HIV is established among CD4+ cells. An
extremely high viral titer can be detected in the blood during
the primary stage of HIV infection, but, over time, infectious
virions became undetectable in the plasma. The initial control
of viral replication is associated with antibody-dependent cel-
lular cytotoxicity activity and HIV-specic cytotoxic T lym-
phocytes. However, neutralizing antibodies also develop.
TABLE 20-17 Ranking of AIDS Cases and Rates per 100,000
Population*
Area of Residence Total Cases
New York 139,248
California 117,521
Florida 78,043
Texas 52,667
New Jersey 41,245
Illinois 24,425
Puerto Rico 24,061
Pennsylvania 23,678
Georgia 22,197
Maryland 20,833
Area of Residence Rates
District of Columbia 189.4
New York 39.4
Virgin Islands, US 37.6
Florida 33.4
Maryland 27.2
Puerto Rico 26.4
Delaware 26.3
Massachusetts 24.4
New Jersey 23.6
South Carolina 20.9
Metropolitan Area of Residence Total Cases
New York, NY 117,792
Los Angeles, CA 42,394
San Francisco, CA 27,567
Miami, FL 23,521
Washington, DC 22,321
Chicago, IL 21,173
Houston, TX 18,735
Philadelphia, PA 18,348
Newark, NJ 16,739
Atlanta, GA 15,524
Metropolitan Area of Residence Rates
New York, NY 68.1
Miami, FL 58.3
Fort Lauderdale, FL 56.9
San Francisco, CA 52.6
West Palm Beach, FL 50.5
Jersey City, NJ 43.2
Newark, NJ 40.3
Columbia, SC 39.7
Baltimore, MD 35.9
Washington, DC 35.8
Adapted from Centers for Disease Control and Prevention.
129
*In the United States reported through June 2000.
Unfortunately, HIV replication is associated with a very high
mutation rate, resulting in a great genetic diversity of HIV quasi-
species in individual patients.
136
This heterogeneity increases
over time. Consequently, it is important to initiate viral sup-
pression as early as possible after infection. This will accomplish
a decrease in viral diversity, resulting in more effective immune
control and less drug resistance. Even a single nucleotide change
in the HIV-1 transcriptase gene is enough to confer high levels
of drug resistance to particular anti-HIV medications.
137
The hallmark of HIV disease is the progressive loss of
CD4+ lymphocytes. Without intervention, an average of 60 to
80 cells/mm
3
are lost every year; this loss is highly variable and
occurs in periods of more stability and rapid decline.
138
An
estimation of the plasma level of these cells (a CD4 cell count)
indicates an individuals immune status. Normal CD4 cell
counts are usually above 500 to 600 cells/mm
3
, whereas levels
below 200 cells/mm
3
are considered to indicate severe immune
suppression. The lower the CD4 cell count, the more suscep-
tible is a patient to develop opportunistic infections. As part of
the latest AIDS denition, a patient has an AIDS diagnosis
when the CD4 cell count drops below 200 cells/mm
3
(see Table
20-16). At this level the patient is at very high risk of develop-
ing specific major opportunistic infections, such as
Pneumocystis carinii pneumonia (PCP), and prophylactic
medications are administered to ward off these infections.
Although the CD4 cell count was used for many years as a
marker for HIV disease progression, other biologic indicators,
such as the level of plasma viral RNA, or viral load, have since
proven to be more reliable and accurate.
139
Today, CD4 cell
counts are mainly used to assess a patients immune status, to
determine when to institute antiretroviral medications, to
determine when to institute prophylaxis against opportunis-
tic infections, and as an indicator for AIDS. Recent advances
in molecular biology have enabled detection of HIV RNA in
plasma and within different tissues.
140
The most common
method used for clinical HIV care is reverse transcription cou-
pled to the polymerase chain reaction (RT-PCR). This method
uses a PCR-based assay to assess the presence, as well as mea-
sure the quantity, of HIV RNA. Numerous retrospective stud-
ies have determined the progression of HIV disease, as well as
the prognosis, based on the quantity of plasma HIV-1 RNA
139
(Table 20-19). Many of these studies show surprising consis-
tency.
141144
According to these studies, the risk for disease
progression and death is reduced by 30% when the viral load
is halved, by 55% with a four-fold reduction in viral load, and
by 65% with a 10-fold reduction in viral load.
As viral load signicantly corresponds with changes in dis-
ease progression, this measure has also been used to assess
efcacy of antiretroviral medications.
145
Effective drug therapy
is reected in reduced viral loads; no or little viral load change
suggests less effective therapy. This association has created new
standards of care for patients with HIV. Acute HIV infection
occurs 2 to 6 weeks after exposure. During the acute stage of
the disease, affected individuals develop high plasma levels of
the virus. An antibody response can only be detected approx-
imately 2 to 3 months after exposure. Twenty to 90% of
exposed individuals develop a self-limited nonspecic illness
characterized by fever, lymphadenopathy, myalgia, arthralgia,
sore throat, and occasional rashes and oral ulcerations. This ill-
ness has sometimes been described as a mononucleosis-like
syndrome and is referred to as the acute seroconversion syn-
drome or acute retroviral syndrome. Identication of indi-
viduals at this stage of the disease is important for several rea-
sons. Of primary importance is the potential for further
transmission. As affected individuals have very high viral loads,
they are highly infectious and can unwittingly transmit the
virus to unsuspected partners.
146
There is epidemiologic evi-
dence that suggests that recently infected individuals are
responsible for a high percentage of transmissions.
147
Evaluation of individuals during the acute retroviral syndrome
needs to include both a virologic test and an antibody test. A
positive HIV RNA test, together with a negative HIV-antibody
test, is diagnostic for primary HIV infection. Due to the pos-
sible false-positive result from an HIV RNA PCR-based assay,
a true positive result is considered when the viral load is above
100,000 copies/mL. Results below 5,000 copies/mL are more
likely to be false-positive than true positive.
148
Another benet of early recognition of HIV infection is the
potential to achieve viral suppression during this stage of the
disease. This may facilitate a more effective immune response
and diminish viral diversity. Institution of antiretroviral ther-
apy during this stage of the disease has been shown to enhance
the immune systems ability to destroy infected cells and to
diminish CD4 cell depletion.
149151
After the acute retroviral syndrome, most individuals
remain asymptomatic for many years. However, the deterio-
rating immune system eventually gives way, and opportunis-
tic infections develop. Without treatment, the median time
from primary infection to AIDS is approximately 10 years.
152
In most industrialized countries, individuals with HIV
have access to antiretroviral therapy. Consequently, the epi-
demiology of HIV disease has changed dramatically since the
mid-1990s. At that point, new and more potent antitretrovi-
ral medications were introduced that decreased the incidence
of opportunistic infections and death rate
153
(see Tables 20-
18 and 20-20). Unfortunately, the rate of decline in the inci-
TABLE 20-18 Estimated Deaths and Rate of Change of Death of Persons with AIDS, in the United States
Measure 1993 1994 1995 1996 1997 1998 1999
Estimated number of deaths 45,381 49,869 50,610 37,787 21,923 17,930 16,273
Change (%) +9.9 +1.5 25.3 42.0 18.2 9.2
dence of opportunistic infections, AIDS incidence, and AIDS-
related deaths has slowed down. These latest trends are most
probably related to the development of resistance to anti-
retroviral drugs, transmission of HIV-resistant strains, and
the inability to maintain complete viral suppression for
extended periods of time in all individuals. Furthermore, sev-
eral new opportunistic syndromes have been described in
patients given antiretroviral medications.
154
It is possible that
this phenomenon, termed reversal syndromes, is due to a
rebounding immune system that initially does not have the
same antigenic divergence as developing nave CD4+ lym-
phocytes. This immune dysfunction may facilitate the devel-
opment of latent opportunistic infections or unmask an undi-
agnosed opportunistic infection.
Apparently, not all individuals exposed to HIV become
infected. Furthermore, the rate of HIV disease progression in
individuals is highly variable. Some infected persons may
progress from infection to AIDS within months, whereas oth-
ers have no signs of opportunistic infections or immune sup-
pression even after 15 to 20 years. Approximately 10% of HIV-
infected persons progress to AIDS within the 2 to 3 years after
infection, whereas 10 to 17% of infected individuals may not
develop AIDS even 20 years after infection.
155
Obviously, these
subgroups of infected persons are of great interest, as they
may provide invaluable information regarding the variables
associated with infection, progression, and even immunity to
HIV, and subsequent treatment.
Numerous studies have focused on the ability and inability
of HIV to enter into target cells, and the capability of the
immune system to rid the body of the virus. During the earli-
est stages of HIV infection, the virus particularly seeks out and
infects macrophages and memory T lymphocytes, using, in
addition to these cells CD4 receptors, the cells chemokine
receptors. The chemokine receptor used in these cells as a co-
receptor for HIV is CCR5. At this stage of the disease it is com-
mon that the virus is referred to as macrophage-tropic,or M-
tropic. M-tropic viruses do not have the ability to form
syncytia in vitro; they are therefore also referred to as nonsyn-
cytia-inducing isolates.In addition, due to the viruss predilec-
tion for cells expressing CCR5, the virus is referred to as an R5
isolate. Investigations of chemokine receptors have indicated
that individuals with a homozygous mutation of CCR5 may be
almost completely resistant to HIV. This specic mutation has
been referred to as CCR5 32, indicating a characteristic 32
base-pair deletion in the gene encoding CCR5. Individuals with
a heterozygous mutation of CCR5 32, one normal and one
altered allele, tend to progress more slowly to AIDS and live
longer than individuals without this mutation.
156,157
Furthermore, a promoter mutation in CCR5 has also been
associated with a slower progression to AIDS.
158
Interestingly,
persons harboring these chemokine receptor changes do not
exhibit any pathologic effects due to these polymorphisms.
Unfortunately, very few individuals, approximately 1% of
Caucasians, exhibit homozygous deletion of the 32 base pair;
10% are heterozygotes. CCR5 32 is rare among Africans,
Native Americans, and East Asians.
All chemokine receptors have natural ligands, cytokines
that bind to the receptor. Three main cytokines have been
identied that bind to and block the CCR5 receptor: MIP-1-
, MIP-1- and RANTES. Interestingly, these cytokines are
generated by CD8+ T lymphocytes, which are cells that have
been implicated in releasing factors suppressing HIV infec-
tion.
159
Selective blockage of CCR5 with these cytokines has
been shown to occur.
During the later stages of HIV disease, the virus predomi-
nantly infects T lymphocytes expressing CD4 receptors and a
chemokine co-receptor designated CXCR4. These T-tropic
viruses can cause multinucleated syncytia formation in vitro
and are therefore referred to as syncytia-inducing isolates
and X4 isolates. The use of the CXCR4 receptor by HIV is
associated with a more rapid depletion of CD4+ T lympho-
cytes and disease progression.
160
Chemokines SDF-1- and
SDF-1- have been identied as ligands to CXCR4 and can
selectively inhibit T-tropic HIV-1 strains.
TABLE 20-19 Prediction of Immune Deterioration, HIV Disease Progression, and AIDS by HIV-1 RNA
Decrease in Yearly Individuals Developing AIDS Individuals Dying
HIV-1 RNA Copies/mL CD4+ Cell Count/mm
3
Within 6 Years (%) Within 6 Years (%)
< 500 36.3 5.4 0.9
5013,000 44.8 16.6 6.3
3,00110,000 55.2 31.7 18.1
10,00130,000 64.8 55.2 34.9
> 30,000 76.5 80.0 69.5
Adapted from Cofn JM.
136
AIDS = acquired immunodeciency syndrome; HIV-1 = human immunodeciency virus type 1; RNA = ribonucleic acid.
TABLE 20-20 Decrease in Rate of Opportunistic Infections in
HIV-Positive Individuals
Rate of Decrease
Disease 19921995 19961998
Pneumocystis carinii pneumonia 3.4 21.5
Mycobacterium avium-intracellulare complex 4.7 39.9
Esophageal candidiasis 0.2 16.7
Adapted from Kaplan JE et al.
153
Use of these chemokine receptors is not exclusive, and
about 40% of HIV-positive individuals use CXCR4 instead of,
and sometimes in addition to, CCR5.
161
These viral isolates
are referred to as R5X4. Unfortunately, several other
chemokine receptors are involved in HIVs selection of target
cells, increasing the complexity of all HIVtarget cell interac-
tions (Table 20-21).
161163
MEDICAL TREATMENT
A better understanding of the pathogenesis of HIV disease has,
in recent years, changed many of the treatment paradigms for
infected individuals during the course of their illness. The
recognition that there exist different individual responses to
HIV infection, and even resistance, has provided clues to inter-
vention strategies based on more accurate predictions of disease
progression. Furthermore, better knowledge of the mechanisms
for viral entry into target cells, integration, transcription, and
subsequent viral replication has enabled a more varied and
focused treatment strategy. Although the mainstay of HIV ther-
apy is based on trying to slow down viral replication with anti-
retroviral medications, an important part of treatment for
patients with HIV disease is also the prevention and treatment
of opportunistic infections. HIV-infected individuals therefore
take many different medications, some which impact on oral
health and provision of dental care (Table 20-22).
The rst antiretroviral drug was introduced in 1997. This
medication, AZT or zidovudine (ZDV), belongs to a group of
medications called nucleoside reverse transcriptase inhibitors
(NRTIs). These medications competitively inhibit the reverse
transcriptase from converting the viral RNA into viral DNA.
Other nucleoside analogues are abacavir (ABC), didanosine
(ddI), lamivudine (3TC), stavudine (d4T), and zalcitabine
(ddC). A similar group of medications that also inhibits reverse
transcriptase is the non-nucleoside reverse transcriptase
inhibitors (NNRTIs). NNRTIs include efavirenz (EFV),
delaviridine (DLV), and nevirapine (NVP). In the mid-1990s,
a new class of antiretroviral medications was introduced
protease inhibitors. These powerful medications prevent the
breakdown of viral proteins into appropriate building blocks
for viral replication. Included in these medications are ampre-
navir (APV), indinavir (IDV), nelfinavir (NFV), ritonavir
(RTV), and saquinavir (SQV). Due to the high level of toxic-
ity and the rapid development of drug resistance, antiretrovi-
ral medications are given as double or triple therapy. This
combination therapy is referred to as highly active antiretro-
viral therapy, or HAART. Antiretroviral therapy is usually insti-
tuted when a patients CD4 cell count drops below a critical
value and/or when a patients viral load exceeds a critical level.
These predetermined values vary as better scientic informa-
tion regarding the pathogenesis of HIV disease is elucidated
and depending on how patients react and respond to new and
better combinations of medications.
Prophylaxis against opportunistic infections is instituted
according to a patients immune status. Usually patients with
CD4 cell counts below 200 cells/mm
3
are considered for pro-
phylaxis to prevent Pneumocystis carinii pneumonia, and, at
even lower levels, prophylaxis is instituted against various fun-
gal and mycobacterial infections. Knowledge about the type of
medications used to treat and prevent opportunistic infec-
tions helps the dental provider to attain additional insight into
a patients health status.
ORAL HEALTH CONSIDERATIONS
Oral health considerations for persons infected with HIV focus
on provision of dental care and oral conditions associated with
their underlying disease.
164166
An appropriate work-up for an
HIV-infected patient needs to ascertain a patients overall
health, immune status, prognosis, presence and history of
opportunistic infections, risk for developing more severe
opportunistic infections and oral lesions, current medications,
and chance for long-term survival (Figure 20-7). The patient
may be able to provide all necessary information, but it is
appropriate to have the patient sign a consent form that
enables the provider to obtain more medical information from
the patients primary care physician (Figure 20-8).
As a general rule, no dental modications are required for
patients based on their HIV status. Most individuals present-
ing for outpatient dental care are sufciently healthy to toler-
ate all types of dental procedures, ranging from scaling to
implants.
167
Also, numerous studies have indicated that
patients with HIV disease are not more susceptible to compli-
cations after dental care, regardless of CD4 cell count.
168,169
As with other medically complex patients, the major con-
cerns are impaired hemostasis, susceptibility to dentally
induced infections, drug actions and interactions, and the
patients ability to withstand the stress and trauma of dental
procedures. Few patients present with increased bleeding ten-
dencies, unless they have concomitant liver disease or idio-
pathic thrombocytopenic purpura.
170
Even when patients
CD4 cell counts are very low, they are not more susceptible to
dentally induced bacteremia. Thus, there are no indications for
routine use of antibiotic prophylaxis based on patients HIV
status. However, patients with neutrophil counts below 500 to
750 cells/mm
3
require antibiotic prophylaxis. Furthermore,
some patients may be at an increased risk for developing sub-
TABLE 20-21 Characteristics of Individuals with Slow Disease
Progression
Attenuated virus
Reduced replication kinetics
Low viral load
Effective cellular immune response
Strong HIV-1specic cytotoxic T lymphocytes
Effective antibody-dependent cellular cytotoxicity
Increased levels of CD8+ T lymphocytes
Increased divergence of the CD4+ T-lymphocyte repertoire, possibly due to
exposure to greater viral diversity
Polymorphisms and inhibition/blockage of chemokine receptors
Homozygote CCR5- 32 genotype
Heterozygote CCR5- 32 genotype
Inhibition/blockage by MIP-1-, MIP-1-, RANTES generated by CD8+ T cells
Data from Berger EA et al;
161
Learmont J et al;
162
Klein MR et al.
163
TABLE 20-22 Impact of Treatments for HIV Infection
Drug Name* Type of Drug Adverse Effects of Signicance for Dentists Co.
(+)-calanolide A* NNRTI Dysgeusia 12

3TC or lamivudine, Epivir; also NRTI Peripheral neuropathy 9
in Combivir and Trizivir
Abacavir (ABC), Ziagen; NRTI Associated with liver damage 9
also in Trizivir
ABC, see abacavir
AG1661* or HIV-1 Immunogen* IBT Not known 2
or Salk vaccine*, Remune*
Agenerase, see amprenavir
Aldesleukin or interleukin-2 IBT Not known 6
(IL-2), Proleukin
Amprenavir (APV), Agenerase PI Associated with hyperglycemia, dygeusia, and paraoral tingling sensations 9
Do not use with the following medications: midazolam, triazolam,
ergotamine, tricyclic antidepressants, vitamin E
Avoid use with the following medications: erythromycin, benzodiazepine,
or itraconazole
APV, see amprenavir
AZT or zidovudine, Retrovir; NRTI Associated with seizures, rapid, uncontrollable eye movements, decreased 9
also in Combivir and Trizivir coordination, liver damage, and peripheral neuropathy
BCH-10652* or dOTC* NRTI None 3
Bis(POC) PMPA*, see tenofovir
disoproxil fumarate*
BMS-232632* PI Not known 5
Capravirine* (CPV) NNRTI Dysgeusia 2
Coactinon*, see emivirine*
Combivir combination of NRTI Associated with liver damage and peripheral neuropathy 9
zidovudine + lamivudine
Coviracil*, see emtricitabine*
and FTC*
CPV*, see capravirine*
Crixivan, see indinavir
d4T or stavudine, Zerit NRTI Peripheral neuropathy 5
DAPD* NRTI Not known 13
ddC or zalcitabine, Hivid NRTI Associated with oral ulcerations, liver damage, and peripheral neuropathy 11
ddI or didanosine, Videx or Videx NRTI Associated with xerostomia, liver damage, and peripheral neuropathy 5
EC (delayed-release capsules) Do not take the following medications within 2 hours of ddI: tetracycline,
doxycycline, minocycline, and ciprooxacin
Take the following medications at least 2 hours before ddI: ketoconazole
and itraconazole
Delaviridine (DLV), Drescriptor NNRTI Do not use with orange and cranberry juice 2
Do not use with the following medications: clarithromycin, dapsone,
ergotamine, alprazolam, midazolam, triazolam, carbamazepine,
phenobarbital, and cimetidine
Didanosine, see ddI
DLV, see delaviridine
DMP-450* PI Not known 13
DOTC* or BCH-10652* NRTI Not known 3
Drescriptor, see delavirdine
Droxia, see hydroxyurea
Efavirenz (EFV), Sustiva NNRTI Associated with confusion, abnormal behavior, or hallucinations 7
Do not use together with the following medications: midazolam and triazolam
Continued
EFV, see efavirenz
Emivirine* (EMV), Coactinon* NNRTI Not known 13
Emtricitabine* or FTC*, Coviracil* NNRTI Not known 13
EMV*, see emivirine*
Epivir, see lamivudine or 3TC
Fortovase, see saquinavir (soft gel cap) PI 11
FTC*, see emtricitabine*
GW-420867X* NNRTI Not known 9
GW-433908* or VX-175* PI Associated with hyperglycemia, dysgeusia, and paraoral tingling sensations 9
Do not use with the following medications: midazolam, triazolam, ergotamine,
tricyclic antidepressants, or vitamin E
Avoid use together with the following medications: erythromycin,
benzodiazepine, or itraconazole
HIV-1 Immunogen* or Salk IBT Not known 2
vaccine* or AG1661*Remune*
Hivid, see zalcitabine or ddC
HU, see hydroxyurea
Hydroxyurea (HU), Droxia CI Oral ulcerations; associated with bleeding and bruising 5
IDV, see indinavir
Indinavir (IDV), Crixivan PI Do not use with the following medications: midazolam, triazolam, or ergotamine 10
Avoid use with the following medications: ketoconazole and dexamethasone
Interleukin-2 (IL-2), or IBT Not known 6
aldesleukin, Proleukin
Invirase, see saquinavir (hard gel cap)
Kaletra, see lopinavir + ritonavir
Lamivudine or 3TC, Epivir; also NRTI Peripheral neuropathy 9
in Combivir and Trizivir
Lopinavir + ritonavir, Kaletra PI Associated with hyperglycemia 1
Do not use with the following medications: midazolam or triazolam
Avoid use with metronidazole
Nelnavir (NFV), Viracept PI Do not use with the following medications: midazolam, triazolam, or ergotamine 2
Nevirapine (NVP), Viramune NNRTI Associated with liver damage 4
NFV, see nelnavir
Norvir, see ritonavir
NVP, see nevirapine
PNU-140690* or tipranavir* PI Not known 4
Proleukin, see aldesleukin or
interleukin-2
Remune,* see HIV-1 Immunogen*
or Salk vaccine* or AG1661*
Retrovir, see zidovudine
Ritonavir (RTV), Norvir; also PI Do not use with the following medications: ergotamine, diazepam, midazolam, 1
in Kaletra triazolam, meperidine, piroxicam, or propoxyphene
Avoid use with the following medications: phenobarbital, dexamethasone,
or metronidazole
RTV, see ritonavir
Salk vaccine* or HIV-1 Immunogen* IBT Not known 2
or AG1661*, Remune*
Saquinavir (SQV) (HGC) PI Associated with liver damage, peripheral neuropathy, and oral ulcerations 11
(hard gel cap), Invirase Do not use with the following medications: midazolam, triazolam, or ergotamine
Avoid use with the following medications: clarithromycin, phenobarbital,
carbamazepine, dexamethasone, ketoconazole, itraconazole, or clindamycin
Continued
TABLE 20-22 Impact of Treatments for HIV Infection (Continued)

acute bacterial endocarditis if they are former intravenous
drug users.
171
Most side effects from medications used to treat HIV dis-
ease are associated with xerostomia. Drug interactions with
medications commonly used in a dental setting also exist (see
Table 20-22). Patients with HIV disease have been shown to
survive longer and are therefore more susceptible to develop
complications, particularly from drug side effects. A trend sug-
gesting increased frequency of cardiovascular disease has been
noticed and should be considered in patients who have taken
protease inhibitors for long periods of time.
Treatment planning for HIV-positive patients needs to
address numerous considerations. The vast majority of
patients have some degree of xerostomia, ranging from very
mild to severe. Thus, when performing simple restorative pro-
cedures or fabricating xed or removable prosthodontics, the
type of restorative material, long-term use, and maintenance
of a restoration need to be taken into consideration.
ORAL LESIONS
There are no oral lesions that are unique to HIV-infected indi-
viduals. All lesions found among HIV-positive patients also
occur with other diseases associated with immune suppres-
sion. It is therefore not surprising to nd a clear correlation
between the appearance of oral lesions and a decreased
immune system. Several lesions such as oral candidiasis, oral
hairy leukoplakia, necrotizing ulcerative periodontal disease,
and Kaposis sarcoma are strongly suggestive of impaired
immune response with CD4 cell counts below 200
cells/mm
3
.
172174
Using oral lesions for markers of immune
Saquinavir (SQV) (SGC) PI Associated with liver damage, peripheral neuropathy, and oral ulcerations 11
(soft gel cap), Fortovase Do not use with the following medications: midazolam, triazolam, or ergotamine
Avoid use with the following medications: clarithromycin, phenobarbital, carbamazepine
dexamethasone, ketoconazole, itraconazole, or clindamycin
SQV, see saquinavir
Stavudine or d4T, Zerit NRTI Peripheral neuropathy 5
Sustiva, see efavirenz
T-20* EI Not known 14
TDF*, see tenofovir disoproxil
fumarate*
Tenofovir disoproxil fumarate* NtRTI Not known 8
(TDF)
Tipranavir* or PNU-140690* PI Not known 4
Trizivir, see abacavir + zidovudine
+lamivudine
Videx, see didanosine or ddI
Videx EC, see didanosine or ddI
Viracept, see nelnavir
Viramune, see nevirapine
SVX-175* or GW-433908* PI Associated with hyperglycemia, dygeusia, and paraoral tingling sensations 9
Do not use with the following medications: midazolam, triazolam, ergotamine,
tricyclic antidepressants, or vitamin E
Avoid use with the following medications: erythromycin, benzodiazepine,
or itraconazole
Zalcitabine or ddC, Hivid NRTI Associated with oral ulcerations, liver damage, and peripheral neuropathy 11
ZDV, see zidovudine
Zerit, see stavudine or d4T
Ziagen, see abacavir
Zidovudine (ZDV) or AZT,
Retrovir; also in Combivir NRTI Associated with seizures, rapid uncontrollable eye movements, decreased 9
and Trizivir coordination, liver damage, and peripheral neuropathy
CI = cellular inhibitor; EI = entry inhibitor (also fusion inhibitor); IBT = immune-based therapy; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside
reverse transcriptase inhibitor; NtRTI = nucleotide reverse transcriptase inhibitor; PI = protease inhibitor.
*Drug not approved by US Food and Drug Administration.
Pharmaceutical companies: 1-Abbott Laboratories; 2-Agouron Pharmaceuticals; 3-BioChem Pharma; 4-Boehringer Ingelheim ; 5-Bristol-Myers Squibb; 6-Chiron Corporation;
7-DuPont Pharmaceuticals; 8-Gilead Sciences; 9-Glaxo Wellcome; 10-Merck & Co.; 11-Roche Laboratories; 12-Sarawak Medichem; 13-Triangle Pharmaceuticals; 14- Trimeris.
TABLE 20-22 Impact of Treatments for HIV Infection (Continued)

suppression and HIV disease progression is important and
can impact on medical intervention and treatment strategies.
T-lymphocyte depletion renders affected individuals more
susceptible to fungal infections, viral infections, and neoplas-
tic growth. Some immune surveillance is also diminished,
enabling bacterial infections to ourish. Thus, it is not sur-
prising to nd oral infections of these types in patients with
HIV disease.
Fungal Infections. Candidiasis. Intraoral candidia-
sis,
175,176
which is mainly caused by Candida albicans, is the
most common oral manifestation in patients with HIV dis-
ease. Although it is not in itself pathognomonic for HIV dis-
ease, oral candidiasis may be an indication of immune dete-
FIGURE 20-7 HIV-relevant history questionnaire.
Date:
Personal and demographic data (including other care providers):
Chief complaint:
History of chief complaint:
Past medical history (including last visit to primary care provider):
HIV test with dates:
First HIV test
Last negative HIV test
First positive HIV test
Reason for HIV test:
Risk factor(s) for HIV:
History of HIV disease (illnesses, signs and symptoms):
CD4 cell count with dates:
Initial count
Lowest count
Latest count
Viral load and dates:
Highest rate
Lowest rate
Latest rate
Complete blood cell count with a differential:
Medications with dosage and schedules:
Antiretrovirals
Anti-infectives
Other
Allergies and drug sensitivity:
Hepatitis (type and status):
Sexually transmitted diseases (type and status):
Tuberculosis (date of test[s] and present status):
Tobacco use (history and present status):
Alcohol use (history and present status):
Recreational drug use (history and present status):
Name and address of person permitted to disclose information:
...............................................................................................................................
...............................................................................................................................
Name and address of individual or organization to which the disclosure is to
be made:
...............................................................................................................................
...............................................................................................................................
Name and address of patient:
...............................................................................................................................
...............................................................................................................................
Purpose of disclosure:
...............................................................................................................................
...............................................................................................................................
Information to be disclosed:
...............................................................................................................................
...............................................................................................................................
I, ........................................................, hereby give my permission for the above
mentioned individual and/or organization/hospital/clinic/laboratory to disclose
pertinent medical records to the individual/organization listed above.
I further understand that I may revoke this consent at anytime. Unless revoked
earlier by me, this consent expires .........................................................................
Patient signature: ..................................................... Date...................................
Witness signature: ................................................... Date...................................
FIGURE 20-8 Consent for transmittal of HIV-related information.
rioration.
177
A tentative diagnosis of oral candidiasis is usu-
ally based on clinical appearance but should be conrmed by
laboratory tests. These tests include cytologic smears with
potassium hydroxide, biopsy for periodic acidSchiff and
Gram staining for tissue inltration by spores and hyphae, or
culture.
178
In general, oral candidiasis has four different clin-
ical presentations, as follows:
1. Pseudomembranous candidiasis, or thrush. This con-
dition is a common type of oral candidiasis. It manifests
as white or yellowish single or conuent plaques that
can easily be rubbed off from the oral mucosa (Figure
20-9). It is found on all oral surfaces and may leave an
erythematous or even bleeding underlying mucosa.
Most patients are not aware of the presence of this form
of candidiasis as pseudomembranous candidiasis is
predominantly asymptomatic. The condition is noticed
most commonly when CD4 cells counts drop below
400 cells/mm
3
.
2. Erythematous or atrophic candidiasis. This condi-
tion appears on any mucosal surface as a reddish
macular lesion, atrophic patches, or depapillation on
the dorsum of tongue (Figure 20-10). Erythematous
candidiasis may be present alone or in combination
with the pseudomembranous type. Patients may
complain of an occasional burning sensation in the
mouth. Long-standing lesions may even present as
mucosal ulcerations.
3. Hyperplastic or chronic candidiasis. This form of can-
didiasis is relatively uncommon and is found mainly in
persons who are severely immunocompromised.
Hyperplastic candidiasis, manifesting as white or dis-
colored plaques that may be solitary or conuent and
cannot be wiped off the mucosa, may be confused with
oral hairy leukoplakia when located on the tongue only
(Figure 20-11). Complaints of a burning sensation, dys-
phagia, and a feeling of having a large piece of cotton
in the mouth are not unusual. This type of oral can-
didiasis is often present with esophageal candidiasis.
4. Angular cheilitis. This condition, which is predomi-
nantly a mixed infection involving C. albicans and
Staphyloccocus aureus, manifests itself as red ssures
originating from the labial commissures of the mouth
(Figure 20-12). Angular cheilitis may be present with
intraoral candidiasis. Concurrent oral dryness also is
not uncommon. Angular cheilitis has been associated
with vitamin B deficiency and decreased vertical
dimension of occlusion from either periodontal dis-
ease or ill-tting dentures. Therefore, it is important to
address concurrent conditions as antifungal treatment
is instituted.
FIGURE 20-9 Pseudomembranous candidiasis (thrush) on the hard
and soft palate in a patient with HIV disease. These white plaques can be
wiped off, leaving an erythematous mucosa.
FIGURE 20-10 Erythematous or atrophic candidiasis on the hard
palate. These erythematous lesions are usually asymptomatic.
FIGURE 20-11 Hyperplastic or chronic candidiasis on the soft and
hard palate of a severely debilitated HIV-infected patient. These lesions can-
not be wiped off and do not respond well to topical antifungal medications.
This type of candidiasis is almost exclusively seen in patients with extremely
low CD4 cell counts and diminished salivary ow.
Treatment of oral candidiasis includes topical and systemic
antifungal medications. Appropriate treatment should be insti-
tuted to reduce symptoms ranging from localized discomfort
to significant dysphagia. Topical therapies include mouth
rinses, troches, ointments, and creams. These formulations
should be used concurrently with systemic agents to resolve the
infection when there is a risk of esophageal candidiasis. Since
there is a high sucrose content in these preparations, which
predisposes patients to develop dental caries, a strict oral
hygiene program and daily ouride treatment should be insti-
tuted while the patient is taking topical antifungal medica-
tions. Topical antifungal therapies are most efficacious in
patients with CD4 counts above 150 to 200 cells/mm
3
. In
patients with atrophic candidiasis, troches should be used with
care since they may aggravate existing ulcerations through
mechanical abrasion against the lesions.
179
Common topical treatments include nystatin oral suspen-
sion (100,000 units/mL; 10 mL swished and swallowed four to
ve times per day) and nystatin troche (dissolved in the mouth
four to ve times per day). Ointments and creams such as 1%
clotrimazole ointment, 2% ketoconazole cream, or nystatin
cream are efcacious in treating angular cheilitis.
The efcacy of systemic antifungal medications may be
signicantly reduced by impaired gastric acid secretion and by
drug interactions with medications such as rifampin.
Furthermore, there exists a potential for liver toxicity that
needs to be addressed. Common systemic antifungals include
ketoconazole (200 mg tablets; one tablet twice a day with
food), uconazole (100 mg tablets; 200 mg on day 1, followed
by 100 mg daily for 14 days),
4
and itraconazole (100 mg tablets;
200 mg daily with food). Resistance to uconazole has been
reported to occur in patients with severe immune deciency.
Treatment of patients who are resistant to uconazole with a
combination of uconazole and terbinane has been success-
ful.
180
It is also possible to increase the uconazole dosage to
600 to 700 mg/d in order to improve efficacy. Another
approach to treat uconazole-resistant fungal infections is to
add a topical medication such as clotrimazole troches. This is
successful if the resistance is owing to the emergence of
Candida krusei, a species resistant to uconazole but suscep-
tible to clotrimazole. Protease inhibitor therapy has been asso-
ciated with a decreased incidence of oral candidiasis.
177,181
This is owing mainly to improved immune status but may
also be a direct result of the protease inhibitors.
Deep-Seated Infections. Intraoral manifestations of deep-
seated fungal infections, caused by Cryptococcus neoformans,
Histoplasma capsulatum, Geotrichum candidum, and
Aspergillus spp, are uncommon and are usually an indication
of a disseminated disease.
182,183
Intraoral lesions associated
with cryptococcosis, histoplasmosis, and aspergillosis have
been reported as being ulcerative, nodular, or necrotic in
nature, whereas geotrichosis lesions are described as being
pseudomembranous. Since oral lesions of this category are
nonspecic, denitive diagnosis requires histologic verica-
tion. Treatment of these lesions is usually reserved for intra-
venous amphotericin B.
Viral Infections. Although there are no specic oral lesions
caused by HIV infection, a patient can display oral manifesta-
tions as an early sign of HIV infection. Such oral symptoms
may include nonspecic oral ulcerations, sore throat, exuda-
tive pharyngitis, and oral candidiasis during the initial acute
infection state.
179
These nonspecic manifestations disappear
after the acute phase.
Herpesvirus. Oral herpes simplex virus (HSV) presents both
as a local and a disseminated infection. The presence of intra-
oral HSV-associated lesions is usually the result of recurrent
infections caused by reactivation of latent viruses. This lesion
is not specically related to HIV; it is also a fairly common
occurrence among non-HIV infected individuals. However,
FIGURE 20-12 A, Angular cheilitis is commonly caused by Candida albicans. This lesion usually manifests with an ulcer at the corner of the mouth,
with erythematous ssures radiating from the ulcer. A pseudomembrane sometimes covers the ulcers. B, Treatment with topical antifungal medications and
antibiotics, for bacterial superinfections, is usually efcacious.
A B
HSV infections among immunocompromised individuals
may be more severe and manifest differently than what is
noticed in immunocompetent patients. Although ulcerations
caused by HSV-1 and HSV-2 are clinically indistinguishable,
HSV-1 is more frequently associated with oral lesions.
However, oral lesions caused by HSV-2 appear to have a
higher recurrence rate and are associated with a higher inci-
dence of resistance to acyclovir.
164
HSV in the oral cavity manifests as single or coalescent
crops of vesicles with subsequent ulceration and healing. The
ulcers are small, shallow, and round to elliptical. In general,
recurrent HSV infections occur primarily on more keratinized
epithelium such as the gingiva. However, there are numerous
reports of oral ulcerations caused by HSV infections on
nonkeratinized epithelium in HIV-infected patients. HSV-
associated ulcerations are usually accompanied by increased
pain during the acute stage, which can affect an individuals
nutritional intake. These ulcerations tend to heal in 7 to 10
days, although this may be extended in immunocompromised
patients. In this particular patient population, lesions tend to
be larger and occur with increased frequency. Furthermore, in
these patients, recurrent HSV may exhibit clinical signs and
symptoms that are similar to those of primary HSV infection,
such as malaise, cervical lymphadenopathy, and intensely
painful linear gingival erythema.
164
Oral manifestations of HSV can be mistaken for other viral
infections such as Cytomegalovirus and varicella-zoster virus,
infection or for aphthous ulcers, and a definitive diagnosis
should be made based on the clinical history and laboratory
tests, such as cytologic staining for Tzanck cells, viral culture
from the ulcer, biopsy, or HSV-1 detection via monoclonal-anti-
body testing. Treatment for HSV-1 infections usually consists of
acyclovir (200 mg orally ve times daily). Although famciclovir
can also be used, valacyclovir is a poor alternative because it may
cause severe side effects in immunocompromised patients.
Foscarnet may be used for resistant infections.
184
Cytomegalovirus. Oral manifestation of Cytomegalovirus
(CMV) infection is only observed in patients with CD4 counts
below 100 cells/mm
3
. Lesions associated with CMV are non-
specic ulcerations that usually appear as a single ulcer, with-
out preceding vesicles, on any oral mucosal tissue. These ulcers
are painful and tend to heal poorly. Differential diagnosis
should include recurrent aphthous ulcers and HSV-associated
lesions. A denitive diagnosis must include a biopsy specimen
that shows basophilic intranuclear inclusions of CMV, or CMV
identification via monoclonal-antibody assay or in situ
hybridization.
185
A recommended regimen for intraoral
lesions is high-dose acyclovir therapy (800 mg orally ve times
a day) for a minimum of 2 weeks. Oral manifestations of CMV
may be associated with disseminated disease, and the patient
needs to be evaluated for ophthamologic and other CMV-
associated diseases once an oral diagnosis is conrmed.
186
Epstein-Barr Virus. Epstein-Barr virus (EBV) infections have
been associated with numerous manifestations, including
infectious mononucleosis, Burkitts lymphoma, nasopharyn-
geal carcinoma, and oral hairy leukoplakia. Oral hairy leuko-
plakia was initially described in individuals with HIV disease,
but it has since been found in many other patient popula-
tions. This lesion may be present in all phases of HIV disease,
but it is most commonly found in individuals with CD4 cell
counts below 200 cells/mm
3
. It manifests as an asymptomatic
white lesion, most frequently with vertical hyperkeratotic striae
that are usually seen on the lateral borders of the tongue
187
(Figure 20-13). The lesion may vary from linear striae to white
patches that cannot be wiped off, and they often have white
hyperkeratotic hairlike projections. Because of its clinical char-
acteristics, differential diagnosis should include hyperplastic
candidiasis. Although it is not thought that Candida albicans
contributes to the clinical appearance of oral hairy leukoplakia,
C. albicans may be present in more than 50% of oral hairy
leukoplakia lesions. When denitive diagnosis of oral hairy
leukoplakia needs to be established, it is necessary to verify the
presence of EBV in the supercial layers of the involved epithe-
lium. Owing to the signicant association between this lesion
and HIV, a biopsy is necessary to rule out oral hairy leuko-
plakia in patients yet to be tested for HIV. In HIV-positive
individuals, an empiric diagnosis can be inferred when a clin-
ical lesion resembling oral hairy leukoplakia does not respond
to antifungal medications.
It is important to assure the patient that the presence of
oral hairy leukoplakia has not been associated with person-to-
person transmission of EBV.
Treatment of this lesion usually is not indicated unless the
patient complains of esthetic disfiguration or masticatory
functional impairment. Antiviral therapy (acyclovir 800 mg
orally ve times a day) is effective to achieve resolution of the
FIGURE 20-13 Oral hairy leukoplakia is an asymtomatic white lesion,
caused by Epstein-Barr virus, that is usually found on the tongue. It is rare
to nd this lesion on other sites in the oral cavity. The lateral borders of the
tongue are most commonly affected.
lesion within 2 weeks. Prophylactic therapy with 800 mg acy-
clovir per day may be necessary to prevent recurrence.
Varicella-Zoster Virus. There have been reports of
increased incidence of human varicella-zoster virus (HZV)
infections among HIV-infected persons, relative to increased
age and degree of immunosuppression. Complications asso-
ciated with HZV in immunocompromised patients are com-
mon and can be severe, especially for those individuals with
CD4 counts fewer than 200 cells/mm
3
.
188
Clinically, oral
HZV infection presents as vesicles that quickly rupture,
resulting in ulcerations. The ulcers are multiple, shallow,
and small, with an erythematous base, and are characteris-
tically distributed unilaterally along a division of the fifth
cranial nerve. Patients frequently complain of pain, neuro-
praxia, and tenderness. Although clinical presentation is dis-
tinct for HZV infection, a definitive diagnosis should be
confirmed by laboratory tests such as histologic staining for
multinucleated giant cells with intranuclear inclusions,
direct immunofluorescence, and cytology smears taken from
the lesion.
Treatment usually is focused on supportive care and is cen-
tered on the prevention of postherpetic neuralgia and dis-
semination. High doses of oral acyclovir (800 mg orally ve
times a day), famciclovir (500 mg orally three times a day), or
valacyclovir (500 mg orally three times a day) have been ef-
cacious in treating HZV infection. Caution is needed when
using valacyclovir in severely immunosuppressed patients as
this medication has been associated with hemolysis in this
particular patient population. For greatly immunosuppressed
patients, intravenous acyclovir therapy may be more appro-
priate. Foscarnet also may be useful for acyclovir-resistant her-
pes zoster.
189
It has been reported that there are high inci-
dences of herpes zoster in patients shortly after they start
treatment with protease inhibitors, which might suggest a need
for prophylaxis for those at increased risk for developing her-
pes zoster infection.
190
Human Herpesvirus 8. Recently, human herpesvirus 8
(HHV8) has been linked to the etiology of Kaposis sarcoma
(KS).
191
Most intraoral KS lesions are found on the hard and
soft palates, manifesting as red-blue or purple-blue macules or
nodules (Figure 20-14). The lesions are initially asymptomatic,
but due to trauma and secondary ulcerations, they can become
symptomatic as they get larger in size. Large lesions may inter-
fere with the individuals ability to speak, swallow, and masti-
cate. Lesions on the gingiva and tongue are also common;
however, extrapalatal lesions are associated with a more rapid
progression of KS, as well as HIV disease.
Oral KS is usually seen in patients with CD4 counts below
200 cells/mm
3
but can be seen in all stages of HIV disease. The
macular lesions can be confused with physiologic pigmenta-
tion; a differential diagnosis should also include bacillary
(epithelioid) angiomatosis, lymphoma, and trauma.
192
As KS
is an AIDS-dening lesion, a denitive diagnosis requires a
biopsy.
Treatment for KS includes radiation (800 to 2,000 rad),
surgical excision, and intralesional injections with chemother-
apeutic agents such as vinblastine sulfate (0.1 mg/mm
2
) or
sodium tetradecyl sulfate (0.1 mg/mm
2
). Intralesional injec-
tions are most effective for small nodular lesions and as an
adjuvant to radiation. It is important to realize that most of
these treatments do not result in a cure but are used to reduce
the size and number of lesions.
193
Recent studies show some
efcacy with antiangiogenesis agents, such as thalidomide, and
oral 9-cis retinoic acid.
194
No antiherpetic medications have
shown any benet as prophylaxis or treatment for KS.
Human Papillomavirus. Oral manifestations with papillo-
maviruses are similar to human papillomavirus (HPV)
infections at other sites. Infections with HPV may cause dif-
ferent distinct appearances, including oral squamous cell
papilloma, verruca vulgaris, focal epithelial hyperplasia, and
condyloma acuminatum (Figure 20-15). Each lesion has a
specific expression of an identified HPV genotype. Oral
FIGURE 20-14 A, Initial lesions of Kaposis sarcoma are usually found on the hard and soft palates. These lesions are commonly bluish-red macules.
B, Long-standing palatal lesions may become nodular and even ulcerative.
A B
squamous cell papillomas may present as exophytic pedun-
culated papules with a cauliflower-like appearance. Verruca
vulgaris (the common wart) is a firm, sessile, exophytic, and
whitish lesion. This form of HPV presentation also has a
hyperkeratinized superficial epithelium with a slight invagi-
nation of the center of the lesion. Focal epithelial hyperpla-
sia (Hecks disease) may present as a single or multiple,
smooth or pebble-like, hyperplastic leukoplakic lesion. Focal
epithelial hyperplasia is commonly found on keratinized tis-
sues such as the alveolar mucosa and the lips. Condyloma
acuminatum presents as small white-to-pink nodules with
a pebbled surface and is most commonly found on the soft
and hard palates and the tongue.
195
The presence of HPV-
associated lesions is not pathognomonic for HIV infection
or progression. However, an increase in the prevalence of
oral HPV infections among HIV-infected persons has been
reported since the introduction of protease inhibitors.
Although most of oral HPV manifestations are asympto-
matic, unless lesions are induced by trauma, they can interfere
with mastication and may raise cosmetic concerns. Treatments
for HPV include surgical removal, laser ablation, cryotherapy,
and topical application of keratinolytic agents. For smaller
lesions, topical application of 25% podophyllum resin may be
used to reduce the size. A more novel approach has been the use
of intralesional injection of antiviral agents. Interferon- in
intralesional injections (1,000,000 IU/cm
2
once weekly) and
subcutaneous injections (3,000,000 IU/cm
2
twice weekly) have
been shown to be effective in long-term resolution of lesions.
196
Bacterial Infection. Periodontal Disease. The most com-
mon oral manifestations of bacterial origin are associated
with periodontal conditions. These conditions are usually cat-
egorized by their clinical appearance and include linear gin-
gival erythema (LGE), necrotizing ulcerative gingivitis
(NUG), and necrotizing ulcerative periodontitis (NUP). It
has also been noted that HIV-seropositive patients with pre-
vious periodontal disease may show faster rates of conven-
tional periodontal deterioration as compared with those of
HIV-seronegative persons. Lamster and colleagues have sug-
gested that the progression of periodontal disease in HIV-
infected persons is dependent on the immunologic compe-
tency of the host and local host response to typical and
atypical microorganisms related to periodontal disease.
197
Thus, the level of immune suppression, as demonstrated by
decreasing number of T-cell lymphocytes, in combination
with the degree of plaque accumulation, may explain these
conditions in HIV-infected patients.
173
Linear gingival erythema is an atypical gingivitis that is
depicted as a 2 to 3 mm distinct band of ery redness at the
marginal gingiva around the teeth (Figure 20-16). Such ery-
thema is not proportional to the plaque accumulation and
seems to only affect the soft tissue, without any ulcerations,
increased pocket depths, or any attachment loss. Patients with
this condition are usually asymptomatic. The true prevalence
of LGE is difcult to determine due to variable diagnostic cri-
teria that have been put forth.
Differential diagnosis should include a localized erythema
due to dry mucosa associated with mouth breathing, lichen
planus, mucous membrane pemphigoid, or an allergic reaction.
The most recent theory regarding the pathogenesis of this lesion
implicates subgingival candida infection as a possible cause.
197
FIGURE 20-15 Human papillomavirus has become more common in individuals whose immune system is undergoing changes, such as reconstitution
after severe CD4 cell depletion. Florid lesions may affect the lips (A) and intraoral mucosa (B).
FIGURE 20-16 Linear gingival erythema of the gingival margin.
A B
Treatments include improved oral home care and conven-
tional dental scaling and root planing, along with the use of
chlorhexidine gluconate (0.12%) mouth rinses (15 mL
swished and expectorated twice a day) for up to 3 months.
Additionally, concomitant use of topical antifungal medica-
tions may be benecial.
Manifestations of NUG and NUP are triggered by changes
in the immune status, most probably aggravated by intraoral
bacteria. The two entities may present as a continuum of the
same disease but also may appear as separate entities. NUG is
limited to the gingiva (Figure 20-17), whereas NUP is charac-
terized by localized to generalized aggressive alveolar bone and
attachment destruction (Figure 20-18). Occurrence of NUG
has been associated with stress, anxiety, malnutrition, and smok-
ing. Patients with NUG complain of spontaneous gingival bleed-
ing and mild to moderate gingival pain. NUP is associated with
complaints of deep-seated bone pain, spontaneous gingival
bleeding, halitosis, and tooth mobility. Clinically, these condi-
tions are presented with initial lesions of limited craterlike
necrosis of gingival papillae. When untreated, NUP may
progress at a rate of 1 to 2 mm of soft- and hard-tissue destruc-
tion per week. NUP is mostly seen with severe immune sup-
pression, with CD4 counts below 100 cells/mm
3
.
173
A denitive diagnosis is based on clinical evaluation and
radiologic evaluation with panoramic radiographs or specic
periapical dental radiographs. Specic laboratory tests may be
needed to rule out conditions and lesions such as bullous lesions
of benign mucous membrane pemphigoid, erythema multi-
forme, acute forms of leukemia, and major aphthous ulceration.
Treatment for both NUG and NUP consists of dbride-
ment of necrotic soft and hard tissue, antibiotic therapy with
metronidazole or tetracycline (500 mg four times a day) for
a week, and a follow-up with scaling and dbridement.
173
Due to the high risk for fungal infections in these patients, an
antifungal regimen may be prescribed together with the
antibiotics. Chlorohexidine gluconate (0.12%) mouth rinses
are recommended as maintenance therapy. Metronidazole
should be used with caution in patients who are taking
lopinavir and retonavir.
Tuberculosis. Intraoral lesions associated with TB may pre-
sent as single nonhealing caseating granulomatous ulcera-
tions that are accompanied by deep-seated pain. The lesions
have been noted on the tongue, the palate, the buccal mucosa,
and the angles of the mouth.
198
Diagnosis by clinical pre-
sentation alone is difficult and needs to be complemented
with demonstration of acid-fast TB bacilli within the
lesion.
199
Treatment is locally palliative as an adjunct to sys-
temic TB therapy.
Syphilis. Clinical presentation of syphilis includes chancres,
snail-track ulcers, and gumma formation.
200
Chancres are
mostly asymptomatic indurated ulcers with a brown crusted
appearance that are usually seen on the lips, oral mucosa,
tongue, palate, and posterior pharyngeal wall. Secondary
syphilis is characterized by highly infectious mucosal ulcers
with an appearance of white lesions surrounded by an ery-
thematous base. Frank ulceration is most common in tertiary
syphilis as a result of gummatous destruction. It is usually
seen on the palate and tongue.
Differential diagnosis should include herpetic cold sores,
deep-seated fungal infections, mycobacteria-associated ulcer,
malignant ulcers, and trauma. A denitive diagnosis is made
by dark-field microscopy that demonstrates the etiologic
agent, Treponema pallidum. Treatment is based on appropri-
ate systemic antibiotic therapy.
Nonspecic Ulcerations. Necrotizing Stomatitis. Necrotizing
stomatitis is a localized acute painful ulcerative lesion on
mucosal surfaces overlying bone (Figure 20-19). This condition
eventually leads to necrosis of tissue and subsequent bone expo-
sure. No specic microbial agent or mechanism has been linked
to its etiology. This condition is seen in patients with CD4 cells
fewer than 100 cells/mm
3
.
168
Differential diagnosis includes
aphthous ulcer and NUP. Treatment consists of careful dbride-
ment, local or systemic steroid therapy, antibiotics, and insti-
tution of a soft-tissue stent to protect the affected area from fur-
ther trauma and for delivery of topical medications.
201
Aphthous Ulcers. Recurrent aphthous ulcerations (RAUs)
are idiopathic oral ulcerations. There are three disease enti-
ties of RAUs: minor, major, and herpetiform. Diagnosis of
RAUs is a diagnosis of exclusion; the clinical impression
should be confirmed with histologic examination and by
response to treatment.
179
Minor (recurrent) aphthous ulcerations are smaller than
10 mm in diameter, well-circumscribed, round, sometimes
covered by a yellow-gray pseudomembrane, and surrounded
by an erythematous halo. The erythematous halo may be
absent in severely immunocompromised patients due to their
lack of an intact inflammatory response. Minor aphthous
ulcerations are usually conned to the nonkeratinized oral
mucosa and tend to recur, often at the same site. Their dura-
tion is about 1 to 2 weeks, and healing occurs without scarring.
Minor aphthous ulcerations are prevalent in both nonHIV-
infected populations and HIV-infected populations.
FIGURE 20-17 Necrotizing ulcerative gingivitis localized to the lower
rst and second molars.
Differential diagnosis includes recurrent HSV infection.
Treatment is focused to provide symptomatic relief. An anal-
gesic mouth rinse, such as 2 to 4% viscous lidocaine solution
(10 mL swished and expectorated), is most commonly insti-
tuted for relief.
Major (recurrent) aphthous ulcerations are larger than 10
mm in diameter, well-circumscribed, round, and shallow or
deep with indurated margins (Figure 20-20). A gray
pseudomembrane covering the lesion may sometimes be pre-
sent. Major aphthous ulcerations can occur on any area of the
oral mucosa. They are usually single ulcerations, but in
immunosuppressed individuals, groups of up to 10 lesions
have been observed. These ulcers tend to persist for more than
3 weeks and to heal with a scar formation. In patients with
HIV, major aphthous ulcers have been associated with severe
immune suppression, with CD4 counts below 100 cells/mm
3
,
and are markers for HIV disease progression.
202
Treatment for major aphthous ulcerations includes
administration of systemic corticosteroids. Topical formula-
tions of clobetasol or uocinonide gel applied directly to the
lesion, dexamethasone elixir mouth rinses (0.5 mg/5 mL),
and systemic administration of 60 to 80 mg of prednisone per
day for 10 days have been used successfully. For steroid-resis-
tant patients, alternative therapy of 100 to 200 mg thalido-
mide may be used. Thalidomide needs to be used with cau-
tion because of its severe adverse side effects. However, despite
its severe side effects, thalidomide has been used with some
success to treat both oral and esophageal ulcerations.
Refractory cases may be treated with other agents including
colchicine or levamisole.
203
Antibiotics and antifungal agents
may be used concurrently when appropriate to prevent bac-
terial or fungal superinfections.
Herpetiform ulcers are the least common type of apht-
hous ulcers. These ulcers are pinpoint (smaller than 1 mm in
diameter) and round, with perilesional erythema. They are
usually found in batches of up to 100, appearing on nonkera-
tinized mucosa such as the ventral surface of the tongue and
soft palate. Healing occurs without scarring. Treatments are
similar to those for minor aphthous ulcers and include symp-
tomatic relief, suppression of the local pathologic immune
reaction, and treatment of any concomitant superinfection.
Drug-Induced Ulcerations. Several medications that are
frequently used for HIV-infected patients have been associ-
ated with the development of oral ulcerations.
204206
These
medications include zidovudine, zalcitabine, foscarnet,
interferon, and ganciclovir.
207
Drug-induced ulcerations are
mainly seen on nonkeratinized mucosa, but they tend to
affect keratinized mucosa in more severely immunocom-
promised patients.
FIGURE 20-18 Necrotizing ulcerative periodontitis of the lower anterior
region. A, Both gingival and alveolar bone are affected. B, Submandibular
lymphadenopathy can also be present.
FIGURE 20-19 Necrotizing stomatitis on the palatal area of the upper
rst and second molars.
A B
Certain antiretroviral therapies induce neutropenia and
are thereby linked to the occurrence of oral ulcerations.
Administration of a growth factor such as granulocyte-
macrophage colony-stimulating factor has shown to be suc-
cessful in resolving ulcerations associated with neutropenia.
208
Xerostomia. Xerostomia, or dry mouth, is a subjective symp-
tomatic complaint that is frequently noted by HIV-infected
patients. It has been reported that reduced salivary ow occurs
in 2 to 10% of HIV-infected individuals
.207
However, the true
prevalence is 80 to 90% of all patients taking HAART. The
effect of oral dryness on quality of life is profound, and many
patients with severe xerostomia sometimes opt to change or
stop their antiretroviral medications in order to regain better
salivary functions.
The most common cause of decreased salivary ow in HIV-
infected patients is side effects of pharmocotherapeutic agents.
Many medications, such as antiretroviral medications (including
nucleoside transcriptase inhibitors, protease inhibitors) as well as
antihistamines, anticholinergics, antihypertensives, deconges-
tants, narcotic analgesics, and tricyclic antidepressants, have been
associated with xerostomia. In addition, xerostomia may be a
result of HIV-associated salivary gland disease in this population.
The parotid glands are most frequently affected; however, minor
salivary glands can also be affected by viral infection such as with
CMV.
209
Another cause of reduced salivary ow is radiation ther-
apy to the head and neck area, causing functional impairment of
salivary glands in the radiated area.
Treatment for xerostomia focuses on symptomatic relief by
encouraging patients to hydrate themselves frequently and to
minimize the intake of caffeine and alcohol, which act as
diuretics. Patients are also recommended to use commercially
available articial saliva substitutes (Xero-lube, Sali-synt, Moi-
stir, Orex) to achieve relief. The use of pilocarpine and
bethanechol to stimulate salivary flow can also be useful.
Ultimately, discontinuation or substitution of xerostomia-
inducing drugs may be necessary.
Oral Lesions in the Pediatric Population. HIV-infected chil-
dren may also develop a spectrum of oral lesions. These lesions
can affect children more severely than adults and can be a sig-
nificant source of pain with subsequent limitation of oral
intake of nutrition and medications.
The most common oral manifestation in immunocompro-
mised children is candidiasis.
210
The presence of oral candidi-
asis in HIV-infected infants, as well as other clinical symptoms,
is used as a clinical marker for disease progression in a prog-
nosis-based clinical staging system. Clinical presentation of oral
candidiasis in the pediatric population is similar to that of the
adult population. Some reports suggest that erythematous can-
didiasis is more common than the pseudomembranous type in
HIV-infected children.
211
A definitive diagnosis should be
accompanied by laboratory tests, as described previously.
Both topical and systemic treatment with antifungal med-
ications can be used to treat oral candidiasis. Several reports
have shown that there are subtypes of Candida that are iso-
lated in candidal lesions.
211,212
Therefore, it is not unrea-
sonable to determine a specific subtype of Candida and to
select a specific antifungal agent directed toward the sub-
type. A report has shown that fluconazole suspension (6
mg/kg loading dose followed by 3 mg/kg/d) has been highly
effective and is superior to routine nystatin rinses.
213
In chil-
dren who are fed by bottle, it is possible to place the anti-
fungal medication inside the nipple, as well as to cover the
nipple with a thin layer of topical medication.
Several of the medications used by children are made to
taste better by the addition of sugar formulations, which also
make them syrupy and sticky. It is advisable to have children
rinse their mouths with water after administration of these
medications in order to reduce the incidence of tooth decay.
FIGURE 20-20 A, Major aphthous ulcer in the retromolar region in an HIV-infected patient. B, The same major aphthous ulcer, after treatment.
A B
REFERENCES
1. Burnet M. Natural history of infectious disease. Cambridge:
Cambridge University Press; 1962.
2. Institute of Medicine. Emerging infections: microbial threats
to health in the United States. Washington: National Academy
Press; 1992.
3. Centers for Disease Control and Prevention. Achievements in
public health, 19901999: control of infectious diseases.
MMWR Morb Mortal Wkly Rep 1999;48:6219.
4. Centers for Disease Control and Prevention. Tuberculosis and
acquired immunodeficiency syndromeFlorida. MMWR
Morb Mortal Wkly Rep 1986; 35:587.
5. Centers for Disease Control and Prevention. Tuberculosis mor-
bidity in the United States: nal data, 1990. MMWR Morb
Mortal Wkly Rep 1991;40(SS-3):23.
6. Bernardo J. Tuberculosis: a disease of the 1990s. Hosp Pract
1991;26:195.
7. Centers for Disease Control and Prevention. Tuberculosis mor-
bidityUnited States, 1997. MMWR Morb Mortal Wkly Rep
1998;47:253.
8. American Thoracic Society. Control of tuberculosis in the
United States. Am Rev Respir Dis 1992;146:1623.
9. Dolin PJ, Raviglione MC, Kochi A. Global tuberculosis inci-
dence and mortality during 19902000. Bull World Health
Org 1994;72:213.
10. World Health Organization. Report on the tuberculosis epi-
demic. Geneva, Switzerland: WHO; 1997.
11. Centers for Disease Control and Prevention. Summary of noti-
fiable diseases1998. MMWR Morb Mortal Wkly Rep
1999;47:70.
12. Centers for Disease Control and Prevention. World TB day
March 24, 2001. MMWR Morb Mortal Wkly Rep 2001;50:201.
13. Centers for Disease Control and Prevention. Core curriculum
on tuberculosis. 3rd ed. Atlanta: US Department of Health
and Human Services; 1994.
14. Bates JH, Stead WW. The history of tuberculosis as a global
epidemic. Med Clin North Am 1993;77:1205.
15. Orme IM, Anderson P, Boom WH. T cell response to
Mycobacterium tuberculosis. J Infect Dis 1993;167:1481.
16. Ellner JJ. The immune response in human tuberculosis: impli-
cations for tuberculosis control. J Infect Dis 1997;176:1351.
17. Mani NJ. Tuberculosis initially diagnosed by asymptomatic
oral lesions. J Oral Med 1985;40:39.
18. Molinari JA, Chandrasekar PH. Mycobacteria. In: Willett NP,
White RR, Rosen S, editors. Essential dental microbiology.
Norwalk: Appleton and Lange; 1991. p. 181.
19. Selwyn PA, Hartel D, Lewis VA, et al. A prospective study of the
risk of tuberculosis among intravenous drug users with human
immunodeciency virus infection. N Engl J Med 1989;320:545.
20. Reider HL, Jereb JA, Frieden TR, et al. Epidemiology of tuber-
culosis in the United States. Epidemiol Rev 1989;11:79.
21. Theuer CP, Hopewell PC, Elias D, et al. Human immunode-
ciency virus infection in tuberculosis patients. J Infect Dis
1990;162:8.
22. Small PM, Schecter GF, Goodman PC, et al. Treatment of
tuberculosis in patients with advanced human immunode-
ciency virus infection. N Engl J Med 1991;324:289.
23. Barnes PF, Bloch AB, Davidson PT, et al. Tuberculosis in
patients with human immunodeficiency virus infection. N
Engl J Med 1991;324:164450.
24. Styblo K. Recent advances in epidemiological research in
tuberculosis. Adv Tuberc Res 1980;20:1.
25. Van Scoy RE, Wilkowske CJ. Antituberculous agents. Mayo
Clin Proc 1992;67:179.
26. Centers for Disease Control and Prevention. Initial therapy
for tuberculosis in the era of multidrug resistance: recom-
mendations of the Advisory Council for the Elimination of
Tuberculosis. J Am Med Assoc 1993;270:696.
27. Cohen ML. Epidemiology of drug resistance: implications for
a post-antimicrobial era. Science 1992;257:1050.
28. Frieden TR, Sterling T, Pablos-Mendez A, et al. The emergence
of drug-resistant tuberculosis in New York City. N Engl J Med
1993;328:521.
29. Shearer BG. MDR-TB: another challenge from the microbial
world. J Am Dent Assoc 1994;125:43.
30. Raviglione MC, Dye C, Schmidt S, et al. Assessment of world-
wide tuberculosis control. WHO global surveillance and mon-
itoring project. Lancet 1997;350:624.
31. Luelmo F. BCG vaccination. Am Rev Respir Dis 1982;125:70.
32. Jacobs JR Jr. Advances in mycobacterial genetics: new promises
for old diseases. Immunobiol 1992;184:147.
33. Cleveland JL, Gooch DF, Bolyard EA, et al. TB infection con-
trol recommendations from the CDC, 1994: considerations
for dentistry. J Am Dent Assoc 1995;126:593.
34. US Department of Health and Human Services, Centers for
Disease Control and Prevention. Guidelines for preventing the
transmission of Mycobacterium tuberculosis in healthcare facil-
ities. MMWR Morb Mortal Wkly Rep 1994;43(RR-13):1.
35. Field MJ, editor. Tuberculosis in the workplace. Washington
(DC): National Academy Press; 2001.
36. Fraser DW, Tsai TR, Orenstein W, et al. Legionnaires disease:
description of an epidemic of pneumonia. N Engl J Med
1977;297:1189.
37. Centers for Disease Control and Prevention. Follow-up on res-
piratory illnessPhiladelphia. MMWR Morb Mortal Wkly
Rep 1977; 26:9.
38. McDade JE, Shepard CC, Fraser DW, et al. Legionnaires dis-
ease: isolation of a bacterium and demonstration of its role in
other respiratory disease. N Engl J Med 1977;297:1197.
39. Brenner DJ, Steigerwalt AG, McDade JE. Classication of the
legionnaires disease bacterium: Legionella pneumophila, genus
novum, species nova, of the family Legionellaceae, family nova.
Ann Intern Med 1978;90:656.
40. McDade JE, Brenner DJ, Bozeman FM. Legionnaires disease
bacterium isolated in 1947. Ann Intern Med 1979;90:659.
41. Rowbotham TJ. Current views on the relationship between
amoebae, legionellae, and man. Isr J Med Sci 1986;22:1218.
42. Rowbotham TJ. Isolation of Legionella pneumophila from clin-
ical specimens via amoebae, and the interaction of those and
other isolates with amoebae. J Clin Pathol 1983;36:978.
43. Stout JE, Yu VL, Best M. Ecology of Legionella pneumophila
within water distribution systems. Appl Environ Microbiol
1985;49:221.
44. Muder R, Yu VL, Woo A. Mode of transmission of Legionella
pneumophila: a critical review. Arch Intern Med 1986;146:1607.
45. Johnson JT, Yu VL, Best M, et al. Nosocomial legionellosis
uncovered in surgical patients with head and neck cancer:
implications for epidemiologic reservoir and mode of trans-
mission. Lancet 1985;2:298.
46. Stout JE, Yu VL, Muraca ME, et al. Potable water as a cause of
sporadic cases of community-acquired pneumonia. N Engl J
Med 1992;326:151.
47. Shands K, Ho J, Meyer R, et al. Potable water as a source of
legionnaires disease. J Am Med Assoc 1985;253:1412.
48. Stout JE, Yu VL, Muraca P. Legionnaires disease acquired
within the homes of two patients: link to the home water sup-
ply. J Am Med Assoc 1987;257:1215.
49. Kaufman AF, McDade J, Patton C, et al. Pontiac fever: isolation
of the etiologic agent (Legionella pneumophila) and demon-
stration of its mode of transmission. Am J Epidemiol
1981;114:337.
50. Fotos PG, Westfall HN, Snyder IS, et al. Prevalence of
Legionellaspecic IgG and IgM antibody in a dental clinic
population. J Dent Res 1985;64:1382.
51. Reinthaler FF, Mascher F, Stunzer D. Serological examinations
for antibodies against Legionella species in dental personnel. J
Dent Res 1988;67:942.
52. Yu VL. Legionella pneumophila (legionnaires disease). In:
Mandell GL, Bennett JE, Dolin R, editors. Principles and prac-
tice of infectious diseases. 5th ed. Churchill Livingstone; 2000.
p. 2424.
53. Centers for Disease Control and Prevention. Sustained trans-
mission of nosocomial legionnairesdiseaseArizona and
Ohio. MMWR Morb Mortal Wkly Rep 1997;46:416.
54. Lowry PW, Tompkins LS. Nosocomial legionnellosis: a review
of pulmonary and extrapulmonary syndromes. Am J Infect
Control 1993;21:21.
55. Kirby BD, Snyder KM, Meyer RD, et al. Legionnaires disease:
report of sixty-ve nosocomially-acquired cases and review of
the literature. Medicine 1980;59:188.
56. Seu P, Winston DJ, Olthoft KM, et al. Legionnaires disease in
liver transplant recipients. Infect Dis Clin Pract 1993;2:109.
57. Singh N, Muder RR, Yu VL, et al. Legionella infection in liver
transplant recipients: implications for management.
Transplantation 1993;56:1549.
58. Tyzzer EE. A sporozoan found in the peptic glands of the com-
mon mouse. Proc Soc Exp Biol Med 1907;5:12.
59. Nime FA, Burek JD, Page DL, et al. Acute gastroenterocolitis in
a human being infected with the protozoan Cryptosporidium.
Gastroenterol 1976;70:592.
60. Current WL. Human cryptosporidiosis. N Engl J Med
1983;309:1325.
61. Peterson C. Cryptosporidiosis in patients infected with the
human immunodeciency virus. Clin Infect Dis 1992;15:903.
62. Laughon BE, Druckman DA, Vernon A, et al. Prevalence of
enteric pathogens in homosexual men with and without
acquired immunodeficiency syndrome. Gastroenterol
1988;94:984.
63. Smith PD, Lane HC, Gill VJ, et al. Intestinal infections in
patients with the acquired immunodeciency syndrome. Ann
Intern Med 1988;108:328.
64. Pederson C, Danner S, Lazzarin A, et al. Epidemiology of cryp-
tosporidiosis among European AIDS patients. Genitourin Med
1996;72:128.
65. Vakil NB, Schwartz SM, Buggy BP, et al. Biliary cryp-
tosporidiosis in HIV-infected people after the waterborne out-
break of cryptosporidiosis in Milwaukee. N Engl J Med
1996;334:19.
66. Haas CN, Rose JB. Reconciliation of microbial risk models
and outbreak epidemiology: the case of the Milwaukee out-
break. Proc Am Water Works Assoc 1994;517.
67. Fricker C, Crabb J. Waterborne cryptosporidiosis: detection
methods and treatment options. Adv Parasitol 1998;40:242.
68. MacKenzie WR, Hoxie NJ, Proctor ME, et al. A massive out-
break in Milwaukee of Cryptosporidiuminfection transmitted
through the public water supply. N Engl J Med 1994;331:161.
69. Hayes EB, Matte TD, OBrien TR, et al. Large community out-
break of cryptosporidiosis due to contamination of a lter
public water supply. N Engl J Med 1989;320:1372.
70. McAnulty JM, Fleming DW, Gonzalez AH. A community-wide
outbreak of cryptosporidiosis associated with swimming at a
wave pool. J Am Med Assoc 1994;272:1597.
71. Goldstein ST, Juranek DD, Ravenholt O, et al. Cryptosporidiosis:
an outbreak associated with drinking water despite state-of-the-
art water treatment. Ann Intern Med 1996;124:459.
72. Newman RD, Zu S-X, Wuhib T, et al. Household epidemiology
of Cryptosporidium parvum infection. Ann Intern Med
1994;120:500.
73. Cordell RL, Addiss DG. Cryptosporidiosis in child care set-
tings: a review of the literature and recommendations for pre-
vention and control. Pediatr Infect Dis 1994;13:311.
74. Koch RL, Phillips DJ, Aber RC, et al. Cryptosporidiosis in hos-
pital personnel. Ann Intern Med 1985;102:593.
75. Miron D, Kenes J, Dagan R. Calves as a source of an outbreak
of cryptosporidiosis among young children in an agricultural
closed community. Pediatr Infect Dis 1991;10:438.
76. Millard PS, Gensheimer KF, Addiss DG, et al. An outbreak of
cryptosporidiosis from fresh-pressed apple cider. J Am Med
Assoc 1994;272:1592.
77. Ungar BLP. Cryptosporidium. In: Mandell GL, Bennett JE,
Dolan R, editors. Principles and practice of infectious diseases.
5th ed. New York: Churchill Livingstone; 2000. p. 2903.
78. Dupont H, Chappell C, Sterling C, et al. The infectivity of
Cryptosporidium parvumin healthy volunteers. N Engl J Med
1995;332:885.
79. Alter HJ, Holland PV, Purcell RH. The emerging pattern of
post-transfusion hepatitis. Am J Med Sci 1975;270:329.
80. Alter HJ, Purcell RH, Holland PV, et al. Clinical and serologi-
cal analysis of transfusion-associated hepatitis. Lancet
1975;2:838.
81. Choo Q-L, Kuo G, Weiner, et al. Isolation of a cDNA clone
derived from a blood-borne non-A, non-B viral hepatitis
genome. Science 1989;244:359.
82. Kuo G, Choo Q-L, Alter HJ, et al. An assay for circulating anti-
bodies to a major etiologic virus of human non-A, non-B
hepatitis. Science 1989;244:362.
83. Bukh J, Miller RH, Purcell RH. Genetic heterogeneity of
hepatitis C virus: quasispecies and genotypes. Semin Liver Dis
1995;15:41.
84. Cha T-A, Beall E, Irvine B, et al. At least ve related, but distinct,
hepatitis C viral genotypes exist. Proc Natl Acad Sci U S A
1992;89:7144.
85. Chan S-W, McOmish F, Holmes EC, et al. Analysis of a new
hepatitis C virus type and its phylogenetic relationship to exist-
ing variants. J Gen Virol 1992;73:1131.
86. Rall CJN, Dienstag JL. Epidemiology of hepatitis C virus infec-
tion. Semin Gastrointest Dis 1995;6:3.
87. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence
of hepatitis C virus infection in the United States, 1988 through
1994. N Engl J Med 1999;341:556.
88. Seeff LB. Natural history of viral hepatitis, type C. Semin
Gastrointest Dis 1995;6:20.
89. Dienstag JL. Non-A, non-B hepatitis. I. Recognition, epidemi-
ology, and clinical features. Gastroenterology 1983;85:439.
90. Koretz RL, Abbey H, Coleman E, et al. Non-A, non-B post-
transfusion hepatitis: looking back on the second decade. Ann
Intern Med 1993;119:110.
91. Centers for Disease Control and Prevention. Recommendations
for prevention and control of hepatitis C virus (HCV) infection
and HCV-related chronic diseases. MMWR Morb Mortal Wkly
Rep 1998;47(RR-19):1.
92. Ohto H, Terazawa S, Sasaki N, et al. Transmission of hepatitis
C virus from mothers to infants. N Engl J Med 1994;330:744.
93. Liang JT, Rhermann J, Seeff LB, et al. NIH conference: patho-
genesis, natural history, treatment, and prevention of hepati-
tis C. Ann Intern Med 2000;132:296.
94. Armstrong GL, Alter MJ, McQuillan GM, et al. The past inci-
dence of hepatitis C virus infection: implications for the future
burden of chronic liver disease in the United States.
Hepatology 2000;31:777.
95. American Health Consultants. Fasten your seat belts: hospitals
face a bumpy ride as hepatitis C cases peak. Hosp Infect Cont
2000;27:129.
96. Food and Drug Administration. New blood screening tests for
hepatitis C. FDA Drug Bull 1990; October: 9.
97. Roth WK, Lee JH, Ruster B, et al. Comparison of two quanti-
tative hepatitis C virus reverse transcriptase PCR assays. J Clin
Microbiol 1996;34:261.
98. Alter MJ, Hadler SC, Judson FN, et al. The natural history of
community-acquired hepatitis C in the United States. N Engl
J Med 1992;327:1899.
99. Aach RD, Stevens CE, Hollinger FB, et al. Hepatitis C infection
in post-transfusion hepatitis: an analysis with rst- and sec-
ond-generation assays. N Engl J Med 1991;325:1325.
100. Tremolada F, Casarin C, Alberti A, et al. Long-term follow-up
of non-A, non-B (type C) post-transfusion hepatitis. J
Hematol 1992;16:273.
101. Alter HJ, Seeff LB: Recovery, persistence and sequelae in
hepatitis C infection: a perspective on long-term outcome.
Semin Liver Dis 2000;20:17.
102. Kiyosawa K, Sodeyama T, Tanaka E, et al. Hepatitis C in hos-
pital employees with needlestick injuries. Ann Intern Med
1991;115:367.
103. Lanphear BP, Linneman CC Jr, Cannon CG, et al. Hepatitis C
virus infection in healthcare workers: risk of exposure and
infection. Infect Control Hosp Epidemiol 1994;15:745.
104. Schlipkoter U, Roggendorf M, Cholmakow K, et al.
Transmission of hepatitis C (HCV) from a hemodialysis patient
to medical staff member. Scand J Infect Dis 1990;22:757.
105. Vaglia A, Nicolin R, Puro V, et al. Needlestick hepatitis C sero-
conversion in a surgeon. Lancet 1990;336:1315.
106. Ippolito G, Puro V, Petrosillo N, et al. Simultaneous infection
with HIV and hepatitis C virus following occupational con-
junctival blood exposure. J Am Med Assoc 1998;280:28.
107. Klein RS, Freeman K, Taylor PE, et al. Occupational risk for
hepatitis C infection among New York City dentists. Lancet
1991;338:1539.
108. Cleveland JL, Gooch BF, Shearer BG, et al. Risk and prevention
of hepatitis C infection: implications for dentistry. J Am Dent
Assoc 1999;130:641.
109. Lanphear BP. Trends and patterns in the transmission of
bloodborne pathogens to health care workers. Epidemiol Rev
1994;16:437.
110. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of
chronic non-A, non-B hepatitis with recombinant human
alpha interferon: a preliminary report. N Engl J Med
1986;315:1575.
111. Thomson BJ, Doran M, Lever AML, et al. Alpha-interferon
therapy for non-A, non-B hepatitis transmitted by gamma-
globulin replacement therapy. Lancet 1987;1:539.
112. Food and Drug Administration. Interferon alfa-2b approved
for hepatitis C. FDA Med Bull 1991;21(2):5.
113. National Institute of Health Consensus Development
Conference Panel Statement. Management of hepatitis C.
Hepatology 1997;26 Suppl 1:28.
114. Alter MJ, Mast EE, Moyer LA. Hepatitis C. Infect Dis Clin
North Am 1998;12:13.
115. Keeffe E. Hepatitis C: current and future treatment. Infect Med
2000;17:603.
116. AIDS epidemic update: December 2000. UNAIDS/WHO;
2000.
117. Centers for Disease Control and Prevention. Pneumocystis
pneumoniaLos Angeles. MMWR Morb Mortal Wkly Rep
1981;30:250.
118. Centers for Disease Control and Prevention. Kaposis sarcoma
and Pneumocystis pneumonia among homosexual menNew
York City and California. MMWR Morb Mortal Wkly Rep
1981;30:305.
119. Centers for Disease Control and Prevention. A cluster of
Kaposis sarcoma and Pneumocystis carinii pneumonia among
homosexual male residents of Los Angeles and Orange coun-
ties, California. MMWR Morb Mortal Wkly Rep 1982;31:305.
120. Jaffe HW, Choi K, Thomas PA, et al. National case-control
study of Kaposis sarcoma and Pneumocystis carinii pneumo-
nia in homosexual men: part 1, epidemiologic results. Ann
Intern Med 1983;99:145.
121. Centers for Disease Control and Prevention. Immunodeciency
among female sexual partners of males with acquired immune
deficiency syndrome (AIDS)New York. MMWR Morb
Mortal Wkly Rep 1983;31:697.
122. Harris C, Small CB, Klein RS, et al. Immunodeficiency in
female sexual partners of men with the acquired immunode-
ciency syndrome. N Engl J Med 1983;308:1181.
123. Centers for Disease Control and Prevention. Pneumocystis
carinii pneumonia among persons with hemophilia A.
124. Centers for Disease Control and Prevention. Possible transfu-
sion-associated acquired immune deficiency syndrome
(AIDS) California. MMWR Morb Mortal Wkly Rep
1982;31:652.
125. Centers for Disease Control and Prevention. Unexplained
immunodeciency and opportunistic infections in infants
New York, New Jersey, and California. MMWR Morb Mortal
Wkly Rep 1982;31:665.
126. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-
lymphotropic retrovirus from a patient at risk for acquired
immune deciency syndrome (AIDS). Science 1983;220:868.
127. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent detection
and isolation of cytopathic retroviruses (HTLV-III) from
patients with AIDS and at risk for AIDS. Science 1984;224:500.
128. Centers for Disease Control and Prevention. 1993 revised clas-
sication system for HIV infection and expanded surveillance
case definition for AIDS among adolescents and adults.
129. Centers for Disease Control and Prevention. HIV/AIDS sur-
veillance report. 2000;12:1.
130. Bozzette S, Berry SH, Duan N, et al. The care of HIV-infected
adults in the United States. N Engl J Med 1998;339:1897.
131. Gao F, Bailes E, Robertson DL, et al. Origin of HIV-1 in the
chimpanzee Pan troglodytes. Nature 1999;396:437.
132. Hahn BH, Shaw GM, De Cook KM, et al. AIDS as a zoonosis; sci-
entic and public health implications. Science 2000;287:6076.
133. Ciesielski CA, Marianos DW, Schochetman G, et al. The 1990
Florida dental investigation. The press and the science. Ann
Intern Med 1994;121:886.
134. Piatak M, Saag MS, Lang LC, et al. High levels of HIV-1 in
plasma during all stages of infection determined by competi-
tive PCR. Science 1993;259:1749.
135. Perelson AS, Neumann AU, Markowitz M, et al. HIV-1 dynam-
ics in vivo: virion clearance rate, infected cell life-span, and
viral generation time. Science 1996;271:1582.
136. Cofn JM. HIV population dynamics in vivo: implications for
genetic variation, pathogenesis, and therapy. Science
1995;267:483.
137. Schuurman R, Nijhuis M, van Leeuwen R, et al. Rapid changes
in human immunodeficiency virus type 1 RNA load and
appearance of drug-resistant virus populations in persons
treated with lamivudine (3TC). J Infect Dis 1995;171:1411.
138. Stein DS, Korvick JA, Vermund SH. CD4+ lymphocyte cell
enumeration for prediction of clinical course of human
immunodeficiency virus disease: a review. J Infect Dis
1992;165:352.
139. Mellors JW, Munoz A, Giorgi J, et al. Plasma load and CD4+
lymphocytes as prognostic markers of HIV-1 infection. Ann
Intern Med 1997;126:946.
140. Mulder J, McKinney N, Christopherson C, et al. A rapid and
simple PCR assay for quantication of HIV-1 RNA in plasma:
application to acute retroviral infection. J Clin Microbiol
1994;32:292.
141. Welles SL, Jackson JB, Yen-Lieberman B, et al. Prognostic value
of plasma human immunodeficiency virus type 1 (HIV-1)
RNA levels in patients with advanced HIV-1 disease and with
little or no prior zidovudine therapy. J Infect Dis 1996;174:696.
142. Coombs RW, Welles SL, Hooper C, et al. Association of plasma
human immunodeciency virus type 1 RNA level with risk of
clinical progression in patients with advanced HIV infection.
J Infect Dis 1996;174:704.
143. OBrien WA, Hartigan PM, Martin D, et al. Changes in plasma
HIV-1 RNA and CD4+ lymphocyte counts and the risk of
progression to AIDS. N Engl J Med 1996;334:425.
144. Katzenstein DA, Hammer SM, Hughes MD, et al. The relation
of virologic and immunologic markers to clinical outcomes
after nucleoside therapy in HIV-infected adults with 200 to 500
CD4 cells per cubic millimeter. N Engl J Med 1996;335:1091.
145. Marschner IC, Collier AC, Coombs RW, et al. Use of changes
in plasma levels of human immunodeficiency virus type-1
RNA to assess the clinical benet of antiretroviral therapy. J
Infect Dis 1998;177:40.
146. Quinn TC, Wawer MJ, Sewankambo N, et al. Viral load and
heterosexual transmission of human immunodeciency virus
type 1. N Engl J Med 2000;342:921.
147. Jacquez J, Koopman J, Simon C, et al. Role of the primary
infection in epidemics of HIV infection in gay cohorts. J Acquir
Immune Dec Syndr 1994;7:1169.
148. Rich JD, Merriman NA, Mylonakis E, et al. Misdiagnosis of
HIV infection by HIV-1 plasma viral load testing: a case series.
Ann Intern Med 1999;130:37.
149. Musey L, Hughes J, Schacker T, et al. Cytotoxic-T-cell responses,
viral load, and disease progression in early human immunod-
eciency virus type 1 infection. N Engl J Med 1997;337:1267.
150. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous
HIV-1-specic CD4+ T-cell responses associated with control
of viremia. Science 1997;278:1447.
151. Daar ES, Little SJ, Pitt JA, et al. Protease inhibitor (PI)- and
non-PI-containing antiretroviral therapy (ART) compared to
no treatment in primary HIV infection (PHI) [abstract402].
Program and abstracts of the 8th Conference on Retroviruses
and Opportunistic Infections; 2001 Feb 48; Chicago, Illinois.
152. Lifson AR, Rutherford TW, Jaffe HW. The natural history of
human immunodeficiency virus infection. J Infect Dis
1988;158:1360.
153. Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of
human immunodeficiency virus-associated opportunistic
infections in the United States in the era of highly active anti-
retroviral therapy. Clin Infect Dis 2000;30:S5.
154. Michelet C, Arvieux C, Franois C, et al. Opportunistic infec-
tions occurring during highly active antiretroviral treatment.
AIDS 1998;12:1815.
155. Haynes BF, Pantaleo G, Fauci AS. Toward an understanding of
the correlates of protective immunity to HIV infection. Science
1996;271:324.
156. Dean M, Carrington M, Winkler C, et al. Genetic restriction of
HIV-1 infection and progression to AIDS by a deletion allele
of the CKR5 structural gene. Hemophilia Growth and
Development Study, Multicenter AIDS Cohort Study,
Multicenter Hemophilia Cohort Study, San Francisco City
Cohort, ALIVE Study. Science 1996;273:1856.
157. Horuk R. Chemokine receptors and HIV-1: the fusion of two
major research elds. Immunol Today 1999;20:89.
158. McDermott DH, Zimmerman PA, Guignard F, et al. CCR5
promoter polymorphism and HIV-1 disease progression.
Lancet 1998;352:866.
159. Levy JA, Mackewicz CE, Barker E. Controlling HIV pathogen-
esis: the role of the noncytotoxic anti-HIV response of CD8(+)
T cells. Immunol Today 1996;17:217.
160. Richman DD, Bozzette SA. The impact of the syncytium-
inducing phenotype of human immunodeciency virus on
disease progression. J Infect Dis 1994;169:968.
161. Berger EA, Murphy PM, Farber JM. Chemokine receptors as
HIV-1 coreceptors: roles in viral entry, tropism, and disease.
Ann Rev Immunol 1999;17:657.
162. Learmont J, Geczy A, Raynes-Greenow C, et al. The Sydney
Blood Bank Cohort infected with attenuated quasispecies of
HIV-1: long-term nonprogression [abstract 13350]. XII World
AIDS Conference; 1998 June 28July 3;Geneva, Switzerland.
163. Klein MR, VanBaalen CA, Holwerden AM, et al. Kinetics of
Gag-specic cytotoxic T lymphocyte responses during the clin-
ical course of HIV-1 infection: a longitudinal analysis of rapid
progressors and long-term asymptomatics. J Exp Med
1995;181:1365.
164. Glick M. Dental management of patients with HIV. Carol
Stream (IL): Quintessence Publishing Co, Inc.; 1994.
165. Abel SN, Croser D, Fischman SL, et al. Dental Alliance for
AIDS/HIV Care (DAAC): principles of dental management
for the HIV-infected patient. Dental Alliance for AIDS/HIV
Care; 1999.
166. Patton LL, Glick M. Clinicians guide to treatment of HIV-
infected patients. 3rd ed. American Academy of Oral
Medicine; 2001.
167. Glick M, Abel S. Dental implants and HIV disease. Implant
Dent 1993;2:149.
168. Dodson TB, Perrott DH, Gongloff RK, et al. Human immun-
odeficiency virus serostatus and the risk of postextraction
complications. Int J Maxillofac Surg 1994;2:100.
169. Glick M, Abel S, Muzyka B, et al. Dental complications after
treating patients with AIDS. J Am Dent Assoc 1994;125:296.
170. Patton LL, Shugars DC. Immunologic and viral markers of
HIV-1 disease progression: implications for dentistry. J Am
Dent Assoc 1999;130:1313.
171. Glick M. Intravenous drug users: a consideration for infective
endocarditis in dentistry? [editorial] Oral Surg Oral Med Oral
172. Glick M, Muzyka BC, Lurie D, et al. Oral manifestations asso-
ciated with HIV disease as markers for immune suppression
and AIDS. Oral Surg Oral Med Oral Pathol 1994;77:344.
173. Glick M, Muzyka BC, Salkin LM, et al. Necrotizing ulcerative
periodontitis: a marker for immune deterioration and a pre-
dictor for the diagnosis of AIDS. J Periodontol 1994;65:393.
174. Patton LL. Sensitivity, specicity, and positive predictive value
of oral opportunistic infections in adults with HIV/AIDS as
markers of immune suppression and viral burden. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2000;90:182.
175. Glick M, Berthold P. Oral manifestations and conditions found
in individuals with HIV infection. In: Buckley RM, editor. HIV
infection in primary care. Philadelphia (PA): W. B. Saunders;
[In press]
176. Muzyka BC, Glick M. A review of oral fungal infections and
appropriate therapy. J Am Dent Assoc 1995;126:63.
177. Patton LL, McKaig R, Strauss R, et al. Changing prevalence of
oral manifestations of human immunodeciency virus in the
era of protease inhibitor therapy. Oral Surg Oral Med Oral
178. Barr CE, Glick M. Diagnosis and management of oral and
cutaneous lesions in HIV-1 disease. Oral Maxillofac Surg Clin
North Am 1998;1:25.
179. Kademani D, Glick M. Oral ulcerations in individuals infected
with human immunodeciency virus: clinical presentations,
diagnosis, management, and relevance to disease progression.
Quintessence Int 1998;29:523.
180. Ghannoum MA, Elewski B. Successful treatment of ucona-
zole resistant oropharyngeal candidiasis by a combination of
fluconazole and terbinafine. Clin Diagn Lab Immunol
1999;6:921.
181. Diz Dios P, Ocampo A, Miralles C, et al. Frequency of oropha-
ryngeal candidiasis in HIV-infected patients on protease
inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 1999:87;437.
182. Glick M, Cohen SG, Cheney RT, et al. Oral manifestations of
disseminated Cryptococcus in a patient with acquired immun-
odeficiency syndrome. Oral Surg Oral Med Oral Pathol
1987;64:454.
183. Heinic GS, Greenspan D, MacPhail LA, et al. Oral Geotrichum
candidum infection associated with HIV infection. A case
report. Oral Surg Oral Med Oral Pathol 1992;73:7268.
184. MacPhail LA, Greenspan D, Shiodt M, et al. Acyclovir-resistant,
foscarnet-sensitive oral herpes simplex type 2 lesion in a patient
with AIDS. Oral Surg Oral Med Oral Pathol 1989;67:427.
185. Heinic GS, Northfelt DW, Greenspan JS, et al. Concurrent oral
CMV and HSV infection in association with HIV infection: a
case report. Oral Surg Oral Med Oral Pathol 1993;75:488.
186. Glick M, Cleveland DB, Salkin LM, et al. Intraoral
Cytomegalovirus lesion and HIV-associated periodontitis in a
patient with acquired immunodeciency syndrome. Oral Surg
Oral Med Oral Pathol 1991;72:716.
187. Kabani S, Greenspan D, deSouze Y, et al. Oral hairy leuko-
plakia with extensive oral mucosal involvement. Oral Surg
Oral Med Oral Pathol 1989;67:411.
188. Glesby MJ, Moore RD, Chaisson RE. Clinical spectrum of her-
pes zoster in adults infected with human immunodeciency
virus. Clin Infect Dis 1995;21:370.
189. Breton G, Fillet AM, Katlama C, et al. Acyclovir-resistant her-
pes zoster in human immunodeficiency virusinfected
patients: results of foscarnet study. Clin Infect Dis
1998;27:1525.
190. Martinez E, Gatell J, MoranY, et al. High incidence of herpes
zoster in patients with AIDS soon after protease inhibitor ther-
apy. Clin Infect Dis 1998;27:1510.
191. Ensoli B, Sgadari C, Barillari G, et al. Biology of Kaposis sar-
coma. Eur J Cancer 2001;1251.
192. Glick M, Cleveland DB. Oral mucosal bacillary (epithelioid)
angiomatosis in a patient with AIDS-associated with rapid
alveolar bone loss: a case report. J Oral Pathol Med 1993;
22:235.
193. Muzyka BC, Glick M. Sclerotherapy for the treatment of nodu-
lar intraoral Kaposis sarcoma in patients with AIDS [corre-
spondence]. N Engl J Med 1993;328:210.
194. Yarchoan R. Therapy for Kaposis sarcoma: recent advances
and experimental approaches. J AIDS 1999;21:S66.
195. Itin PH, Latenschlager S. Viral lesions of the mouth in HIV-
infected patients. Dermotology 1997;194:1.
196. Lozada-Nur F, Glick M, Shubert M, et al. Use of intralesional
interferon-alpha for the treatment of recalcitrant oral warts in
patients with AIDS: report of 4 cases. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod. [In press]
197. Lamster IB, Grbic JT, Mitchell-Lewis D, et al. New concepts
regarding the pathogenesis of periodontal disease in HIV
infection. Ann Periodontol 1998;3:62.
198. Dimitrakopolous I, Zouloumis L, Lazaridis N, et al. Primary
tuberculosis of the oral cavity. Oral Surg Oral Med Oral Pathol
1991;72:712.
199. Eng HL, Lu SY, Yang CH, et al. Oral tuberculosis. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 1996;81:415.
200. Ficarra G, Zaragoza AM, Stendardi L, et al. Early oral presen-
tation of lues maligna in a patient with HIV infection. Oral
Surg Oral Med Oral Pathol 1993;75:728.
201. Muzyka BC, Glick M. Necrotizing stomatitis and AIDS. Gen
Dent 1994;42:66.
202. Muzyka BC, Glick M. Major aphthous ulceration in patients
with HIV disease. Oral Surg Oral Med Oral Pathol 1994;77:116.
203. Glick M, Muzyka BC. Alternative therapies for major aphthous
ulcers in AIDS patients. J Am Dent Assoc 1992;123:61.
204. Gilquin J, Weiss L, Kazatchkine MD. Genital and oral erosions
induced by foscarnet. Lancet 1990;335:287.
205. McLeod GX, Hammer SM. Zidovudine: ve years later. Ann
Intern Med 1992;117:487.
206. McNeely MC, Yarchoan R, Broder S, et al. Dermatologic com-
plications associated with administration of 23-dideoxycyti-
dine in patients with human immunodeciency virus. J Am
Acad Dermatol 1989;21:1213.
207. Shiodt M. Less common oral lesions associated with HIV
infection: prevalence and classication. Oral Dis 1997;3:S208.
208. Luzzi GA, Jones BJ. Treatment of neutropenic oral ulceration
in human immunodeciency virus infection with G-CSF. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:53.
209. Greenberg MS, Glick M, Nghiem L, et al. Relationship of
Cytomegalovirus to salivary gland dysfunction in HIV-infected
patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1997;83:334.
210. Flaitz CM, Hicks MJ. Oral candidiasis in children with immune
suppression: clinical appearance and therapeutic considera-
tions. ASDC J Dent Child 1999;66:161.
211. Nicolatou O, Theodoridou M, Mostrou G, et al. Oral lesions in
children with perinatally acquired human immunodeciency
virus infection. J Oral Pathol Med 1999;28:49.
212. Velegraki A, Nicolatou O, Theodoridou M, et al. Paediatric
AIDS-related linear gingival erythema: a form of erythematous
candidiasis? J Oral Pathol Med 1999;28:178.
213. Flynn PM, Cunningham CK, Kerkering T, et al. Oropharyngeal
candidiasis in immunocompromised children: a randomized,
multicenter study of orally administered uconazole suspen-
sion versus nystatin. J Pediatr 1995;127;322.

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