Case Report

Characterization of Patients Presenting for Treatmentto a University Refractory Periodontal Diseases Unit:Three Case Reports

Vinay M. Bhide,* Howard C. Tenenbaum,*† and Michael B. Goldberg*

Background: Of the many forms of periodontaldisease, refractory periodontal diseases are the leastcharacterized. They are defined as the continued de-generation of the periodontium despite adequateman-agement. This has led to the suggestion that theremaybea systemic component that is a contributing factor tothedevelopment of this condition. The objectives of thisreportwere to follow theprogressionof clinical changesassociated with periodontal disease over a number ofyears in this unique population and reviewvarious he-matologic and microbiologic factors that may be con-tributing to the disease progression.

Methods: Three subjects were profiled. They werereferred to the Refractory Periodontal Disease Unit atthe University of Toronto by periodontists or generalpractitioners in the Southern Ontario region. Com-pletemedical and dental historieswere obtained alongwith baseline clinical measurements. Periodontalexaminations were facilitated with the use of acomputer-assisted periodontal probe. A microbiologicanalysis using immunofluorescence techniques wasable to detect Prevotella intermedia, Porphyromonasgingivalis, Tannerella forsythia, and Actinobacillusactinomycetemcomitans and spirochetes. A hemato-logic analysis, including a complete blood count(CBC), immune profile, and glycosylated hemoglobinassay, was also performed.

Results: The clinical presentation revealed that pa-tients receiving adequate maintenance therapy andwith good to excellent oral hygiene demonstrated siteswith continual loss of attachment. Few periodontalpathogens were detected. However, the most signifi-cant finding appeared to be the report elevated levelsof CD8+ cells within this group of patients comparedto normal laboratory ranges.

Conclusions: This report is an attempt at character-izing a unique population within the periodontalrealm. The long-term monitoring of these patientsallowed for an assessment of factors that may be in-volved in the continued decline of the periodontal

health of these patients. Based on the immune profile,it is possible that a hyperresponsive state may be theprimary feature of this population. Future assessments,including full-mouth interleukin (IL)-1 and matrix me-talloproteinase (MMP)-8 levels,may assist in character-izing this population further, with the goal ofproducingmarkers thatwill assist clinicians in predict-ing treatment outcome. J Periodontol 2006;77:316-322.

KEY WORDS

Immunology; microbiology; periodontal diseases,refractory; treatment.

Periodontal diseases comprise a variety of com-plex bacterial infections, which frequently oc-cur as inflammatory and destructive lesions of

the periodontium. Periodontitis is prevalent in hu-mans and is characterized by degradation of soft andmineralized connective tissues. If allowed to progress,periodontitis has been shown to be the most commoncause of tooth loss in adults.1 The clinical manifes-tations of most forms of periodontitis are sufficientto permit an accurate diagnosis when evaluated inconjunction with a thorough history and clinical ex-amination.2 However, diagnosing periodontitis can becomplicated due to the alternating active and quies-cent phases of the disease and the requirement forrepeated treatments over a long period of time. Fur-thermore, a tremendous variation of severity can existwithin the same subject. These features of periodon-titis are indicative of the need to develop diagnosticmodalities, which extend beyond the traditional clas-sification of disease based solely on oral clinical signsand symptoms.3

Of the different categories of periodontal diseases,refractory periodontal diseases have received someattention recently in the literature.4 Although differentforms of chronic and aggressive periodontal diseaseshave been studied and characterized extensively, re-fractory periodontitis as a periodontal disease entity is

* Faculty of Dentistry, University of Toronto, Toronto, ON.† Department of Laboratory Medicine and Pathobiology, Faculty of Medicine,

University of Toronto. doi: 10.1902/jop.2006.050108

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still not clearly understood. Refractory periodontaldiseases are characterized by continued degenerationof the periodontium despite ongoing sanative, surgi-cal, and/or pharmacological therapy.5 This has ledinvestigators to suspect that perhaps a systemic com-ponent is more influential to the development of re-fractory periodontal diseases than otherwise thought.A few studies have been reported in the literature at-tempting to elucidate the association between hostimmune response and refractory periodontal dis-eases.6,7 In particular, the role of T lymphocytes asa direct mediator in the immune response as well asits potential role in the production of inflammatory cy-tokines has been considered.8 Other factors such asthe role of serum lipids, hyperresponsive monocytes/polymorphonuclear leukocytes (PMNs), and hypo-responsive macrophages have also been consideredpotential contributors to periodontal destruction.9

However, improved screening methods and earlydiagnosis of patients more likely to develop refractoryperiodontitis will facilitate risk assessment and opti-mize treatment of persons at risk for this condition.These can only be made possible with a thorough un-derstanding of clinical, microbiological, systemic, andimmune parameters, their relationship, and how theyare represented in current and potential periodontitispatients.

The objectives of this report were as follows: 1) toobtain long-term measurements of clinical parame-ters in patients presenting to a university-based re-fractory periodontal disease unit including probingdepth (PD), bleeding on probing (BOP), tooth mobil-ity, and percentage of sites with plaque and calculus;2) to obtain an oral microbiologic profile of these pa-tients with respect to common putative periodontalpathogens such as Prevotella intermedia, Porphyro-monas gingivalis, Tannerella forsythia, andActinoba-cillus actinomycetemcomitans and spirochetes; 3) tocharacterize these patients on the basis of the follow-ing markers of host immune response status: whiteblood cell count and associated components, CD4+,CD8+, and CD4:CD8 ratio; and 4) to assess thepatient’s status with respect to blood sugar levelsand chronic levels by measuring the amount ofglycated hemoglobin (HbA1c); and 5) to assess thepatient’s potential genetic susceptibility to peri-odontal disease based on the genotype characteristicrelated to interleukin-1 alpha (IL-1a) and beta (IL-1b)using the periodontal susceptibility test (PST).‡

METHODS

Patients who were deemed to have refractory peri-odontitis were referred to the Severe and RefractoryPeriodontal Disease Research and Treatment Unit, asubgroup of the University of Toronto’s DentalResearch Institute. All patients were referred to this

unit by general practitioners or specialists in perio-dontics in the Southern Ontario region and had beentreated previously for periodontitis using either surgi-cal or non-surgical modalities.

A complete medical history, dental treatmenthistory, and baseline measurements including full-mouth PD were obtained using a periodontal probe§

for each subject. Included in the examination werethe presence of BOP for buccal and lingual surfacesof each tooth and the number of mobile teeth and siteswith plaque/calculus.

A detailed microbiologic profile was obtained foreach patient. The oral microbiologic analysis wasdone to determine levels of commonly known putativeperiodontal pathogens such as P. intermedia (Pi), P.gingivalis (Pg), T. forsythia (Tf ), and A. actinomyce-temcomitans (Aa) and spirochetes. Crevicular fluidsamples from the mesio-buccal pockets of teeth #3,#9, #19, and #25 were obtained for analysis using pa-per points.

The levels of the variousperiodontalpathogens weremeasured using immunofluorescence techniques. He-matologic analysis was performed in conjunction withthe DepartmentofLaboratory Medicine and Pathology,Mount Sinai Hospital, Toronto. This analysis includedtotal white cell count and its associated individualcomponents (i.e., neutrophil, lymphocyte, monocyte,eosinophil, and basophil) presented in absolute num-bersand fractionalpercentages.Additionally, thenum-bers and percentages of CD3 (data not shown), CD4,and CD8 and the CD4:CD8 ratio were analyzed.

Once the information from the initial assessmentwas gathered, treatment recommendations were madeto the referring dentist. Recommended treatment in-cluded scaling and root planing with local anesthetic,systemic antimicrobial therapy, subantimicrobial dosedoxycycline (SDD), and bisphosphonate therapy. Pa-tients were seen for follow-up in our clinic with a repeatof the parameters taken. If patients demonstrated con-tinued attachment loss with this mode of care, theywere deemed to be refractory to treatment.

The three patients described here were examined inour clinic, semiannually, from 1998 until the present.The clinical and hematologic parameters trace thelong-term results of these patients’ maintenance his-tory. Prior to presenting to our clinic, each patientunderwent sanative therapy and antimicrobial treat-ment. Surgical therapy was also performed in two ofthe cases. Informed consent was obtained for all treat-ment and evaluation procedures rendered for the pa-tients described in this report. The investigation wasconducted in accordance with the Helsinki Declara-tion of 1975, as revised in 2000.

‡ Kimball Genetics, Denver, CO.§ Florida Probe, Gainesville, FL.

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CASE 1

AW is a 33-year-old female who presented for as-sessment in the Severe and Refractory PeriodontalDisease Research Unit. She had been seeing a peri-odontist since 1993. At that time, she underwentperiodontal scaling and root planing with local anes-thetic and sedation. Periodontal flap surgery in thefour posterior sextants and three mucogingival proce-dures in the anterior region were performed in 1995.Since those treatments, she had numerous coursesof antibiotic therapy, including amoxicillin and met-ronidazole. She was a non-smoker. The concern ofthe referring periodontist was the continued attach-ment loss, noted both clinically and radiographically(Fig. 1) despite superlative home care and regularmaintenance every 3 months.

Upon presentation, the clinical examination indi-cated 34% of probing depths >4 mm. However, only8% of sites demonstrated bleeding on probing. Itwas also noted that 26 of 28 teeth demonstrated re-cession ‡2 mm, with a range of 2 to 4 mm. In addition,supragingival plaque was found in only seven of 168sites. The microbiologic assessment showed that themesio-buccal side of tooth #3 was the only site har-boring any periodontal pathogen (P. intermedia),and even then, the levels were classified as beingvery low (Fig. 4A). The percentage of CD8+ levelswas elevated above the normal range (Fig. 2). CD4+

levels were within a normal range. AW was found tobe PST positive. The mean glycated hemoglobin level,measured from 1999 until the present, was 5.2% –0.07%.

AW was placed on SDD and bisphosphonatesalong with continued 3-month recalls of scaling androot planing under sedation. Despite this treatment,probing depth and attachment loss continued to pro-gress (Fig. 3). Bacterial deposits were minimal, asnoted in Figure 4. However, CD8+ levels remainedelevated relative to maximal baseline values.

CASE 2

WB is a 44-year-old female who has a past history ofsevere bulimia and malnutrition. However, WB main-tained a constant weight and has been symptom freesince 1994. She never smoked. WB saw a periodontistevery 3 months since 1996. The periodontist’s pri-mary concern was that of continued recession despiteadequate maintenance for many years. She had nopast history of periodontal surgical intervention.

Although probing depth remained relatively shal-low and constant, WB noted significant and pro-gressive recession since 1999, as noted in Figure 5.Microbiologic deposits were minimal. However, theCD8+ level was elevated relative to the normal maxi-mal range (Fig. 6). In addition, yeast hyphae on the

tongue and gingiva were noted. WB was found to bePST negative. The mean glycated hemoglobin levelwas 5.0% – 0.02% as measured over the course oftreatment.

Past treatment forWB included mycostatin 100,000IU rinse to address the candida superinfections. Also,

Figure 1.Serial radiographs of AW (case 1) demonstrating progressive bone lossover the course of 5 years (A: 1997; B: 2002).

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she maintained a 3- to 4-month recall schedule withher periodontist. Despite the low levels of pathogensand the excellent oral hygiene, WB continued to loseattachment. She was placed on a dose of alendronate,70 mg orally per week. Short courses of metronida-zole, 500 mg three times a day, and amoxicillin,500 mg three times a day, were administered whenbacterial levels increased slightly. When the progres-sion of attachment loss was noted, WB was placed ona regimen of SDD, which continues at the presenttime.

CASE 3

HP is a 43-year-old male who presented to the clinicwith a diagnosis of severe, generalized chronic peri-odontitis. HP never smoked. HP had periodontal sur-gery performed in all six sextants, yet continued todemonstrate progressive bone loss (Fig. 7). Upon

presentation to our clinic, immunofluorescence wasunable to detect the presence of bacterial deposits.Initially, HP was placed on a course of SDD. CD8+

levels were elevated at each assessment and re-mained so throughout the study period. At onefollow-up appointment, mild increases in P. gingivalisand P. intermedia were noted. HP was placed on acourse of metronidazole, 500 mg three times a day,

Figure 2.CD8+ percentage for subject AW (case 1). The levels remainedelevated throughout the study period.

Figure 3.AW (case 1) demonstrated progressive attachment loss over thecourse of 4 years, despite adequate maintenance therapy.

Figure 4.Comparison of bacterial levels from 1999 (A) to 2003 (B) for AW(case 1).

Figure 5.Relative attachment level changes in patient WB (case 2) from 2000to 2004.

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plus amoxicillin, 500 mg three times a day for 7 days.Although bacterial counts returned to undetectablelevels, progressive attachment loss continued. HPwas PST negative. The mean glycated hemoglobinlevel was 5.2% – 0.04% over the course of the studyperiod.

In January 2004, a dental implant was placed dueto tooth loss in the posterior mandible (Fig. 8). How-ever, within 3 months of placement, crestal bone lossaround the neck of the fixture occurred, bringing intodoubt the prognosis of the implant.

DISCUSSION

The long-term outcome of periodontal therapy in aprivate practice setting has been reviewed, and itwas concluded that there was a cohort of patientswho, despite seemingly adequate therapy and faithfullong-term dental maintenance, continued to showperiodontal breakdown.10 Refractory periodontal dis-eases were once considered a separate and possiblymore prevalent disease entity based on previous diag-nostic categories.11 In fact, more recent definitionsconsider this condition as a subset of all periodontaldisease categories not responsive to conventionaltherapies.12 The goal of this report was to identifycharacteristics unique to this population, insofar asthese parameters may assist clinicians in long-termtreatment planning and prognostication once theyare identified.

Prior to identifying a case of periodontal disease asrefractory to treatment, it is important to assure thatall modalities of conventional therapy have been un-dertaken. Two of the three subjects reviewed here hadat least one surgical therapy performed, and, in onecase, all six sextants underwent surgery. Each subjectwas on a regular recall schedule and received supra-

and subgingival maintenance therapy. Additionally, aperiodontist saw each patient every 3 months for recallmaintenance. This form of treatment is consistentwith that demonstrated by Westfelt et al.13 in thatsupra- and sub-gingival scaling was required to pre-vent further periodontal destruction in cases with ad-vanced disease.

A review of the medical history was done for allsubjects to confirm that a systemic disease was not

Figure 6.CD8+ percentage for WB (case 2). The levels remained elevatedthroughout the study.

Figure 7.Radiographs of HP (case 3) demonstrating progressive crestal boneloss despite adequate surgical and maintenance therapy.

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contributing to the progression of the condition. Theglycated hemoglobin measurements,14 which werenormal in all three cases, and immunodeficiency pro-files15 that were performed were meant to rule out di-abetes and HIV, respectively, as sources of systemicdisease.

One seemingly unique variable is that of smoking.It has been known for some time that smoking is a ma-jor risk factor in the development of periodontal dis-ease. It has been suggested that current smokers arefour times more likely to develop periodontal diseasecompared to persons who never smoked.16 Yet, in ourparticular cohort of patients, none of the patients eversmoked, thereby eliminating this factor as an entityassociated with the lack of response to therapy.

The involvement of T lymphocytes in periodontalbone destruction and the inflammatory lesion has beenstudied for some time. Evidence suggesting a host-antibody response to the presence of Aa is indicativeof the fact that a T-cell response occurs in the pres-ence of oral microorganisms.17 In particular, this studyfocused on T-cell receptor subtypes CD4+ and CD8+.CD4+ cells are thought to be associated with the initi-ation of clonal expansion of B and T cells, resulting in aperpetuation of the inflammatory process. Lymphoidcells with the CD8+ cell receptor are thought to be nat-ural killer cells. Although it has yet to be fully eluci-dated, there are many ways that these subgroups ofcells may contribute to the activity of a periodontal le-sion, including elevated production of IL-1.18

Although it must be noted that the fractionatedwhite blood count values for the study populationwere all within normal laboratory ranges, it is interest-ing to observe that the CD8+ values were elevated rel-ative to the normal laboratory ranges. Although two ofthe three cases were PST negative, this still may sug-gest an inherent hyperresponsiveness of a refractory

patient to the presence of plaque, such that excessivebreakdown, possibly facilitated by the inflammatorymediators associated with this T-cell subset, may beoccurring.

Although our report focused on T-cell subsets aspotential markers for refractory periodontal diseases,other studies have demonstrated a possible role forserum lipids, PMN/monocyte, and macrophage func-tion in association with tissue destruction. Recent ev-idence has suggested a bidirectional relationshipbetween periodontal disease and hyperlipidemia,such that elevated serum lipid levels induce an in-crease in PMN production of proinflammatory cyto-kines such as IL-1B.19 Indeed, data currently underanalysis in our treatment/research program suggestthat patients with ongoing breakdown may actuallyhave hypersensitive and hyperreactive PMN cells(data not shown). Also, a survey of all 50 patients be-ing treated in the unit (albeit recognizing that somesmall proportion might not be refractory accordingto our criteria) confirmed that higher mean CD8+

levels were seen compared to the external controllab values. As for the elevated PMN activity observedin refractory patients, these cells were compared toPMNs from patients with periodontitis who respondedto treatment and accordingly had PMNs with a morenormal activity level and number.

From the data gathered, it may be possible to con-struct a profile of a patient who may fit the category ofsevere/refractory. The purpose of this would be toidentify characteristics that may be unique to thispopulation that may assist in early identification of apatient who may potentially experience severe or re-fractory disease that is unresponsive to conventionaltherapies. In doing so, a change in treatment strategy(i.e., extraction and implant therapy rather than fur-ther conventional periodontal therapy) may be con-sidered early on in the case. However, in the case ofsubject 3 (HP), it is possible that even implant therapymay be more susceptible to breakdown in this uniquepopulation. Further work is being performed in theUniversity of Toronto’s Dental Research Institute todetermine if there is indeed an immune profile or char-acteristic that may make an individual more suscep-tible to periodontal breakdown and/or implant failure.

CONCLUSIONS

Given the limitations of this report, it is difficult to drawany firm conclusions because control patients (i.e.,healthy and those with non-refractory disease) werenot included. However, there appears to be a cohortof patients who demonstrate a continual decline intheir periodontal condition despite adequate treat-ment and maintenance. Speculation varies widelyas to the reason for this decline6,20 but tends to fo-cus on the microbiologic aspect of disease. A new

Figure 8.Periapical radiograph of implant placed 3 months earlier in HP(case 3).

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concept21 introduced in 2002 suggested that someforms of refractory disease might present with pro-gressive loss of attachment and alveolar bone, the ab-sence of gingival inflammation or microbial deposits,and the failure of the disease to respond to traditionalperiodontal therapies. This condition was termed‘‘non-inflammatory destructive periodontal disease.’’

The mechanism by which refractory periodontaldiseases progress requires further investigation. How-ever, it is possible that patients who do not respond toconventional therapy may, in fact, be hyperrespon-sive hosts who react even to a small pathogenic bac-terial load. It is possible that those with elevated CD8+

levels may show susceptibility to refractory periodon-tal diseases. Future studies will expand on identifyingthe levels of inflammatory mediators present in thispopulation, including IL-1 and MMP-8 (samples al-ready collected and being analyzed), such that furthercharacterization of this population may provide forearly recognition of future breakdown and modifica-tion of treatment approaches. Moreover, in the ab-sence of adequate understanding of and treatmentsfor refractory periodontal diseases, parameters thatare currently under study in the Refractory PeriodontalDisease Unit at the University of Toronto could lead tothe identification of prognostic markers that wouldpermit the clinician to direct a patient toward ongoingperiodontal maintenance and intervention or perhapsto earlier implementation of endosseous implants.Furthermore, ongoing studies in this unit will focuson quality of life indices to determine the psychosocialeffects of diagnosis, treatment, and daily manage-ment of refractory periodontitis. This could providea database to compare the quality of life among otherparameters in patients receiving ongoing periodon-tal intervention compared to similar patients treatedsooner with endosseous implants.

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and Other Animals: A Comparative Review. Basel,Switzerland: Karger; 1982:6-57.

2. Carranza FA, Newman MG. Clinical Periodontology,8th ed. Toronto: Saunders; 1996:344-374.

3. Greenstein G, Caton J. Periodontal disease activity: Acritical assessment. J Periodontol 1990;61:543-552.

4. Levine M, LaPolla S, Owne WL, Socransky SS.Antibody-based diagnostic for ‘‘refractory’’ periodon-titis. J Clin Periodontol 2002;29:935-943.

5. American Academy of Periodontology. Parameteron ‘‘refractory’’ periodontitis. J Periodontol 2000;71(Suppl.):859-860.

6. Hernichel-Gorbach E, Kornman KS, Holt SC, et al.Host responses in patients with generalized refractoryperiodontitis. J Periodontol 1994;65:8-16.

7. Takahashi K, Ohyama H, Kitanaka M, et al. Hetero-geneity of host immunological risk factors in patientswith aggressive periodontitis. J Periodontol 2001;72:425-437.

8. Baker PJ. The role of immune responses in bone lossduring periodontal disease. Microbes Infect 2000;2:1181-1192.

9. Iacopino AM, Cutler CW. Pathophysiological relation-ships between periodontitis and systemic disease:Recent concepts involving serum lipids. J Periodontol2000;71:1375-1384.

10. Hirschfeld L, Wasserman BA. Long-term survey oftooth loss in 600 treated periodontal patients.J Periodontol 1978;49:225-237.

11. American Academy of Periodontology. Proceedings ofthe World Workshop in Clinical Periodontics. Chicago:American Academy of Periodontology; 1989:I-4.

12. Armitage GC. Development of a classification systemfor periodontal diseases and conditions. Ann Peri-odontol 1999;4:1-6.

13. Westfelt E, Rylander H, Dahlen G, Lindhe J. The effectof supragingival plaque control on the progression ofadvanced periodontal disease. J Clin Periodontol1998;25:536-541.

14. Oliver RC, Tervonen T. Diabetes – A risk factor forperiodontitis in adults? J Periodontol 1994;65:530-538.

15. Tenenbaum HC, Mock D, Simor AE. Periodontitis asan early presentation of HIV infection. CMAJ 1991;144:1265-1269.

16. Tomar SL, Asma S. Smoking-attributable periodontitisin the United States: Findings from NHANES III. JPeriodontol 2000;71:743-751.

17. Wilson ME. IgG antibody response of localized juvenileperiodontitis patients of the 29 kilodalton outer mem-brane protein of Actinobacillus actinomycetemcomi-tans. J Periodontol 1991;62:211-218.

18. Taubman MA, Kawai T. Involvement of T-lympho-cytes in periodontal disease and in direct and indirectinduction of bone resorption. Crit Rev Oral Biol Med2001;12:125-135.

19. Cutler CW, Iacopino AM. Periodontal disease: Linkswith serum lipid/triglyceride levels? Review and newdata. J Int Acad Periodontol 2003;5:47-51.

20. Adriaens PA, De Boever JA, Loesche WJ. Bacterialinvasion in root cementum and radicular dentin ofperiodontally diseased teeth in humans: A reservoirof periodontopathic bacteria. J Periodontol 1988;59:222-230.

21. Page RC, Aturdivant EC. Noninflammatory destructiveperiodontal disease (NDPD). Periodontol 2000 2002;30:24-39.

Correspondence: Dr. Michael B. Goldberg, Faculty ofDentistry, 124 Edward St., Toronto, ON M5G 1X5. Fax:416/586-5010; e-mail: m.goldberg@utoronto.ca.

Accepted for publication June 16, 2005.

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