Oral Soft Tissue Manifestations and CD4 Lymphocyte Counts in HIV-Infected Children

Home , Gingival disease, Linear gingival erythema

Oral soft tissue manifestationsand CD4 lymphocytecounts in HIV-infected children

R. Bruce Howell, DMDJohn J. Jandinski, DMD Paul Palumbo,MD Zia Shey, DMD,MS Milton I. Houpt, DDS, PhD

Abstract a range of I to 18 years. The sampleconsisted of mostly African Americans (62%, 37/60), followed by equal This study investigated the prevalenceof oral soft tis- numbers of Caucasians (17%, 10/60) and Hispanics sue lesions in children infected with HIVand the relation- (18%, 11/60). The remaining children were Asian (2/ ship of CD4lymphocyte levels with the prevalenceof those lesions. Sixty HIV-positive children enrolled in the 60) or Haitian (2/60). Malesaccounted for 43%(N = and females accounted for 57%(N = 34). Fifty-five Children’s Hospital AIDS Program(age 5.8 + 3 years) were selected for study. Only five subjects (8%) had the 60 patients had contracted the disease perinatally, healthy gingiva and a low meanplaque index (22%). The three were infected by blood transfusion, and two had been sexually abused. All children had acquired the remainderhad gingivitis or periodontitis with relatively high plaqueindices (47, 55, and 94%,respectively). A de- infection prior to 13 years of age. clining CD4lymphocyte count (1357 to 35) was associ- Oral examinations ated with an increasing severity of gingival disease. Informed consent was obtained from the patients’ (Pediatr Dent 18:117-20, 1996) parents or guardians and oral examinations were performed at the CHAPindependently by two investiga- tors (RBH,JJJ). The two sets of examinations were then ’IV infection in children was first described in comparedto establish inter-rater reliability of 96%.Soft H 1983.1~2 Since then, there have been a limited tissue lesions were diagnosed using criteria suggested .number of reports of the oral manifestations at the time that this study was conducted,is and diag- associated with this disease.3-9 Several reports list oral noses were based only upon clinical findings. candidiasis as the most prevalent lesion. 9-11 Other oral Pseudomembranous and erythematous candidiasis manifestations of HIV infection in children include were grouped together with angular cheilitis. Herpes parotid gland enlargement, herpes simplex, and hairy simplex was diagnosed by clustered vesicles or mul- leukoplakia.6, 9,12,13 Onlytwo studies have included the tiple, painful intra-oral ulcers and a clinical response prevalence of gingival lesions, s, 7 Likewise, there are to Acyclovir® ( Burroughs Wellcome/ Glaxo Wellcome limited data concerningoral soft tissue lesions and their Inc, Research Triangle Park, NC). relationship to CD4lymphocyte levels, s, 7 This study A simplified gingival index (modified from the in- investigated the prevalence of soft tissue and gingival dex developed by L6e and Silness) 16 was performed lesions in 60 HIV-infected pediatric patients and the with a 0-3 scale. The gingiva examined was divided relationship of CD4lymphocyte levels with the preva- into four scoring units: distofacial papilla, facial, lence of selected commonoral lesions. mesiofacial papilla, and the lingual margin. The maxillary central and lateral incisors (primary or perma- Methods and materials nent) were the only areas examined, to ensure consis- Sixty HIV-infected children in the Children’s Hos- tency of teeth available for examination. A composite pital AIDS Program (CHAP)who were consecutively score was obtained by averaging the individual scores enrolled in 1990 received a comprehensiveoral exami- for the gingiva around each tooth sampled to give an nation. All of the children were confirmed to be HIV+ overall gingival index (0-3) for the entire segment. by positive ELISA(HIV), confirmed by Western Blot, A plaque index of the maxillary central and lateral and met the Centers for Disease Control and Preven- incisors was also performed. This was a version of the tion14 (CDC)diagnostic criteria of Class P-2 infection. Modified Plaque Index developed by the department The meanage of those examinedwas 5.8 + 3 years with of pediatric dentistry at the NewJersey Dental School.

PediatricDentistry- 18:2, 1996 AmericanAcademy of PediatricDentistry 117 TABLE. CORRELATIONOFPLAQU[ GINGIVAL INDICES AND DISEASE STATUS WITHCD4 LYMPHOCYTE COUNT (N ---- 60)

Nulnberof Patients CD4 Diagnosis (N = 60) % Plaque Index" Gingival Index" Counts/m~n2"

Healthy gingiva 5 (8%) 22 + 34 0.0 1357 + 693 Conventional gingivitis 27 (45%) 47 23 1.29 0.5 486 446 Linear gingival erythema 23 (38%) 55 25 1.64 0.5 333 415 HIV periodontitis 5 (8%) 94 + 9 2.80 + 0.3 35 + 40

"All valuesare mean _+ 1 SD.

Only the labial surfaces were scored, with TABLE2. CORRELATIONOF CD4 LYMPHOCYTE COUNTS" IN PATIENTS each tooth surface divided into five sec- WITHAND WITHOUT ORAL CANDIDIASIS tions: mesial, distal, gingival middle, middle middle, and occlusal middle. Number of CD4~ Counts~ram Each of the five sections were examined Patients (%) Mean Age (Range) for the plaque presence (score = 1) absence (score = 0). The individual scores With candidiasis 19 (32) 6.1 218 + 349 (11-1371) for the four teeth were totaled (range 0- Without candidiasis 41 (68) 5.7 663 + 349 (1-2639) 20) and then multiplied by 5 to give percentage of plaque on all four teeth. ¯ 11 of 19patients with candidiasishad CD4 counts below 200 mm2; 11 of 41 2. Linear gingival erythema (LGE) was patients without candidiasishad CD4 counts below 200 mm diagnosed as a distinct red linear band of erythema extending 2-3 millimeters apically from and the Tukey-Kramer multiple comparisons q-test and the free gingival margin. 17,1~ An additional criterion with the unpaired t-test. The 95%level (P < 0.05) was se- was the lack of attachment loss and pocketing. The di- lected for statistical significance. agnosis was confirmed by the failure to respond to conventional therapy consisting of the removal of plaque Results ® and calculus, as well as the use of Peridex (Poctor The findings of this study appear in Table 1. Subjects Gamble, Cincinnati, OH) for I month. are separated into four groups according to health of the Periodontal disease was diagnosed based upon the gingiva or periosteum. Table 1 reports the mean plaque extreme aggressiveness of the lesion. Clinically, this index, gingival index, and CD4counts/ram 2 for each was manifested by attachment loss, spontaneous bleed- group. Subjects with healthy gingiva had significantly less ing, severe inflammation, and radiographic evidence plaque (22%) than those with diseased gingiva (47%; of moderate to severe bone loss. Pain and fever were 0.05, F = 13.1). There were no differences in plaque be- also universal observations. Only one subject demon- tween subjects with conventional gingivitis (47%) and strated moderate to severe ulceration and necrosis of those with linear gingival erythema (55%; P > 0.05, q the attached gingiva, however, all five subjects with 2.1). However, both groups had significantly less plaque periodontal disease had at least several areas of soft than subjects with HlV-periodontitis (94%). The gingival tissue necrosis. Of the five patients with periodontal indices of all four groups differed significantly (P < 0.05, disease only one satisfied the criteria for necrotizing F = 41.0). Healthy subjects had a mean gingival index of ulcerative periodontitis. Consequently, these subjects 0.0. Those subjects with conventional gingivitis had a were not labeled according to the current EC Clearing- mean index of 1.29, those with linear gingival erythema house categories, and the term HIV-associated peri- had an index of 1.64, and those with periodontitis were odontalIs disease is used. most severe with an index of 2.8 compared to a maximum Laboratory of 3.0. The CD4counts/mm 2 were significantly different For this study, CD4lymphocyte counts were obtained among the four groups (P < 0.05, F=14.6), however, they within 3 months of oral examination with the exception were most different between those with healthy gingiva of one subject whose counts were obtained 6 months with high counts (1357) and the other groups with rela- later. Since the age range of subjects was 1-18 years, the tively low counts (486, 333, and 35), (P > 0.05, q = 7.3, CD4 levels used were with the following reference and 8.5). There were no significant differences between ranges: 24-60 months, absolute CD4 count 900-2860/ those with conventional gingivitis and those with linear mm2, and older than 60 months, 689-1566/mm229 gingival erythema (P > 0.05, q = 2.2), or between those with gingival erythema and those with periodontitis (P Dataanalysis > 0.05, q = 2.5). The data were analyzed for statistical differences be- Table 2 differentiates subjects according to the ab- tween groups with a one-way analysis of variance F test sence or presence of candidiasis. The 19 subjects (32%)

118 AmericanAcademy of Pediatric Dentistry PediatricDentistry - 18:2, 1996 TABLE3. CD4LYMPHOCYTE COUNTS IN PATIENTS WITH AND have a pre-existing conventional periodontal disease at WITHOUTANY SOFT TISSUE ORAL DISEASE ASSOCIATEDWITH the time of the HIV infection. In both adults and chil- HIV INFECTION INCLUDING LINEAR GINGIVAL ERYTHEMAr dren who are HIV+, the underlying problem is an ir- r 24-26 HIV~PERIODONTITIS~ HERPESSIMPLEXp AND CANDIDIASIS regular host response to the oral miroflora. Although it is well established that profound wasting occurs subsequent to HIV infection, neither the Numberof Patients Mean Age CD42 Count~ram (%) (Range) prevalence nor the severity of endocrine dysfunction can totally explain the wasting observed in children. 27 Oral 27 (45) 6.7 287 + 396 (1-1571) lesions may have an important impact on the nutritional 33 (55) 5.1 705 + 673 (5-1524) status of these children 28, 29 by reducing the food intake. Symptomatic treatment of oral soft tissue lesions may improve food intake thereby reducing generalized wast- with candidiasis had significantly lower CD4 counts ing. This influence should be studied further. (218) than the 41 subjects (68%) without the disease (CD4 count 663); (P < 0.05, t = 2.82). Conclusions Table 3 differentiates subjects according to the ab- 1. Medically well-managed children infected with sence or presence of any soft tissue oral disease associ- HIV usually have significant oral disease. ated with HIV infection, including linear gingival 2. Gingivitis in HIV-positive children is associated erythema, HIV-periodontitis, herpes simplex, or candidiasis. The 27 subjects with oral disease had signifi- with poor oral hygiene. cantly lower CD4counts (287) than the 33 subjects with- 3. Soft tissue lesions in HIV-positive children are as- out oral disease (705); (P < 0.05, t = 2.80). sociated with low CD4 lymphocyte counts.

Discussion The authors thank Mr. Martin Feuerman,Department of Informa- This study demonstrates that medically well-managed, tion Services and Technology,University of Medicineand Den- HIV-infected children usually have significant oral dis- tistry of NewJersey for assistance with the data analysis. ease. Since almost 50%of the subjects exhibited some soft Dr. Howellis in private practice in Salt LakeCity, Utah, and was tissue oral manifestations of the H1Vinfection, oral find- formerly a graduate student, UMDNJ-NJDS,department of pedi- ings may suggest the presence the disease. Oral candidi- atric dentistry; Dr. Jandinskiis associate professor, departmentof oral pathology, biology and diagnostic sciences, NewJersey Den- asis occurred in one-third of the subjects, which was simi- tal Schooland director of dental services, ChildrensHospital AIDS lar to the prevalence previously reported. 7 In addition, the Program, NewJersey Medical School; Dr. Palumbois assistant candidiasis occurred in subjects whose CD4 lymphocyte professor, departmentof pediatrics, NewJersey MedicalSchool; counts2. (except for one subject) were less than 1000/mm Dr. Shey is professor and associate dean for student affairs and graduate dental education, NewJersey Dental School; and Dr. This finding suggests that the relationship of low CD4 Houptis professor and chairman, department of pediatric den- counts and occurrence of oral candidiasis should be in- tistry, NewJersey Dental School. vestigated further. It has been reported that linear gingival erythema 1. Oleske J, MinneforA, CooperR Jr, et al: Immunedeficiency syndromein children. J AmMed Assoc 249:2345-49, 1983. (LGE) is a characteristic oral manifestation of HIV in- 2. Rubinstein A, Sicklick M, Gupta A, et al: Acquired immu- 17,18 fection in adults, and the prevalence of this condi- nodeficiency with reversed T4/T8ratios in infants born to tion in intravenous drug users has been estimated to promiscuous and drug addicted mothers. J AmMed Assoc be as high as 49%.2° In this study of young children, 249:2350-56,1983. 3. Howell RB: Oral manifestations and laboratory values in LGEwas found to be present in 38% of the subjects, 2~- children infected with the humanimmunodeficiency virus whereas other studies reported a lower prevalence. type I. MSthesis, University of Medicineand Dentistry of 23 The difference in prevalence of LGEmay be related NewJersey, 1991. to the levels of immunosuppression in the subjects of 4. HowellRB, Jandinski J, PalumboP, Shey Z, HouptM: Den- the various studies. tal caries in HIV-infectedchildren. Pediatr Dent14:370-71, In this study, there was an association between CD4 1991. 5. Moniaci D, Cavallari M, Greco D, Bruatto M, Raiteri R, counts and the severity of periodontal disease, which PalomboE, ToroPA, Sinicco A: Oral lesions in children born suggests that periodontal disease may be associated with to HIV-1positive women.J Oral Pathol Med22:8-11, 1993. immunological dysfunction rather than local factors. This 6. Leggott J: Oral Manifestationsof HIVinfection in children. suggestion is supported by the finding of a similar plaque Oral Surg Oral MedOral Pathol 73:187-92, 1992. 7. KetchemL, BerkowitzRJ, McllveenL, Forrester D, Rakuson index in conventional gingivitis and LGE. T: Oral findings in HIV-seropositivechildren. Pediatr Dent The finding of HIV-periodontitis in 8% of the sample 12:143-46,1990. is2° less than that reported in adults infected with HIV. 8. Ramos-GomezFJ, Greenspan D, Greenspan JS: Orofacial This may be due to the multiple antibiotics and intra- manifestations and managementof HIVinfected children. venous gammaglobulin 23 prescribed for HIV+ children Oral Maxillofac Surg Clin N Am6:37-47, 1994. 9. Katz MH,Mastrucci MT,Leggott PJ, et al: Prognostic sig- and these agents may help to prevent periodontal dis- nificance of oral lesions in children with perinatally ac- ease. In addition, the epidemiology of periodontitis quired humanimmunodeficiency virus infection. AmerJ differs in adults and children. Adults will frequently Dis Child 147:45-48, 1993.

Pediatric Dentistry- 18:2, 1996 AmericanAcademy of Pediatric Dentistry 119 10. Tovo P, DeMartinoM, GabianoC, et al: Prognostic factors 20. Murray PA, Fenesy K, Huber H, Scorziello T, Lynch M, and survival in children with perinatal HIV-1infection. The Najjar T, Jandinski J: HIV-associatedperiodontal diseases Italian register for HIV infection in children. Lancet in intravenous drug users. J Dent Res 70:415, 1991 (Abstr 339:1249-53,1992. 1195). 11. Principi N, MarchisioP, Tornaghi R, Massironi E, Onorato 21. San Martin T, Jandinski JJ, PalumboP, MurrayP: Periodon- J, Picco P, Libretti C: Occurrenceof infections in children tal diseases in children infected with HIV.J DentRes 7:151, infected with humanimmunodeficiency virus. Pediatr In- 1992(Abstract 366). fect Dis J 10:190-93,1991. 22. Leggott PJ, Robertson PB, Greenspan DG, Wara DW, 12. Nadal D, deRocheB, Buisson M, Seger RA:Oral hairy leu- GreenspanJS: Oral manifestation of primary and acquired koplakia in vertically and horizontally acquired HIVinfec- immunodeficiencydiseases in children. Pediatr Dent 9:98- tion. ArchDis Child 67:1296-97,1992. 104, 1987. 13. Ferguson F, Archard H, NuovoG, NachmanS: Hairy leu- 23. PalumboP, Jandinski J, ConnorE, FenesyK, Oleske J: Medi- koplakia in a child with AIDS- a rare symptom:case re- cal managementof children with HIVinfection. Pediatr port. Pediatr Dent 15:280-81,1993. Dent 12:139-42, 1990. 14. Centers for Disease Control. Classification systemfor hu- 24. WorkingGroup on Anti Retroviral Therapy: National Pe- manimmunodeficiency virus (HIV) infection in Children diatric ResourceCenter; Antiretroviral therapy and medi- under 13 years of age. MMWR36:225-30, 1987. cal managementof the humanimmunodeficiency virus-in- 15. EuropeanCommunity - Clearinghouse on oral problems re- fected child. Pediatr Infect Dis J 12:513-22,1993. lated to HIVinfection and WHOcollaborating center on oral 25. LynchM, Jandinski J, HusainA, Tiu B and MurrayPA: Pres- manifestations of the humanimmunodeficiency virus: an ence of Interleukin 1Bin Crevicular fluid from HIV-infected update of the classification and diagnostic criteria of oral Adults, J Dent Res 71:155, 1992 (Abstract #394). lesions in HIVinfection. J Oral Pathol Med20:97-100, 1991. 26. Jandinski J, SanMartin T, PalumboP, Cai H, Parulis A, 16. L6eH, Silness J: Periodontal disease in pregnancy.I. Preva- CampbellF, Oleske J: Presence of interleukin-lB in crevicu- lence and severity. Acta Odont Scandinavica 21:532-51, lar fluid from HIV-infectedchildren. J DentRes 73:257,1994 1963. (Abstract 1247). 17. WinklerJR, MurrayPA: Periodontal disease -- A potential 27. Lane L, Gutler GB:Abnormalities in growth and develop- intra-oral expression of AIDSmaybe a rapidly progressive ment. In: Pediatric AIDS,2nd Ed., Pizzo PA, Wilfere T, CM periodontitis. Calif Dent AssocJ 15:20-24, Jan 1987. Eds. Philadelphia: Williamsand Wilkens, 1994, pp 575-87. 18. Winkler JR, Murray PA, Grassi M, HammerleC: Diagnosis 28. MugrditchianL, Arent-FineJ, DwyerJ: The nutrition of the and Managementof HIV-associated periodontal lesions. J HIV-infectedchild: Part I: A Reviewof Clinical issues and AmerDent Assoc 119:25S-34S, 1987 (Nov Suppl). TherapeuticStrategies. TopClin Nutr 7(2):1-10, 1992. 19. DennyT, YogevR, GelmanR, Skuza C, Oleske J, Chadwick 29. WinterHS, Miller TL: Gastrointestinal and nutritional prob- E, Cheng S-C, Connor E: Lymphocytesubsets in healthy lems in pediatric HIVdisease. In: Pediatric AIDS,2nd Ed. children during the first 5 years of life. JAMA267:1484-88, Pizzo PA, Wilfert CM,Eds. Philadelphia: Williams and 1992. Wilkins 1994, pp. 513-33.

Excess lead exposure associated with increased risk for antisocial and delinquent behavior

Children with high bone lead levels tend to be The study included 301 public school boys whose more aggressive and antisocial, according to an ar- lead levels were determined by X-ray fluorescence of ticle in a recent issue of The Journal of the American the tibia. The other outcome measures included the Medical Association. CBCL,teachers’ and parents’ reports, and subjects’ Herbert L. Needleman, MD, from the Depart- self-report of antisocial behavior and delinquency at ment of Psychiatry, University of Pittsburgh School 7 and 11 years of age. of Medicine, and colleagues conducted a study to At 7 years, borderline associations between teach- evaluate the association between body lead levels ers’ aggression, delinquency, and externalizing scores and social adjustment. and lead levels were observed after adjustment for The authors write: "In this study, male children covariates. At 11 years, parents reported a signifi- considered asymptomatic for lead toxicity with el- cant lead-related association with the several CBCL evated bone lead levels at 11 years of age were judged cluster scores. by both parents and teachers to be more aggressive, The researchers write: "The appearance of lead- have higher delinquent scores, and have more so- related effects at the median bone lead level suggests matic complaints than their low-lead counterparts. that in some samples lead may contribute to dys- "The subjects themselves reported lead-related function in an appreciable proportion of the com- increases in antisocial acts at the same age. High-lead munity. subjects were more likely than low-lead subjects to "These data argue that environmental lead expo- worsen on all scores of parents’ and teachers’ Child sure, a preventable occurrence, should be included Behavior Checklist (CBCL)during the 4-year obser- when considering the many factors contributing to vation period." delinquent behavior."

120 A~nericanAcademy of Pediatric Dentistry PediatricDentistry - 18:2, 1996