Download Oral mucosal lesions caused by infective microorganisms I. Viruses

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Periodontology 2000, Voi. 21, 1999, 106-124
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PERIODONTOLOGY 2000
ISSN 0906-6713
Oral mucosal lesions caused by
infective microorganisms
I. Viruses and bacteria
-
FRANCISCO
RIVERA-HIDALGO
& THOMAS
W. STANFORD
The purpose of this chapter is to concisely review
oral lesions that are caused by viruses and bacteria
infecting the oral tissues. In this context we adhere
to the classical concept of infection: the state of injury or damage that results from the process by
which organisms, capable of causing disease, gain
entry to the body and establish colonies.a Oral
lesions may originate from local infections or may
represent the oral manifestations or consequences of
a systemic infection.
The oral mucosal environment is characterized by
the presence of a large complex microbiota that,
under normal circumstances, does not cause pathosis. The health status of the mouth is largely the
result of a balance resulting from the interaction between microorganisms and the local defensive
mechanisms, and thus, any changes that may alter
this interaction may lead to disease. Factors that may
alter this balance include changes in the integrity of
the epithelium, changes in lubrication of the mucosa
and changes in secretion of saliva.
This oral environmental balance might also be altered by changes in the systemic defensive posture
that result from a compromised immune system.
When the defensive system is temporarily weakened
by stress, smoking and poor oral hygiene, diseases
such as acute necrotizing ulcerative gingivitis can
ensue. Normal microbiota microorganisms can become opportunistic pathogens in an altered oral environment.
Lesions of infective origin may affect any of the
oral mucosal structures: the masticatory mucosa, the
lining mucosa and the specialized mucosa. The term
infective stomatitis, used as an inclusive term, is preferred to group these lesions. For the purpose of this
Modified from: Collins dictionary of medicine. Glasgow, Harper Collins.
I06
review, the lesions of infective stomatitis are categorized according to the type of microorganism causing
the infection. The literature reports on bacterial
stomatitis, fungal stomatitis, parasitic stomatitis and
viral stomatitis. This chapter presents reviews of viruses and bacteria. Part I1 presents reviews of fungi
and parasites.
Incidence of infective stomatitis
Infective stomatitis is infrequently observed in the
healthy individual, but there exists an impression of
an overall increase in incidence during the past few
years due to increased incidence rates of tuberculosis (189) and syphilis (55). There have also been
reports of an increased incidence of opportunistic
oral infections (3) and other types of oral infections
(99), especially in human immunodeficiency virus
(HIV)-positivepatients.
One may speculate that the ever-increasing use of
antibiotics, an expanding population of immunosuppressed individuals and a more mobile global
society are factors that have contributed to the rise
in the incidence of oral infections. By far, immunosuppression represents the major contributing factor. With the appearance of HIV disease, many of the
previously rare diseases have reappeared and sometimes with a different presentation.
The development of molecular biology techniques
and better understanding of immune mechanisms
have contributed significantly in the detection of
previously unrecognized pathogens in a disease process. This is particularly true for virally induced diseases.
It is with this background that we review the
literature for oral infectious diseases.
Oral mucosal lesions caused bv infectiue microorganisms. I. Viruses and bacteria
Table 1. Oral viral infections
Infection
~-
Causative virus
Strains or other names
or acronyms
Measles
Measles virus
Mumps
Mumps virus
Hand, foot and mouth disease
Herpanaina
Coxsackievirus
Coxsackievirus
(A5, A10, A16)
(A2-6,A10)
Primary herpetic gingivostomatitis
Recurrent intraoral herpes
Recurrent herpes labialis
Herpes simplex type 1 (HSV-1) or type 2 virus
HSV-1, HSV-2
HSV-1, HSV-2
(HHV-1, HHV-2)
(HHV-1, HHV-2)
Varicella (chickenpox1
Shingles
Infectious mononucleosis
Hairy leukoplakia
Varicella-zoster virus
Varicella-zoster virus
Epstein-Barr virus
Epstein-Barr virus
(HHV-3)
(HHV-3)
(HHV-4)
(HHV-4)
(HHV-5)
a
Roseola (exanthema subitum)"
Heterophil-negative infectious mononucleosis
Human herpesvirus 6
(HHV-6)
Kaposi's sarcoma
Kaposi's sarcoma herpesvirus
(HHV-8)
Oral lesions have not been reported: this is included from completion. High proportions of oral squamous carcinoma lesions have been shown to be
positive for HHV-6.
A recent report supports a role for HHV-7 in pityriasis rosea.
Infective stomatitis:
infections caused by viruses
Oral lesions secondary to viral infections are relatively common during an individual's lifetime. Diseases of the infancy and childhood such as measles
and mumps are caused by an RNA virus (paramyxoviridae) and may present oral lesions. Coxsackieviruses, a subgroup of the RNA enteroviruses, cause
herpangina and hand, foot and mouth diseases,
which present oral lesions. Oral papillomas, oral verrucous carcinoma and focal epithelial hyperplasia
are caused by a DNA virus (human papillomavirus
of the papovavirus family). Oral lesions are also produced by the human herpesvirus family, which are
DNA viruses. Viruses belonging to the herpes family
are major pathogens in oral disease. A summary of
oral viral infections appears in Table 1.
Paramyxoviridae
Paramyxoviridae is a family of RNA viruses composed of three genera: Paramyxovirus, Morbillivirus
and Pneumovirus.
Measles. An enveloped RNA virus that belongs to the
Morbillivirus genus causes measles (rubeola) (8, 74).
This virus, which was first isolated in cultures in
1954, preferentially infects monocytes. Measles is a
highly communicable disease transmitted by inhalation of infective droplets with an incubation period
of 10 to 14 days. Measles remains a major cause of
childhood mortality in developing countries (36).
Measles is one of a group of vaccine-preventable diseases in which vaccination programs have greatly reduced its incidence. It is an acute systemic condition
with a prodrome in which the patient suffers from
cough, conjunctivitis, fever, photophobia, rhinitis
and Kopliks spots. Kopliks spots, the bluish-gray
specks on a red base, are pathognomonic for
measles, as they appear approximately 48 hours before the irregular red-brick maculopapular skin rash.
Kopliks spots appear on the mucosa next to the molar teeth and may last for 4 days. Shedding of the
measles virus starts during the prodromal stage and
continues through the acute stage. A recent report
has shown that laboratory confirmation of measles
is possible using oral fluids for the detection of
measles-specific immunoglobulin M (IgM) (76). In a
recent report, cases originally diagnosed as measles
or rubella (German measles) were later diagnosed as
primary herpesvirus 6 and herpesvirus 7 infections
(181.
Mumps. Mumps (epidemic parotiditis) (8, 74) is
caused by the mumps virus, an RNA virus that be-
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longs to the Paramyxovirus genus. Parotid salivary
gland infection may occur unilaterally or bilaterally,
and viremia can lead to orchitis, aseptic meningitis,
pancreatitis and oophoritis, especially in unvaccinated individuals. Affected salivary glands may be
swollen and painful and may be accompanied by
erythema and swelling of the parotid (Stensen’s)
duct. Mumps is a highly communicable disease
transmitted by inhalation of infective droplets with
an incubation period of 14 to 21 days. Similar to
measles, the disease is one of a group of vaccinepreventable diseases, and vaccination programs
have greatly reduced its incidence.
Picornaviridae
Picornaviridae is a family of single-stranded nonenveloped RNA viruses composed of three genera: Enterovirus, Poliovirus and Rhinovirus. The Enterovirus
genus includes the coxsackievirus (A and B), echoviruses, enteroviruses and poliovirus (types 1, 2 and
3).
Coxsackieviruses. Coxsackieviruses are antigenically
divided into groups A and B comprising more than
50 serotypes. Infections are more common during
the summer months and are transmitted by contaminated aerosol (74). Many of these viruses can
cause oropharyngeal vesiculoulcerative lesions and
are clinically differentiated by the location of the
lesions (47). These viruses are responsible for hand,
foot and mouth disease, herpangina, lymphonodular
pharyngitis and ulcerative oropharyngitis, all producing oral lesions. Lymphonodular pharyngitis features orange slightly painful papules in the soft palate while ulcerative pharyngitis produces ulcerations
in the soft palate, lips and buccal mucosa (47).
Hand, foot and mouth disease. Hand, foot and
mouth disease can be caused by coxsackieviruses A5,
A10 and, most commonly, by A16. It is a disease of
children with an incubation period of 3 to 5 days,
but the disease has been reported in adults as well
(97). The lesions appear as ulcerations on buccal
mucosa (rhomboidal vesicles “square blisters” (162))
and soft palate, often in conjunction with ulcers on
the hands and feet. In the largest reported epidemic
in England and Wales during 1994, most of 950 cases
were children 1-4 years of age and disease severity
was associated with the degree of mouth lesions
(14). Treatment with acyclovir has been reported to
be effective (162). The disease is benign and resolves
in 7 to 10 days.
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Herpangina. Herpangina is caused by coxsackieviruses A2, A3, A4, A5, A6 and A10. It features clustered petechiae in the soft palate that become shallow ulcers in a few days and then heal. Headache,
high fever, myalgia and sore throat precede soft palate lesions. Treatment is palliative.
Papovaviridae
Papovaviridae are a family of DNA viruses that are
responsible for producing tumors and capable of
transforming animal cell lines. The family is composed of the Papillomavirus genus and the Polyomavirus genus.
Papillomavirus. The human papillomavirus is composed of more than 60 serological types (39). Papillomaviruses cause lesions in many areas of the body,
including genitalia, the nasal cavity, larynx, trachea,
esophagus and the mouth. Diagnosis of papillomavirus lesions is made based on the histopathological appearance. Characteristic features include koilocytosis, acanthosis and papillomatosis which,
coupled to the clinical appearance, suggest the infection (39). The classical oral lesions associated with human papillomavirus are squamous cell papilloma (58,
143, 182), condyloma acuminatum (58, 1431, verruca
vulgaris (58, 143) and focal epithelial hyperplasia (58,
143).
Squamous cell papilloma is a cauliflower-like
lesion with a narrow base. It is a small, pink exophytic growth of the oral mucosa. The lesion of condyloma acuminatum is similar, presenting multiple
small, soft, pale lesions with a cauliflower-like surface. Histologically, both lesions have the same appearance, and human papillomavirus types 6 and 11
are involved (135, 197). Treatment is by surgical excision.
Verruca vulgaris or the common wart is a narrow
exophytic growth, wider at the base, sessile and firm.
The lesion is usually found on the gingiva, labial mucosa, commissure, hard palate or tongue (113, 135,
137). Human papillomavirus types 2 and 57 have
been identified in the lesions (125, 135). Treatment
is by surgical excision.
Focal epithelial hyperplasia (Heck‘s disease)
usually presents as multiple plaque-like or papular
lesions, flat or convex, in the mucosa mostly of
children (34). The color may vary from red to gray to
white (135). Lesions occur on oral mucosa exclusively (135). There may be a genetic predisposition,
and contrary to the initial reports, the condition is
not limited to certain ethnic groups (136). The
Oral mucosal lesions caused by infective microorganisms. I. Viruses and bacteria
lesions are benign and may resolve spontaneously.
Human papillomavirus types 13 and 32 have been
implicated as causative agents (124, 135).
Other oral lesions (135) that have been associated
with human papillomavirus include erythroplakia
(HPV-16), proliferative verrucous leukoplakia (HPV16) (1261, candidal leukoplakia (1881, oral squamous
cell carcinoma (HPV-16 and HPV-19) (9, 109, 135,
188) and lichen planus (HPV-6, HPV-11 and HPV-16)
(87, 135, 179). Overall, HPV types 2, 4, 6, 11, 13 and
32 have been associated with benign oral lesions
while HPV types 16 and 18 have been associated
with malignant lesions (58). Transmission of the virus can occur with direct contact and from mother
to child during delivery (138).
Herpetoviridae
The Herpetoviridue family contains only one genus:
Herpesvirus. Viruses of the herpes family are doublestranded DNA viruses transmitted from host to host
by direct contact with saliva or genital secretions,
where they are shed by asymptomatic hosts (67). The
herpes viruses are classified into three groups (30).
The alpha group (subfamilyAlphuherpesvirinue) includes the herpes simplex virus 1 (HSV-l),the herpes
simplex virus 2 (HSV-2) and the varicellazoster virus.
The beta group (subfamily Betuherpesvirinae) includes the human cytomegalovirus, while the
gamma group (subfamily Gummuherpesvirinae) includes the Epstein-Barr virus. The species names
and the acronyms of herpes viruses used in the
literature are as follows: human herpesvirus 1 (HSV11, human herpesvirus 2 (HSV-21, human herpesvirus 3 (varicellazoster virus), human herpesvirus 4
(Epstein-Barr virus), human herpesvirus 5 (human
cytomegalovirus), human herpesvirus 6 (HHV-61,
human herpesvirus 7 (HHV-7)and human herpesvirus 8 (HHV-8 or Kaposi’s sarcoma herpesvirus).
Herpesviruses cause a primary infection after
which they remain latent within the host’s cells for
the life of the individual. While latent, the virus may
become reactivated and may cause symptomatic or
asymptomatic recurrent infection (160). Factors that
may trigger reactivation of the virus include trauma,
stress, immunosuppression, immune dysfunction
and radiotherapy (22, 123). Latency is maintained
(67) for HSV-1, HSV-2 and varicellazoster virus in
sensory nerve ganglia; Epstein-Barr virus in B
lymphocytes and salivary gland tissue (1131, human
cytomegalovirus in lymphocytes and salivary gland
tissue, HHV-6 in mononuclear cells in ductal epithelium (192), HHV-7 in salivary gland tissue primarily
the submandibular gland (153) and HHV-8 in salivary gland tissue (102). It has been proposed that the
clinical patterns of reactivation of HSV-1, HSV-2 and
varicellazoster virus are different (170).
Herpes simplex virus types 1 and 2. The primary infection with herpes simplex virus usually occurs in infants or children and may cause a prodrome of fever,
malaise and nausea. The infection may go unnoticed,
be subclinical or produce pharyngitis (67). Usually,
the infection presents vesicles on the mucosa of the
mouth and pharynx that break to produce ulcers. A
generalized marginal gingivitis may occur in conjunction with ulcers in the alveolar mucosa and gingiva,
and crusting of the lips is a common feature. Lesions
can occur extraorally, while systemic symptoms
usually include fever and chills. This primary herpetic
gingivostomatitis is usually accompanied by cervical
lymphadenopathy, and it may be more severe when
it occurs in adults (47). Disseminated herpes simplex
virus infections have been reported with a flu-like
prodrome and a severe generalized outbreak of vesiculo-ulcerative lesions. The disseminated herpes simplex virus infection can occur during pregnancy, and
infants born during the course of such infection have
a high mortality rate (196).
After the primary infection, the virus goes dormant in the sensory and autonomic trigeminal or
sacral ganglia to be reactivated by certain conditions.
Latent infection exists when the viral genome is
present in the tissue without production of infective
viral particles (169). Recurrent infections affect 20%
to 40% of individuals after the primary infection (67).
Recurrent infections with type 1herpes simplex virus
are classically described as occurring above the
waist, whereas type 2 infections occur below the
waist, but either can appear in the other region.
There is regional preference of reactivation for each
virus; type 1 virus appears to arise more frequently
from the trigeminal ganglia, affecting the oral cavity,
whereas type 2 is most often reactivated from the
sacral ganglia, producing genital lesions (195). The
typical appearance of intraoral recurrent lesions (recurrent intraoral herpes) is of a cluster of small ulcers in the attached gingiva. The initially discrete
and usually painful ulcers may coalesce to form
larger lesions that heal in 10 to 12 days. In HIV-positive patients and other immunocompromised individuals, atypically deep and large ulcers may occur
that persist for weeks to months.
Herpes labialis (cold sores) is a common expression of recurrent herpes infection. Lesions may affect
the lips and perioral skin as a result of triggering of
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a latent ganglion infection, usually by ultraviolet
radiation (96), other local stimuli, fever, emotional
stress or menstruation (169). Lesions appear as
closely clustered vesicles that tend to reappear in the
same area with each outbreak (170). It is interesting
to note that, even after repeated infection, there appears to be no sensory loss in the area (65).
Trigeminal neuralgia has been described in conjunction with episodes of herpes labialis, suggesting
that the neuro-sensory abnormalities may be induced by reactivation of herpes simplex virus (65). In
addition, herpetic reactions may sometimes trigger
unilateral or bilateral facial paralysis (herpetic facial
paralysis), which may be identical to Bell’s palsy
(157). Herpetic infection of the fingers (herpetic
Whitlow) can induce painful locally severe lesions in
which surgical intervention may lead to spread of
the virus and is thus contraindicated (89, 90). Herpetic Whitlow was an occupational hazard for dental
professionals prior to initiation of universal infection
control measures such as gloving for all patient care
in dental practice. Acyclovir has been recommended
in treatment of the various forms of recurrent HSV1 and HSV-2 infections, but the drug appears more
predictably successful in the management of genital
herpes as opposed to oral lesions. Oral lesions are
quite responsive to acyclovir, however, in immunocompromised individuals (147).
In HIV-positive patients, herpes simplex virus has
been recovered from persistent oral ulcers in more
than 30% of cases (48). In another report, cultures
from 40 HIV-positive patients with persistent oral ulcers yielded herpes simplex virus in 19% of the cases,
cytomegalovirus in 53% and coinfection of herpes
simplex virus and cytomegalovirus in 28% (53). In
this study, treatment with systemic ganciclovir in
conjunction with oral acyclovir resulted in lesion resolution in all but one case.
Diagnosis of herpes simplex virus from lesions can
be made using cultures, which take up to 10 days, or
by using enzyme-linked immunosorbent assay (961,
polymerase chain reaction (65, 169) or direct immunofluorescence. Cultures are more predictably diagnostic if obtained from an early vesicular lesion
rather than an ulcer.
Varicella zoster virus (HHV-3). The varicella zoster
virus causes varicella (chickenpox) as a primary infection mainly in children and later, in adults, its reactivation causes herpes zoster (shingles). Varicella
is a highly infectious disease transmitted by inhalation of infective droplets and by direct contact with
lesions. It is self-limiting in children and more severe
110
in adults. The pruritic skin rash progresses through
macules, papules, vesicles, drying vesicles and scabs,
with healing occurring over 2 to 3 weeks. Oral lesions
include vesicles on the lips, hard palate and soft palate (113). After the primary infection, the virus remains latent in the dorsal root ganglion (it is not
clear whether it resides in neurons or in satellite cells
(156)) to be reactivated later.
Herpes zoster results from reactivation of the latent virus. Fever and malaise may accompany the appearance of lesions. Vesicles quickly break to form
ulcerated lesions with prominent red borders, resembling apthae. Lesions are unilaterally distributed
along the infected nerve (113). Paresthesia, pain and
tenderness are the initial symptoms of herpes zoster,
which may appear prodromally 3-5 days before the
lesions (67).The infection is more frequent in elderly
individuals, and it has been suggested that shingles
may signal the presence of systemic disease. When
reactivation occurs from the trigeminal ganglion,
there seems to be a preference for the second or
third divisions (67). It is not known what induces reactivation, but alterations in cell-mediated immunity have been implicated (91). In most patients, the
infection is self-limiting. Antiviral agents (acyclovir,
valacyclovir and famciclovir (67, 130))are effective in
reducing the course of the disease in varicella and in
reducing the effects of secondary infections. Antiviral agents should be used as early as possible in
disease development (113).
Prolonged postherpetic neuralgia is a common aftermath of herpes zoster (118).It is hypothesized that
the neuralgia results from virally induced lesions in
the neurons (145).Necrosis of alveolar bone followed
by tooth exfoliation has been described as a complication of intraoral herpes zoster (118).
In immunocompromised individuals, including
those with HIV, there is increased incidence and recurrence (170) of herpes zoster infection. Chronic
varicella occurs in HIV-positive patients and is an
atypical persistent form of the disease. Treatment
with intravenous acyclovir and foscarnet has been
effective in controlling the infection (27). Clinical
presentation and occurrence of complications of virus reactivation are related to degree of immunodeficiency (178).
Epstein-Barr virus (HHV-4). The Epstein-Barr virus
is transmitted by blood or saliva. Primary infection
can occur at any age. It is often subclinical in
children. Epstein-Barr virus can cause infectious
mononucleosis in adolescents and young adults.
The symptoms of infectious mononucleosis in-
Oral mucosal lesions caused by infective microorganisnu. I. Viruses and bacteria
clude fever, lymphadenopathy (especially the posterior cervical chain), malaise and sore throat (pharyngitis). Oral ulcers, multiple palatal petechia and
infrequently gingival ulcerations have been reported
(67, 113). Diagnostic tests for heterophile antibodies
produced by Epstein-Barr virus are available
(Monospot test). The disease is self-limiting, requiring bed rest and analgesics, with recovery usually occurring in about 4 weeks. Acyclovir has not been effective in treatment.
Occasionally, a latent infection of Epstein-Barr virus can be reactivated, leading to viral shedding into
the oral mucosa. It has been hypothesized that constant shedding can lead to infection of epithelial
cells, and this may explain the appearance of oral
hairy leukoplakia in HIV-positive patients (82).
Oral hairy leukoplakia was first described in HIVpositive homosexual men (69). Clinically, it presents
as a white lesion most often on the ventral-lateral
surface of the tongue that can be unilateral or bilateral (156). Lesions have a corrugated appearance
with keratin projections that look like hair. The histological features include parakeratosis with hair-like
projections, hyperplasia, acanthosis and koilocytelike cells within the epithelium and an absence of
inflammation in the connective tissue (156).Langerhans cells are also absent (37).There is evidence that
Epstein-Barr virus replicates within epithelial cells
(70). The appearance of oral hairy leukoplakia in
HIV-positive patients may be highly predictive of the
development of AIDS (71). Reports indicate, however, that in some cases, oral hairy leukoplakia can
appear in the absence of HIV, and oral hairy leukoplakia has been reported in patients who are not immunosuppressed (102, 113). Additionally, there are
reports of lesions similar to oral hairy leukoplakia in
cases that were Epstein-Barr virus negative (66, 111).
Epstein-Barr virus has also been found in malignancies (nasopharyngeal carcinoma, Burkitt’s
lymphoma, B-cell lymphoma (67) and oral squamous cell carcinoma (52)) and in periodontal disease
(35), although its role in periodontal disease has not
been determined.
Human cytomegalovirus (HHV-5). Human cytomegalovirus is found in many of the body secretions (including blood, milk and saliva) of infected
individuals. However, it is one of the least prevalent herpesvirus infections (113). Most primary infections are asymptomatic, and it is not clear
where the virus remains latent, although it is recoverable from 25% of salivary glands (74). Endothelial and ductal epithelial cells seem to be a tar-
get for human cytomegalovirus (86). Antibody to
human cytomegalovirus is present in the serum of
most homosexual men (74).
Human cytomegalovirus infection produces
three recognizable clinical syndromes (74): perinatal disease and human cytornegalovirus inclusion disease, acute acquired human cytoinegalovirus infection and human cytomegalovirus disease in immunocompromised hosts. Perinatal
disease is the result of a primary infection while
the mother is pregnant. The infection may affect
the fetus, causing severe consequences. When the
infection is acquired neonatally, it resembles infectious mononucleosis or it may be asymptomatic.
The second syndrome is similar to infectious
mononucleosis except that there is no (or milder)
pharyngitis associated and no production of heterophil antibodies. The third syndrome is observed
in immunocompromised individuals, tissue and
bone marrow transplant patients, and in HIV-infected patients. Human cytomegalovirus infection
in these patients is in itself immunosuppressive
and can worsen HIV opportunistic infections.
Oral lesions in patients infected with human cytomegalovirus occur in the latter two syndromes. The
most common manifestation of primary infection is
heterophil-negative infectious mononucleosis (1131,
which occurs in adults (113). Infection can result
from sexual contact and blood transfusions (67).The
disease follows a course similar to that seen with
Epstein-Barr virus infection and is self-limiting.
Oral ulcerations related to human cytomegalovirus have been described in immunodepressed patients (53, 86, 141). It has been reported that, in a
group of HIV-positive patients, more than half (53%)
of persistent ulcers were associated with human
cytomegalovirus, and another 28% were associated
with human cytomegalovirus and herpes simplex virus coinfection (53).Tissue biopsies of suspected human cytomegalovirus-induced oral ulcers can be diagnosed by a combination of histological and immuno cytochemical met hods (53).Treatment with a
combination of oral acyclovir and systemic ganciclovir has proved successful (53).
Human herpesvirus 6 (HHV-6). The originally
named human B-lymphotropic virus (154) has recently been reclassified as a herpesvirus and renamed HHV-6 (168). In infants, this virus is associated with roseola (exanthema subitum or sixth disease), a self-limiting condition that causes a mild
skin exanthem and fever (1). HHV-6 is commonly
isolated from saliva (in mononuclear cells in ductal
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epithelium) and has affinity for CD4 lymphocytes
(192). It is also suspected of causing mononucleosis,
pneumonia, meningitis, encephalitis and as a cofactor in accelerated immunosuppression in HIV-infected individuals. Infection with HHV-6 can induce
the expression of CD4 on CD8+ cells (lymphocytes
and natural killer cells), thus rendering them susceptible to infection by HIV-1 (106). It is believed that
HHV-6 is responsible for short-lived febrile illnesses
and active hepatitis in previously healthy individuals
as well as prolonged febrile illness in patients that
are immunodeficient (168). Two variants have been
identified, A and B (94). The B variant is sensitive to
ganciclovir, and both are sensitive to foscarnet (74).
There are instances where infectious mononucleosis cannot be associated with either Epstein-Barr
virus or human cytomegalovirus infection. There is
evidence that HHV-6 is responsible for some of these
infections, although is not clear whether these represent primary infections or reactivation of latent virus
(168). There is also evidence that both H W - 6 and
Epstein-Barr virus, as coinfectants, are responsible
for some acute infectious mononucleosis (17).
HHV-6 has been found in oral squamous carcinoma lesions (191, 192) and in cervical carcinoma
(191). In a study of 51 squamous cell carcinomas, 18
non-malignant lesions and 7 normal mucosa
samples, HHV-6 was found in 79% of malignancies,
67% of lichen planus lesions and leukoplakia and
was not present in normal mucosa (193). In this
study, HHV-6 variant B was found in 60% of the malignancies.
Human herpesvirus 7 (HHV-7). HHV-7 is a ubiquitous virus, that is very similar to HHV-6 in that it has
serological cross-reactivity with some antibodies to
HHV-6 (102). Infection is usually acquired in childhood with most adults being seropositive. The virus
is found in saliva and is secreted for many years after
initial infection (173). Saliva represents the major
mode of transmission, and transmission has been
detected from a grandparent to a parent to a child
(173). In general, initial infection occurs later in life
than with HHV-6 infection. Minor labial salivary
glands have been shown to harbor the virus, and
these glands may sometimes be the sites where replication occurs (193). In a study of more than 100
specimens from the three salivary glands, HHV-7
was found in 100% of submandibular gland samples,
85% of the parotid gland samples and in 59% of lip
minor salivary gland samples (153). HHV-7 has been
reported to enhance the cytotoxicity of natural killer
cells through induction of interleukin 15 (5).
112
HHV-7 appears to be associated with at least
two conditions: roseola and pityriasis rosea. Patients recovering from roseola were found to have
sera positive to both HHV-6 and HHV-7, suggesting
a role for both viruses in the disease (120). Patients
with pityriasis rosea showed HHV-7 DNA in
plasma, supporting a role for viral replication and
virulence (42). Pityriasis rosea is a self-limiting exanthem without systemic signs or symptoms characterized by crops of maculopapular pale-red oval
lesions on skin that may last for up to 2 weeks
(60). Oral lesions of the tongue and cheek have
been reported in pityriasis rosea (180). There is
evidence that infections misdiagnosed as measles
and rubella could be caused by primary infections
of HHV-6 or HHV-7 (18).
Human herpesvirus 8 (HHV-8). Newly discovered,
the human herpesvirus 8 is believed to be associated
with the pathogenesis of human lymphomas (22,
30). Originally, the virus was called Kaposi’s sarcoma
herpesvirus and was later renamed HHV-8 (57, 93).
HHV-8 DNA sequences have been identified in body
cavity-based non-Hodgkin’s lymphomas, Castleman’s disease, angioimmunoblastic lymphadenopathy and all forms of Kaposi’s sarcoma (102, 105).
Serological evidence indicates that HHV-8 is found
in 25% of the adult population and in up to 8% of
children in the United States (100). It is also evident
that women with AIDS are much less likely to develop Kaposi’s sarcoma than men (63).
Kaposi’s sarcoma was originally described as a
rare vascular malignant tumor occurring in elderly
men of mainly Mediterranean, eastern European or
Middle Eastern origin. The tumor has become more
prevalent with the advent of the AIDS epidemic, although it has been reported in the skin of an HIVnegative immunosuppressed patient with bullous
pemphigoid (59). These reports suggest that immunosuppression may serve to activate a latent
HHV-8 infection. In one study, HHV-8 DNA sequences were identified in 53 of 54 AIDS related oral
Kaposi’s sarcoma lesions (54). Palliative treatment of
the oral lesions has been reported using an intralesional injection of vinblastine (46).
Infective stomatitis:
infections caused by bacteria
Bacterial infective stomatitis has been reported in
both immunocompetent and immunocompromised
patients. Some of these infections can become es-
Oral mucosal lesions caused bv infective microornanisms. I. Viruses and bacteria
tablished as a result of transmission during sexual
activity; others result from a weakening in the host’s
defense posture and are thus opportunistic in nature. In these section we review the reported bacterial infections that can present oral lesions. A summary of oral bacterial infections and responsible organisms appears in Table 2.
Acute necrotizing ulcerative stomatitis
Acute necrotizing ulcerative gingivitis (or necrotizing
gingivostomatitis or necrotizing ulcerative gingivitis)
is an acute infection of the gingiva that has been
known by different names through the years (78).
Because of its prevalence in the soldiers fighting in
the trenches during World War I, it was called trench
mouth; because of a description of the microorganisms in the lesions by Vincent, it was also called Vincent’s infection. Vincent’s angina refers to an infection of the tonsils and pharynx usually associated
with acute necrotizing ulcerative gingivitis. Likewise,
noma or cancrum oris or gangrenous stomatitis is
often an extension of acute necrotizing ulcerative
gingivitis into the adjacent tissues. Noma is at best
disfiguring and can be lethal if not treated promptly.
In recent years, the disease has become a common
cause of mortality and disability in children of
underdeveloped areas of Africa, Asia and South
America (2, 38, 174). Noma has been reported in patients with HW, where local removal of necrotic
tissue along with lavage with providone-iodine has
been effective in controlling the disease (31).
Acute necrotizing ulcerative gingivitis is an infec-
tious disease of the gingiva causing gingival
bleeding, gingival ulceration (that may lead to the
loss of the tissue forming the papilla) and pain. It
has been reported more commonly in young adults,
although recently it has been reported with increasing frequency in children in developing countries.
Factors that may predispose to the initiation of this
disease include episodes of stress, smoking, malnutrition and poor oral hygiene (80). These factors suggest that, given the condition where poor oral hygiene exists, events that can depress the host’s immune response can precipitate the disease.
A mixed flora of spirochetes (Treportema spp.),
fusobacteria (Fusobacterium n u c l e a t u m ) , Preuotella
intermedia, Veillonella spp. and streptococci and
have been implicated in the disease. Early attempts
to induce the disease by the subcutaneous injection
of cultures from active patients have only produced
abscesses and not the disease (150). From the lesions
created, Fusobacterium fusiforme and Borwlia irincentii (a spirochete) can be recovered. However, later
work showed that the spirochete found in the lesion
was not B. vincentii (104). Listgarten showed spirochetes infiltrating healthy tissue ahead of the lesion.
Other bacteria and viruses have been found associated to the lesions, but no cause-effect relationship
has been established (116).
Acute necrotizing ulcerative gingivitis has been reported in recent years in patients with HIV infection
or AIDS. Acute necrotizing ulcerative gingivitis has
been included in a classification of periodontal diseases associated with HIV infection (43, 112). 1he
classification includes: linear gingival erythema, nec-
Table 2. Oral bacterial infections
Infection
Causative bacteria
Mixed bacterial flora
including spirochetes and Fusobacteria
~
Acute necrotizing ulcerative gingivitis (necrotizing ulcerative gingivitis,
necrotizing gingivostomatitis,necrotizing stomatitis, noma (cancrum oris),
Vincent’s infection, trench mouth)
__
Actinomycosis
~~
Actinomyces israelii
Actinomyces viscosus
Actinomyces odontolyticus
Actinomyces naeslundii
Bartonella quintana
BaronteZlu
henselae
__ _ _ _ _ _ _ _ _
Neisseria gonorrhoeae
Bacillary angiomatosis (epithelioid angiomatosis)
__
-
Gonorrhea
~~
.-
__
~
Streptococcal stomatitis
______
~
.
__.
~~
~~~
~~~~
~
~~~
~
~
~~
Mycobacterium tuberculosis
Mycobacterium leprae
rium avium and intracellulare
rium bovis
rium chelonae
Mycobacterium-kansasii
Streptococci
Group A beta-hemolytic
streptococci
~.
~~~~
113
Rivera-Hidalgo & Stanford
~~~
rotizing ulcerative gingivitis and necrotizing ulcerative periodontitis. In this classification acute necrotizing ulcerative gingivitis is described as destruction of one or more gingival papilla, with ulceration,
cratering and necrosis. In a study of naval personnel,
Horning & Cohen reported that acute necrotizing ulcerative gingivitis cases in seropositive and in seronegative HIV cases were clinically indistinguishable
(80).
Necrotizing ulcerative periodontitis is described as
producing very rapid bone loss in addition to the
findings for acute necrotizing ulcerative gingivitis
(116). Severe deep aching pain with a very rapid rate
of bone destruction is characteristic of necrotizing ulcerative periodontitis. It is believed by some that necrotizing ulcerative periodontitis is an extension of
acute necrotizing ulcerative gingivitis.Acute necrotizing ulcerative gingivitis and necrotizing ulcerative
periodontitis have been correlated with decreased
CD4 counts (<200/mm3). Glick et al. (62) reported
that HIV-seropositive individuals presenting with
necrotizing ulcerative periodontitis were 20.8 times
(odds ratio) more likely to have CD4 counts below 200
cells/mm? compared with HIV-seropositive individuals without necrotizing ulcerative periodontitis. In
this study, the predictive value of a CD4 count below
200 cells/mm3 in patients with necrotizing ulcerative
periodontitis was 95%. Further, the cumulative probability of death within 24 months of a necrotizing ulcerative periodontitis diagnosis was 73%. Necrotizing
ulcerative periodontitis can extend into the alveolar
mucosa and adjacent tissues, in which case it is designated necrotizing stomatitis (117). Periodontal disease in HIV-positive patients, like in non-seropositive
patients, seems to be the result of the interaction between the host’s immune response and the microorganisms in dental plaque. There is increased rate of
progression of periodontal disease in HIV patients,
which seems to be modified by the interaction between typical and atypical microorganisms and the
level of immunocompetence (98).
In treating acute necrotizing ulcerative gingivitis
in both normal and HIV patients, the fundamental
activity must be the debridement of teeth and
affected soft tissue areas. In classical cases of acute
necrotizing ulcerative gingivitis the use of antibiotics
without debridement has only served to suppress
the infection while the medication is being taken.
Actinomycosis
Actinomycosis is a chronic disease characterized by
the formation of abscesses, fibrosis of tissues and
114
draining sinuses. It is caused by non-spore-forming,
anaerobic or microaerophilic bacterial species of the
genus Actinoinyces. These organisms were once considered fungi because of their branching, but are
now classified as bacteria (165). The pathogenic actinomycetes do not exist free in nature but are commensals and normal inhabitants of the oropharyngeal cavity and the gastrointestinal tract. The Actinomyces are gram-positive, pleomorphic and
diphtheroidal or, more commonly, filamentous.
Actinomycosis may present in the cervicofacial, thoracic and abdominal areas of the body, as well as the
central nervous system. Cervico-facial actinomycosis
is the most common form of this disease, and oral
manifestations are part of this form (99).
Actinomyces organisms access the host tissues
when there is an interruption of the mucosal barrier.
In the oral cavity actinomycosis has been reported
following tooth extraction and may be a complication of endodontic treatment (49, 79, 183). Actinomyces involving localized atypical gingivitis has
been described, and cases involving most of the oral
tissues including the tongue and palate have been
reported (49, 50, 73, 151, 183). As the Actinomyces
infection spreads into the tissues, a hard, slow growing, relatively nontender swelling may form. Lesions
of the bone and soft tissues may also show multiple
abscesses that drain to the surface by sinus tracts.
The discharge from the tracts typically contains visible yellowish colonies of organisms called “sulfur
granules”. In late stages, osteomyelitis with extensive
bone destruction may take place. The disease may
become chronic, with old lesions healing, but new
sinuses and abscesses develop (99, 151, 165). Most
human infections are caused by Actinomyces israelii,
but other species, Actinomyces viscosus, Actinomyces
odontolyticus and Actinomyces naeslundii, have been
identified in occasional cases (15, 23, 50, 64, 152,
183).
Diagnosis is made most accurately by isolation
of Actinomyces species in cultures of clinical specimens. Indirect immunofluorescence microscopy
has also been utilized (64). The demonstration of
actinomycotic granules in exudates or in histological sections is strongly supportive of the diagnosis.
The granules consist of tangled filaments of organisms, which are apparent on microscopic examination of a Gram-stained smear. Histological diagnosis is difficult because many specimens contain
only a few granules (165). Nagler et al. (119) recently discussed the diagnostic challenge associated with actinomycosis infections. In addition to
the wide variety of clinical presentations, the
Oral mucosal lesions caused by infectiue microorganisms. I. Viruses and bacteria
authors also noted the difficulty associated with
obtaining positive cultures.
Actinomycosis was included in a list of bacterial
diseases with oral manifestations, which have been
reported to be associated with HIV (194) infection.
In 1989, Pindborg noted a single case of actinomycosis in an HIV-positive patient (132). Since then,
other cases have been reported, and although rare,
actinomycosis should be carefully considered when
diagnosing infections involving the cervicofacial
areas in patients with AIDS (107, 183).
Bacillary angiomatosis
Bacillary angiomatosis, also called epithelioid angiomatosis, is a rare vasoproliferative disorder that occurs almost exclusively in severely immunocompromised persons, primarily AIDS and cancer patients and organ transplant recipients (6, 13, 32, 33,
61, 144, 146, 166, 172). It is known to cause both cutaneous and disseminated visceral disease in these
patients. It has, however, also been reported, in immunocompetent individuals (128). It was first described by Stoler et al. in 1983 (171) as an unusual
subcutaneous vascular infection in a patient with
AIDS. The most common clinical presentation is a
cutaneous vascular lesion similar to that of Kaposi’s
sarcoma.
There have been a limited number of reports of
bacillary angiomatosis involving the oral cavity. The
lesions have been described as bluish or purple macules, pale bluish patches, and red, edematous lesions
occurring on the palate, buccal mucosa and attached
gingiva (6, 33, 61, 166, 172). Only one report describes alveolar bone loss associated with the
lesions, and in this patient, two teeth were extracted
without complication (61).
The challenge to the accurate diagnosis of bacillary angiomatosis lies in its clinical similarity to
Kaposi’s sarcoma. Bacillary angiomatosis is treatable,
and in most cases curable with antibiotic therapy.
Biopsy confirmation of cases of suspected Kaposi’s
sarcoma, particularly in patients with AIDS, is considered essential (32).The histological appearance of
bacillary angiomatosis is one of lobular proliferation
of small round blood vessels with plump endothelial
cells that protrude into the vascular lumen. The aggregates of bacteria appear as variably sized, amphophilic granular masses, within the vessels, when
stained with the Warthin-Starry stains (32). The
causative organisms have been identified as Rochalimaea quintana and Rochalimaea henselae (6, 7, 13,
144, 164, 187) and have recently been reclassified as
members of the genus Bartonella based on ribosomal RNA.
Gonorrhea
Gonorrhea is a sexually transmitted infection with a
worldwide distribution. It is caused by Neisseria
gonorrhoeae, a nonmotile, spherical or oval coccus,
which is usually found in pairs. The organism is aerobic, gram-negative and stains readily. It cannot
cross intact stratified squamous epithelium, such as
skin and oral mucous membranes, but can invade
columnar and transitional epithelium, such as that
which lines the urinary and respiratory tracts. The
urethra, pharynx, endocervix and conjunctivae may
be infected directly. From these sites, the infection
may spread locally along mucosal surfaces or systemically to produce disseminated disease (72, 159,
163). N. gonorrhoeae has been cultured from saliva
of patients with oropharyngeal infections (81). The
human is the only known host for N. gonorrhoeae
(115).
Gonorrhea continues to be the most frequently reported sexually transmitted disease in the United
States. However, the 392,848 cases reported in 1995
do represent a decline from 439,673 cases reported
in 1993 and reflect a steady reduction that has continued over the last decade (29). The most frequently
affected population is adolescents between the ages
of 15 and 24, although almost any age group can
be afflicted (28). The most common cause of oral
infections is orogenital contact with an infected sexual partner.
Twenty percent of patients with gonorrhea have
oral, pharyngeal or tonsillar involvement (186). The
tonsils become red and swollen, with a grayish exudate, and may include cervical lymphadenitis.
Lesions of the oral mucosa may present as a fiery
red, edematous and occasionally painful ulceration.
Case reports have described single or multiple ulcers
of the tongue, gingiva, and buccal mucosa as well as
the hard and soft palate (161). Diagnosis is made by
culture and identification of N. gonorrhoeae. Sugar
fermentation tests aid in species differentiation, and
rapid identification of gonococci by fluorescent antibody techniques is possible (115). Systemic antibiotic treatment, usually with penicillin, has been effective in managing gonococcal infections. Beta-lactamase-producing strains of N. gonorrhoeae resistant
to penicillin and tetracycline have been reported.
More recently, ceftriaxone and ciprofloxacin have
also been used successfully in treating gonorrhea
(163).
115
Mycobacterial infections
The term tuberculosis is usually reserved for infection with Rlycohacteriurn tuberculosis, just as leprosy
is an infection with Mycobacterium Zeprae. Nontuberculous atypical mycobacterial diseases are generally identified as mycobacterial diseases with a specific organism - Mycobacteriurn kansasii, Mycobacteriiim chelonei and the Mycobacterium aviumirz tracellu lure complex ( 184).
Most medical mycobacterial infections are not
from M. tuberculosis but from nontuberculous opportunistic atypical mycobacteria. Cervical lymphadenitis caused by these bacteria can be successfully
treated by surgical excision. These infections are not
communicable from person to person and usually
do not require systemic medication for months, as is
the case with tuberculosis. Mycobacterial infections
are among the most common opportunistic infections in I-IIV patients.
Tuberculosis - M. tuberculosis. Tuberculosis is a
chronic, infectious disease caused by the bacteria M.
tuberculosis. It most commonly affects the lungs but
may also involve any organ of the body. The disease
is an airborne infection spread almost exclusively by
droplets from a person with active disease (114, 131,
184). It is characterized by the formation of granulomas with caseation necrosis caused by a cell-mediated response in infected tissue.
Tuberculosis, an ancient disease, reached its peak
incidence in the United States in the nineteenth century, at that time being responsible for up to 25%
of all deaths. Since then, there has been a dramatic
decline, mainly as a result of improvements in living
conditions, nutrition and chemotherapy (114). Recently, however, tuberculosis has resurfaced as a
public health threat, in part because of its association with HIV infection. There is particular concern
regarding increasing reports of multi-drug-resistant
tuberculosis in patients with AIDS. This resurgence
has renewed interest in tuberculosis among health
care providers, especially those who treat hospitalized patients with AIDS (110, 114, 131, 184).
Primary tuberculosis involves a person who has
no previous exposure and has never established an
iniiiiune response to the tubercle bacilli. The majority of cases are subclinical, and only about 10% of
people infected develop the disease (131). Secondary
tuberculosis is an infection that arises in a previously
sensitized person, usually because of reactivation of
a primary infection, and may occur months to years
later. Oral lesions of tuberculosis are rare, occurring
116
in less than 1% of all pulmonary cases (110). Most
reported cases have been attributed to secondary infection from pulmonary lesions. Self-inoculation
from infected sputum and hematogenous spread account for initiation of the lesions.
The most common oral tuberculosis lesion is a
chronic, painless, irregular ulcer, with a vegetating
surface covered by a gray or yellowish exudate. Other
reports describe a nodular, granular or leukoplakic
appearance. The lesion is usually surrounded by
edematous and hyperemic mucosa. The dorsal surface of the tongue is the most common oral site, followed by the palate, gingiva, buccal mucosa, and lips.
Tuberculosis of the cervical lymph nodes is called
scrofula and may result in breakdown of the skin overlying the nodes and fistula formation (41, 44, 45, 83,
127, 131, 139). Primary oral mucosal infection with
the tubercle bacillus has been reported in patients
treated by a dentist with active tuberculosis after the
dentist performed dental extractions. This occurred
prior to the use of barrier protection for infection control (149). Other case reports described primary tuberculosis and oral lesions in patients with no evidence of disseminated disease (41,56,83,95,185).
Diagnosis of infection with M. tuberculosis is derived from the medical history, demonstration of the
acid-fast mycobacteria in clinical specimens, a positive delayed hypersensitivity (tuberculin) skin reaction to purified protein derivative and chest radiographs. Mycobacterial culture of the organism from
sputum is the most reliable means of diagnosis;
however, 6-12 weeks is required to isolate and identify the organism. Recent developments in rapid detection and identification are reducing laboratory
time (44, 114, 131).
Leprosy - M. leprae. Leprosy is a chronic disease
caused by M. Zeprae. The most characteristic feature
of the disease is damage to nerves and skin, which
results in deformities and disabilities. While the global prevalence has been reduced, leprosy remains a
major public health problem in most countries of
Africa, Asia and Latin America (85).
M. Zeprae is a gram-positive, acid-fast, non-sporeforming, nonmotile, pleomorphic bacillus. It has not
been cultivated on artificial medium or in tissue cultures, but it has been grown in armadillos and the
footpads of some mice (85, 155). A relationship has
been demonstrated between the clinical, histopathological and bacteriological manifestations of the disease and the degree of cell-mediated immunity of
the patient. The Mitsuda reaction is used to assess
cellular immunity, with a positive test reflecting re-
Oral rnucosal Lesions caused bv infectiue microornanisms. 1. Viruses and bacteria
sistance to the organism. There are four types of leprosy listed, from least to most involved: indeterminate, tuberculoid, borderline and lepromatous. In
addition to skin and peripheral nerves, the disease
also affects oral and respiratory mucosa, bones and
viscera (85).
Oral lesions have been reported in the tuberculoid, borderline, and lepromatous types of leprosy. The
incidence varies from less than 20% in the borderline
type, to as high as 60% in patients with lepromatous
leprosy (4, 24, 77, 155). The lesions present as nodules (lepromas) that progress to necrosis and ulceration. The ulcers may then heal with scarring, or
progress on to cause further tissue destruction. The
lepromas are filled with M. leprae. The oral lesions
of leprosy occur on the palate, dorsum of the tongue,
gingiva, uvula and the lips, and when untreated, may
cause extensive destruction of the oral tissues (4, 24,
77, 142, 155).
Diagnosis is based on the clinical signs of anesthetic skin lesions, enlarged peripheral nerves and
the presence of acid-fast bacilli in smears taken from
skin lesions. Histological examination of biopsy
specimens is occasionally necessary. At this time,
there is no immunological test that is useful in the
diagnosis of leprosy (85).
Mycobacterium avium-intracellulare complex infection. Opportunistic infection by the M. avium-intracellulare complex is a common complication of
the latter stages of AIDS (16, 175). Oral lesions of the
M. avium-intracellulare complex are uncommon
and have been reported only in two patients. The
lesions presented as ulcerations with firm borders
and necrotic centers which extended to bone. They
were located in the incisive papilla and edentulous
maxillary ridge areas of one patient, and in the buccal gingiva of the maxillary premolars and molars of
the other patient. Diagnosis in both cases was made
from histopathological examinations and culture of
the organisms from tissue biopsy. Both patients also
demonstrated widespread disseminated infection
with the M. avium-intracellulare complex (148, 181).
Mycobacterium bovis infection. On rare occasions,
human tuberculosis has been caused by M. bovis,
and infections of the tongue and gingiva have been
reported. The pathogenesis is similar to M. tuberculosis except that the primary inoculation occurs in
the mouth, probably the result of ingesting unpasteurized or infected milk. Primary lesions of the
tongue without evidence of tuberculosis elsewhere
in the body have been described (41).
Mycobacterium chelonae infection. M. chelonae is
an opportunistic pathogen that causes abscess formation, usually in skin, following trauma or subcutaneous injections. The organism is rapidly growing
and resistant to standard antituberculosis agents as
well as to antibiotics. Lesions in immunocompetent
patients heal spontaneously, however surgical excision, debridement and drainage are recommended
to enhance healing. There have been two case reports of intraoral infections attributed to M.
chelonae. Both cases were diagnosed after biopsy
and laboratory evaluations and healed slowly, but
without incident (21, 129). Cervicofacial infection
with M. chelonae has also been reported with similar
findings (19).
Mycobacterium kansasii infection. Several cases of
disseminated M. kansasii infection have been reported in patients with AIDS (10, 25, 122). Only one
patient, however, has demonstrated oral manifestations associated with the M. kansasii infection.
This consisted of an ulcerated lesion in the area of
the palatoglottic arch in a patient with disseminated
disease. M. kansasii was cultured from the ulcer biopsy. The patient did not demonstrate signs or
symptoms of pneumonia, and the disseminated infection was diagnosed from bone marrow and blood
specimens (122).
Streptococcal stomatitis
Streptococcal stomatitis is a rare condition, usually
characterized by a diffuse erythema of the posterior
areas of the oral mucosa, but sometimes includes
the gingiva. Acute gingival streptococcal infections
have been described as acute streptococcal gingivostomatitis, acute streptococcal gingivitis and streptococcal gingivostomatitis, with only a few case reports
in the literature (20, 26, 104, 121). It is, however, described in several periodontal textbooks (26, 121,
133, 134).
Acute streptococcal gingivostomatitis is usually
preceded by tonsillitis, and the patients present clinically with an acutely inflamed, diffuse, red and
swollen gingiva with an increased tendency to bleed.
The gingiva is not ulcerated and necrosis is not present (20, 104, 177).Gingival abscesses in the interdental papillae and areas with discrete yellowish or
white plaques were described in a few patients.
When the plaques were wiped off, a bleeding surface
was produced (20, 177). In some patients, the erythema also involved areas of oral mucosa with submandibular lymph node enlargement. Fever, mal-
117
I? i vem - Hidalgo & Stanford
aise, and gingival pain accompany these symptoms
(20, 104, 177).
‘The causative agent of streptococcal stomatitis
was originally thought to be Streptococcus viriduns,
but microbial analysis in recent reports found group
A beta-hemolytic streptococci as the predominant
culture organisms. All patients were treated with systemic penicillin and healed without complications. A
few patients also received a tetracycline mouthrinse
concurrently (104).
‘The symptoms attributed to streptococcal gingivostomatitis - diffusely swollen, bright red gingiva,
fever, malaise, and lymph node enlargement - may
also be associated with viral infections, and careful
diagnosis is necessary.
Syphilis
Syphilis is a venereal disease that has infected
humans for centuries. It is caused by the spirochete
li.qionernn pallidurn. Syphilis is the fourth most
comrnonly reported infectious disease in the United
States. In 1995, the total number of reported cases
of primary and secondary syphilis was 16,500. This
represented a decrease from the 26,498 reported in
1993 and continues a downward trend in the number of annually reported cases since the epidemic
proportions during the years 1986 through 1990 (29,
163).
Syphilis has been classified as either congenital or
acquired. Congenital syphilis occurs most frequently
when the fetus becomes infected in utero, although
it is possible for the neonate to acquire the infection
as it passes through the birth canal (176). Acquired
syphilis may be contracted by sexual contact, by
transfusion with fresh human blood or by accidental
direct inoculation. The acquisition of syphilis
through transfusion has become rare due to screening procedures for blood donors and modern blood
bank procedures. Accidental direct inoculation has
also been reduced by improved laboratory proceduies for handling infected clinical material and
by the use of infection control and barrier procedures in clinical settings. There have been no reports of occupationally acquired syphilis in a dental
office since the advent of improved infection control
procedures. The overwhelming majority of syphilis
cases, however, continue to be transmitted by sexual
intercourse (161, 163, 176).
Early congenital syphilis may manifest as papulosquanious lesions ot the skin and oral mucous membranes. ‘The lesions at the conimissures of the lips,
the angle of the nose and the eyes may heal with
118
radiating scars called rhagades. Oral manifestation
of late congenital syphilis includes Hutchinson’s
triad of deafness, interstitial keratitis and malformed
incisors. In addition to the malformed incisors (Hutchinson’s teeth), other dental anomalies include permanent molars with hypoplastic, poorly developed
cusps called mulberry molars, and maxillary incisors
with crowns that are wider towards the cementoenamel junction than at the incisal edge, producing
a screwdriver appearance.
Acquired syphilis occurs clinically in three classical phases (primary, secondary and tertiary). Primary syphilis features formation of a chancre at the
site of inoculation, usually 3 weeks (3 to 90 days)
after contact. The chancre appears on skin or in the
oral cavity as an asymptomatic, centrally ulcerated
granulomatous papule with a raised indurated border. Spirochetes are present in large numbers in
these highly infectious lesions. Chancres usually heal
spontaneously in 2-8 weeks but may persist in immunocompromised hosts (161, 163, 176). Secondary
syphilis is the systemic or disseminated phase, and
it may occur 2-12 weeks (mean, 6 weeks) after contact. The healing chancre may still be present. Signs
and symptoms of this phase include fever, headache,
malaise, a rash that is usually symmetrical and generalized painless lymph node involvement. The oral
lesion of this stage is the mucous patch, a characteristic grayish-white, glistening patch seen on the soft
palate, tongue, buccal mucosa and, rarely, the gingiva (11, 51, 88, 108, 140). During this phase, elevated, sessile plaques of the labial commissure (condyloma lata) may also occur. After the secondary
stage subsides, the patient enters a latent period in
which diagnosis can only be made by serological
tests. Tertiary syphilis develops in 30% to 40% of untreated patients. This phase includes multiorgan involvement, and most frequently involves the cardiovascular and nervous systems. The gumma is the
characteristic lesion of this phase and appears on
skin or mucosa as a localized granuloma. The most
common intraoral location for the gumma is the
hard palate, although the soft palate, lips and tongue
may also be involved (40, 84, 92). Tertiary syphilis is
not infectious (163).
Clinical examination and serological testing
usually diagnose syphilis. Darkfield microscopy and
histopathological examination also assist in diagnosis. The serological tests are of two types: treponema1 and non-treponemal. Non-treponemal (nonspecific) tests are for the nonspecific nontreponemal
reaginic antibody, and include the Venereal Disease
Research Laboratory test, the rapid plasma reagin
Oral mucosal lesions caused bv infective microorganisms. I. Viruses and bacteria
test and the automated reagin test. Positive Venereal
Disease Research Laboratory tests will occur towards
the end of primary syphilis, remain positive in untreated secondary or tertiary syphilis, but is usually
negative in treated syphilis. Treponemal (specific)
tests are for the specific antitreponemal antibody,
and include the Reiter protein complement fixation
test, the fluorescent treponemal antibody (absorbed)
test, the treponemal hemagglutination test and the
treponemal immobilization test. Specific tests become positive during primary syphilis, and remain
positive throughout untreated secondary and tertiary syphilis. In contrast to the Venereal Disease Research Laboratory test, most specific tests remain
positive in treated syphilis (161). Darkfield microscopy can be useful in primary syphilis when serology may be negative, and occasionally in secondary
or tertiary syphilis. Histopathological examination
demonstrates an obliterative endarteritis, and with
special stains, the I: pallidurn microorganism. The
gumma demonstrate large areas of necrosis and occasional microorganisms (161, 163, 176).
Penicillin is the pharmaceutical treatment of
choice. Treatment given in any of the three stages of
acquired syphilis can cure the disease (176).
Concomitant HW and syphilis infections are common, and variations in the clinical presentation and
response to syphilis may be related to the degree of
immunosuppression (40, 51, 176).
Oral infection with enteric organisms
A small number of cases of oral infections with enteric bacteria have been reported (12, 68, 158, 167).
Schmidt-Westhausen et al. (158) using oral swabs,
compared the incidence of enteric bacteria in the
oral cavity of 144 HIV patients and 166 controls.
They found enteric bacteria in 5.0% of HW patients
and 4.8% of the controls. The isolation of the enteric
organisms from the oral cavity was not associated
with clinical abnormalities. The bacteria were found
to coexist with yeast (68). Barone et al. (12) reported
on an HIV-seropositive patient with glossitis from
whom Escherichia coli could be isolated. In another
report, Stark et al. (167) reported that, of 14 patients
treated with a combination of antibiotics for Helicobacter pylori infection, two patients had colonization
of the oral cavity with Enterobacteriaceae.Heitman &
Brasher (75) reported an oral infection due to Klebsiella pneumoniae, an organism indigenous to the
respiratory tract, in a patient following periodontal
surgery. Culture and antibiotic sensitivity testing, followed by treatment with tetracycline resolved this
infection (75). It seems unlikely that oral infection
with enteric organisms is a significant cause of morbidity in people infected with HW.
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