Oral Manifestations of Pediatric Vertical HIV Infection

AIDS PATIENT CARE and STDs Volume 14, Number 2, 2000 Mary Ann Liebert, Inc. Oral Manifestations of Pediatric Vertical HIV Infection CLAUDIA A. KOZINETZ, Ph.D., M.P.H., 1 A. BRUCE CARTER, D.D.S.,1 CARA SIMON, R.N., M.S.N., C.P.N.P., 1 M. JOHN HICKS, D.D.S., M.D., Ph.D.,2 SUSAN N. ROSSM ANN, M.D., Ph.D.,2 CATHERINE M. FLAITZ, D.D.S., 3 STANLEY G. CRON, M.S.P.H., 1 and MARK W. KLINE, M.D.1 ABSTRACT To assess the prevalence and prognostic significance of the history of oral manifestations in children with human immunodeficiency virus infection (HIV), a cohort study of 73 children with vertical HIV infection was conducted. The study subjects were exam ined every 6 months for oral manifestations. The period prevalence of oral manifestations ranged from a low of 1% for submandibular enlargement and 3% for hairy leukoplakia to a high of 36% for xerostomia and 51% for cervical lymphadenopathy. The occurrence of oral manifestations did not change significantly over time from 1995 to 1998. Finally, the odds of occurrence of cervical lymphadenopathy, xerostomia, and oral candidiasis were greater among children in whom these manifestations had been diagnosed in the preceding 6–18 months than in children without prior diagnosis. Oral manifestations are significant clinical outcomes in pediatric vertical HIV infection, particularly for children diagnosed previously with an oral manifestation. HIV-infected children ranging in age from 3 months to 6 1/2 years. The most common oral lesion observed was oral candidiasis (26%), followed by gingivitis (3%), and parotid enlargement (2%). Similar results were reported by Moniaci et al., 4 with oral candidiasis as the most prevalent oral manifestation observed in their study population of 47 HIV-infected patients ranging in age from 3 months to 8 years.4 In a hospital-based, cross-sectional study, 40 HIV-infected children were enrolled in an oral examination study by Valdez et al.5 Oral candidiasis was the most frequent soft-tissue manifestation noted (35%). Of the 28 HIV-infected children studied by Del Toro et al., 6 39% had an oral finding. The most common oral finding, oral candidiasis, was found in five patients. INTRODUCTION are often among the first symptom in HIV-infected children. 1 Persistent oral candidiasis and recurrent herpes simplex stomatitis in children are indicators of moderately symptomatic disease in the U.S. Centers for Disease Control and Prevention classification system for HIV infection.2 Relatively little is known, however, about predictors of oral lesions, although such information would improve the understanding of these conditions. Most of the studies conducted, to date, on the oral manifestations of pediatric HIV infection have been based on cross-sectional oral examinations. Ketchem et al. 3 evaluated 47 vertically O RA L LES IO N S 1 Departments of 1 Pediatrics and 2 Pathology, Baylor College of Medicine; and 3 Division of Oral Pathology, University of Texas-Houston Health Science Center Dental Branch, Houston, Texas. 89 90 KOZINETZ ET AL. The second most frequent oral soft-tissue lesion, found in two patients, was minor aphthous ulceration. Bilateral swelling of the parotid glands was present in one patient and one other patient presented with palatal petechiae. Ramos-Gomez et al.7 conducted a retrospective cohort study of oral manifestations in 91 HIV-infected and 185 vertically exposed children. The rates of oral candidiasis, parotid gland enlargement, and herpes simplex virus infection were 67, 4, and 3%, respectively, in the infected group versus 8, 0, and 0% in their control group. In the only prospective cohort study of oral manifestations of pediatric HIV infection, Katz et al. 8 reported the cumulative presence of lesions as 72% for oral candidiasis, 47% for parotid enlargem ent, and 24% for herpes simplex during the follow-up of 99 children with vertical HIV infection. 8 In a time-dependent proportional-hazards model, oral candidiasis was associated with a more rapid rate of progression to death (relative hazard, 14.2; 95% confidence interval, 4.8 to 41.8), while parotid enlargem ent was associated with a less rapid rate of progression to death (relative hazard, 0.38; 95% confidence interval, 0.16 to 0.88) and herpes simplex was unrelated to the rate of progression (relative hazard, 1.3; 95% confidence interval, 0.5 to 3.1). The purposes of this study were to evaluate the prevalence of oral manifestations over time and to investigate potential predictors of oral manifestations, particularly a history of the manifestation, in a cohort of HIV-infected children followed in a longitudinal study. Multivariate, repeated-measures transition models for longitudinal data were used to identify the predictors. These models account for intrasubject correlations among repeated visit data while determining whether the occurrences depend upon prior episodes of the manifestations. MATERIALS AND METHODS Data collection Subjects were a cohort of HIV-positive children vertically infected with the virus and enrolled in a longitudinal study of oral manifestations. Standard definitions for HIV infection in infants and children were used. Informed consent was obtained for all subjects prior to participation. Oral examinations were conducted between December 1994 and April 1998. Study visits for each subject were scheduled every 6 months. A pediatric dentist performed the oral examinations and completed standardized forms to document the findings at each visit. In addition to the oral examination, a physical assessment, medication and therapy histories, and immunological status measurem ents (CD4, CD3, CD8, and CD19 cell counts) were obtained. Data analyses The chi-square test for trend was used to evaluate the prevalence of oral manifestations over time. We analyzed occurrences of oral manifestations using transition models for longitudinal data to account for intrasubject correlations among responses while determining whether the occurrences depended on prior episodes of oral manifestations. We considered prior diagnoses of a manifestation at the three most recent examinations, as well as two-way interactions among these three events. Model fitting was performed using SAS software.9 Other subject characteristics were added to the set of variables defined by the baseline transition model. These variables included current age, years since enrollment to current oral ex- T A BLE 1. S TU D Y S U BJEC T C H A R AC T ER ISTIC S Characteristic Gender Male Female Race/Ethnicity White/non-Hispanic Black/non-Hispanic Hispanic American Indian/Alaskan Native CDC HIV classificatio n categories Clinical Not symptomatic Mildly symptomatic Moderately symptomatic Severely symptomatic Immunological No evidence of suppression Moderate suppression Severe suppression AT E N RO L LM E N T n (%) 39 34 53 47 14 50 8 1 19 69 11 1 13 12 29 19 18 16 40 26 9 30 34 12 41 47 91 ORAL MANIFESTATIONS AND PEDIATRIC HIV T AB LE 2. A V A ILA BLE D A TA ON E P ISO D ES OF O R A L M A N IFESTA TIO N S A M O N G HIV 1 SU BJEC TS No. of diagnoses Minimum no. of exams No. of subjects No. of exams 73 64 49 43 32 73 73 289 280 247 229 185 1 2 3 4 5 Baseline prevalence Period prevalence Oral ulceration Oral candidiasis 17 (5.9)*1 17 (6.1)1. 15 (6.1)1. 14 (6.1)1. 11 (5.9)1. 5 (6.8) † 12 (16.4) 40 38 33 26 21 13 24 Parotid enlargement Mucositis (13.8) (13.6) (13.4) (11.4) (11.4) (17.8) (32.9) 16 16 13 12 12 8 10 (5.5)1 (5.7)1 (5.3)1 (5.2)1 (6.5)1 (10.9) (13.7) 12 12 11 10 10 3 8 (4.2)1 (4.3)1 (4.5)1 (4.4)1 (5.4)1 (4.1)1 (10.9) No. of diagnoses Submandibular enlargement 1 2 3 4 5 Baseline prevalence Period prevalence 1 1 1 1 1 0 1 (0.3) (0.4) (0.4) (0.4) (0.5) (0.0) (1.4) Hairy leukoplakia 2 2 2 0 0 0 2 Herpetic labialis (0.7) (0.7) (0.8) (0.0) (0.0) (0.0) (2.7) 1 1 1 1 1 0 1 (0.3) (0.4) (0.4) (0.4) (0.5) (0.0) (1.4) Xerostomia 48 47 41 39 32 11 26 Cervical lym phadenopathy (16.6) (16.8) (16.6) (17.0) (17.3) (15.1) (35.6) 63 62 51 49 37 9 37 (21.8) (22.1) (20.6) (21.4) (20.0) (12.3) (50.7) *Numbers in parentheses, percentage of examinations. † Numbers in parentheses, prevalence. amination, CD4 percent, CD4:CD8 cell ratio, and medications (PCP prophylaxis, antifungal agents). All subjects received antiretroviral medication during the period of the study, so this variable was not included. RESULTS from 6 months to 9 years (median 5 2.8 years). Characteristics of the study subjects at enrollment are presented in Table 1. All subjects were receiving antiretroviral medication at all study visits. The number of examinations per subject ranged from 1 to 9; 59% had four oral examinations for which data for three prior oral examinations were available. Subjects A total of 73 subjects with a total of 289 oral examinations met the criteria for these analyses. Age of the subjects at enrollment ranged T A BLE 3. P ER IO D P R EV A LE N C E OF O R A L M A N IFESTA T IO N S Prevalence Diagnoses of oral manifestations by number of oral examinations, as well as the baseline and BY CDC HIV C L ASSIF IC AT IO N , I M M U N O LO G IC A L C A TEG O R Y * Immunologic category Manifestation No. suppression (n 5 9) n (%) Oral ulcer Oral candidiasis Mucositis Parotid enlargement Hairy leukoplakia Xerostomia Cervical Lymphadenopathy 1 4 1 1 0 2 5 *Category at study baseline. 11 44 11 11 0 22 56 Moderate suppression (n 5 30) n (%) 5 6 3 3 0 9 11 17 20 10 10 0 30 37 Severe suppression (n 5 34) n (%) 6 14 6 4 1 15 21 18 41 18 12 3 44 62 92 KOZINETZ ET AL. T A BLE 4. O C C U RR EN C E OF O R A L M A N IF ESTA TIO N S O V ER TH E T IM E P ER IO D O F THE S TU D Y , 1995– 1998 Study year 1995 (n 5 56)* 1996 (n 5 103) 1997 (n 5 105) 1998 (n 5 18) Manifestation n (%) n (%) n (%) n (%) Oral ulcer Oral candidiasis Mucositis† Parotid enlargement Hairy leukoplakia Xerostomia Cervical Lymphadenopathy † Total 2 11 11 3 0 9 5 41 3.4 19.6 19.6 5.4 0.0 16.1 8.9 73.2 6 16 3 7 1 22 22 76 5.8 15.5 2.9 6.8 1.0 21.4 21.4 73.8 8 10 2 1 1 15 28 64 7.6 9.5 1.9 0.9 0.9 14.3 26.6 60.9 1 3 0 1 0 2 8 15 5.6 16.7 0.0 5.6 0.0 11.1 44.4 83.3 *Total number of oral examinations. † Significant trend over time, p , 0.001. period prevalences, are presented in Table 2. Period prevalence was calculated as ever versus never occurring for each of the 73 subjects. In this study population, cervical lymphadenopathy, xerostomia, and oral candidiasis were the most prevalent oral manifestations of pediatric HIV with period prevalences of 51, 36, and 33%, respectively. Period prevalences of the manifestations by baseline immunological category of the CDC HIV classification are presented in Table 3. As expected, subjects classified as having severe immunological suppression at baseline also had more occurrences of oral manifestations throughout the study period. The prevalence of a diagnosis of an oral manifestation at an oral examination over the period of the study remained relatively constant from 1995 through 1998 (Table 4). The occurrence of mucositis, however, decreased significantly between 1995 and 1998 from 20 to 0%, while the occurrence of cervical lymph- adenopathy increased significantly during that same period from 9 to 44% (p , 0.001). Overall, the percentages of oral manifestation diagnoses at oral examinations from 1995 through 1998 remained relatively stable. Predictors Occurrences of the oral manifestations of cervical lymphadenopathy, xerostomia, and oral candidiasis were modeled with logistic transition models. Because of the small number of cases for the other observed oral manifestations, modeling was not applied. The first step of the modeling was conducted to examine the relationship of the manifestation’s status at each of the three most recent visits with the current status of the manifestation. The two-way interactions between prior study visits also were examined. As shown in Table 5, study subjects were at increased risk of an oral manifestation if they had a history of that manifes- T A BLE 5. O D D S R A TIO S F O R TH E O C C U R R EN C E O F O R A L M A N IF ESTA TIO N S A M O N G HIV-IN FEC T ED C H ILD R EN IN T R A N SITIO N M O DEL S * Cervical lymphadenopat hy Xerostom ia Oral candidiasis Predictor OR † 95% CI OR 95% CI OR 95% CI Prior exam ‡ Prior exam 3 2 Prior exam 3 3 1.02 1.91 1.91 0.1–5.71 0.4–10.2 0.1–52.4 61.7 1.4 17.2 3.4– ,111111 0.1–33.81 0.8–554.0 999.0 0.0 0.0 11.4– ,1111 0.0–0.41 0.0–37.6 *No two-way interaction terms were significant. † OR, Odds ratio. ‡ Diagnosis of manifestation at a prior exam. 93 ORAL MANIFESTATIONS AND PEDIATRIC HIV T A BLE 6. O DD S R A TIO S FO R T H E O C C UR R EN C E O F O R A L M A N IF ESTA TIO N S A D JU STED BY S ELEC T SU BJEC T C H A R A C TER ISTIC S A M O N G HIV-I N F EC TED C H IL DR EN Predictor OR* Cervical lymphadenopa thy Prior exam 1.1 Prior exam 3 2 2.3 Prior exam 3 3 1.2 Age at most recent visit 1.1 Xerostomia Prior exam 338.6 Prior exam 3 3 999.0 Other prophylaxis 999.0 Total time in study 999.0 Oral candidiasis Prior exam 111.2 Prior exam 3 3 0.0 CD4% 1.1 95% Confidence interval 0.2–5.7 0.4–12.8 0.1–36.1 0.9–1.5 2.7– , 24.9– , 3.1– , 4.8– , 2.3–999.0 0.0–3.8 0.9–1.3 *OR, Odds ratio. tation at prior oral examinations. The wide confidence intervals and large odds ratios are due to the relatively small number of oral outcomes in each category. Additional subject characteristics were added to the baseline transition model, which contained the previous exams data only. Subject characteristics including age at most recent exam, gender, race/ethnicity, CD4%, CD4 cell count, CD8%, CD8 cell count, CD4:CD8, PCP or other prophylaxis, and CDC clinical and immunological categories were added one by one to the model. Only variables that contributed significantly to the model, based on the Akaike Information Criterion and the Schwarz Criterion, both goodness-of-fit measures, were maintained in the model. For each of the three manifestations modeled, history of the manifestation at prior examinations remained predictive of the manifestation (Table 6). Age at most recent visit, total time of follow-up in the study, and CD4 percent were the additional subject characteristics which contributed to the models. ported prevalences from other cross-sectional studies.3– 7 This is not surprising since our baseline figures were derived during the same years in which the other cross-sectional studies were conducted. Our period prevalences (longitudinal) were lower than those resulting from the cohort study of 150 children and reported by Katz et al.8 In that study, the prevalence of oral candidiasis was 72%, parotid enlargem ent was 47%, and hairy leukoplakia was 2%. In our study, the number of new occurrences of oral outcomes remained stable over time. Most interesting were our results indicating the odds of occurrence of cervical lymphadenopathy, xerostomia, and oral candidiasis were greater among children in whom these manifestations had been diagnosed in the preceding 6–18 months than in children without prior diagnosis. Prior manifestations remained the strongest predictors after adjustment by a set of subject characteristics. A limitation of this study was the low number of oral manifestation occurrences available for the analyses. Occurrences ranged from a low of 21 for oral candidiasis to 49 for cervical lymphadenopathy. This resulted in a large amount of variation around the odds ratio estimations. Our data suggest that oral manifestations of pediatric HIV infection remain a concern for these children and their caregivers. Children who have experienced an oral manifestation are at increased odds of repeat occurrences. ACKNOWLEDGMENTS This study was supported by grant number R01 DE11363 from the National Institute of Dental Research and grant number M01 RR00188 from the General Clinical Research Centers program. REFERENCES DISCUSSION The baseline (cross-sectional) prevalences of oral manifestations observed in the present study were within a comparable range to re- 1. Rosenberg ZF, Fauci AS. Immunopathology and pathogenesis of HIV infection. In: Pizzo AP, Wilfert CM, eds. Pediatric AIDS: The Challenge of HIV Infection in Infants, Children, and Adolescents, 2nd ed. Baltimore: Williams and Wilkins 1994, pp. 115–127. 2. CDC. 1994 Revised classification system for human im- 94 3. 4. 5. 6. 7. KOZINETZ ET AL. munodeficiency virus infection in children less than 13 years of age. MMWR 1994;43(No. RR-12):1– 10. Ketchem L, Berkowitz RJ, McIlveen L, et al. Oral findings in HIV-seropositive children. Pediatr Dent 1990; 12:143– 146. Moniaci D, Cavallari M, Greco D, et al. Oral lesions in children born to HIV-1 positive women. J Oral Pathol Med 1993;22:8– 11. Valdez IH, Pizzo PA, Atkinson JC. Oral health of pediatric AIDS patients: A hospital-based study. J Dent Child 1994;61:114– 118. Del Toro A, Berkowitz R, Meyerowitz C, et al. Oral findings in asymptomatic (P-1) and symptomatic (P-2) HIV-infected children. Amer Acad Pediatr Dent 1996;18:114– 116. Ramos-Gomez FJ, Hilton JF, Canchola AJ, et al. Risk factors for HIV-related orofacial soft-tissue manifestations in children. Pediatr Dent 1996;18:121– 126. 8. Katz MH, Mastrucci MT, Leggott PJ, et al. Prognostic significance of oral lesions in children with perinatally acquired human immunodeficiency virus infection. Am J Dis Child 1993;147:45– 48. 9. SAS Institute, Inc. SAS Statistical software, vers. 6.12 for Microsoft Windows. Cary, NC: SAS Institute, Inc., 1994. Address reprint requests to: Claudia A. Kozinetz, Ph.D., M.P.H. 6621 Fannin, M.C. 3-2316 Houston, Texas 77030 E-mail: kozinetz@ bcm.tmc.edu