Ann Periodontol

Necrotizing Ulcerative Gingivitis

Randal W. Rowland*
* University of California San Francisco, San Francisco, California.

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 specic 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/classication.

ecrotizing ulcerative gingivitis (NUG) is unique among the periodontal diseases. It has an acute clinical presentation with the distinctive characteristics of rapid onset of gingival pain, interdental gingival necrosis, and bleeding. Necrotizing ulcerative gingivitis has been recognized for centuries. It has been known by many names: Vincents disease, fusospirochetal gingivitis, trench mouth, acute ulcerative gingivitis, necrotizing gingivitis, and acute necrotizing ulcerative gingivitis or ANUG, to name a few.1-6 The onset of NUG is associated with increased psychological stress, increased physical demand, and decreased nutrient intake.1-10 It is not surprising that early historical documentations of NUG were made in the military and especially at times of war. The rst reference to an oral disease distinguished by these clinical signs and symptoms is credited to the historical war records of Xenophons troops during the fourth century BC.11-13 These records included descriptions of painful decaying tissue between the teeth which allowed for the distinction between NUG and scurvy, another common gingival lesion of that era.13 A NUG-like condition was also reported in the Roman army of the first century AD.12 In general, this clinical description is still in use today in the diagnosis of NUG. John Hunter rst delineated the clinical differences between NUG, scurvy, and chronic periodontitis in 1778.12,14 Necrotizing ulcerative gingivitis was commonly found among the French soldiers in the nine65

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teenth century. Hirsch added secondary ndings to the clinical presentation of NUG in 1886 and Bergeron described both acute and chronic forms of the disease in 1895.12 Although its clinical signs are easy to identify, much is still not understood regarding the etiology and pathogenesis of NUG. For example, with such a profound bacterial mass and concomitant inammation, why is NUG usually self-limited to the interdental and marginal gingiva? Does NUG in the immunocompromised host (e.g., acquired immune deciency syndrome [AIDS]) progress to include much of the periodontium resulting in severe loss of clinical attachment and bone? Does NUG in extremely nutritionally decient children (e.g., Kwashiorkor) progress to include the external structures of the face sometimes leading to death? The literature concerning the clinical diagnosis, pathogenic mechanisms, and progression of NUG is often in conict. The purpose of this paper is to critically review data that exist in relation to NUG as a clinical diagnosis. A comprehensive understanding of NUG will assist in clinical diagnosis and delivery of appropriate therapy for this infrequent, yet clinically signicant, periodontal condition. DEFINING CHARACTERISTICS OF NUG Clinical Presentation Necrotizing ulcerative gingivitis is different from the other periodontal diseases, in that it presents with interdental gingival necrosis as often described by punched out ulcerated papillae, gingival bleeding, and pain.1-6 Interproximal gingival necrosis is easy to detect. However, tooth shape, size, and alignment may alter the form of papillae. Consequently, these factors must be considered when assessing interdental papillae. It is possible for inexperienced clinicians to misclassify papillae as necrotic when in fact the papillae are blunted due to the presence of a diastema and inamed due to bacterial plaque. Loss of attachment and bone in NUG are infrequent findings, but can occur after multiple recurrences of the disease. Gingival bleeding associated with NUG is probably the least distinctive of the clinical signs of NUG, since it is a frequent nding in other periodontal diseases. However in other periodontal diseases, a substantial stimulus such as tooth brushing or periodontal probing is required to elicit bleeding. In comparison, gingival bleeding in NUG occurs with little or no provocation. Pain is the hallmark of NUG. The quality of pain in NUG is intense and results in patients seeking treatment. Typical gingivitis and periodontitis are not associated with severe gingival pain. Periodontal abscesses and herpetic infections are painful but can be easily distinguished from NUG. If any of the 3 criteria (interproximal necrosis, bleeding, and pain) are absent, a diagnosis of NUG cannot be made. Other signs and symptoms that have
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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 nding 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 misidentication 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 classication. 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 signicantly 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 ndings 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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Rowland

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 specic 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 specic infectious disease should be associated with a specic 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 ora 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 ndings 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 identied.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 inltrated 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

neutrophil rich, necrotic, and spirochetal infiltration zones are unique to NUG. The histologic appearance of NUG is different from other gingival and periodontal diseases,37-39 but it is complex and may be misleading, as cells associated with chronic lesions such as lymphocytes may be present also. These are probably due in part to a preexisting established gingivitis.39 Microbial studies have also characterized the genera and species of the cultivable ora in NUG.24,40 In one study, the cultivable ora and microscopic ndings were evaluated on the same plaque samples.40 It was reported that both the cultivable and microscopic ora had what the authors identied as constant and variable components. The constant cultivable ora consisted of a limited number of predominant organisms, B. melaninogenicus ssp. intermedius, now known as Prevotella intermedia, and Fusobacterium sp. Microscopically, Treponema and Selenomonas sp. comprised the constant ora. The concept of a predominant constant ora suggests an association of these ora with the disease. As with other periodontal diseases however, this association does not necessarily demonstrate an etiologic role for these bacteria in the initiation of NUG. Attempts to satisfy Kochs postulates by transfer of the disease from one animal to another have been attempted. When inoculated subcutaneously into the groin of guinea pigs, scrapings from lesions of NUG have produced fusospirochetal infections.41 It was also possible to pass this infection from animal to animal by the same route. Skin abscesses have been produced in guinea pigs by injecting pure cultures of T. vincentii and T. buccalis separately and in combination with other oral isolates.42 However, several different organisms singly or in combination have been demonstrated to be capable of producing similar lesions.43 Using a steroid-induced immunosuppression in the beagle dog, it has been possible to transmit NUG from animal to animal.44-48 Some histologic differences were noted in the dog model compared to the earlier studies of human specimens; however, spirochetes were seen penetrating normal epithelium, which may suggest that spirochetes were involved in the initiation of the pathogenesis in NUG.48 In other forms of periodontal disease, spirochetes are involved in advanced gingivitis and periodontitis lesions but are not associated with sites of early periodontitis or gingival health.24,49,50 Studies of the bacterial etiology of NUG indicate that NUG is different from other periodontal diseases. For many years, NUG was considered a communicable disease. A diagnosis of NUG often required a report to community health departments in a similar fashion as a venereal disease. A particularly insightful discussion of the data in regards to the communicability of NUG led the American Dental Association to conclude that NUG was not communicable.51
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Predisposing Factors Psychological stress. Development of NUG is closely associated with specic 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, signicantly 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

was true on the rst day of attendance and up to one month after the disease started.64 In another study, saliva was assayed for all 5 classes of immunoglobulins as well as secretory IgA. A decrease in total immunoglobulin levels but an increase in secretory IgA was found in NUG subjects when compared to the control subjects.65 Another study of the humoral response reported a depressed total serum IgG and increased total serum IgM concentrations in patients with NUG and patients with recurrent NUG compared to the control subjects.66 Taken together, these early reports provide interesting ndings. The onset of NUG is associated with a large microbial plaque load. Furthermore an established or pre-existing gingivitis is considered necessary for the onset of NUG. Therefore these early studies of the immune response indicate that a lack of protective antibodies may be involved in the development of NUG. In contrast to these early studies, two more recent investigations of antibody response have reported conicting ndings.24,67 Both studies used specic bacterial strains and measured antibody levels by an enzymelinked immunosorbent assay. One study found signicantly higher IgG and IgM levels to an intermediate size spirochete and higher IgG levels to B. intermedius (P. intermedia) in NUG subjects compared to healthy and gingivitis subjects.67 Examination of the results, however, indicated that signicantly higher IgG titers were present against only 1 of 2 P. intermedia strains tested. In addition, the source for the intermediate size spirochete in this study was reported to have been deep periodontal pockets. The other study was carefully controlled for confounding factors: plaque levels, age, race, gender, and socio-economic status. In this study, a depressed IgG and IgM response in NUG subjects compared to control subjects was reported for 4 isolates of P. intermedia (2 from NUG patients, 2 from control subjects). In addition, no differences in IgG levels to spirochetes isolated from NUG subjects or control subjects, or IgM levels to the spirochetes from NUG individuals were found.24 It is arguable that antibody levels, both non-specic and specic, are either similar or depressed in NUG patients compared to control subjects. However, lymphocyte function as measured by mitogenic response is severely depressed in NUG.57,60,61 It is apparent that regardless of the mechanisms involved, a general immune suppression (PMN function, antibody response, and lymphocyte mitogenesis) is associated with the onset of NUG. Thus, it is not surprising that NUG has been associated with infection by human immunodeciency virus (HIV) and acquired immune deficiency syndrome (AIDS).6,7,60 Moreover, it has been reported that NUG may be the rst sign of HIV infection.60 Several controversies regarding the association of HIV disease and NUG exist. Early in the AIDS epidemic, atypical forms

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Rowland

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 Immunodeciency 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 dene these entities.73-75 It is important to note that these early ndings 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 ora to be different from adult periodontitis76 and the same as adult periodontitis.77 Both studies however found the ora 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 dene small clinical differences for use in clinical studies of periodontal disease.79 This approach is time consuming, but would be useful in specic situations; e.g., assessment of disease progression and treatment outcomes. Others have sought to broadly group clinical ndings.69,80 Such an approach would be applicable for use in epidemiologic studies of oral manifestations but would lack sensitivity for identication of periodontal diseases such as NUG and NUP. Excellent reviews of periodontal diseases in HIV infection have been written by peri-

odontists and others experienced with this area of HIV manifestations.73-75,81,82 Malnutrition. Malnutrition also has been reported to be a predisposing factor in the onset of NUG.1-6 Necrotizing ulcerative gingivitis is considered to be a disease of young adults in Europe and the United States. In contrast, NUG occurs in very young children in developing countries.83-89 The development of NUG in children appears to be related to poor nutritional status especially in protein intake83,84 and secondary to viral infections such as measles.85 Necrotizing ulcerative gingivitis, which occurs in malnourished children, especially after viral and protozoal infections, may also progress to a fulminating disguring and often lethal infection known as noma.1-6 Noma has been known by other names such as cancrum oris in Africa, and dzo-ma-gan in China. Dzo-ma-gan, which translates as running horse gangrene, is a historical name and is a reference to the rapid progression noma exhibits.5,90 While it is generally accepted that NUG will progress to noma in the compromised patient,1-6 a review of the literature nds only rare cases that clearly began as NUG and progressed to noma.88 Moreover, reports purported to document the progression of NUG to noma contain photographs of initial presentation that appear to indicate that patients had more than interproximal gingival necrosis. These included cellulitis of the external facial structures, advanced lesions involving the entire periodontium (necrotizing ulcerative periodontitis), or lesions extending past the periodontium into surrounding bone (necrotizing stomatitis).83-89 While it may seem appropriate to consider noma as an extension of NUG, this is not well documented. A recent study indicates that noma is associated with elevated cortisol levels and reduced levels of zinc and amino acids in children previously infected with measles or herpesviruses in consort with F. necrophorum infection.91 This nding is in agreement with earlier studies that reported the association of viral infections with the development of noma.83,86 The underlying mechanisms of the pathogenesis of noma, however, still need to be identied. Other Predisposing Factors. Tobacco smoking, pre-existing gingivitis, and trauma have been reported as predisposing factors in NUG also. Tobacco smoking in particular is associated with the onset of NUG.10,92-94 An earlier report suggested an association between NUG and venereal disease.95 SYSTEMIC DETERMINANTS UNKNOWN The majority of patients with NUG will still present with systemic determinants unknown. In other words, the clinician will make a presumption of the etiologic and pathogenic mechanisms that are ongoing based upon the identification of predisposing factors. A smaller
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Psychological Stress and Anxiety Pre-Existing Gingivitis Increased Corticosteroid Production Immunosuppression Increased Bacteria Growth and Invasion Viral Infection Necrotizing Ulcerative Gingivitis HIV Infection Candida Infection Decient Nutrition Viral Infections Protozoal Infections Linear Gingival Erythema Noma Necrotizing Ulcerative Periodontitis Immunosuppression

Necrotizing Stomatitis

Figure 1. Necrotizing ulcerative gingivitis: possible etiological mechanisms and sequelae.

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-specic 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.
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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. REFERENCES
1. Johnson BD, Engel D. Acute necrotizing ulcerative gingivitis. A review of diagnosis, etiology, and treatment. J Periodontol 1986;57:141-150.

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2. Goldhaber P, Giddon DB. Present concepts concerning the etiology and treatment of acute necrotizing ulcerative gingivitis. Int Dent J 1964;14:468-496. 3. Shinn DL. Vincents disease and its treatment. In: Finegold SM ed. Metronidazole, Proceedings of the International Metronidazole Conference Montreal, Quebec, Canada. Amsterdam: Excerpta Medica; 1977:334-340. 4. Grupe HE, Wilder LS. Observations of necrotizing gingivitis in 870 military trainees. J Periodontol 1956; 27:255-261. 5. Armitage GC. Acute periodontal lesions. In: Biologic Basis of Periodontal Maintenance Therapy. Berkeley, CA: Praxis Publishing Company; 1980:145-164. 6. Cogen RB. Acute necrotizing ulcerative gingivitis. In: Genco RJ, Goldman HM, Cohen DW, eds. Contemporary Periodontics. St. Louis: The C.V. Mosby Company; 1990:459-465. 7. Moulton R, Ewen S, Thieman W. Emotional factors in periodontal disease. Oral Surg Oral Med Oral Pathol 1952;5:833-860. 8. Davis RK, Baer PN. Necrotic ulcerative gingivitis in drug addict patients being withdrawn from drugs. Report of two cases Oral Surg Surg Oral Med Oral Pathol 1971;31: 200-204. 9. Giddon DB, Zackin SJ, Goldhaber P. Acute necrotizing gingivitis in college students. J Am Dent Assoc 1964; 68:381-386. 10. Stevens AW Jr., Cogen RB, Cohen-Cole S, Freeman A. Demographic and clinical data associated with acute necrotizing ulcerative gingivitis in a dental school population. (ANUGdemographic and clinical data). J Clin Periodontol 1984;11:487-93. 11. Prinz H, Greenbaum SS. In: Diseases of the Mouth and Their Treatment. Philadelphia: Lea & Febinger; 1935:153166. 12. Hirschfeld I, Beube F, Siegel EH. The history of Vincents infection. J Periodontol 1940;11:89-98. 13. Pickard HM. Historical aspects of Vincents disease. Proc Royal Soc Med 1973;66:695-699. 14. Hunter J. A treatise on the natural history and diseases of the human teeth (1778). In: Complete Works of John Hunter, Philadelphia, 1841:81. 15. Murayama Y, Kurihara H, Nagai A, Dompkowski D, Van Dyke TE. Acute necrotizing ulcerative gingivitis: risk factors involving host defense mechanisms. Periodontol 2000 1994;6:116-124. 16. Wilson JR. Etiology and diagnosis of bacterial gingivitis including Vincents disease. J Am Dent Assoc 1952; 44:671-679. 17. Schluger S. The etiology and treatment of Vincents infection. J Am Dent Assoc 1943;30:524-532. 18. Manson JD, Rand H. Recurrent Vincents disease. A survey of 61 cases. Br Dent J 1961;110:386-390. 19. Shields WD. Acute necrotizing ulcerative gingivitis. A study of some of the contributing factors and their validity in an army population. J Periodontol 1977;48: 346-349. 20. Stammers AF. Vincents infection: Observations and conclusions regarding the aetiology and treatment of 1,017 civilian cases. Br Dent J 1944;76:147-155, 171-177, 205-209. 21. Kristoffersen T, Lie T. Necrotizing gingivitis. In: Lindhe J, ed. Textbook of Clinical Periodontology, 2nd ed. Copenhagen: Munksgaard; 1989:202-218. 22. Pindborg JJ. Inuence of service in armed forces on the incidence of gingivitis. J Am Dent Assoc 1951;42:517522.

23. Silver JG, Southcott RJ, Wade AB. Acute necrotizing ulcerative gingivitisan evaluation of the ulcer improvement index. J Periodontol 1974;45:308-311. 24. Rowland RW, Mestecky J, Gunsolley JC, Cogen RB. Serum IgG and IgM levels to bacterial antigens in necrotizing ulcerative gingivitis. J Periodontol 1993;64:195201. 25. MacCarthy D, Claffey N. Acute necrotizing ulcerative gingivitis is associated with attachment loss. J Clin Periodontol 1991;18:776-779. 26. Duckworth R, Waterhouse JP, Britton DER, et al. Acute ulcerative gingivitis: A double-blind controlled clinical trial of metronidazole. Br Dent J 1966;120:599-602. 27. Hartnett AC, Shiloah J. The treatment of acute necrotizing ulcerative gingivitis. Quintessence Int 1991;22:95100. 28. Axelsson P, Lindhe J. Effect of controlled oral hygiene procedures on caries and periodontal disease in adults. Results after 6 years. J Clin Periodontol 1981;8:239-248. 29. Loesche WJ. Chemotherapy of dental plaque infections. Oral Sci Rev 1976;9:65-107. 30. Socransky SS, Haffajee AD. Evidence of bacterial etiology: a historical perspective. Periodontol 2000 1994; 5:7-25. 31. Plaut HC. Bacterial diagnostic studies of diphtheria and oral diseases. (Studien zur bakteriellen Diagnostik der Diphtherie und der Anginen). Dtsch Med Wochnschr, 1894;20:920-923. 32. Vincent H. The etiology and the histopathology of hospital rot. (Sur letiolgie et surn les lesions anatomopathologiques, de la pourriture dhopital). Ann de lInsti Pasteur, 1896;10:488-510. 33. Loesche WJ, Laughon BE. Role of spirochetes in periodontal disease. In: Genco RJ, Mergenhagen, SE, eds. Host-Parasite Interactions in Periodontal Diseases, Washington, DC: American Society for Microbiology; 1982:6275. 34. Listgarten MA. Electron microscopic observations on the bacterial flora of acute necrotizing ulcerative gingivitis. J Periodontol 1965;36:328-339. 35. Heylings RT. Electron microscopy of acute ulcerative gingivitis (Vincents type). Demonstration of the fusospirochaetal complex of bacteria within pre-necrotic gingival epithelium. Br Dent J 1967;122:51-56. 36. Courtois GJ, Cobb CM, Killoy WJ. Acute necrotizing ulcerative gingivitis. A transmission electron microscope study. J Periodontol 1983;54:671-679. 37. Freedman HL, Listgarten MA, Taichman NS. Electron microscopic features of chronically inamed human gingiva. J Periodont Res 1968;3:313-327. 38. Melcher AH. Some histological and histochemical observations on the connective tissue of chronically inamed human gingiva. J Periodont Res 1967;2:127-146. 39. Hooper PA, Seymour GJ. The histopathogenesis of acute ulcerative gingivitis. J Periodontol 1979;50:419-423. 40. Loesche WJ, Syed SA, Laughon BE, Stoall J. The bacteriology of acute necrotizing ulcerative gingivitis. J Periodontol 1982;53:223-230. 41. Rosebury T, MacDonald JB, Clark AR. A bacteriologic survey of gingival scrapings from periodontal infections by direct examination, guinea pig inoculation and anaerobic cultivation. J Dent Res 1950;29:718-731. 42. Hamp EG, Mergenhagen SE. Experimental intracutaneous fusobacterial and fusospirochetal infections. J Infect Dis 1963; 112:84-99. 43. MacDonald JB, Socransky SS, Gibbons RJ. Aspects of the pathogenesis of mixed anaerobic infections of 71

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6:50-67. 83. Enwonwu CO. Epidemiological and biochemical studies of necrotizing ulcerative gingivitis and noma (cancrum oris) in Nigerian children. Arch Oral Biol 1972;17:13571371. 84. Pindborg JJ, Bhat M, Roed-Petersen B. Oral changes in South Indian children with severe protein deciency. J Periodontol 1967;38:218-221. 85. Osuji OO. Necrotizing ulcerative gingivitis and cancrum oris (noma) in Ibadan, Nigeria. J Periodontol 1990;61: 769-772. 86. Malberger E. Acute infectious oral necrosis among young children in the Gambia, West Africa. J Periodont Res 1967;2:154-162. 87. Sheiham A. An epidemiological survey of acute ulcerative gingivitis in Nigerians. Arch Oral Biol 1966;11:937942. 88. Uohara GI, Knapp MJ. Oral fusospirochetosis and associated lesions. Oral Surg Oral Med Oral Pathol 1967; 24:113-123. 89. Taiwo JO. Severity of necrotizing ulcerative gingivitis in Nigerian children. Periodontal Clin Investig 1995;17:2427. 90. Sung CCW, Sung RY. Some clinical observations concerning noma. Am J Orthodont Oral Surg 1947;33:284287. 91. Enwonwu CO, Falkler WA Jr, Idigbe EO, et al. Pathogenesis of cancrum oris (noma): confounding interactions of malnutrition with infection. Am J Trop Med Hyg 1999;60:223-232. 92. Pindborg JJ. Tobacco and gingivitis. I. Statistical examination of the significance of tobacco in the development of ulceromembranous gingivitis and in the formation of calculus. J Dent Res 1947;26:261-264.

93. Pindborg JJ. Tobacco and gingivitis. II. Correlation between consumption of tobacco, ulceromembranous gingivitis and calculus. J Dent Res 1949;28:460-463. 94. The American Academy of Periodontology. Tobacco use and the periodontal patient (Position Paper). J Periodontol 1996;67:51-56. 95. Wirthlin MR, Devine L. Venery and Vincents? 15 case reports and discussion. J Periodontol 1978;49:449-456. 96. Melnick SL, Roseman JM, Engel D, Cogen RB., Epidemiology of acute necrotizing ulcerative gingivitis. Epidemiol Rev 1988;10:191-211. Send reprint requests to: Dr. Randal W. Rowland, University of California at San Francisco, Box 650, Room C628, 521 Parnassus Avenue, San Francisco, CA 94143. Fax: 415/5024990; e-mail: r2perio@itsa.ucsf.edu

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