Professional Documents
Culture Documents
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Ann Periodontol
Necrotizing periodontal diseases are unique in their clinical presentation and course. Data suggest that the etiology and pathogenesis of necrotizing periodontal diseases may also be distinctive from other periodontal diseases. Necrotizing ulcerative
gingivitis (NUG) is a type of necrotizing periodontal disease in
which the necrosis is limited to the gingival tissues. Three specific clinical characteristics must be present to diagnose NUG,
pain (usually of rapid onset) interdental necrosis, and bleeding.
Epidemiological and prospective clinical studies have found an
altered ability to cope with psychological stress, immunosuppression, and tobacco use to be strongly associated with the
onset of NUG. Ann Periodontol 1999;4:65-73.
KEY WORDS
Gingivitis, necrotizing ulcerative/etiology; gingivitis,
necrotizing ulcerative/pathogenesis; gingivitis, necrotizing
ulcerative/classification.
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been reported to occur in NUG include lymphadenopathy, fetor ex ore, fever, and malaise.15-17
However, none of these are pathognomonic since they
frequently occur in many other forms of periodontal
disease. Lymphadenopathy is an infrequent finding in
NUG. Its presence is probably related to the severity
of the disease since it is usually observed in severe,
advanced cases.3,18 The strong malodor (fetor ex ore)
that has often been associated with NUG is not always
noted4,18 and may be associated with many other oral
diseases such as chronic periodontitis. While there are
reports that fever and malaise are common clinical
features of NUG,1,16 most clinical studies have indicated that their presence may suggest primary herpetic gingivostomatitis or mononucleosis.2,4,19,20 If one
compares the features that are unique to NUG to those
that are common, it is easy to distinguish NUG clinically from other gingival and periodontal diseases.
It has been suggested that there are acute and
chronic forms of NUG.21,22 Patients presenting with
NUG are indeed often susceptible to future recurrences.1-6,23 However, the historical terminology of
chronic should be considered a misidentification of
a recurrence of disease. In addition, the rapid onset
of NUG has led many, especially in the United States,
to refer to NUG as ANUG. The term acute in ANUG
is a clinical descriptive term and should not be used
as a diagnostic classification. As there is no chronic
form of NUG, it is also best to consider ANUG a misnomer.
Necrotizing ulcerative gingivitis is diagnosed at the
onset of specific clinical signs and symptoms.5,6,24
Episodes of NUG will usually resolve within a few days
after receiving adequate treatment. Such response is
extraordinary among plaque-associated periodontal
diseases. Furthermore, unlike other forms of periodontal infection, NUG primarily affects the interdental and marginal soft tissue with little osseous involvement. It may be superimposed upon periodontitis and
complicate the diagnosis.2,6 Some reports indicate that
NUG is associated with attachment loss. In a study of
13 patients with a history of NUG, it was found that
mean probing attachment loss in the interdental crater
sites were significantly greater than the mean for all
other sites. The presence of interdental craters was
assumed to be the previous sites of NUG. An association between NUG and attachment loss was made in
this report.25 Attachment loss has also been noted
upon recurrences of NUG.17 Such findings have led
some to support the surgical treatment of any residual interdental soft tissue craters.2,3,17
Even if clinical attachment loss is associated with
NUG, it is obvious that this disease presents with a
different response to therapy than other forms of periodontal disease. Resolution is quick upon removing
the bacterial challenge.2,20,23,26 In addition, it has been
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reported that even with conservative treatment, regeneration of the affected interdental sites is possible.27
Using periodic scaling, root planing, and antimicrobial
rinses, this study showed that the disease process was
not only halted, but that regeneration of the necrotic
papillae was possible.27 In contrast, longitudinal studies involving similar therapeutic regimens in the maintenance of post-therapy periodontitis sites found stabilization, but not necessarily regeneration, of the lost
periodontium.28 The clinical presentation, course, and
response to therapy for NUG are specific among the
periodontal diseases and support a unique clinical disease category.
Etiology
Necrotizing ulcerative gingivitis is an infectious disease. Dramatic resolution of signs and symptoms can
be affected by reduction of the microbial plaque either
by antibiotic therapy,3,26,29 mechanical debridement,2,17,20 or both.1,5,6,27 A specific infectious disease should be associated with a specific etiology. The
bacterial etiology of NUG provides one of our strongest
examples of a primary bacterial etiology in a periodontal disease.30 This bacterial etiology was first
proposed by Plaut in 189431 and Vincent in 1896.32
Working independently, they both reported that
fusiform-spirochete bacterial flora were associated with
the lesions of necrotizing ulcerative gingivitis. Even
though fusiforms and spirochetes are commonly found
in patients who do not have NUG,33 it does appear
that these and perhaps other bacteria play a major
role in the pathogenesis of NUG. First, electron microscopic studies of gingival biopsies from NUG patients
have provided some of the most well known findings
in support of bacterial invasion in a periodontal disease.
In a classic electron microscopic investigation in 1965,
four zones associated with the gingival lesion of NUG
were identified.34
1. Bacterial zone: composed of a large mass of bacteria with varying morphotypes, including some spirochetes.
2. Neutrophil rich zone: underlies the bacterial zone,
contains many leukocytes with neutrophils predominating. Bacteria, including many spirochetes, are
located between the cells.
3. Necrotic zone: characterized by disintegrating
cells and many spirochetes (large and intermediate)
and other bacteria that appear to be fusiforms.
4. Spirochetal infiltration zone: tissue elements
appear well preserved but are infiltrated by spirochetes,
both large and intermediate in size. No other bacteria
were observed.
Essentially the same findings were reported in
another study 2 years later.35 A later study also found
cocci and rods in addition to the spirochetes, within the
adjacent non-necrotic connective tissue region.36 The
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Predisposing Factors
Psychological stress. Development of NUG is closely
associated with specific predisposing secondary factors such as psychological stress, immune suppression, smoking, malnutrition, pre-existing gingivitis, and
tissue trauma. Acute psychological stress in particular appears to be associated with the onset of NUG.7
It is well documented that the prevalence of NUG in
the military increases under conditions which produce
high levels of acute stress4,19,22,52 and in drug addicts
during periods of drug withdrawal.8 Additionally, it is
not uncommon to have outbreaks of NUG among college students during examinations.9
During periods of psychological stress, oral hygiene
measures may decrease, nutrition may become inadequate, tobacco smoking may increase, and immune
function may be suppressed. Stressful life events may
lead to an activation of the hypothalamic-pituitaryadrenal axis, resulting in an elevation of serum and
urine corticosteroid levels.53 Increases in urinary levels of 17 hydroxycorticosteroid (17-OHCS) have been
associated with psychological stress. Accordingly, significantly higher levels of urinary 17-OHCS have been
reported in NUG patients when compared with levels
measured after resolution of the disease.54 Another
study reported significantly higher levels of urinary
cortisol in NUG patients in comparison to control subjects.55 Increased corticosteroid levels may play several roles in the development of NUG such as immunosuppression.
Immunosuppression. Increased cortisol levels have
been associated with a depression of polymorphonuclear leukocyte (PMN) function.56 Depressed PMN
function as measured by chemotactic, phagocytic, and
bactericidal abilities has been reported in NUG
patients.57-59 In addition, altered lymphocyte function
has been reported in NUG and will be discussed
below.57,60,61 Further evidence to support the relationship of immune suppression via increased levels of
corticosteroids was demonstrated by the transfer of
NUG in the beagle dog after pretreatment with steroids
as previously discussed.44-48 Furthermore, it has also
been suggested that elevated steroid levels may provide essential nutrients for specific bacterial growth
(Prevotella intermedia).40,62
Studies of immune responses in NUG have found, for
the most part, a lack of protective functions. One of
the earliest studies found no differences in antibody
levels to Fusobacterium fusiforme, B. melaninogenicus, and Borrelia vincentii of NUG patients compared
to control subjects.63 A follow-up study using a different methodology from the same laboratory looked
at the immune response to Actinomyces viscosus, F.
fusiforme, Veillonella alcalescens, and B. melaninogenicus. They also found no differences in serum antibody levels between patients and control subjects. This
68
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of gingivitis and periodontitis were reported to be associated with HIV infection.68 The gingivitis was described
as a distinct erythematous band of the marginal gingiva with either diffuse or punctate erythema of the
attached gingiva with little dental plaque. It was named
HIV-associated gingivitis (HIV-G).68 Spontaneous bleeding was often present in HIV-G. Unlike conventional
gingivitis, it was reported that HIV-G did not respond
to oral hygiene measures. It may be due at least in
part to a candidal infection.69 These early studies from
San Francisco also reported a progression from HIVG to NUG to a necrotizing ulcerative periodontitis.68 In
1993, HIV-G was renamed as linear gingival erythema
(LGE) by a collaboration of the EC-Clearinghouse on
Oral Problems related to HIV infection and the WHO
Collaboration Centre on Oral Manifestations of the
Immunodeficiency Virus.69
The distinct periodontitis in the San Francisco HIVinfected population was described as an ANUG type
of lesion (i.e., NUG) superimposed upon a rapidly progressing periodontitis; a lesion in which severe loss of
attachment and bone was noted. Patients presenting
with this disease did not have a history of NUG in these
areas.68 The authors referred to this disease as HIVassociated periodontitis (HIV-P). HIV-associated periodontitis was subsequently renamed as necrotizing
ulcerative periodontitis or NUP.69 Necrotizing stomatitis (NS) occurs when the necrosis extends into the
mucosa and bone outside the periodontium.68,69
Through the years NUP in HIV-infected patients has
been either misinterpreted as NUG or as a NUG-like
lesion, which quickly progressed to a necrosis of
bone.70-72 This has occurred in spite of the original
report and subsequent attempts to clearly define these
entities.73-75 It is important to note that these early
findings were generated from essentially non-medically
treated HIV-infected patients. In a sense the actual disease process of NUG and NUP could be studied. Studies of the bacterial etiology of NUP (HIV-P) found the
flora to be different from adult periodontitis76 and the
same as adult periodontitis.77 Both studies however
found the flora to be different from that associated with
NUG.40 The issue of periodontal disease in HIV-infected
individuals has become much more complex than warranted.78 There have been attempts to address this
problem. One approach is to clearly define small clinical differences for use in clinical studies of periodontal disease.79 This approach is time consuming, but
would be useful in specific situations; e.g., assessment
of disease progression and treatment outcomes. Others have sought to broadly group clinical findings.69,80
Such an approach would be applicable for use in epidemiologic studies of oral manifestations but would
lack sensitivity for identification of periodontal diseases
such as NUG and NUP. Excellent reviews of periodontal
diseases in HIV infection have been written by peri-
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Immunosuppression
Necrotizing Ulcerative Gingivitis
HIV Infection
Deficient Nutrition
Candida Infection
Viral Infections
Protozoal Infections
Necrotizing
Stomatitis
percentage of NUG cases will be attributable to systemic determinants known; e.g., immunosuppression
secondary to HIV infection.
SUMMARY
Necrotizing ulcerative gingivitis is a distinct painful
infectious disease primarily of the interdental and marginal gingiva. These clinical signs and symptoms of
NUG will usually resolve within a few days after receiving adequate treatment; however, patients remain at
risk for recurrences of disease. As with other plaqueassociated periodontal diseases, opportunistic bacteria are the primary etiologic agents in NUG. There are
also non-specific predisposing factors for the development of NUG: acute psychological stress, tobacco
smoke, and pre-existing gingivitis. From this review
of the literature it is evident that the predominant factor in the development of NUG is immunosuppression.
Furthermore, immunosuppression may be associated
with all of the predisposing factors.
70
The epidemiology and etiology of NUG have interested the research community for many years. Several excellent reviews are available for reference.1,15,96
While this interest has led to an extensive body of
knowledge in regards to NUG, there is still much
not known. It has been proposed by many that NUG
may progress to involve the periodontium (NUP) and
surrounding oral tissues (necrotizing stomatitis and
noma) depending upon the health status of the
patient. While the clinical presentation of NUG may
be modified by the systemic health status of the
patient, it has a unique presentation, etiology, and
pathogenesis and warrants a separate disease classification. Figure 1 depicts the various interactions
thought to occur in NUG.
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