HIV and Periodontal Health

A STUDV OF MILITARY PERSONNEL W ITH HIV P H IL IP A. S W A N G O , D.D .S ., M .P .H .; D U S H A N K A V. KLE IN M A N , D .D.S., M .S C .D .; J O S E P H L. K O N Z E L M A N , D .D .S.

h en evidence of the worldwide HIV epidem ic began to emerge in th e early 1980s, few anticipated the im pact the disease would have on virtually every medical and dental practice and across all segm ents of society. The epidemic was of particular concern to health authorities in the U.S. military services because young males were predom inantly affected and because sexual contact was the chief mode of transm ission. In 1985, all active duty military personnel as well as those applying for recruitm ent were subjected to m andatory blood testing for the HIV antibody to protect HIV-infected persons from receiving live-virus vaccinations routinely given to recruits, and to identify infected active duty personnel so th at they would not be deployed to areas in which medical services were limited. As part of the testing program, persons identified as HIV-positive w ere evaluated and treated at regional medical care centers and scheduled for six-month follow-up. The screening program also provided a unique opportunity to study HIV infection. Because of its pioneering work in medical virology and immunology, the W alter Reed Army Institute of Research in Washington, D.C., was charged with determ ining the

ABSTRACT

In 230 military personnel who were seropositive for the human immunode­ ficiency virus, the prevalence o f viral and fungal infections in the mouth was clearly related to the degree o f immune dysfunction as measured by T4-lymphocyte counts. The relation between periodontal health and T4 counts was less clear. Tobacco use was related to the increased occurrence of both mucosal lesions and periodontal diseases. medical param eters under which HIV-infected service members could perform and initiated a natural history study to elucidate the medical effects of HIV infection. Oral symptoms of HIV infection, such as oral candidiasis and hairy leukoplakia, were noted early in the epidemic and indicated disease progression.14Oral lesions of Kaposi’s sarcoma and unusually aggressive forms of periodontal disease were docum ented as part of the HIV syndrom e.5'6

Recognizing the im portance of oral disease, WRAIR researchers collaborated with scientists at the National Institute of Dental Research to ensure inclusion of oral symptoms in the natural history study. The NIDR-WRAIR collaboration began in 1987, and in 1989 the NIDR’s Oral Health Research Activity began operating at the W alter Reed Army Medical Center. The Army’s HIV research effort was unique because of the large study population, and because patients w ere m onitored every six m onths to assess their medical and oral health status, as well as their immunologic competence. Study subjects were identified early in the course of infection as a result of the m ilitary screening program. Therefore, volunteers could be observed from presym ptom atic stages through the onset of oral and medical m anifestations. Also the Army had developed an effective system for staging HIVdisease progression, w hich could be used to assess im m une breakdown in relation to the onset of oral pathologies. The oral health research protocol had four major objectives: ■■ to docum ent the incidence and prevalence of oral mucosal pathologies in relation to im m une dysfunction progression; **■ to study the occurrence and JADA, Vol. 122, July 1991

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causes of HIV-related periodontal destruction; ™ to elucidate the clinical and immunologic aspects of oral candidiasis; and ™ to investigate the role of salivary components in relation to the occurrence of mucosal pathologies. This report summarizes initial oral findings from HIV-infected military personnel and dependents examined in the first year of the project (1989-90), focusing on viral and fungal infections of the oral mucosa and the periodontal effects of immune dysfunction. METHODS

A total of 230 seropositive active duty or retired military personnel or dependents identified through the military testing program were studied. After serostatus determination, subjects were evaluated and treated at the Walter Reed Army Medical Center and invited to participate in one or more research protocols. Volunteers for the medical research protocols were assessed for HIV disease progression by means of the Walter Reed Staging Classification System.7The system assigns subjects to one of six progressive stages of infection based on a composite profile of clinical and laboratory findings. Staging of infected individuals ranges from stages 1 and 2, in which the patient is essentially asymptomatic with T4-lymphocyte counts of greater than 400 cells per millimeter3, to progressively higher stages in which T4 lymphocytes are less than 400 cells per mm3and clinical signs and symptoms occur. Stage 6 essentially corresponds to the CDC classification of frank AIDS. For this analysis, subjects were grouped into two categories: those 50

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in stages 1 or 2 (T4-lymphocyte counts of 400 or more) and those in stages 3-6 (T4-cell counts of less than 400). Oral examinations were conducted by a specialist in oral medicine who received additional training in diagnosing HIV-related conditions and in using epidemiologic indexes of oral health status including indexes for the assessment of root and coronal caries, dental plaque and calculus, and gingival bleeding, erythema and papillary destruction. In addition to visual examination of the mouth and perioral tissues for mucosal pathologies, normal buccal mucosa and lesions suspected to be of candidal origin were smeared to detect candidal hyphae. Smears were stained by the periodic acidSchiff method and examined microscopically by the hospital pathology service. Samples of unstimulated whole saliva and subgingival plaque were collected from each subject. Subjects completed a questionnaire on oral health status, behavior and risk factors before the examination. To assess periodontal health in this study, we included measures commonly used in epidemiologic evaluations of periodontal status, such as measurements of periodontal attachment loss and pocket depth, assessment of gingival bleeding based on approaches developed by Loe and Silness,8assessments of sub- and supragingival calculus, and assessments of oral hygiene status using the method of Loe and Silness.9 In addition, two new measures were developed to assess specific types of periodontal pathology frequently reported in relation to HIV infection. To assess erythematous gingival banding, we recorded the number of tooth sites

affected by erythema at the gingival margin—defined as a continuous erythematous band at least 1 mm in width extending across the entire margin from papilla to papilla. This assessment was conducted on all teeth present, excluding third molars. We measured papillary destruction by visually assessing each interdental papilla for ulceration, cratering or pseudomembrane formation. This classification was similar to the score of GI-3 in the gingival index of Loe and Silness,8except that only sites with visible ulceration or cratering were included in the analysis, and the assessment was restricted to the gingival papillae. Oral examinations were conducted at entry into the study and every six months thereafter, or until subjects were lost to followup. Findings for this analysis are gathered from baseline examinations; longitudinal evaluations are still in progress and analyses are incomplete. RESULTS

Subjects ranged in age from 18 to 65 years, with a mean age of 32.5 years. About 90 percent were male and about half were white. Fifty percent of subjects reported current use of tobacco, usually cigarette smoking. Distribution by stage showed that about 44 percent were in stages 1 and 2, with T4-cell counts of 400 or more per mm3, and the remainder were in stages 3-6, with cell counts of less than 400. Only 14 of 230 subjects (6 percent) were in stage 6, approximating the CDC classification of AIDS. Overall, about 30 percent of the subjects had oral mucosal pathology of a type that plausibly could be associated with HIV infection. These included any of the oral conditions reported in the

50

40 0-399 T4 CELLS/MM

CURRENT SMOKERS

35 400+ T4 CELLS/MM

NONSMOKERS

30

h

25

Z

LU

o

20

K

III

a

15

1 0

ANY ORAL LESIONS

CANDIDIASIS

HAIRY LEUKOPLAKIA

Prevalence of oral mucosal pathologies by stage of immune dysfunction as measured by T4-cell counts.

HIV literature, as reviewed and prom ulgated internationally by the European economic com m unity and the World Health Organization.10 The m ost prevalent HIV-related mucosal conditions were oral candidiasis, w hich was found in 16 percent of subjects, and oral hairy leukoplakia, which occurred in about 14 percent. Clinical forms of candidiasis included erythe­ m atous (6 percent), pseudom em ­ branous (11 percent), and angular cheilitis (3 percent). Other HIVrelated conditions were aphthous ulcers (2 percent), and Kaposi’s sarcoma, nonspecific ulcers and verruca vulgaris, which were found in one subject each. To exam ine the relation between the occurrence of mucosal pathologies and the degree of im m une dysfunction, we analyzed the prevalence of these conditions separately for subjects with T4-lymphocyte counts of 400 or more and those with counts of less than 400 cells per mm3. The HIV-related pathologies occurred in 15.8 p ercent of subjects in the group w ith higher T4 cell counts, and in 41.1 percent of those with

ANY ORAL LESIONS

CANDIDIASIS

HAIRY LEUKOPLAKIA

Prevalence of oral mucosal pathologies in current smokers and nonsmokers.

counts of less th an 400. The odds ratio of 3.84 for this association was significant (FO.OOl). Prevalence of oral candidiasis was 7.9 percent in subjects with cell counts of 400 or m ore and 22.5 percent in those with counts of less than 400. Similar findings were noted for hairy leukoplakia, with prevalence rates of 5.9 percent and 20.2 percent, respectively, for the high and low T4 cell groups. The odds ratios of these differences were statistically significant for both conditions (P<0.01). We also analyzed the pre­ valence of oral lesions in relation to the current use of tobacco. As a group, HIV-related lesions were found in 19.3 percent of nonsmok­ ers and in 38.1 percent of current smokers (F<0.01). A significant tobacco effect was seen for oral candidiasis, which occurred in 7.3 percent of nonsm okers and 23.7 percent of smokers (P<0.01). Hairy leukoplakia was also m ore com­ mon in current smokers, but the effect was not statistically signifi­ cant (P=0.24). A significant smoking effect for oral mucosal lesions raised the issue of current tobacco use as a

confounder in the association between oral lesions and T4-cell levels. To adjust for the smoking effect, we perform ed stratified analyses using the MantelHaenszel Chi-square procedure. The statistical associations between oral lesions and im m une status are thus reported as MantelHaenszel adjusted odds ratios, controlling for tobacco use. There were no statistically significant associations between the prevalence of oral mucosal lesions and the age, race or gender of subjects. To assess the effect of im m une dysfunction on the periodontium , we m easured the prevalence and extent of three param eters, as described previously: gingival bleeding on gentle probing, erythem atous banding at the gingival m argin and destruction of gingival papillae. These m easures were obtained from 189 subjects for whom complete periodontal data were available. All bu t six subjects (97 percent) had bleeding on probing, w ith a mean of 11 bleeding tooth sites per person. Forty-nine percent had erythem atous bands involving one JADA, Vol. 122, July 1991

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or m ore teeth and 25 percent had necrotic destruction of one or m ore gingival papillae. Subjects with gingival banding had an average of 6.2 tooth sites affected, and those w ith papillary destruction had an average of 4.7 papillae showing evidence of cratering or necrosis. Analysis of periodontal findings in relation to the degree of im m une dysfunction did not show the clear-cut pattern observed for mucosal pathologies. Analysis of variance showed th at subjects with T4-cell counts of 400 or more had significantly m ore bleeding sites (.P<0.05) and m ore papillae with tissue destruction (P=0.06) than those w ith counts of less than 400. While subjects in the low T4 group had m ore sites affected by banding than those in the high group, the difference was not statistically significant. Thus, gingival bleeding and papillary destruction w ere less extensive in subjects in m ore advanced stages of HIV infection, w hereas gingival banding occurred independently of the stage of im m une deficiency. We also analyzed the periodon­

tal findings in relation to current tobacco use. The prevalence of all three periodontal m easures was sim ilar in smokers and nonsmokers, but the extent of gingival banding and papillary destruction as m easured by the num ber of sites affected showed significant tobacco effects. For subjects with gingival banding, smokers had a m ean of 7.5 teeth affected while nonsm okers were affected on only five sites per person (F<0.01). Differences in papillary destruction were even more pronounced, with smokers having an average of six sites affected as com pared with three sites for nonsm okers (P<0.03). Thus while tobacco use had no apparent effect on the prevalence of these conditions, it was a significant determ inant of the num ber of sites affected. D IS C U S S I O N

Numerous investigators have reported the prevalence of oral mucosal pathology in HIV-infected persons, particularly for oral candidiasis and hairy leukoplakia.

These findings have varied widely, depending on the study population, the m ethods of diagnosis and perhaps other factors. To place our findings in proper context, it is necessary to point out im portant differences between our methods and those of most other investigations. First, our subjects were typically exam ined soon after they were found to be seropositive, often before the onset of oral signs or symptoms. Most other studies have exam ined subjects who were treated at a dental care facility after oral lesions developed. In addition, all subjects in our analysis were subjected to immunologic staging, enabling us to relate oral findings to the degree of im m une dysfunction. Our diagnostic confirmation m ethods also differed from previous studies; all diagnoses of candidiasis were confirmed by cytologic evaluation of smears. Our diagnoses of hairy leukoplakia, however, were based on visual exam inations alone, whereas some other investigators have used confirming biopsies or assays of

12

15

CURRENT SMOKERS NONSM OKERS

10

12

0-399 T4 CELLS/MM

□

400+ T4 CELLS/MM

llln

GINGIVAL ERYTHEMATOUS PAPILLA BLEEDING BANDS DESTRUCTION

Mean number of gingival sites with bleeding, ery­ thema or papillary destruction, by T4-cell counts.

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GINGIVAL BLEEDING

ERYTHEMATOUS

PAPILLA BANDSDESTRUCTIO

Mean number of gingival sites with bleeding, erythema or papillary destruction in smokers and nonsmokers.

tissue scrapings using in situ hybridization procedures. All diagnoses in our study were made by a dentist w ith specialty training and experience in oral medicine; the discipline, training and experience of exam iners in other reports have varied widely. In this population, the prevalence of oral viral and fungal infections was clearly related to the degree of im m une dysfunction as m easured by declining T4-cell counts. This finding is characteristic of T-cell deficiencies in general, and confirms the suggestion by others th at these conditions have usefulness as markers of disease progression in HIV infection. Oral candidiasis was also associated with tobacco use; current smokers had alm ost four times the prevalence of candidiasis as nonsmokers. The relation betw een tobacco use and oral candidiasis in the general population is well docum ented in the literature, and others have reported similar findings in an HIV-infected population.1213 The relation between periodontal health and im mune status was less clear. Gingival erythem a was present in about half of our subjects, b u t showed no significant association with im m une dysfunction as m easured by T4-lymphocyte counts. Gingival bleeding and papillary destruction occurred in all stages of infection, but were somewhat less extensive in subjects with lower T4 levels, representing later stages of HIV disease. These findings are consistent with other published reports of periodontal disease in im munodeficient subjects. Schuller and others14reported decreased levels of periodontal inflam m ation in renal transplant patients receiving im munosuppressive drugs, and

Robertson and others15found similar effects in a group of subjects w ith prim ary im munodeficiency syndromes. While T-lymphocytes are im portant m ediators of inflammatory processes in general,16and of periodontal inflam m ation in particular,1117they are only one of m any immunologic param eters th at can affect disease outcomes. Lehner has pointed out that cellular im m une deficiencies can result in either increases or decreases in periodontal pathology, depending on a variety of etiologic and immunologic influences.11The role of specific immune system com ponents in the developm ent and progression of periodontal disease in HIVinfected individuals needs further clarification. Comparisons of our periodontal findings with those of other investigators are difficult, prim arily as a result of the diagnostic approaches used. Most existing reports have classified periodontal conditions as HIV gingivitis, HIV periodontitis, or a necrotizing condition clinically similar to acute necrotizing ulcerative gingivitis. These entities have not always been clearly defined, however, and their relationship to HIV infection remains unclear, since clinically similar conditions may occur in noninfected subjects as well. Winkler and Murray6have described a detailed diagnostic profile of HIV gingivitis th at may be useful in differentiating this condition from ordinary gingivitis, but it has not been widely applied by others. Clinical descriptions of an aggressive necrotizing destruction of the gingival tissues with rapid horizontal bone loss are common in the HIV literature, but the prevalence of this condition and its relation to im m une status

has not been well characterized. To avoid some of the ambiguities of existing diagnostic schemes, we recorded distinct clinical signs that could be m easured and classified unequivocally. Thus, we recorded measures of gingival bleeding, marginal erythem a and papillary destruction as separate entities, and analyzed each independently of im mune dysfunction. We did not attem pt to reach a diagnosis of HIV gingivitis or HIV periodontitis, because these term s have not always been consistently defined in research reports. In this study population, gingival bleeding, marginal erythem a and papillary destruction were common: about half of the subjects showed signs of erythem atous banding at the gingival margin and 25 percent had evidence of ulceration or cratering of one or more papillae. Cases of rapid and severe periodontal destruction, however, were rare. Only 12 of the 189 subjects (6 percent) had as many as eight papillae with signs of tissue destruction, and 11 of these were current smokers (92 percent). Associations between tobacco use and periodontal status in the general population have been found by num erous other investigators over the past 30 years.18This relationship m erits further investigation in HIVinfected persons. CONCLUSIONS

In this population, fungal and viral infections of the oral mucosa were prevalent, and were strongly associated with the degree of im mune dysfunction in infected persons. Oral candidiasis was also strongly associated with current tobacco use. Periodontal inflammation and destruction were prevalent, but the severe JADA, Vol. 122, July 1991 53

form of HIV-related periodontal destruction reported by others was rarely seen. The relation between periodontal health and degree of im m une dysfunction as m easured by T4-lymphocyte counts rem ains unclear. Cigarette smoking was found to be a determ inant of the extent of periodontal inflam m ation and destruction in persons affected by these conditions. ■ Dr. Swango is acting chief, Soft Tissue, Craniofacial Defects and Pain Section, and Dr. Kleinman is dental epidemiologist, Epidemiology and Oral Disease Prevention Program, National Institute of Dental Research, National Institutes of Health, Department of Health and Human Services, Westwood Building, Room 549, Bethesda, Md. 20892. Dr. Konzelman is clinical director of oral research, Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Md. Address requests for reprints to Dr. Swango. This paper was presented in April 1991 at the Scientific Frontiers in Clinical Dentistry Symposium, National Institute for Dental Research, Bethesda, MD. 1. Phelan J, Saltzman B, Friedland G, Klein R. Oral findings in patients with acquired immunodeficiency syndrome. Oral Surg Oral Med Oral Pathol 1987;64:50-6. 2. Klein R, Harris C, Small C, Moll B, Lesser M, Friedland G. Oral candidiasis in high-risk patients as the initial manifestations of the acquired immunodeficiency syndrome. N Engl J Med 1984;311:354-8. 3. Silverman S, Migliorati C, Lozada-Nur F, Greenspan D, Conant M. Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. JADA 1986;112:187-92. 4. Greenspan J, Greenspan D, Lennette E, et al. Replication of Epstein-Barr virus within the epithelial cells of oral “hairy” leukoplakia, an AIDS-associated lesion. N Engl J Med 1985;313:1564-71. 5. Winkler J, Murray P. Periodontal disease as related to HIV infection. Calif Dent Assoc J 1984;12:21-5. 6. Winkler J, Murray P. Periodontal disease: a potential intraoral expression of AIDS may be

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rapidly progressing periodontitis. Calif Dent Assoc J 1987;15:2-24. 7. Redfield R, Wright D, Tramont E. The Walter Reed Staging Classification System for HTLVIII/LAV Infection. N Engl J Med 1981;314:131-2. 8. Loe H, Silness J. Periodontal disease in pregnancy: I. Prevalence and severity. Acta Odontol Scand 1963;21:533-51. 9. Loe H, Silness J. Periodontal disease in pregnancy: II. Correlation between oral hygiene and periodontal conditions. Acta Odontol Scand 1964;22:112-35. 10. EEC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Human Immunodeficiency Virus. An update on the classification and diagnostic criteria of oral lesions in HIV infection. J Oral Pathol Med 1991;20:97-100. 11. Lehner T. Cellular immunity in periodontal disease: an overview. In: Genco R, Mergenhagen S, eds. Host-parasite interaction in periodontal diseases. Washington, D.C.: American Society for Microbiology;1982:202-16. 12. Melnick S, Engel D, Truelove E, et al. Oral mucosal lesions: association with the presence of antibodies to the human immunodeficiency virus. Oral Surg Oral Med Oral Pathol 1989;68:37-43. 13. Syrjanen S, Valle S, Antonen J, et al. Oral candidal infection as a sign of HIV infection in homosexual men. Oral Surg Oral Med Oral Pathol 1988;65:36-40. 14. Schuller P, Freedman H, Lewis D. Periodontal status of renal transplant patients receiving immunosuppressive therapy. J Periodontol 1973;44:167-70. 15. Robertson P, Wright T, Mackler B, Lenerts D, Levy B. Periodontal status of patients with abnormalities of the immune system. J Periodont Res 1978;13:37-45. 16. Hood L, Weissman I, Wood W, Wilson J, eds. Immunology. 2nd ed. Menlo Park, Calif.: Benjamin/Cummings; 1984:441*4. 17. Roitt I, Lehner T, eds. Immunology of oral diseases. 2nd ed. Oxford, England: Blackwell Scientific; 1983:375-94. 18. Ismail A, Burt B, Eklund S. Epidemiologic patterns of smoking and periodontal disease in the United States. JADA 1983;106:617-21.