Periodontal Disease and Overall Health: A Clinician's Guide

ivCONTRIBUTORSSrividya Kidambi, MDAssistantProfessorofMedicineMedicalCollegeofWisconsinMilwaukee,WI,USADenis F. Kinane, BDS, PhD, FDSRCS, FDSRCPSDean,UniversityofPennsylvaniaSchoolofDentalMedicinePhiladelphia,PA,USAEvanthia Lalla, DDS, MSAssociateProfessorofDentalMedicineColumbiaUniversityCollegeofDentalMedicineNewYork,NY,USAIra B. Lamster, DDS, MMScDeanandProfessorofDentalMedicineColumbiaUniversityCollegeofDentalMedicineNewYork,NY,USANéstor J. López, DDSProfessorofPeriodontologyUniversityofChileSchoolofDentistrySantiago,ChileJohn H. Loughran, MDFellowofCardiovascularDiseaseUniversityofLouisvilleSchoolofMedicineLouisville,KY,USAPhoebus N. Madianos, DDS, PhDProfessorDepartmentofPeriodontologyUniversityofAthensSchoolofDentistryAthens,GreeceAngelo J. Mariotti, DDS, PhDProfessorandChairDivisionofPeriodontologyTheOhioStateUniversityCollegeofDentistryColumbus,OH,USAJoseph M. Mylotte, MDProfessorofMedicineEmeritusDepartmentofMedicineUniversityatBuffaloSchoolofMedicineandBiomedicalSciencesBuffalo,NY,USATimothy C. Nichols, MDProfessorofMedicine,Pathology,andLaboratoryMedicineDirector,FrancisOwenBloodResearchLaboratoryUniversityofNorthCarolinaatChapelHillChapel,Hill,NC,USASteven Offenbacher, DDS, PhD, MMScOraPharmaDistinguishedProfessorofPeriodontalMedicineDirector,CenterforOralandSystemicDiseasesUniversityofNorthCarolinaSchoolofDentistryChapelHill,NC,USADavid W. Paquette, DMD, MPH, DMScProfessorandAssociateDeanforEducationStonyBrookUniversitySchoolofDentalMedicineStonyBrook,NY,USAShailendra B. Patel, BM, ChB, DPhilProfessorofMedicineDivisionofEndocrinology,MetabolismandClinicalNutritionMedicalCollegeofWisconsinMilwaukee,WI,USAIoannis Polyzois, DMD, MDentCh, MMedSciLecturer,DepartmentofRestorativeDentistryandPeriodontologyDublinDentalSchool&HospitalTrinityCollegeDublinDublin,IrelandHector F. Rios, DDS, PhDAssistantProfessor,DepartmentofPeriodonticsandOralMedicineUniversityofMichiganSchoolofDentistryAnnArbor,MI,USAMaria Emanuel Ryan, DDS, PhDAssociateDeanforStrategicPlanningandExternalAffairsDirectorofClinicalResearchProfessor,DepartmentofOralBiologyandPathologyMedicalStaffUniversityHospitalStonyBrookUniversitySchoolofDentalMedicineStonyBrook,NY,USAFrank A. Scannapieco, DMD, PhDProfessorandChairDepartmentofOralBiologyUniversityatBuffaloSchoolofDentalMedicineBuffalo,NY,USAGeorge W. Taylor, DMD, MPH, DrPHProfessor,DepartmentofCariology,RestorativeSciencesandEndodonticsUniversityofMichiganSchoolofDentistryAnnArbor,MI,USA

CHAPTER 1OverviewRobert J. Genco, Ray C. Williams“A person can’t have good general health without good oral health.”—Former US Surgeon General C. Everett KoopINTRODUCTIONPeriodontaldiseaseisone ofthemostcommondiseasesofmanandisresponsibleformostofthetoothlossinadults.Thisoraldiseasehasreceivedconsiderableattentioninthepastseveraldecadesandanewunderstandingofitisemerging.Themicrobialcausesofperiodontaldisease,themechanismsthroughwhichperiodontaltissuesaredestroyed,theeffectofthehostonperiodontaldiseaseexpression,andtheimpactperiodontaldiseasehason overallhealthhavebeensubjectsofintensestudy.Understandingthecomplexinteractionbetweenchronicinfections,suchasperiodontaldisease,andsystemicconditionssuchascardiovasculardisease,hasledtoanewwayofthinkingabouttheimportanceofperiodontaldiseaseinoverallhealth.Periodontal Disease as anIntegral Link to Systemic DiseaseAccordingtothe NationalCenterforHealthStatistics,thesixleadingcausesofdeathintheUnitedStatesin2005wereheartdisease(652,091),cancer(559,312),stroke/cerebrovasculardiseases(143,579),chroniclowerrespiratorydisease(130,933),unintentionalaccidentalinjuries(117,809),anddiabetes(75,119). 1 Fiveofthesechronic diseasesarerelatedtoperiodontaldisease.Bysuccessfullymeetingthechallengetoimproveoralhealthandthemanagementofperiodontaldisease, generalhealthwillalsobeadvancedthroughsharedapproachestargetingcommonriskfactors.Tobestaddressthecommonriskfactorsandinteractionsbetweenoralandsystemicdisease,itisimportanttounderstandtheextenttowhichperiodontaldiseaseisrelatedtocertainsystemicdiseases,thehistoricalfoundationsofcurrenttherapeuticapproaches,theroleofinflammation,andthepossibilitiesforintervention.THREE HISTORICAL ERAS OFPERIODONTAL DISEASE RESEARCHInthelast50years,therehasbeenconsiderableprogressinunderstandingtheetiologyandpathogenesisofperiodontaldiseaseanditsinteractionswiththehost.Thestudiesandconceptscanbedescribedashavingoccurredinthreephasesoreras:theetiopathologic(orhost-parasite)era,theriskfactorera,andmostrecently,theperiodon-taldisease-systemicdiseaseera.Etiopathologic EraThe etiopathologiceraincludedlandmarkinvestigationsintothemicrobialetiologyandpathogenesisofperiodontaldisease.Theroleofbacteriaasacauseofperiodontaldiseasewasdemonstratedbyaseriesofseminalstudiesconductedfromthe1960stothe1980s.ClassicstudiesbyLöeandcolleaguesclearlydemonstratedthatmicrobialplaquebuildupontheteethwasassociatedwiththeonsetofgingivitis,andthattheremovalofmicrobialplaqueresultedintheresolutionofgingivitis. 2,3 Thesestudiesprovidedunarguableevidencethatmicrobialdentalplaquebuildup,ratherthanothersuspectedagentssuchascalculus,wasresponsibleforgingivitis.

CHAPTER 1 Overview 3alphaandinterleukins1and6,oftenfoundinthe circulationofpatientswithperiodontaldisease.Thereareotherconditionsthatalsocontributetoasystemicinflammatoryresponseincludingrheumatoidarthritis,psoriasis,andobesity. Thischronicsystemicinflammatoryresponseinturnincreasestheriskforatheroscleroticdisease,diabetesandcomplicationsofdiabetes, adversepregnancyoutcomes,andpossiblysomecancers.Theresearchsupportingtheseassociationswillbediscussedindetailinthefollowingchapters.GOALS FOR THIS TEXTBOOKMuchresearchisfocusedonunderstandinghowperiodontaldiseaseincreasestheriskforsystemicdiseases.Itisnotyetclearwhatimpactthebiofilmintheoralcavitymighthaveondistantsitesandorgans;likewisetheroleoftheinflammatoryresponseisnotfullyunderstood.Someofthechaptersinthistextbookwillreviewthebiologicplausibilityforperiodontaldiseaseasariskforsystemicconditions.Mechanismsthroughwhichperiodontaldiseasecanconferthisriskwillalsobepresented.Theoverallgoalofthistextbookistopresenttheemergingandcompellingevidencethatperiodontaldiseaseisariskforseveralsystemicconditionsandtolookattheroleoforalhealthincontributingtooverallhealth.Thisbookalsoseekstoprovidethereaderwithaguidetopatientmanagementinwhichdentistryandmedicineworktogether.Textbook OrganizationThechaptersinthisbook areorganizedinthefollowingmanner: Theinitialchaptersfollowingthisoneoutlinethebasicsofunderstandingperiodontaldiseaseanditsinterrelationshipwithsystemicdisease:Chapter2discussesthecausesandpathogenesisofperiodontaldisease;theroleofinfectionandinflammationinperiodontaldiseaseisexaminedinChapter3;andthehistoryoftheoraldisease-systemicdiseaserelationshipisexplainedinChapter4.Anoverviewofdiabetes(Chapter5)andatheroscleroticdiseases(Chapter7)arefollowedbychaptersthatdescribetherelationshipofperiodontaldiseasetotheseconditions(Chapters6and8,respectively).Thenextchaptersexaminetheevidenceforperiodontaldiseaseasariskforadversepregnancyoutcomes(Chapter9),respiratorydiseases(Chapter10),osteoporosis(Chapter11),rheumatoidarthritis(Chapter12),andcancer(Chapter13).The finalsectionofthetextbook discussescomanagementofperiodontaldiseaseindiabetes(Chapter14),cardiovasculardisease(Chapter15),pregnancy(Chapter16),andotherconditions thatareassociatedwithperiodontaldisease(Chapter17).Finally,Chapter18describestheroleofdentalprofessionalsintheeducationofthepublicandotherhealthprofessionals about theoralhealth-generalhealthinter-relationship.Our Hope for This TextbookItisthehopeoftheauthorsandeditorsthatthistextbookwillprovideanup-to-dateunderstandingoftheinformationthatdetailstherelationshipofperiodontaldiseasetosystemicdisease,witheachchapteroutliningastate-of-the-art understandingoftheoptimalmanagementofpatients.Thistextbookhasbeenpreparedasaresourcefordentalstudents,dentalhygienestudents,facultymembersofdentaleducationalinstitutions,andfordentalprofessionalsingeneral.Wealsobelievethisresourcewillprovevaluabletostudentsaswellaspracticingmembersofotherhealthprofessionsinthemedicalcommunity.Theintegrationofmedicineanddentistrygrowsdaily,andacommonresourcesuchasthistextbookcouldserveasaconstructivetooltohelpthetwodisciplinesworkcollaboratively.Theeditorswouldliketothanktheauthorsandcoauthorsfortheirroleinpreparing

4 Periodontal Disease and Overall Health: A Clinician's Guideandpresentingcurrentinformationinacomplete,yetconciseandreadablemanner.Wearehopefulthatthistextbookwillfindbroadreadershipandwillbeusefultothedentalandmedicalcommunity.REFERENCES1. HeronM,HoyertDL,MurphySL,XuJ,KochanekKD,Tejada-VeraB.Deaths:finaldatafor2006.Natl Vital Stat Rep 2009;57:1–34.2. LöeH,TheiladeE,JensenSB.Experimentalgingivitisinman.JPeriodontol 1965;36:177–187.3. TheiladeE,WrightWH,JensenSB,LöeH.Experimentalgingivitisinman.II.Alongitudinalclinicalandbacteriologicalinvestigation.JPeriodontalRes 1966;1:1–13.4. SocranskySS,HaffajeeAD.Periodontalmicrobialecology.Periodontol 2000 2005;38:135–187.5. GencoRJ,SlotsJ,MoutonC,MurrayP.Systemicimmuneresponsestooralanaerobicorganisms.In:Anaerobic Bacteria: Selected Topics, LambeDWJr,GencoRJ,Mayberry-CarsonKJ,eds.,PlenumPublishingCorp.,NewYork,277,1980.6. EbersoleJL,TaubmanMA,SmithDJ,GencoRJ,FreyDE.Humanimmuneresponsestooralmicroorganisms.I.Associationoflocalizedjuvenileperiodontitis(LJP)withserumantibodyresponsestoActinobacillus actinomycetemcomitans.Clin ExpImmunol 1982;47:43–52.7. GencoRJ.Hostresponsesinperiodontaldiseases:Currentconcepts.J Periodontol 1992;63(Suppl):338–355.8. PageRC,OffenbacherS,SchroederHE,SeymourGJ,KornmanKS.Advancesinthepathogenesisofperiodontitis:Summaryofdevelopments,clinicalimplicationsandfuturedirections.Periodontol2000 1997;14:216–248.9. GencoRJ,LöeH.Theroleofsystemicconditionsanddisordersinperiodontaldisease.Periodontol2000 1993;2:98–116.10. GrossiSG,GencoRJ,MachteiEE,HoAW,KochG,Dunford R, Zambon JJ, Hausmann E.Assessmentofriskforperiodontaldisease.II.Riskindicatorsforalveolarboneloss. J Periodontol1995;66:23–29.11. MattilaK,NieminenM,ValtonenV,RasiVP,KesäniemiYA,SyrjäläSL,JungellPS,IsoluomaM,HietaniemiK,JokinenMJ.Associationbetweendentalhealthandacutemyocardialinfarction.BMJ1989;298:779–781.12. DeStefanoF,AndaRF,KahnHS,WilliamsonDF,RussellCM.Dentaldiseaseandriskofcoronaryheartdiseaseandmortality. BMJ 1993;306:688–691.13. TaylorGW,BurtBA,BeckerMP,GencoRJ,ShlossmanM, Knowler WC, Pettitt DJ. Severeperiodontitisandriskforpoorglycemiccontrolinpatientswithnon-insulin-dependentdiabetesmellitus.JPeriodontol 1996;67:1085–1093.14. GrossiSG,GencoRJ.Periodontaldiseaseanddiabetesmellitus:Atwo-wayrelationship.AnnPeriodontol 1998;3:52–61.15. TaylorGW,BorgnakkeWS.Periodontaldisease:Associationswithdiabetes,glycemiccontrolandcomplications.Oral Dis 2008;14:191–203.16. OffenbacherS,KatzV,FertikG,CollinsJ,BoydD,MaynorG,McKaigR,BeckJ.Periodontalinfectionasapossibleriskfactorforpretermlowbirthweight.J Periodontol 1996;67:1103–1113.17. ScannapiecoFA.Roleoforalbacteriainrespiratoryinfection.J Periodontol 1999;70:793–802.

CHAPTER 2Overview of Periodontal Disease:Causes, Pathogenesis, andCharacteristicsYing Gu, Maria E. RyanINTRODUCTIONPeriodontal diseases are serious chronicinfections that involve destruction of thetooth-supporting apparatus, including thegingiva, the periodontal ligament, and alveolarbone. These diseases are initiated by alocal accumulation of bacteria adjacent tothe tooth. Periodontal diseases, includinggingivitis and periodontitis, can affect onetooth or many teeth and, if left untreated,can lead to tooth loss, particularly in adults.It is the most common dental condition inadults, and is also one of the most commonchronic inflammatory diseases affecting amajority of the population throughout theworld. Although plaque is essential for theinitiation of periodontal diseases, the majorityof the destructive processes associatedwith these diseases are due to an excessivehost response to the bacterial challenge.Therefore, periodontal disease is a multifactorial,complex disease. The purpose of thischapter is to provide a general overview ofthe types of periodontal disease, risk factorsassociated with them, and the etiology,pathogenesis, and management of periodontaldiseases.TYPES OF PERIODONTAL DISEASEPeriodontal diseases include two generalcategories based on whether there is attachmentor bone loss: gingivitis and periodontitis.Gingivitis is considered a reversibleform of the disease, and generally involvesinflammation of the gingival tissues withoutloss of connective tissue attachment. 1Periodontitis has been defined as the presenceof gingival inflammation at sites wherethere has been a pathological detachment ofcollagen fibers from cementum, the junctionalepithelium has migrated apically, andbone loss can be detected radiographically.The inflammatory events associated withconnective tissue attachment loss lead tothe resorption of coronal portions of toothsupporting alveolar bone. 2 The understandingof periodontal disease is continuouslychanging as new research evidence emerges.There fore, the classification of periodontaldisease has changed since the system developedat the 1989 World Workshop in ClinicalPeriodontics. The classification presentedin this chapter is based on the results developedat the 1999 International Workshop organizedby the American Academy of Perio -dontology (AAP).The classification of periodontal diseasesnow includes eight general types 3 :1. Gingivitis2. Chronic periodontitis3. Aggressive periodontitis4. Periodontitis as a manifestation ofsystemic diseases5. Necrotizing periodontal diseases6. Abscesses of the periodontium7. Periodontitis associated with endo -dontic lesions8. Developmental or acquired deformitiesand conditionsThe overall classification system ispresented in Table 1. 3 In addition, the aboveclassification is different from case types

6 Periodontal Disease and Overall Health: A Clinician's GuideTable 1. Periodontal DiseasesVIII. Gingival DiseasesDental plaque-induced gingival diseasesNonplaque-induced gingival lesionsIV.II. Chronic PeriodontitisLocalizedGeneralizedVIII. Aggressive PeriodontitisLocalizedGeneralizedIIIV. Periodontitis as a Manifestation ofIV. Systemic DiseasesIIIV. Necrotizing Periodontal DiseasesNecrotizing ulcerative gingivitisNecrotizing ulcerative periodontitisIIVI. Abscesses of the PeriodontiumGingival abscessPeriodonal abscessPericoronal abscessIVII. Periodontitis Associated withEndodontic LesionsVIII. Developmental or Acquired Deformitiesand ConditionsAdapted from: Ann Periodontol 1999;4:1–6. 3previously developed by the AAP. 4,5 Thecurrent case types for periodontal diseasesinclude:• Gingivitis (Case Type I)• Mild periodontitis (Case Type II)• Moderate periodontitis (Case Type III)• Advanced periodontitis (Case Type IV)• Refractory periodontitis (Case Type V)Gingival DiseasesGingival disease is further characterizedinto plaque-induced and nonplaque-inducedcategories. 3Plaque-Induced Gingival DiseasesGingivitis is gingival inflammation associated with plaque and calculus accumulation.It is the most common form of gin -gival disease. Gingivitis may or may notprogress to periodontitis, in which clinicalattachment and alveolar bone loss willdevelop. Gingivitis can occur on teeth withno attachment loss; it also occurs in the gingivaof teeth previously treated for periodontitiswith no further attachment loss.Dental Plaque Only: Gingivitis is initiatedby local accumulation of bacteria (i.e.,dental plaque) adjacent to the tooth. 6 Thebacterial antigens and their metabolic products(e.g., endotoxin) stimulate epithelial andconnective tissue cells to produce inflammatorymediators that result in a localizedinflammatory response recruiting polymorphonuclearleukocytes (PMNLs or neutro -phils) to the site. An antibody response tothese bacterial antigens is also mounted. Inflammatorycells and their products (e.g.,cytokines, enzymes, and antigens) are presentat the site of inflammation. Thus, a hostimmuno-inflammatory response is establishedin the gingival tissues and the clinicalsigns of gingivitis develop, including redness,swelling, and bleeding. The plaquehostinteraction can be altered by the effectsof local factors, systemic factors, or both.Systemic Factors: Systemic hormonalchanges associated with puberty, menstrualcycle, or pregnancy, as well as with chronicdiseases such as diabetes, can alter the hostresponse to dental plaque. 1,7 Hormonalchanges and certain diseases can upregulatesystemic cellular and immunologic functionresulting in local severe gingival inflammation,even in the presence of minimal plaqueor with an equivalent bacterial bioburden toa person who does not have these systemicchallenges. This is commonly seen in pregnantwomen who have not had adequate oralhygiene before becoming pregnant. Blooddyscrasias such as leukemia may also alterimmune function by decreasing normal immunologicalfunction. Patients usually presentwith gingival enlargement and bleedingassociated with spongy gingival tissues andexcessive vascularity.Medications: Medications such as anticonvulsantdrugs (e.g., dilantin), immuno-

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 7suppressive drugs (e.g., cyclosporine), andcalcium channel blockers (e.g., diltiazem)can cause severe gingival enlargement andpseudo-periodontal pocketing (i.e., increasedprobing depths with no associated attachmentor bone loss). 8 Medication-associatedgingival conditions are often reversed afterdiscontinuation of the offending agents.Malnutrition: The host immune systemcan be diminished when malnutritiondevelops, resulting in excessive gingival inflammation.Severe ascorbic acid (vitamin C)deficiencies (i.e., scurvy) can produce brightred, swollen, and bleeding gingival tissues. 1 Inthe case of vitamin C deficiency, gingivitis isassociated with a suppressed synthesis ofboth connective tissue collagens (e.g., TypesI and III) and basement membrane collagen(Type IV). Treatment with vitamin C supplementscan reverse this condition.Nonplaque-Induced Gingival LesionsThese types of lesions usually are rareand mainly due to systemic conditions. Bacteria,viruses, or fungi can cause these typesof gingival lesions. Sexually transmitted diseasessuch as gonorrhea (Neisseria gonorrhoeae)and syphilis (Treponema pallidum)can cause lesions in the tissues of the periodontium.9 Primary streptococcal gingivitisis an acute inflammation of the oral mucosa.It is associated with pain and fever, as wellas red swollen gingival tissues with bleedingor abscess formation, and can be treated withroutine periodontal scaling and root plan ingin addition to antibiotic therapy. Herpessimplex virus Type I is a common virus thatcan cause gingival lesions. 10 In children andyoung adults, herpes infections can be primaryand usually without symptoms, but insome cases pain and fever are reported. Inthese cases, the gingival tissues appear redand swollen, and are followed by the formationof small blisters, which eventuallybreak down to form shallow, painful ulcers.These lesions are usually self-limiting andheal within one to two weeks. After a primaryinfection, the herpes virus becomes latentand will be preserved in the ganglion ofthe trigeminal nerve. The virus may be reactivatedlater in life by reduced immunefunction or stress, resulting in recurrent herpeslabialis, gingivitis, and stomatitis. Gingivallesions of fungal origin usually occur inpeople with diabetes or other immunocompromisedstates. A shift in the normal oralflora related to the long-term use of systemicallyadministered antibiotics can also leadto lesions of fungal origin. 11 The most commonfungal infection is candidiasis, causedby Candida albicans, often seen in patientswearing removable prosthetic devices (e.g.,dentures) and in patients with dry mouthdue to multiple medications or salivary glanddysfunction. Clinical manifestations includewhite patches on the gingiva, tongue, or oralmucous membranes that can be removedwith a cotton swab or gauze, leaving behinda bright red bleeding surface. Treatment withantifungal agents is often necessary to resolvethese conditions.Gingival lesions can also be caused bygenetic systemic mucocutaneous disorders,allergic reactions, trauma, or foreign-bodyreactions. One of the most common geneticconditions associated with gingival lesionsis autosomal-dominant hereditary gingivalfibromatosis. 12 It is a benign condition affectingboth arches. The gingival tissues areenlarged and asymptomatic. It may be anisolated finding or associated with othersyndromes. Treatment is gingivectomy andrecurrence is possible. Systemic conditionssuch as pemphigoid, pemphigus vulgaris,erythema multiforma, and lupus erythematosuscan cause desquamative lesions andulceration. 10,13 Gingival changes due to allergicreactions to certain restorative ma -terials, dentifrices, or mouthrinses are rare,but have been observed. 10 Traumatic lesionsare usually produced unintentionally. 10 Aggressivetooth brushing and flossing can

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 9active inflammatory cells producing highlevels of cytokines and enzymes causingrapid, aggressive destruction of periodontaltissues. Aggressive periodontitis can be furthercharacterized as localized and generalizedforms. The localized form usuallyaffects first molar and incisor sites. The generalizedform usually involves at least threeteeth other than first molars and incisors.Periodontitis as a Manifestationof Systemic DiseasesSystemic conditions such as diabetesare associated with this form of periodontitis.16 Several hematologic and genetic disordershave also been associated with the developmentof periodontitis such as acquired,familial, and cyclic neutropenias, leukemias,Down’s syndrome, certain types of Ehlers-Danlos syndrome, Papillon-Lefevre syndrome,Cohen syndrome, and hypophospha -tasia. The mechanisms by which all of thesedisorders affect the health of the periodontiumare not fully understood and continue tobe investigated by many basic and clinical researchers.It is speculated that these diseasescan alter host defense mechanisms and upregulateinflammatory responses, resultingin progressive periodontal destruction.Necrotizing Periodontal DiseasesThese lesions are most commonly observedin individuals with systemic conditions,such as human immunodeficiency virusinfection, malnutrition, and immunosuppression.Necrotizing periodontal diseasesare further divided into two forms: necrotizingulcerative gingivitis (NUG) and necrotizingulcerative periodontitis (NUP). Thesetwo diseases have the same etiology andclinical signs, except NUP involves clinicalattachment and alveolar bone loss. 17Abscesses of the PeriodontiumPeriodontal abscess is a localized purulentinfection of the periodontal tissues. 18Periodontal abscesses usually develop inperiodontitis patients who may have fooddebris lodged in a pocket, or deep depositsof calculus where drainage from a pocketbecomes blocked. Iatrogenic abscess formationcan be precipitated after inadequate scalingand root planing, leading to a tighteningof the coronal epithelial cuff with continuedsubgingival calculus driving inflammation.Abscesses can also occur in healthy periodontaltissues due to the presence of foreignobjects lodged in the gingival crevice, suchas a toothbrush bristle or a popcorn kernelbeing tightly packed into the interproximalspaces or between the tooth and the tissues.A pericoronal abscess is an infection of thegingiva around a partially erupted tooth leadingto pericoronitis. A small flap of tissuemay cover a partially erupted tooth surface,serving as a nidus for food and debris to accumulateand become trapped beneath thetissue flap. Patients usually find it very difficultto keep these areas clean, and can developinflammation and infection. In addition,trauma due to constant contact betweenthe tissue flap and a tooth in the opposingarch can also lead to a pericoronal abscess.The areas most commonly affected are associatedwith mandibular third molars. Pain,swelling, redness, and suppuration are associatedwith periodontal abscess. Treatmentmay include incision and drainage, use ofantibiotics, and removal of the offendingsource.EPIDEMIOLOGY ANDRISK FACTORSEpidemiology of GingivitisGingivitis can occur in early childhood,becomes more prevalent during teenageyears, and decreases in older individuals. 19 In1986-1987, the National Institute of DentalResearch conducted a nationwide survey oforal health in US school children 20 andreported that approximately 60% of chil -dren 14 to 17 years of age were found to

10 Periodontal Disease and Overall Health: A Clinician's Guidehave gingivitis. In 1960–1962, the first USnational survey of periodontal disease inadults reported that 85% of men and 79% ofwomen have some degree of gingivitis. 21 Inthe most recent National Health and NutritionExamination Survey (NHANES III)conducted from 1988 to 1994, 22 more than50% of adults had gingivitis on an average ofthree or four teeth, while 63% of 13- to 17-year-old teenagers had gingival bleeding.Both surveys assessed gingival bleeding bya gingival sweep method. 21,22Epidemiology of PeriodontitisBasic clinical measurements for perio -dontitis are gingival bleeding on probing,clinical attachment loss, and pocket depthsaccompanied by radiographic bone loss.These types of clinical measurements maybe somewhat subjective. As our knowledgeof the pathogenesis of periodontitis improves,new diagnostic markers for the diseasemay emerge to help better diagnose it.Inflammatory cytokines, enzymes, and bonebreakdown products released into gingivalcrevicular fluid reflect the host response tothe bacterial challenge. These biochemicalmarkers may be good candidates for newdiagnostic or prognostic markers of disease.A number of cytokines have been asso ciatedwith active disease, including prostaglandinE2 (PGE2), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta (IL-1β), andothers. 23,24 Enzymes such as matrix metalloproteinases(MMPs) and breakdown productssuch as the collagen telopeptide havebeen studied as well. To date, these biochemicalmarkers in gingival crevicularfluid are still being investigated. It will behelpful to both clinicians and researchersif one or more of these markers can be developedas a more objective chairside tool tomeasure active periodontitis. The devel -opment of these markers will also helpto facilitate screening for periodontaldiseases by medical professionals or evenself- assessment by patients, thereby promptingreferrals to the dental office for clinicalassessment.The national data suggest that the milderforms of periodontitis are close to uni -versal. 25 The more severe forms are lessprevalent. According to a review of the literatureby Brown and Löe 26 focused on anumber of epidemiologic studies resultingfrom a 1981 national probability survey, theprevalence of CP is about 36% for the adultUS population as assessed by pocket depthmeasurements. The prevalence of periodontitisincreases with age; 29% in those aged 19to 44 had CP; this rate increased to 50% forpeople 45 years or older. In general, moderateperiodontitis occurred in 28% of all peoplewhile 8% had advanced disease. However,the prevalence of moderate and severeperiodontitis increased to 44% in the populationolder than 45. Based on the presenceof periodontal pockets ≥ 4 mm, it was determinedthat 30% of the population hasperiodontitis on an average of three or fourteeth. Severe pockets of ≥ 6 mm were foundin less than 5% of the population. 22 Theprevalence of aggressive periodontitis waslow with less than 1%. 27 More recently,NHANES III (1988–1994) reported theprevalence of periodontitis for adults 30 to90 years old. 28 Attachment loss and probingdepths were assessed at two sites per tooth.When assessed by the level of attachmentloss, 53% of the population was found tohave ≥ 3 mm attachment loss. The prevalenceof attachment loss increased with age,from approximately 35% for the 30-yearoldparticipants to 89% for the 80-year-oldparticipants. When assessed by probingdepth, approximately 64% of the populationhad probing depths of ≥ 3 mm. The prevalenceof periodontitis increases with age andwas found to be more prevalent in malesthan females, and in African-Americans andMexican-Americans than in non-HispanicCaucasians.

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 11Risk FactorsThere are a number of risk factors associatedwith periodontal diseases. 29-34 Determiningrisk is helpful in developing recommendationsfor prevention and indetermining strategies for the overall managementof periodontitis. It has been recognizedthat the severity and progression ofperiodontal disease varies from individualto individual. Bacteria are essential for theinitiation of the disease, but it is the host responseto the bacterial challenge that determinesthe severity and rate of progression ofthe periodontitis. Therefore, it is the host’simmunologic reaction that determines susceptibilityto the disease.General categories of risk factors associatedwith the development of periodontitisinclude genetic, environmental (e.g., tobaccouse), and acquired risk factors (e.g., systemicdisease). Risk factors (Table 2) and riskreduction strategies (Table 3) should be consideredwhen assessing each patient. 35 Somerisk factors can be modified to reduce apatient’s susceptibility. Environmental factorssuch as tobacco use and stress can bemanaged with smoking cessation and stressmanagement; for acquired factors such assystemic diseases, medications usuallyprescribed by the physician can be used tohelp in the management and control ofchronic disorders (Table 3). The use ofchemotherapeutic agents specifically designedto improve the clinical outcomes ofmechanical treatments for periodontal diseasesmay be particularly useful in the managementof those individuals with single ormultiple risk factors. Risk assessment canTable 2. Risk Assessment for Periodontitis1. Heredity as determined by genetic testing and family history2. Smoking, including frequency, current use, and history3. Hormonal variations such as those seen in:a. Pregnancy, in which there are increased levels of estradiol and progesterone that may change theenvironment and permit virulent organisms to become more destructiveb. Menopause, in which the reduction in estrogen levels leads to osteopenia and eventually osteoporosis4. Systemic diseases such as:a. Diabetes (the duration and level of control are important)b. Osteoporosisc. Immune system disorders such as HIVd. Hematologic disorders such as neutropeniase. Connective tissue disorders such as Marfan’s and Ehlers-Danlos syndromes5. Stress as reported by the patient6. Nutritional deficiencies and obesity that may require a dietary analysis7. Medications such as:a. Calcium channel blockersb. Immunomodulatory agentsc. Anticonvulsantsd. Those known to cause dry mouth or xerostomia8. Faulty dentistry such as overhangs and subgingival margins9. Poor oral hygiene resulting in excessive plaque and calculus10. History of periodontal diseaseSources: J Periodontol 1994;65:260–267. 29 J Periodontol 1995;66:23–29. 30 J Periodontol 1999;70:711–723. 31J Periodontol 2000;71:1057–1066. 32 J Periodontol 2000;71:1215–1223. 33 J Periodontol 2000;71:1492–1498. 34

12 Periodontal Disease and Overall Health: A Clinician's GuideTable 3. Risk Reduction Strategies1. More frequent visits for those with a genetic predisposition; use of pharmacotherapeutics for the2.management of periodontitis2. Smoking cessation using one or more of the six approved regimens; these regimens are rarely2. successful as sole therapies (multiple forms of therapy often are used in combination with2. counseling to achieve success)3. Hormonal variations such as those seen in:a. Pregnancy, which requires good oral care before conception to prevent complications duringa. pregnancy; treatment during pregnancy may be necessary to prevent adverse pregnancy outcomesb. Menopause, which may require hormonal supplements, calcium, and other medications anda. supplements prescribed by the physician to prevent osteopenia4. Systemic diseases that require consultation with the physician include:a. Diabetes (for improved glycemic control)b. Osteoporosis (requiring calcium supplements, bisphosphonates)c. Immune system and hematologic disordersd. Connective tissue disorders5. Stress management; possible referral to a psychologist or psychiatrist6. Nutritional supplementation and weight reduction; possible referral to a nutritionist7. Medications can be changed in consultation with the physician8. Corrective dentistry9. Improved oral hygiene (brushing, flossing, use of antiseptics)10. Occlusal adjustmentsSource: Dent Clin North Am 2005;49:611–636. 35help the practitioner to establish an accuratediagnosis, provide an optimal treatment plan,and determine appropriate maintenance programs.In patients with multiple risk factors,the practitioner may aggressively use pharmacologicadjuncts such as antimicrobialsand host-modulatory therapy in addition tomechanical therapy. It is also important toupdate and assess risk factors for each patienton a regular basis as some of these factorsare subject to change throughout life.ETIOLOGY AND PATHOGENESISOF PERIODONTAL DISEASEInitially, periodontal disease wasthought to be related to aging and was thereforeuniformly distributed in the population,with disease severity being directly correlatedwith plaque levels. Now as a result ofextensive research, it has been shown thatperiodontal disease is initiated by plaque,but the severity and progression of the diseaseis determined by the host response tothe bacterial biofilm. People with severeplaque and calculus accumulation will havegingivitis, but not necessarily periodontitis.On the other hand, certain individuals, despitemaintaining adequate oral hygiene, findthemselves susceptible to aggressive formsof periodontitis, with deep pocketing, toothmobility, and early tooth loss. Clearly, the responseof the periodontal tissues to plaque isdifferent in these two different scenarios. Periodontaldisease does not appear to behaveas a classic infection, but more as an opportunisticinfection. 35 These observations ledresearchers to realize that the host responseto the bacterial challenge, presented by subgingivalplaque, is the important determinantof disease severity. Although plaque bacteriaare capable of causing direct damage to theperiodontal tissues, it is now recognized that

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 13the host immuno-inflammatory response toplaque bacteria produces destructive cytokinesand enzymes resulting in periodontaltissue destruction. The host response is essentiallyprotective by intent but can alsoresult in tissue damage, including the breakdownof connective tissue fibers in the periodontalligament and the resorption of alveolarbone. The host response to the plaquebiofilm is modified by genetic factors (helpingto explain why aggressive periodontitistends to have a familial aggregation), as wellas systemic and environmental factors (e.g.,diabetes, stress, smoking).To better treat and manage periodontaldiseases, we need a more detailed understandingof periodontal pathogenesis (Figure1). 35-37 The bacteria and their metabolic products(e.g., endotoxin) stimulate the junctionalepithelium to proliferate, and to produce tissue-destructiveproteinases. This infectionalso increases the permeability of the junctionalepithelium that allows microbes andtheir products to gain access to the subepithelialconnective tissue. Epithelial and connectivetissue cells are thus stimulated toproduce inflammatory mediators that resultin an inflammatory response within the tissues.Microbial products also chemotacticallyattract a constant flux of pro-inflamma -tory cells migrating from the circulation tothe gingival crevice. Neutrophils, or PMNLs,are predominant in the early stages of gingivalinflammation. Thus, an immune responseis generated in the periodontal tissues andpro-inflammatory cytokines such as IL-1β,TNF-α, and MMPs are produced by inflammatorycells recruited to the lesion site. Thefunctions of PMNLs include phagocytosisand destruction of bacteria. Initially the clinicalsigns of gingivitis are evident. This responseis essentially protective in nature toFigure 1. Schematic Illustration of the Pathogenesis of PeriodontitisGenetic risk factorsMicrobialchallengeAntibodyPMNsAntigensLPSOthervirulencefactorsHostimmuneinflammatoryresponseCytokinesProstanoidsMMPsConnectivetissue andbonemetabolismClinicalsigns ofdiseaseEnvironmental and acquiredrisk factorsTissue breakdown products and ecological changesCopyright 2006 by Saunders, an imprint of Elsevier Inc.Source: Carranza’s Clinical Periodontology, 10th Ed. WB Saunders Company; 2006:275–282. 36 Reproducedwith permission.

14 Periodontal Disease and Overall Health: A Clinician's Guidecontrol bacterial infection. In persons whoare not susceptible to periodontitis, the primarydefense mechanisms control the infection,and chronic inflammation (i.e., chronicgingivitis) may persist. However, in individualssusceptible to periodontitis, theabove inflammatory process will eventuallyextend apically and laterally to involvedeeper connective tissues and alveolar bone,recruiting monocytes and lymphocytes tothe site of infection at these later stages.These monocytes and macrophages areactivated by the bacterial endotoxins leadingto the production of high levels ofprostaglandins (e.g., PGE 2), interleukins(e.g., IL-1α, IL-1β, IL-6), TNF-α, and MMPsby the host cells. The MMPs break downcollagen fibers, disrupting the normalanatomy of the gingival tissues, resulting indestruction of the periodontal apparatus. Ifleft untreated, the inflammation continuesto extend apically, and osteoclasts are stimulatedto resorb alveolar bone triggered bythe high levels of PGs, ILs, and TNF-α in thetissues. The elevated levels of pro-inflammatorymediators and MMPs are counterbalancedby a protective response in the hostwith elevations in anti-inflammatory mediatorssuch as the cytokines IL-4 and IL-10, aswell as other mediators such as IL-1ra (receptorantagonist) and tissue inhibitors ofMMPs (TIMPs; Figure 2). 36,37 Under normal,healthy conditions, the anti-inflammatorymediators are balanced with inflammatorymediators, thereby controlling tissue destruc -tion. If an imbalance is seen, with excessivelevels of the pro-inflammatory mediators,upregulated MMP expression and activity,and insufficient levels of protective antiinflammatorymediators, loss of periodontalconnective tissue and bone will occur.Thus, plaque bacteria initiate an inflammatoryresponse by the host, resulting inexcessive levels of pro-inflammatory mediatorsand enzymes, leading to the destructionof periodontal tissues. If this inflammationFigure 2. The Periodontal BalanceRisk factors (e.g., genetics,smoking, diabetes)Overproduction of proinflammatory ordestructive mediators and enzymes (e.g.,IL-1, IL-6, PGE 2, TNF-, MMPsReduction ofrisk factorsExpression of host-derived antiinflammatoryor protective mediators(e.g., IL-4, IL-10, IL-1ra, TIMPs)Underactivity or overactivityof aspects of host responseHost modulatorytherapyResolution ofinflammationPoor compliancePoor plaque controlSubgingivalbioburdenOHI, SRP, surgery, antiseptics, antibioticsto reduce bacterial challengeDISEASEHEALTHCopyright 2006 by Saunders, an imprint of Elsevier Inc.Source: Carranza’s Clinical Periodontology, 10th Ed. WB Saunders Company; 2006:275–282. 36 Reproducedwith permission.

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 15continues and extends further apically, morebone is resorbed, and more periodontal tissueis broken down, leading to deeper and deeperpockets and associated attachment and boneloss revealed as the clinical and radiographicsigns of periodontitis. In people with periodontitis,these inflammatory mediators(e.g., prostanoids and cytokines) and localoral bacteria will eventually enter into thecirculation, stimulating the liver to produceacute-phase proteins (notably C-reactive protein,but also fibrinogen, haptoglobin, etc.)which are “biomarkers” of a systemic inflammatoryresponse. The ever-expandingdata supporting the fact that this systemicinflammatory response driven by the chronicinfection and inflammation associated withperiodontitis will eventually increase an individual’srisk for developing a number ofsystemic diseases, including cardiovasculardiseases, adverse pregnancy outcomes, anddiabetic complications.MANAGEMENT OFPERIODONTAL DISEASESPeriodontal management includes acomplete assessment of each individual patient.Medical and dental history, clinical andradiographic examination, as well as an assessmentof risk factors are all important tomaking an accurate diagnosis, prognosis,and developing an optimal treatment plan.There are many treatment options availablefor the management of periodontal diseases,and review of treatment outcomes or re-evaluationis key to successful management andlong-term maintenance. In the past, treatmentsthat focused on reduction of the microbialload were basically the sole considerationfor all periodontal therapy. Currently,due to a better understanding of the host response,host-modulation therapies have beenused as adjunctive approaches to both nonsurgicaland surgical treatments to aid inreducing probing depths, increasing clinicalattachment levels, and in regeneration ofthe lost attachment apparatus. It is likely thatthe most effective therapeutic approacheswill include multiple, synergistic hostmodulationtherapies combined with treatmentsthat target the microbial etiology.In addition to reducing the bacterialchallenge and modulating the host response,reduction of risk is also a key treatmentstra tegy when managing periodontitis. Forexample, it is known that smoking cancontribute to the development of periodontaldisease and make management of the diseasemore difficult; 38,39 therefore smokingces sation would benefit all patients withperiodontitis. Smoking cessation can beundertaken in the dental office (if staffis appropriately trained) or in a medicalsetting. There are a variety of medications toaid with smoking cessation, counseling isimportant as well, and alternative medicinesuch as acupuncture may be used. Systemicdiseases such as diabetes will increase patients’risk for periodontitis when poorlycontrolled. 40 When treating people with diabetes,knowing the patient’s level of diabeticcontrol is important to assessing risk, andcollaborating with medical colleagues toimprove control of diabetes is essential toassure successful periodontal treatment.Perio dontitis is also prevalent in patientswith cardiovascular disease, and periodontaltherapy may have a positive impact on theoverall health status of these individuals.The management of patients with periodontitis can therefore involve the followingcomplementary treatment strategies: 41• Patient education, including oral hygieneinstruction and explanation ofthe rationale for any adjunctive treatments• Risk factor modification and risk reduction• Reduction of bacterial burden withtraditional scaling and root planing• Intensive periodontal treatment withlocal delivery systems or general

16 Periodontal Disease and Overall Health: A Clinician's Guideantimicrobial therapy with oral administrationof antibiotics• Host-modulation therapy• Periodontal surgeryIt is the responsibility of the dentist toprovide appropriate treatments on an individualizedbasis. A combination of treatmentapproaches (discussed below) for each patientas listed in Figure 3 will provide theultimate periodontal treatment and result ina better prognosis. 41The Antimicrobial ApproachTraditional periodontal therapy basedon the antimicrobial approach consists ofmechanical nonsurgical and surgical therapiesthat may or may not be supplemented bylocal antiseptics and/or local or systemicantibiotics.Mechanical TherapyA regimen of brushing and flossing,combined with the use of dentifrices and/ormouthrinses containing antiseptics is themost basic approach to microbial reductionand control. Good oral hygiene can effectivelyreduce bacterial loads to prevent gingivitisand aid in the treatment and managementof periodontitis. This simple approachrelies on an individual’s knowledge of thecorrect techniques and compliance with homecare instructions. Unfortunately, many patientsare not compliant, lose motiva tion, and do notspend a sufficient amount of time brushing orflossing on a daily basis. 42 It is for this reasonthat dentifrices and mouth rinses containingantiseptics have been devel oped. Antisepticshave been found to improve plaque reduction,as well as reduce gingival inflammationFigure 3. Complementary Treatment Strategies in PeriodontitisReduction ofbacterial burden:SRP, local orsystemic antimicrobialssurgical pocketreductionBest chancefor clinicalimprovementRisk factormodification:cessation therapy,Diabetes controlHost modulation therapy:subantimicrobial dose therapy,enamel matrix proteins, rhPDGF, BMP-2Adapted from: Carranza’s Clinical Periodontology, 10th Ed. WB Saunders Company; 2006:813–827. 41 Reproducedwith permission.

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 17seen with brushing and flossing alone. Therefore,antiseptic-containing dentifrices andmouth rinses have been accepted as adjunctsto the mechanical approach of brushing andflossing.Routine tooth scaling every six monthsby the dental care provider is also a key componentin treating and preventing gingivitis.Scaling and root planing is the traditionalnonsurgical treatment of periodontitis, withmultiple clinical studies demonstrating thatit effectively reduces the microbial load andleads to reductions in bleeding on probingand probing depths, and allows for gains inclinical attachment. 43 However, this procedurecan be very time-consuming and is operator-dependent.44 Surgical procedures canbe used to visualize the remaining subgingivalcalculus, and through resective or regenerativeprocedures will also lead to decreased probingdepths that are more manageable for thelong-term maintenance of patients with periodontitis.Although nonsurgical and surgicalprocedures aimed at reducing the bacterialload and restoring the attachment apparatuscontinue to be the most widely used methodsof treating periodontitis, these strategies alonemay be insufficient at reducing the bacterialload as significant numbers of micro-organismsmay be left behind. In addition, many ofthe putative pathogens will remain within theoral cavity at distant sites allowing for repopulationin the future. Therefore, the needfor the development of chemotherapeuticagents as adjuncts to mechanical debridementwas deemed necessary.Mouthrinses and DentifricesAntiseptic MouthrinsesAntiseptic mouthrinses have been used toreduce plaque levels and gingivitis. Two clinicallyproven American Dental Associationacceptedantiseptic mouthrinses are chlorhexidinegluconate (Peridex ® ) and the fouressential oils in Listerine ® . An associationbetween oral conditions such as periodontaldisease and several respiratory conditionssuch as pneumonia and chronic obstructivepulmonary disease has been noted. Theplaque surrounding the teeth is an excellentharbor for respiratory pathogens. Studies haveshown that using a chlorhexidine oral rinsecan reduce the risk of pneumonia in institutionalizedpatients with poor oral hygiene. 45Locally Applied AntisepticsPeriochip ® contains the active ingredientchlorhexidine gluconate (2.5 mg) that isreleased into the pocket over a period ofseven to 10 days. It has been found to suppressthe bacteria in the pocket for up to 11weeks post-application. 46 Periochip is theonly locally applied antiseptic that is approvedby the Food and Drug Administration(FDA) for use as an adjunct to scaling androot planing procedures to aid in the reductionof pocket depths. Other locally appliedantimicrobials are antibiotics.DentifricesMajor improvements in the oral healthof populations in developed countries havebeen seen over the last 50 years. Most of thisresulted from the reduction in the caries rateof about 50%, and the principle reason forthis is thought to be the addition of fluorideto dentifrices. Modern, commercially availabledentifrices, in addition to providing anti -caries effects of fluoride, also contribute tothe reduction of plaque, gingivitis, cal culusformation, relief of dentin hypersenitivity,and tooth stain. They also reduce halitosis andresult in a clean, fresh mouth feel. Two den tifricesavailable in the US that are approved bythe FDA for their effects on reduction of gingivitisinclude a stannous fluoride/sodiumhexametaphosphate den ti frice and a triclosan/copolymer/sodium fluoride dentifrice.There is a large amount of literature onthese and other dentifrices containing chlor -hexidine and other agents in the control of

18 Periodontal Disease and Overall Health: A Clinician's Guidegingivitis. A review of the clinical efficacyand safety of a triclosan/copolymer/sodiumfluoride dentifrice was carried out by Blink -horn and colleagues. 47 They found about 200articles dating from 1998 to 2008 relating tothis dentifrice and concluded that twice dailyuse of this dentifrice will result in clinicallysignificant improvement in plaque controland gingivitis and slower progression ofperio dontal disease. Further long-term studiesextending over several years with thesedentifrices are needed to establish whether ornot short-term effects seen will be sustainedover the long term, and indeed result in preventingthe initiation of perio dontitis andslowing the progression of already existingperiodontitis.It should be noted that the antiplaqueand antigingivitis effects of dentifrices duringa tooth brushing regimen are mainly on theocclusal and smooth surfaces of the teeth,and that interproximal plaque and gingivitiscontrol is not optimally reduced with toothbrushing alone, with or without a dentifrice.Interproximal aids such as flossing, interproximalbrushing, and to some extent, flushingwith effective mouthrinses is often neededfor full plaque control on interproximal surfacesof the teeth. As periodontal disease isoften initiated and progresses more rapidly ininterproximal spaces, it is clear that interproximalcleansing is an important adjunct totoothbrushing with dentifrices.Locally Delivered AntimicrobialsAtridoxAtridox ® is an FDA-approved locallydelivered tetracycline system. It comes witha 10% formulation of doxycycline in a bio -absorbable, “flowable” poly-DL lactide andN-methyl-2-pyrrolidone mixture deliverysystem that allows for controlled release overseven days. This system is applied subgin -givally to the base of the pocket through acannula. Atridox is a resorbable site-specificlocally delivered antibiotic proven to promoteclinical attachment gains and reduce pocketdepths, bleeding on probing, and levels ofpathogenic bacteria for up to six months postplacement.35 Periodontal disease has beenlinked to systemic diseases such as diabetes.Research has shown that periodontal treatmentwith locally delivered doxycycline 10mg in periodontal pockets produced favorableclinical results in diabetic patients. 48ArestinArestin ® is an FDA-approved minocyclinemicrosphere system that is bioadhesiveand bioresorbable, allowing for sustained releaseof 1 mg of minocycline up to 19 days.Arestin can be used as an adjunct to scalingand root planing procedures for reduction ofpocket depth in patients with adult perio -dontitis. Arestin is delivered to sites of 5 mmor greater. Periodontitis has been associatedwith increased systemic inflammation, whichis directly linked to diabetes and cardiovasculardiseases. Recent research has shownthat periodontal therapy with local Arestinadministration resulted in decreased HbA1clevels in diabetic subjects 49 and significantreductions in systemic inflammatory biomarkersthat are risk factors for cardiovasculardisease. 50Systemic AntimicrobialsSystemic antimicrobial therapy is usuallyreserved for advanced cases of periodontitis:1) for sites that have not respondedto treatment, so-called “refractory periodontitis,”and 2) for patients demonstrating progressiveperiodontal destruction. 35 Systemicantibiotics can be used as adjuncts to conventionalmechanical therapy as strong evidencefor their use as a monotherapy has notbeen developed. For these special situations,randomized double-blinded clinical trials andlongitudinal assessments of patients indicatethat systemic antimicrobials may be usefulin slowing disease progression. 51 Metroni -

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 19dazole can be used to treat acute necrotizingulcerative gingivitis (NUG), 52 and metronidazole/amoxicillincombination therapy canbe used to treat aggressive adolescent periodontitisassociated with A. actinomycetemcomitans.53 Systemic antibiotic therapy hasthe advantage of simple, easy administrationof drugs to multiple periodontal sites. However,patient compliance needs to be considered,inability to achieve adequate concentrationsat the site of infection, adverse drugreactions, and the develop ment of antibioticresistance can be issues. 54 Common antibiotictherapies for the treatment of periodontitisinclude metronidazole, clindamycin, doxycyclineor minocycline, ciprofloxacin,azithromycin, metronidazole/amoxicillin,and metronidazole/cipro floxacin. 55 For adultpatients with acute periodontal abscesses,amoxicillin is used as an adjunct to incisionand drainage. For patients with allergies tobeta-lactam drugs (e.g., amoxicillin), azith -romycin or clindamycin would be the choice.Researchers have shown that periodontaltreatment can benefit some systemic diseasesknown to be associated with periodontitis,such as diabetes and preterm delivery.Grossi and colleagues reported that diabeticpatients receiving scaling and root planingwith systemic doxycycline showed significantreductions in mean HbA1c. 56 Effectivetreatment of periodontal infection and reduc -tion of periodontal inflammation is associatedwith a reduction in levels of glycatedhemo globin. Clothier and colleagues alsoshowed that performing scaling and root planingin pregnant women with periodontitismay reduce preterm delivery. 57 However, ad -junc tive metronidazole therapy did not im -prove pregnancy outcomes. Two recent studieshave not shown improvements in adversepregnancy outcomes with scaling and rootplaning. 58 However, the level of perio dontaltreatment provided may have been veryinadequate. More studies are needed in thisfield to determine the effect of periodontaltreatment on the outcomes of adverse pregnancyand the extent of therapy that mayneed to be provided in order to have a significantimpact.Host-Modulation TherapyBacteria and the host are two essentialfactors to the development of periodontitis.Reduction of bacterial load is the con -ventional approach for the management ofperiodontal diseases. More recently, periodontaltreatment strategies have includedhost-modulation therapy as an adjunctivetreatment option. Host-modulation therapy istreating the host response to either reduce theexcess production of cytokines and destructiveenzymes so there is less damage to theperiodontal tissues, or to stimulate the regenerative process, allowing for the restorationof connective tissue attachment andbone formation to occur.Host modulation was first introduced todentistry by Williams 59 and Golub and colleagues.60 Williams stated: “There are compellingdata from studies in animals and humantrials indicating that pharmacologicagents that modulate the host responses believedto be involved in the pathogenesis ofperiodontal destruction may be efficacious inslowing the progression of periodontitis.” 59Golub and colleagues discussed “host modulationwith tetracyclines and their chemicallymodified analogues.” 60 A variety of differentdrug classes have been evaluated ashost-modulation agents, including the non -steroidal anti-inflammatory drugs, bisphosphonates,tetracyclines (Figure 4), 36 enamelmatrix proteins, growth factors, and bonemorphogenetic proteins.Systemically Administered AgentsSubantimicrobial-Dose DoxycyclineSubantimicrobial-dose doxycycline (SDD)is the only FDA-approved MMP inhibitorand systemic host-modulation therapy for the

20 Periodontal Disease and Overall Health: A Clinician's GuideFigure 4. Potential Adjunctive Therapeutic ApproachesAntimicrobialsBacterialproductsHostcellsNSAIDSPeriostatProstaglandinsCytokines(IL-1, IL-6, TNF)MMPsPeriostatBisphosphonatesPeriostatOsteoclastsBoneresorptionConnectivetissuebreakdownPocketsandCALToothmobilityandkissBacterialcomponent+ Host response component= ClinicalsequelaeSource: Carranza’s Clinical Periodontology, 10th Ed. WB Saunders Company; 2006:275–282. 36 Reproducedwith permission.management of periodontitis. SDD is a 20-mgdose of doxycycline (Periostat ® ) taken twicedaily for three months and used in multicenterclinical trials for up to a maximum of 24months of continuous dosing. SDD is used asan adjunct to scaling and root planing in thetreatment of CP. The host-modulation effectsof SDD include enzyme inhibition, cytokinereductions, and effects on osteoclast function.Since perio dontitis is associated with manysystemic diseases (e.g., osteoporosis, diabetes,cardiovascular disease), researchers have investigatedthe effect of SDD on these system -ic conditions. Studies have shown that SDD:• Can effectively reduce the levels oflocalized and systemic inflammatorymediators in osteopenic patients, inaddition to improving on the clinicalmeasurements of periodontitis 61• Has been shown to reduce systemicinflammatory biomarkers in CVDpatients 62• Decreases HbA1c in patients whoare taking normally prescribed hypoglycemicagents 63The impact of SDD therapy on periodontitismay be amplified by an independentbenefit for other inflammatory diseases;additional studies are being conducted to investigatethe impact of this host-modulationtherapy.Locally Administered AgentsEnamel Matrix Proteins, Growth Factors,and Bone Morphogenetic ProteinsA number of local host-modulationagents have been investigated for potentialuse as adjuncts to surgical procedures to improveperiodontal health. These have includedenamel matrix proteins (Emdogain ® ),bone morphogenetic proteins, and plateletderivedgrowth factors (PDGF). The initiallocal host-modulation agent approved by theFDA for adjunctive use during surgery toassist with clinical attachment gain andwound healing was Emdogain; this has beenfollowed by PDGF combined with a resorbablesynthetic bone matrix growth-factorenhanced matrix (GEM 21S) to assist in

CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 21regenerative procedures approved recentlyby the FDA, as well as recombinant humanbone morphogenetic protein-2 (rhBMP-2)contained within an absorbable collagensponge to assist with ridge and sinus augmentation.The technology behind GEM 21Shas already been marketed for use in woundhealing, particularly in people with diabetes,and rhBMP-2 has been used for quite sometime by the orthopedic community for thehealing of fractures.The findings discussed with regard to theuse of host-modulation therapy to better managechronic periodontal disease may have applicationsto other chronic systemic diseasessuch as arthritis, diabetes, osteoporosis, andcardiovascular disease. In addition, studiesutilizing locally delivered antimicrobials aspart of an intensive periodontal therapy regimenhave shown very promising results.Future studies may demonstrate that in additionto our current standard therapies, intensiveperiodontal therapy with adjunctiveantibiotics and/or host modulation for themanagement of periodontal disease mayhave profound positive effects on the overallhealth status of high-risk patients. Theproper management of local infection andinflammation (periodontitis) will have a significantimpact on general overall health ofthe population.AcknowledgmentsThe authors would like to acknowledge Dr.Hsi-ming Lee, René Martin, and LauraBertolotti for their assistance in the organizationof this manuscript.Supplemental ReadingsWilliams RC. Periodontal disease. N Engl J Med 1990;322:373-382.Page RC, Offenbacher S, Schroeder HE, Seymour GJ,Kornman KS. Advances in the pathogenesis of perio -dontitis: summary of developments, clinical implicationsand future directions. Periodontol 2000 1997;14:216-248.Brown LJ, Löe H. Prevalence, extent, severity and progressionof periodontal disease. Periodontol 2000 1993;2:57-71.Burt B. Research, Science and Therapy Committee of theAmerican Academy of Periodontology. Position paper:Epidemiology of periodontal diseases. J Periodontol2005;76:1406-1419.Ryan EM. Nonsurgical approaches for the treatment ofperiodontal diseases. Dent Clin North Am 2005;49:611–636.Ryan ME, Preshaw PM. Host modulation. In: NewmanMG, Takei HH, Klokkevold PR, Carranza FA, eds.Carranza’s Clinical Periodontology, Edition 10. WBSaunders Co. 2006; pp. 275-282.Preshaw PM, Ryan ME, Giannobile WV. Host modulationagents. In: Newman MG, Takei HH, KlokkevoldPR, Carranza FA, eds. Carranza’s Clinical Periodontology,Edition 10. WB Saunders Co. 2006; pp. 813-827.REFERENCES1. Mariotti A. Dental plaque-induced gingival diseases.Ann Periodontol 1999;4:7–19.2. Van Dyke TE. The management of inflammation inperiodontal disease. J Periodontol 2008;79(8 Suppl):1601–1608.3. Armitage GC. Development of a classification systemfor periodontal diseases and conditions. AnnPeriodontol 1999;4:1–6.4. Novak MJ. Classification of diseases and conditionsaffecting the periodontium. In: Newman MG,Takei HH, Carranza FA, eds. Carranza’s ClinicalPeriodontology, 9th Ed. WB Saunders Company;2002:64–73.5. Flemmig TF. Periodontitis. Ann Periodontol 1999;4:32–38.6. Armitage GC. Periodontal diseases: diagnosis. AnnPeriodontol 1996;1:37–215.7. Kinane DF. Blood and lymphoreticular disorders.Periodontol 2000 1999;21:84–93.8. Rees TD. Drugs and oral disorders. Periodontol2000 1998;18:21–36.9. Scully C, Monteil R, Sposto MR. Infectious andtropical diseases affecting the human mouth. Periodontol2000 1998;18:47–70.10. Holmstrup P. Non-plaque induced gingival lesions.Ann Periodontol 1999;4:20–31.11. Stanford TW, Rivera-Hidalgo F. Oral mucosal lesionscaused by infective microorganisms II. Fungi& parasites. Periodontol 2000 1999;21:125–144.12. Aldred MJ, Bartold PM. Genetic disorders of thegingivae and periodontium. Periodontol 2000 1998;18:7–20.

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CHAPTER 2 Overview of Periodontal Disease:CHAPTER 2 Causes, Pathogenesis, and Characteristics 23Pneumonia and cardiovascular disease. Ned TijdschrTandheelkd. 2006;113:186–190.46. Stabholz A, Sela MN, Friedman M, Golomb G,Soskolne A. Clinical and microbiological effects ofsustained release chlorhexidine in periodontal pockets.J Clin Periodontol 1986;13:783–788.47. Blinkhorn A, Bartold PM, Cullinan MP, MaddenTE, Marshall RI, Raphael SL, Seymour GJ. Is therea role for triclosan/copolymer toothpaste in themanagement of periodontal disease? Br Dent J2009;207:117–125.48. Martorelli de Lima AF, Cury CC, Palioto DB, DuroAM, da Silva RC, Wolff LF. Therapy with adjunctivedoxycycline local delivery in patients with type1 diabetes mellitus and periodontitis. J Clin Perio -dontol 2004;31:648–653.49. Skaleric U, Schara R, Medvescek M, Hanlon A,Doherty F, Lessem J. Periodontal treatment byArestin and its effects on glycemic control in type1 diabetes patients. J Int Acad Periodontol 2004;64(Suppl.):160–165.50. D’Aiuto F, Nibali L, Parkar M, Suvan J, TonettiMS. Short-term effects of intensive periodontaltherapy on serum inflammatory markers and cholesterol.J Dent Res 2005;84:269–273.51. Haffajee AD, Socransky SS, Dzink JL, TaubmanMA, Ebersole JL. Clinical, microbiological andimmunological features of subjects with refractoryperiodontal diseases. J Clin Periodontol 1988;15:390–398.52. Duckworth R, Waterhouse JP, Britton DE, Nuki K,Sheiham A, Winter R, Blake GC. Acute ulcerativegingivitis. A double-blind controlled clinical trial ofmetronidazole. Br Dent J 1966;120:599–602.53. van Winkelhoff AJ, Rodenburg JP, Goene RJ, AbbasF, Winkel EG, de Graaff J. Metronidazole plusamoxicillin in the treatment of Actinobacillus actinomycetemcomitansassociated periodontitis. J ClinPeriodontol 1989;16:128–131.54. Slots J. Research, Science and Therapy Committee.Systemic antibiotics in periodontics. J Periodontol2004;75:1553–1565.55. Slots J, van Winkelhoff AJ. Antimicrobial therapyin periodontics. J Calif Dent Assoc 1993;21:51–56.56. Grossi SG, Skrepcinski FB, DeCaro T, RobertsonDC, Ho AW, Dunford RG, Genco RJ. Treatment ofperiodontal disease in diabetics reduces glycatedhemoglobin. J Periodontol 1997;68:713–719.57. Clothier B, Stringer M, Jeffcoat MK. Periodontaldisease and pregnancy outcomes: exposure, riskand intervention. Best Pract Res Clin Obstet Gynaecol2007;21:451–466.58. Michalowicz BS, Hodges JS, DiAngelis AJ, LupoVR, Novak MJ, Ferguson JE, Buchanan W, BofillJ, Papapanou PN, Mitchell DA, Matseoane S,Tschida PA. OPT Study. Treatment of periodontaldisease and the risk of preterm birth. N Engl J Med2006;355:1885–1894.59. Williams RC. Periodontal disease. N Engl J Med1990;322:373–382.60. Golub LM, Suomalainen K, Sorsa T. Host modulationwith tetracyclines and their chemically modifiedanalogues. Curr Opin Dent 1992;2:80–90.61. Golub LM, Lee HM, Stoner JA, Sorsa T, ReinhardtRA, Wolff MS, Ryan ME, Nummikoski PV, PayneJB. Subantimicrobial-dose doxycycline modulatesgingival crevicular fluid biomarkers of periodontitisin postmenopausal osteopenic women. J Perio -dontol 2008;79:1409–1418.62. Brown DL, Desai KK, Vakili BA, Nouneh C, LeeHM, Golub LM. Clinical and biochemical results ofthe metalloproteinase inhibition with subanti -microbial doses of doxycycline to prevent acutecoronary syndromes (MIDAS) pilot trial. Arterio -scler Thromb Vasc Biol 2004;24:733–738.63. Engebretson SP, Hey-Hadavi J, Celenti R, LamsterIB. Low-dose doxycycline treatment reducesglycosylated hemoglobin in patients with type 2diabetes: a randomized controlled trial. J Dent Res2003;82(Spec Iss):Abstract #1445.

CHAPTER 3Infection and InflammationPhoebus N. Madianos, Yiorgos A. Bobetsis, Thomas E. Van DykeINTRODUCTIONPeriodontal diseases (gingivitis and periodontitis)are destructive inflammatory diseasesof the gingiva and the supporting structures ofthe teeth, induced by a microbial biofilmcommonly called dental plaque. The fundamentalprinciple of the bacterial etiology ofgingivitis was first established in a landmarkstudy by Löe et al. in 1965. 1 Using a novel,now classic, experimental design, it wasdemonstrated that when students withhealthy gingiva abstained from oral hygienepractices for 10–21 days, marginal inflammationof the gingiva (gingivitis) developedas a result of plaque accumulation. Onceoral hygiene was reinstated, gingival healthreturned. Today, in vitro and in vivo experiments,along with histological assessmentsof inflamed and healthy gingiva, have provideda clearer understanding of the nature ofthe interactions between bacteria and hostcells. However, current understanding of theetiology and pathogenesis of the periodontaldiseases is far from complete.Periodontal bacteria possess a plethoraof virulence factors that, upon interactionwith host cells, induce production of inflammatorymediators at the gingival level.These mediators are thought to be importantfor the initiation and progression of an inflammatoryresponse, which although intendedto eliminate the bacterial challenge,inevitably results in tissue damage when thebacterial challenge persists. It is also importantto note that inflammation is not confinedonly to periodontal tissues. Bacteria and inflammatory mediators may enter blood circu -lation to induce systemic inflammation. Thereis increasing evidence that cardiovasculardisease, 2 adverse pregnancy outcomes, 3 anddiabetes mellitus 4 are associated with elevatedsystemic inflammation, suggesting a commonpathway in the pathogenesis of a number ofinflammatory diseases.Depending upon the effectiveness ofthe innate immune response, bacterial infectionmay persist and lead to perpetuation ofinflammation, which may become chronicwith development of acquired immunity.However, if the infection is cleared, then resolutionof inflammation occurs with the returnof tissue homeostasis without permanentdamage. Recent discoveries have alteredour understanding of inflammation resolutionand return of tissue homeostasis. Wenow understand that resolution of inflammationis an active process, not the passivedecrease of pro-inflammatory signals as oncethought. The ability to manipulate theseprocesses may provide a new treatment paradigmfor both local and systemic inflammatorydiseases (see Serhan et al.). 5Chapter GoalsThis chapter is structured to: (a) providebackground information regarding the initiationand orchestration of inflammation atthe gingival level after the interaction of thebiofilm with host cells; (b) examine the evidencefor periodontal disease influencingsystemic inflammation and describe the possiblebiological pathways, as well as the cellularand molecular events that may occur;(c) explore the idea that systemic inflammationmay be the link that associates periodontalwith other systemic diseases focusingon the potential mechanisms of action;(d) address the role of resolution of inflammationin the pathogenesis of inflammatorydiseases; and (e) introduce new strategies

CHAPTER 3 Infection and Inflammation 25directed at mechanisms of inflammationresolution that may be used in treating in -flammatory diseases.PART I: INFLAMMATIONAT THE GINGIVAL LEVELPeriodontal disease is an inflammatorydisorder of the gingiva initiated by bacteriathat leads to the destruction of the supportingtissues of the teeth in a susceptible host. Bacteriain the oral cavity colonize the teeth, thegingival sulcus, and eventually the perio -dontal pocket, forming an organized biofilm.Depending upon the stage of maturation, thebiofilm may consist of several hundred differentbacterial species, many of which haveyet to be identified. 6 Some of these speciesare associated with health, whereas othersare associated with pathology. 7 However,which organisms actually initiate disease remainsunknown.Bacterial ComponentsThe formation of organized biofilmsenhances the ability of bacteria to survive.Bacteria have also evolved a variety of virulencefactors to further enhance their survival,such as toxins, proteases, and glyco -sidases. Virulence factors are presumablyintended to hide the bacteria from host detectionas well as to provide essential moleculesfor nourishment. Conversely, the hosthas evolved mechanisms for detection ofbacteria through the recognition of structuralcomponents of the bacterial surface, such aslipopolysaccharide (LPS), peptidoglycan(PGN), and other cell surface componentssuch as fimbriae that perform essential physiologicfunctions for the bacteria. Variationsof these bacterial components may be seenbetween various species, or even betweendifferent strains of the same species. Despitetheir structural heterogeneity, most of thesemolecules have conserved motifs known aspathogen-associated molecular patterns(PAMPs) that are recognized by host cellreceptors called pattern recognition receptors(PRRs). These highly conserved innate immunereceptors evolved for detection of invadingbacteria. Binding of PAMPs by PRRsactivates specific signaling pathways in hostcells that are important for the initiation of aninflammatory response. Although this responseis intended to eliminate the microbialchallenge, the inflammatory mediators thatare secreted may lead to further tissue damageif bacterial clearance is not achieved.Today, the most studied bacterial factorsinclude LPS, PGN, lipoteichoic acids (LTAs),fimbriae, proteases, heat-shock proteins(HSPs), formyl-methionyl-leucyl-phenyl -alanine (fMLP) and toxins. Host PRRs includethe Toll-like receptors (TLRs) and theG-protein-coupled receptors (GPCRs). Table1 presents a summary of the results by actionsof various bacterial factors after inter -action with specific host cells. 8Bacteria and GI EquilibriumThe oral cavity, as part of the gastro -intestinal tract, is naturally colonized by awide variety of bacteria. This is a physiologicsituation that does not always result inpathology. The tooth-gingival interface is thesite of a variety of natural, innate host defensemechanisms, including the regular sheddingof epithelial cells, the washing effect of thesaliva and the gingival crevicular fluid (GCF),and most importantly, the phagocytic actionof neutrophils that migrate continuouslythrough the junctional epithelium into thegingival sulcus. However, if this equilibriumis disturbed, pathogenic bacteria may overgrow,initiating the pathogenesis of gingivitisand possibly periodontitis. Current under -standing of the steps leading to overgrowthof pathogens includes periodontal bacteriaattaching to epithelial cells using their fimbriaeand PRR recognition of PAMPs, inducingepithelial cell secretion of pro-inflammatorycytokines (TNF-, IL-1, IL-6)and the chemokine IL-8 in the connective

26 Periodontal Disease and Overall Health: A Clinician's GuideTable 1. Summary of Main Effects of Bacterial Virulence Factors on Host CellsResponses of Host CellsBacterial Epithelial Monocytes/ Endothelial FibroblastFactor Cells Macrophages Cells Cells Mast CellsIL-1βTNF-αIFN-γIL-6IL-1βIL-12 MCP-1 TNF-αIP-10 IL-1β IFN-γLPS IL-8MCP-5 E-, P-selectin IL-6 IL-6IL-8 MCP-1 IL-8 IL-12MIP-1α, MIP-2 ICAM-1 IP-10PGE 2NOL-selectinCD11α/CD18,CD11β/CD18IL-1βHistamineTNF-αTNF-αPGN IL-8IL-6ICAM-1ProstaglandinsIL-8IL-8 IL-8 IL-4MIP-1αIL-5NOIL-10IL-1βTNF-αIFN-γIL-6LTA IL-8 IL-6 IL-8IL-8E-selectinIL-10NOIL-1β IL-1β MCP-1FimbriaeTNF-α TNF-α IL-8 IL-1βIL-6 IL-6 ICAM-1, TNF-αIL-8 VCAM-1 IL-6P-, E-selectinProteasesHSPfMLPToxinsIL-6β-defensinsIL-6TNF-αCD11α/CD18CD11β/CD18IL-1βIFN-γIL-6IL-8IL-10Adapted from J Clin Periodontol 2005;32(Suppl 6):57–71. 8IL-6IL-8

CHAPTER 3 Infection and Inflammation 27tissue. Normally, the intact sulcular and junctionalepithelium serves as an effective naturalbarrier that keeps the bacteria from enteringhost tissues. However, severalperiodontopathogens (e.g., P. gingivalis, A.actinomycetemcomitans) have been shownto invade and transverse epithelial cells togain access to the connective tissue. Moreover,bacterial components (e.g., LPS, PGN)and products (e.g., proteases, toxins) that areeither shed or secreted can also diffusethrough the epithelial junctions to the connectivetissue. 9Bacteria in Connective TissueBacteria and/or their virulence factorsfound in the connective tissue directly stimulatehost cells residing in this area, includingleukocytes, fibroblasts, mast cells, endo -thelial cells, dendritic cells and lymphocytes.Neutrophils, macrophages, fibroblasts andmast cells release more proinflammatory cytokines(TNF-, IL-1, IL-6, IL-12), chemoattractants(IL-8, MIP-1- , MIP-2, MCP-1,MCP-5) and PGE 2in the connective tissue.In addition, degranulation of mast cells resultsin the secretion of histamine andleukotrienes further amplifying the inflammatorycascade. 10,11Mediators that are secreted from activatedhost cells (e.g., IL-1, TNF-, PGE 2,and histamine) will further assist bacterialvirulence factors in the activation of endo -thelial cells. This leads to secretion of morechemokines (IL-8, MCP-1) and expressionof adhesion molecules on the surface of endothelialcells, which are important forleukocyte extravasation (P- and E-selectinsas wells as ICAM-1 and -2). 12 Specifically,P- and E-selectins interact with glyco proteinson leukocytes allowing the cells to adhere reversiblyto the vessel wall, causing circulatingleukocytes to appear to “roll” along theactivated endothelium. Then, IL-8 and otherchemokines, bound to proteoglycans on thesurface of leukocytes, trigger a conformationalchange of integrins (LFA-1, CD11b:CD18). As a result, adhesive properties increasedramatically and leukocytes attachfirmly to ICAM-1 expressed on endothelialcells. TNF-, PGE 2and histamine increasevascular permeability, allowing leukocytesto squeeze between the endo thelial cells,thereby entering the connective tissue ina process known as diapedesis. Finally,chemokines, such as IL-8 that are producedat the site of infection and bind to proteoglycansof the extracellular matrix, alongwith bacterial chemo-attractants (fMLP,fimbriae) form a concentration gradient thatguides the leukocytes to migrate to the focusof infection.The Inflammatory CascadeNeutrophils are the first leukocytes toarrive followed by mononuclear phagocytesthat subsequently differentiate into macro -phages. The interaction of these cells withbacterial virulence factors induces further activation,which enhances their phagocytic activityby increasing the production of nitricoxide (NO) and the expression of complementreceptors (CR3). If the innate immuneresponse is successful, the bacteria are eliminatedand resolution of inflammation follows.However, persistence of bacteria leadsto a chronic response characterized by extracelluarrelease of neutrophil granule contents,including degradative enzymes and reactiveoxygen species that spill into the extracellularmilieu, leading to local tissue damage andamplification of acute inflammatory signals. 13Pro-inflammatory cytokines (TNF-,IL-1, IL-6) from the site of inflammationenter the circulation and reach the liverwhere they activate hepatocytes. This leads,among other events, to the synthesis ofplasma proteins known as acute-phase proteins,including LPS binding protein (LBP)and CD14, which are important for therecognition of bacterial virulence factors.Complement proteins and C-reactive protein

28 Periodontal Disease and Overall Health: A Clinician's Guide(CRP), contribute by opsonizing bacteria,thereby aiding in recognition for phagocytosis.These products enter the circulation andbecause of increased vascular permeability,diffuse into the inflamed gingival tissues.Figure 1 illustrates the initiation of inflammationat the gingiva.The Immune ResponseIf the infection persists, the acquiredimmune response is initiated and the “establishedlesion” is created as described byPage and Schroeder. 14 Briefly, dendritic cellswithin the epithelium take up bacterial antigensand migrate to the peripheral lymphnodes. The antigens are processed into aform that is recognizable by the immune system,i.e., the antigenic peptide binds to aClass II major histocompatibility complex(MHC) receptor, and consequently “present”the antigen. As a result, antigen-specific effectorT cells and antibody-secreting B cellsare generated by clonal expansion and differentiationover the course of several days,Figure 1. Initiation of Inflammation at the Gingival LevelNeutrophils in the GCF and epithelial cells comprise the first line of defense to prevent bacteria from invading thehost. The interaction of the bacterial biofilm with epithelial cells leads to activation and secretion of pro-inflammatorycytokines (green). Bacteria and their virulence factors (red) may penetrate the epithelial lining and enterthe connective tissue. In this compartment they may interact with host cells, such as macrophages, fibroblasts, andmast cells to stimulate these cells to release more pro-inflammatory mediators such as TNF-α, IL-1β, IL-8,LTB-4, and histamine. These mediators, along with bacteria/virulence factors, may activate endothelial cells to attractcirculating leukocytes in the connective tissues. In this compartment, phagocytic cells take up bacteria and theirantigenic molecules. This process, if further enhanced by acute-phase response proteins, such as CRP, that areproduced from activated hepatocytes, enter the connective tissue via circulation due to increased vascularpermeability. If the noxious agents are eliminated, resolution of inflammation follows. However, if the bacterialchallenge persists, the more efficient adaptive immune response takes over.Adapted from J Clin Periodontol 2005;32(Suppl 6):57–71. 8

CHAPTER 3 Infection and Inflammation 29during which time the induced responses ofinnate immunity continue to function. Eventually,antigen-specific T cells and then antibodiesare released into the blood to targetthe infection site. 15 Macrophages that engulfbacteria at the site of infection express costimulatorymolecules (MHC-II) and presentbacterial antigens on their surface. AntigenspecificT cells “see” the antigens and activatethe macrophages, enabling them to destroyintracellular bacteria more efficiently.In addition, secreted antibodies protect thehost from infection by: (a) inhibiting thetoxic effects or infectivity of pathogens bybinding (neutralization); (b) opsonizing thepathogens and promoting phagocytosis; and(c) activating the complement system.Failureto clear the infection at this point leads to furthertissue damage. Activated macrophagesproduce oxygen radicals, NO, and proteasesin the gingival tissues that are toxic to thehost cells. Moreover, recent work on a mousemodel revealed that the induction of anadaptive immune response to colonizingpathogens results in receptor activator of nuclearfactor-kappaB ligand-dependent perio -dontal bone loss. 16Summary of Part IThe trigger that causes the shift fromtissue homeostasis to pathology remains unclear.The logical extension of Löe’s observationis that this is caused by specific bacteriaand indeed, a large body of evidencesuggests that certain bacteria are associatedwith progressive disease. However, studies ofthe microbiota of the periodontal lesion arecross-sectional and definitive cause/effectrelationships have not been demonstrated.Recently, a longitudinal study of periodontaldisease progression failed to implicate anysingle organism or group of organisms inthe initiation of periodontal attachmentloss. 17 In addition, recent animal studies suggestthat the level of host inflammation hasa major impact on the composition of thebiofilm. Interestingly, inflammation is astronger predictor of periodontal attachmentloss than the composition or quantity of theoral biofilm. 17 Clearly, the etiology andpathogenesis of periodontitis requires furtherstudy. It is also apparent that “traditional”periodontal pathogens (Socransky’s“red complex”) contribute to and acceleratedisease when they overgrow in the perio -dontal environment. However, the role of inflammationand the host immune responsehas taken on a new perspective, potentiallydetermining susceptibility and providing anovel therapeutic target.PART II: SYSTEMIC INFLAMMATIONDUE TO PERIODONTAL INFECTIONDespite the localized nature of perio -dontal disease, infection of the sulcus/perio -dontal pocket with periodontopathogens maybe responsible for inflammatory responsesthat develop beyond the periodontium. Todate, several biological pathways have beenrecognized that present reasonable hypothesesfor periodontal disease induction of systemicinflammation.Inflammatory PathwaysIn health, the sulcular epithelium alongwith innate immune molecules acts as a naturalbarrier system that inhibits and eliminatespenetrating bacteria. Hence, only asmall number of bacteria, mostly facultative,manage to enter the gingival tissues and thebloodstream. However, in cases of perio -dontal disease, the inflamed and ulceratedpocket epithelium is vulnerable to bacterialpenetration and forms an easy port of entryfor the bacteria. This leads to an increase inthe number of periodontopathogens, mainlyanaerobic Gram-negative, in the gingival tissuesand consequently in the circulation.Bacteremia can be initiated after mechanicalirritation of the inflamed gingiva during toothbrushing, chewing, oral examination, andscaling and root planing. 18 The microorgan-

30 Periodontal Disease and Overall Health: A Clinician's Guideisms that gain access to the blood and circulatethroughout the body are usually eliminatedby the reticulo-endothelial systemwithin minutes (transient bacteremia) andusually there are no other clinical symptomsother than possibly a slight increase in bodytemperature. 19 However, if the disseminatedbacteria find favorable conditions, they maycolonize distant sites and form ectopic foci ofinfection. Similarly, bacterial virulence factorsthat are secreted or shed in the gingivaltissues may also disseminate via the circulationand stimulate remote tissues. 20 Bacteriaand bacterial antigens that are systemicallydispersed can trigger significant systemicinflammation. Leukocytes as well as endo -thelial cells and hepatocytes respond tobacteria/virulence factors, producing proinflammatoryimmune mediators. Moreover,soluble antigens may react with circulatingspecific antibodies, forming macromolec ularcomplexes. These immune complexes mayfurther amplify inflammatory reactions atsites of deposition. 21Pro-Inflammatory MediatorsA different biological pathway that mayexplain the systemic inflammation inducedby periodontal disease involves pro-inflamma -tory mediators, such as IL-1, IL-6, TNF-and PGE 2that are produced by host cells inthe inflamed gingival tissues. These mediatorsare secreted locally in response to bacterialchallenge, but may “spill” into the circulationand exert distant or systemic effects.Specifically, cytokines may reach distantsites and further activate endothelialcells leading, in some cases, to endothelialdysfunction. 22 Moreover, the circulating mediators,due to the increased vascular permeabilityat the sites of inflammation, mayenter inflamed tissues and exacerbate the inflammatoryprocesses. However, the mostimportant impact of these circulating mediatorsis systemic. Pro-inflammatory cyto -kines may induce leukocytosis, which is anincrease in circulating neutrophils. Moreover,IL-1, TNF-, and especially IL-6 mayreach the liver and activate hepatocytes toproduce acute-phase proteins. The most importantacute-phase reactants include CRP,serum amyloid A (SAA) protein, fibrinogen,plasminogen activator inhibitor 1 (PAI-1),complement proteins, LBP, and solubleCD14. These proteins are released in theplasma and possess a wide variety of functions,such as multiple pro-inflammatory activitiesand stimulation of tissue repair mechanisms.The production of these proteins ispart of an acute-phase response that is characterizedby fever, increased vascular permeability,and a general elevation of metabolicprocesses. An acute-phase responsestarts within hours or days of most forms ofacute tissue damage or inflammation and despiteits name, persists with chronic inflammation.As acute-phase reactants enter thecirculation, they may return to the inflamedgingival tissues. However, since they circulatethroughout the body they can affect ectopicsites, causing inflammation or exacerbationof existing inflammatory processes.This concept takes on new meaning in lightof the recent implication of CRP in thepathogenesis of cardiovascular disease. 23Because there is to date no consensuson the mechanisms that induce systemic inflammationfrom periodontal disease, any ofthe above pathways (bacteremia, systemicspilling of cytokines, and activation of theacute-phase response) must be considered acandidate for the generation of systemic inflammation.It is also possible that dependingupon the severity of periodontal disease,any of these mechanisms may occur alone orin combination, leading to variations of inducedsystemic inflammation.Acute-Phase ProteinsCRP is produced mainly by the liver,but it may also be synthesized locally at sitesof inflammation. CRP opsonizes different

CHAPTER 3 Infection and Inflammation 31bacteria by binding to phosphorylcholinefound on the surface, thereby assisting inbacterial uptake by phagocytes. 24 Opsonizationand phagocytosis are further enhancedby activation of the complement system byCRP. Other pro-inflammatory activities ofCRP include the up-regulation of the expres -sion of adhesion molecules, such as ICAM-1 and E-selectin on endothelial cells and theinduction of IL-6, IL-1, and TNF-, and ofthe chemokines IL-8 and MCP-1. Otherproperties of CRP that may not be of obviousimportance in periodontal disease but maysignificantly affect other systemic inflammatorydiseases (e.g., atherosclerotic lesions),include thrombosis due to the procoagulantactivity and reduction offibrinolysis by inducing an increase in theexpression of PAI-1, the main inhibitor offibrinolysis. 25 Finally, CRP mediates proliferationand activation of smooth muscle cells(SMCs) and decreases the expression of endothelialnitric oxide synthase (eNOS). CRPmay also have anti-inflammatory propertiesand hence its primary role is likely to be theregulation of acute inflammation.SAASAA proteins are a family of apolipo -proteins associated with high-densitylipoprotein in plasma. They have several proinflammatoryfunctions, such as the recruitmentof immune cells to inflammatory sitesand the induction of enzymes that degradeextracellular matrix. Also, SAA proteinstransport cholesterol to the liver for secretioninto the bile.FibrinogenFibrinogen is a soluble plasma glycoprotein.Processes in the coagulation cascadeactivate prothrombin to thrombin, which isresponsible for converting fibrinogen into fibrin.Fibrin is then cross-linked by factor XIIIto form a clot. Thus, fibrinogen is involved inblood coagulation and platelet activation.PAI-1PAI-1 is produced by the liver and endothelialcells. It inhibits the serine proteasestPA and uPA/urokinase, and therefore is aninhibitor of fibrinolysis, the physiologicalprocess that degrades blood clots.Complement ProteinsThese proteins take part in a triggeredenzymecascade that activates the complementsystem. There are three ways by whichcomplement is involved in inflammatoryprocesses. First, activated complement proteinsmay bind covalently to pathogens asopsonins for engulfment by phagocytes bearingreceptors for complement. Second, thesmall fragments of some complement proteinsact as chemo-attractants to recruit moreleukocytes to the site of complement activation.Third, terminal complement componentsdamage certain bacteria by creatingpores in the bacterial membrane. 26LBP and Soluble CD14These proteins play an important role intransferring LPS and PGN to the Toll-like receptors.Hence, their presence is critical forinitiating and organizing an inflammatoryimmune response after bacterial challenge.Systemic Cellular and MolecularMarkers of InflammationPeriodontal infection may induce an inflammatoryresponse that is not limited to thetissues surrounding the teeth, but is also extendedsystemically. The main cellular andmolecular markers of systemic inflammationinduced by periodontal disease includethe increased number of peripheral leukocytes,the higher concentrations of serumanti bodies against periodontopathogens,and the elevated levels of circulating proinflammatorycytokines and acute-phase proteins.With the exception of serum antibodiesagainst periodontopathogens, these markersare not specific for periodontal disease, but

32 Periodontal Disease and Overall Health: A Clinician's Guidecould be shared with distant inflammatoryprocesses that have systemic effects. As such,these markers can be affected by other inflammatorydiseases that could occur concomitantly.The following systemic markershave been associated with the presence of periodontal disease and are usually affected bythe severity of inflammation in the gingiva.Peripheral Blood LeukocytesIn periodontitis patients, leukocytecounts have been shown to be slightly elevatedcompared to healthy subjects, althoughnot always significantly. 27 The elevated levelof circulating leukocytes depends largely onthe extent and severity of periodontal disease.Periodontal therapy may lead to a reductionin the number of peripheral leukocytes.28 PMNs are the main leukocytes thatare increased, and it is possible that these cellsare recruited at higher levels during episodesof bacteremia and leakage of bacterial virulencefactors during periodontal disease.Serum Antibodies AgainstPeriodontopathogensIn chronic periodontal disease, in whichthe adaptive immune response has been activated,local and systemic exposure to periodontopathogensleads to an increase in thelevels of circulating antibodies against thepathogenic antigens. Treatment of disease isfollowed by a reduction in antibody levels.Serum Pro-Inflammatory CytokinesIn healthy subjects, the levels of circulatingpro-inflammatory cytokines are verylow or nondetectable. However, in perio -dontitis patients, several pro-inflammatorycytokines may “spill” into the bloodstreamand increase the concentration in the plasma.Of the pro-inflammatory mediators studied,only the levels of IL-6 have been consistentlyshown to be elevated in the serum. Thisincrease is related to the extent and severityof inflammation in periodontal tissues. 29However, controversial reports have beenpublished on the impact of periodontal therapyon IL-6 levels suggesting the need forfurther research on the topic. Finally, most ofthe studies looking at the levels of serumIL-1 and TNF-α among healthy and perio -dontitis patients failed to report any differences,and in most cases cytokine levels werenot measurable. 30Acute-Phase ProteinsThe levels of several acute-phase reactants,such as CRP, fibrinogen, LBP and solubleCD14 have been studied and have beenshown to be elevated in patients with perio -dontal disease. However, the acute-phaseproteins that have received most attentionand are consistent markers of systemic inflammationin periodontal disease are CRPand fibrinogen. A large number of studies,both in animal models and humans, have revealeda positive association between periodontaldisease and circulating CRP levels,while a recent meta-analysis limited to humanstudies has confirmed that plasma CRPis elevated in patients with periodontitis comparedto healthy individuals. 31 Moreover, thisincrease was proportional to the extent andseverity of the disease. Several studies reporta decrease of plasma CRP after periodontalintervention, but there is modest evidencethat periodontal therapy lowers the levels ofthis protein. Finally, in several studies, thelevels of fibrinogen have also been found tobe elevated in periodontitis patients comparedto healthy individuals. 32 However, todate there is no available evidence to supportthat periodontal therapy actually reduces theamount of circulating fibrinogen.Possible Role of Systemic Inflammationin Various DisordersDuring the late nineteenth and earlytwentieth centuries, the “focal infection” theorydominated the medical world. 33 This theoryheld that foci of sepsis were responsible

CHAPTER 3 Infection and Inflammation 33for the initiation and progression of a varietyof inflammatory diseases, including arthritis,peptic ulcers, and appendicitis. As a result,therapeutic full-mouth extractions became acommon dental practice. However, many teethwere extracted without evidence of infection.When it was finally realized that there wasno therapeutic benefit, the theory was finallydiscredited and the practice abandoned. Duringthe final two decades of the twentiethcentury—as our knowledge concerning theinflammatory component of systemic diseaseswas enriched and our understanding ofthe relationship of periodontal disease tosystemic inflammation increased—the ideathat periodontal infection may affect theprogression of systemic disorders such ascardiovascular disease, adverse pregnancycomplications, diabetes mellitus, and otherdiseases re-emerged.In this possible association, systemicinflammation seems to play a key role.Specifically, on one hand, periodontal diseasemay induce systemic inflammation andon the other, there is increasing evidencesuggesting that elevated levels of the markersof systemic inflammation are associatedwith an increased risk for systemic diseases.Cardiovascular Disease (CVD)There is now abundant clinical evidencedemonstrating that many biomarkers of inflammationare elevated years in advance offirst-ever myocardial infarction (MI) orthrombotic stroke, and that these same biomarkersare highly predictive of recurrentMI, recurrent stroke, and death due to CVD. 2Moreover, studies demonstrate that serumIL-6 levels were significantly elevated insubjects who subsequently experienced anMI compared to age-matched controls. 34Similarly, plasma levels of soluble P-selectin,soluble CD40L, and macrophage-inhibitorycytokine-1 were all significantly increased inhealthy subjects who subsequently developedCVD events compared to matched controls. 35Elevated plasma concentrations of TNF-αhave also been associated with CVD, andspecifically with recurrent nonfatal MI orother CVD events. Moreover, TNF-α levelswere persistently higher among post-MIpatients at increased risk for recurrent coronaryevents.Besides these pro-inflammatory cyto -kines, several acute-phase reactants have alsobeen associated with CVD. One of the factorswith the strongest evidence as a biomarkerfor predicting CVD events is CRP(specifically, high sensitivity CRP, hsCRP).When measured in the blood, hsCRP provedto be a strong, independent predictor of futureMI and stroke among apparently healthyasymptomatic men. Also, the relative riskfor first MI and ischemic stroke increasedsignificantly with each increasing quartileof baseline concentrations of CRP. 36 As describedalready, CRP may contribute to theinitiation and development of atherothromboticlesions not only by up-regulating theexpression of pro-inflammatory cytokines,but also by mediating proliferation and activationof SMCs and by activating the procoagulantsystem. This last property may befurther enhanced by another acute-phase protein,fibrinogen, which is often found to beelevated in CVD patients.Adverse Pregnancy OutcomesSystemic inflammation has also beenimplicated in adverse pregnancy outcomes,since elevated concentrations of CRP in earlypregnancy are associated with an increasedrisk of preterm birth and very-preterm birth.Diabetes MellitusFinally, systemic inflammation hasbeen associated with both Type 1 and Type2 diabetes mellitus. Recent studies suggestthat in Type 1 diabetes, the levels of systemicmarkers of inflammation, such as CRP,do not differ between healthy individualsand subjects for which Type 1 diabetes has

34 Periodontal Disease and Overall Health: A Clinician's Guidebeen just diagnosed. However, the levels ofcirculating CRP are significantly higher inindividuals with long-term diabetes. 37 It isalso believed that inflammatory processesmay have a more pronounced effect on thedevelopment of complications of Type 1 diabetes.Thus, elevated levels of plasma CRPand of the pro-inflammatory soluble adhesionmolecule, vascular cell adhesion molecule-1(VCAM-1), have been found in patientswith microvascular disease comparedto those without.In Type 2 diabetes, inflammatoryprocesses are more strongly associated withthe development of the disease. Systemicmarkers of inflammation are found to be increasedin healthy individuals who developType 2 diabetes later in their lives. AmongPima Indians, a population with a high prevalenceof Type 2 diabetes, subjects with whiteblood cell counts within the highest tertilewere more likely to develop Type 2 diabetesover a period of 20 years compared to those inthe lowest tertile. Moreover, in two other studies,healthy individuals demonstrating serumlevels of CRP and IL-6 within the highestquartiles were more likely to develop Type 2diabetes in the next four to seven years comparedto subjects in the lowest quartile. 4 Similarresults were found with increased levelsof another acute-phase protein, PAI-1.Insulin resistance, which is associatedwith Type 2 diabetes and usually procedesthe development of frank diabetes, may alsobe affected by pre-existing systemic inflammationsince several pro-inflammatory andacute-phase proteins, such as TNF-, IL-6,MCP-1, PAI-1, and SAA are associated withthe induction of insulin resistance. 38Summary of Part IIBased on available evidence, it is possiblethat systemic inflammation may actuallybe the link that associates periodontaldisease with other systemic diseases. Detailsof the plausible biological mechanisms thatmay associate periodontal disease with varioussystemic diseases are further analyzed inother chapters of this book.PART III: RESOLUTION OFINFLAMMATION IN PERIODONTITISAND OTHER SYSTEMIC DISEASESInflammation is thought to play a centralrole in the progression of periodontaland a number of systemic diseases. Experimentsin animal models and in man havedemonstrated that periodontal destruction ismediated primarily by the inflammatory response,although periodontal pathogens area necessary etiologic factor. 20,39,40 Geneticpolymorphisms and other factors may alsobe responsible for a “hyperinflammatoryphenotype” that may further affect the susceptibilityof the host to periodontal diseaseand tissue destruction. Currently, it is believedthat in chronic periodontal disease, destructiondoes not follow a linear pattern withtime, but occurs in “random bursts” with periodsof remission and exacerbation. However,the reasons behind this random progressionare not fully understood. Diseaseprogression becomes even more enigmaticconsidering that it is not always clear why achronic inflammation of the gingiva may remainas gingivitis in some patients andprogress to periodontitis in others. Irrespectiveof the nature of periodontal disease progression,the perpetuation of the inflammatoryprocess in the gingiva may lead to achronic low-grade systemic inflammatory response,which in turn potentially contributesto the progression of systemic diseases.The Process of Inflammatory ResolutionThe landmark events during inflammationinclude the accumulation of leukocytesin the infected area and phagocytosis of thebacteria and/or their virulence factors. Aspart of the inflammatory process, activationof neutrophil lysosomal phospholipase releasesfree arachidonic acid from membrane

CHAPTER 3 Infection and Inflammation 35phospholipids. Once free arachidonic acidis available, two different pathways can beinitiated: (a) the cyclo-oxygenase (COX)pathway that leads to the production ofprostaglandins (e.g., PGE 2), and (b) the lipoxygenase(LO) pathways that lead to the productionof a series of hydroxyl acids characterizedby the 5-LO products, the leukotrienes(e.g., LTB 4). There are three cell type-specificLOs; the 5-LO from myeloid cells, the 12-LOfrom platelets, and the 15-LO of epithelial andendothelial cells. PGE 2is a potent activator ofosteoclast-mediated bone resorption, and withother eicosanoids mediates inflammation andperiodontal tissue destruction. LTB 4attractsneutrophils, stimulates the release of granuleassociatedenzymes from neutro phils, and contributesto pro-inflammatory processes and tofurther tissue damage.Returning to HomeostasisOnce the bacteria have been removedby phagocytosis, resolution of inflammationoccurs with the reduction or removal ofleukocytes and debris from inflamed siteswith a return to homeostasis. 5 Until recently,resolution of inflammation was considered tobe a passive process in which the lack ofbacterial stimuli decreased the production ofinflammatory mediators, which in turn reducedthe inflammatory response, therebyreturning to normal function. New data suggestthat resolution of inflammation is an activebiochemical and metabolic process thatis initiated by a newly identified class of receptoragonists that emerge temporally asthe inflammatory lesion matures. 5 Althoughprostaglandins and leukotrienes secreted byneutrophils have pro-inflammatory properties,as inflammation proceeds the sameprostaglandins (PGE 2and PGD 2) may promoteexpression of the 15-LO gene, leadingto a switch in the expression of biosyntheticenzymes by infiltrating neutrophils (Figure2). Binding of lipoxin A4 to neutrophils leadsto a phenotypic change, stopping all proinflammatoryactivity of neutrophils andleading to apoptosis. As a result, they stopsecreting the chemo-attractant LTB 4andseveral cellular pathways are activated, producing,at a local level, other dual-actinganti- inflammatory and proresolution lipidmediators, including resolvins and protectins.Mechanisms of Inflammation ResolutionResolvins and protectins provide potentsignals that orchestrate and accelerate mechanismsthat promote resolution of inflammationand homeostasis. Specifically, as depictedin Figure 3, pro-resolution mediatorsstop neutrophil infiltration and drive neutrophilsto apoptosis, while at the same timeattracting monocytes to the lesion. 41 Lipoxinstimulatedmonocytes/macrophages obtaina nonphlogistic phenotype, which resultsin phagocytosis of apoptotic neutrophilsand enhanced mucosal clearance of bacteriawithout concomitant secretion of pro- inflam -matory mediators that could contribute totissue damage. 42 Moreover, pro-resolutionlipid molecules increase the exit of phagocytesfrom the inflamed site through the lymphatics.Finally, some of these moleculesmay also stimulate the uptake and clearanceof local cytokines by apoptotic neutrophils.After neutrophils and debris are removed,homeostasis returns and repair mechanismsare initiated; lipoxins are antifibrotic andallow for complete tissue healing withoutscarring.Hence, it can be argued that the persistenceof an inflammatory disease, such asperiodontal disease, may be caused by toomuch pro-inflammatory signal or not enoughproresolution signal. In other words, a “hyperinflammatoryphenotype” due to a particulargenetic background of the host mayresult in oversecretion of inflammatory mediatorsin response to bacterial stimuli, whichin turn contributes to periodontal disease susceptibility,or a failure of resolution pathways.As high levels of inflammatory cyto kines are

36 Periodontal Disease and Overall Health: A Clinician's GuideFigure 2. Progression and Biosynthesis of Lipid Mediators During Inflammation ResolutionChemical mediators involved in the initiation of acute inflammation, such as prostaglandins (PGs) and leukotrienes(LTs), induce “class switching” toward pro-resolving lipid mediators. The pro-resolving mediators include -6PUFAs, AA- derived LXs, ATLs, -3 PUFA EPA-derived RvEs, docosahexanoic acid (DHA)-derived RvDs, andprotectins (PDs) (or neuroprotectins in neural tissues).Reprinted by permission from Wiley-Blackwell: Br J Pharmacol 2008;153(Suppl)S200–S215.Figure 3. Dual Anti-Inflammatory and Pro-Resolution Actions of Specific Lipoxins,Figure 3. Resolvins and ProtectinsReprinted by permission from Macmillan Publishers Ltd: Nat Rev Immunol 2008;8:349-361. 5

CHAPTER 3 Infection and Inflammation 37maintained, tissue destruction continues andinflammation persists. If pro-resolution signalsare weak, neutrophils are not removedand monocytes/macrophages maintain aphlogistic phenotype. This results in furtherproduction of inflammatory cytokines andperpetuation of the inflamed state.New Treatment ParadigmsIt is reasonable to suggest that the understandingand ability to manipulate resolutionof inflammation may provide a newtreatment paradigm for inflammatory diseases,local and systemic. Although humandata are not yet available, there is a growingand promising literature from in vitro workand animal models that supports the bene -ficial actions of resolution agonists both onperio dontal and other systemic diseases. 5The Role of Pro-Resolution MediatorsExamples of the actions of therapeuticpro-resolution mediators in periodontal diseaseinclude over-expression of lipoxin A 4intransgenic rabbits protecting against perio -dontitis and atherosclerosis. 43 In anotherstudy, topical treatment with resolvins (-3fatty acid derived resolution agonists, videinfra) prevented more than 95% of alveolarbone destruction in rabbits. Moreover, histologicalanalysis revealed few, if any, neutrophils in the tissue and little tissue damage.At the same time, the numbers of osteoclastswere also found to be reduced. In addition,treatment of periodontitis with resolvins systemicallyreversed the observed increase inCRP and IL-1 levels. Finally, in establishedperiodontal disease, resolvins prevented furthertissue destruction, and both gingival andosseous tissues that were lost during diseasewere regenerated. 44Resolvins, lipoxins, and protectins havealso been shown in animal models to havebeneficial impact on a variety of other inflammatorydiseases. For example, lipoxinsstopped neutrophil recruitment and promotedlymphatic removal of phagocytes in perio -tonitis. 42 Moreover, in cystic fibrosis, lipoxinsdecreased neutrophil inflammation, pulmo -nary bacterial burden, and disease severity. 45Resolvins in a colitis model in mice decreasedneutrophil recruitment and pro-inflammatorygene expression, improved survival, andreduced weight loss. 46 In addition, resolvinsprotected against neovascularization inretinopathy. 47 Finally, in an asthma model,protectins protected against lung damage,airway inflammation, and airway hyperresponsiveness.48 Table 2 lists the impact oflipoxins, resolvins, and protectins on variousinflammatory disease models.It is conceivable that the use of proresolutionmediators in managing periodontaland other inflammatory diseases mayprove to be beneficial in humans as well.Mechanical debridement, which aims at thereduction of the bacterial load in the gingivalpocket, may help the host/patient to clearthe infection. In addition, it is possible thatthe use of locally applied pro-resolution mediatorscould prevent further tissue damage,enhance the resolution of inflammation(which would lead to healthy gingiva), andideally result in periodontal tissue regenerationrather than scarring and repair. Moreover,resolution of inflammation at the gingi -val level may minimize systemic inflammationinduced by periodontal disease, therebyattenuating the possible negative effects ofperio dontal disease on systemic diseases.Origins of Pro-Resolution MediatorsIn order to manipulate resolution ofinflammation more effectively, it is imperativeto understand the biological origin of the proresolutionmediators. Lipoxins (e.g., lipoxinA 4) derive from arachidonic acid after acti -vation of the 12-/5-LO or the 15-/5-LO pathways.Resolvins and protectins are bio synthesizedfrom omega-3 essential poly -unsaturatedfatty acids (-3 PUFAs), such as eicosapentanoicacid (EPA) and docosahexanoic acid

38 Periodontal Disease and Overall Health: A Clinician's GuideTable 2. Impact of Lipoxins, Resolvins, and Protectins on Various Inflammatory Disease ModelsDisease Model Species Action(s)Lipoxin A4/ATLPeriodontitis Rabbit –Reduces neutrophil infiltration–Prevents connective tissue and bone lossPeritonitis Mouse Stops neutrophil recruitment and lymphatic removal of phagocytesDorsal air pouch Mouse Stops neutrophil recruitmentDermal inflammation Mouse Stops neutrophil recruitment and vascular leakageColitis Mouse –Attenuates pro-inflammatory gene expression–Reduces severity of colitis–Inhibits weight loss, inflammation, pulmonary dysfunctionAsthma Mouse Inhibits airway hyper-responsiveness and pulmonary inflammationCystic fibrosis Mouse Decreases neutrophilic inflammation, pulmonary bacterial burden, and disease severityIschemia-reperfusion injury Mouse –Attenuates hind-limb ischemia-reperfusion lung injury–Causes detachment of adherent leukocytes in mesenteric ischemia-reperfusion injuryCorneal disorders Mouse –Accelerates cornea re-epithilialization–Limits sequelae of thermal injury (such as neovascularization and opacity)–Promotes host defenseAngiogenesis Mouse Reduces angiogenic phenotype: endothelial-cell proliferation and migrationBone-marrow transplant Mouse Protects against bone-marrow-transplant-induced graft-versus-host diseasesGlomerulonephritis Mouse –Reduces leukocyte rolling and adherence–Decreases neutrophil recruitmentHyperalgesia Rat –Prolongs paw withdraw latency and reduces hyperalgesic index–Reduces paw oedemaPleuritis Rat Shortens the duration of pleural exudationResolvin E1Periodontitis Rabbit –Reduces neutrophil infiltration–Prevents connective tissue and bone loss–Promotes healing of diseased tissues–Regenerates lost soft tissue and bonePeritonitis Mouse –Stops neutrophil recruitment–Regulates chemokine and/or cytokine production–Promotes lymphatic removal of phagocytesDorsal air pouch Mouse Stops neutrophil recruitmentRetinopathy Mouse Protects against neovascularizationColitis Mouse –Decreases neutrophil recruitment and pro-inflammatory gene expression–Improves survival–Reduces weight lossResolvin D1Peritonitis Mouse Stops neutrophil recruitmentDorsal skin air pouch Mouse Stops neutrophil recruitmentKidney ischemia- Mouse –Protects from ischemia-reperfusion kidney damage and loss of functionreperfusion injury Mouse Regulates macrophageRetinopathy Mouse Protects against neovascularizationProtectin D1Peritonitis Mouse –Inhibits neutrophil recruitment–Regulates chemokine and/or cytokine production–Promotes lymphatic removal of phagocytes–Regulates T-cell migrationAsthma Mouse Protects from lung damage, airway inflammation, and airway hyper-responsivenessAsthma Human Protectin D1 is generated in humans and appears to be diminished in asthmaticsKidney ischemia- Mouse Protects from ischemia-reperfusion kidney damage and loss of functionreperfusion injuryRegulates macrophages functionRetinopathy Mouse Protects against neovascularizationIschemic stroke Rat –Stops leukocyte infiltration–Inhibits nuclear factor-kB and cyclo-oxygenase-2 inductionAlzheimer’s disease Human Diminishes protecting D1 production in human Alzheimer’s disease

CHAPTER 3 Infection and Inflammation 39Figure 4. Schematic Illustration of Lipid-Mediated Pro-Inflammatory andFigure 4. Pro-Resolution Pathways(DHA). EPA and DHA can be metabolizedby aspirin-modified COX-2 pathways toform resolvins, while DHA can be convertedto protectins via an LO-mediated pathway(Figure 4).Another aspect of current anti-inflammatorystrategies was the discovery that disruptionof biosynthesis of these pro-resolutionmediators by either COX-2 or LOinhibitors may lead to a “resolution deficit”phenotype, which is characterized by impairedphagocyte removal, delayed resolution,and prolonged inflammation. This mayexplain why several anti-inflammatory agents,such as selective COX-2 inhibitors and certainLO inhibitors, have been shown to impairresolution of inflammation and lead to systemicinflammatory complications.Summary of Part IIITheoretically, combining proresolutionmediators and anti-inflammatory agents suchas aspirin and statins—agents that decreasethe extent of inflammation without inter -fering with the endogenous pro- resolu tionprocesses—may be a useful strategy to controlexcessive inflammation and restore homeo -stasis. More research is necessary to obtainsolid information on the efficacy and safetyof these interventions in humans. However,it is possible that in the future we can expectthat new treatment strategies will be availablefor the treatment of periodontal diseaseand its systemic complications.Supplemental ReadingsSerhan CN, Chiang N, Van Dyke TE. Resolving inflammation:dual anti-inflammatory and pro-resolutionlipid mediators. Nat Rev Immunol 2008;8(5):349–61.Madianos PN, Bobetsis YA, Kinane DF. Generation ofinflammatory stimuli: how bacteria set up inflammatoryresponses in the gingiva. J Clin Periodontol 2005;32(Suppl 6):57–71.Loos BG. Systemic markers of inflammation in perio -dontitis. J Periodontol 2005;76(Suppl 11):2106–2115.Ridker PM, Silvertown JD. Inflammation, C-reactiveprotein, and atherothrombosis. J Periodontol 2008;79(Suppl 8):1544–1551.REFERENCES1. Löe H, Theilade E, Jensen SB. Experimental gingivitisin man. J Periodontol 1965;36:177–187.

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CHAPTER 3 Infection and Inflammation 41disease. 5th Edition. Garland Publishing, NewYork; 2001:44.27. Loos BG. Systemic markers of inflammation inperiodontitis. J Periodontol 2005;76:2106–2115.28. Christan C, Dietrich T, Hägewald S, Kage A, BernimoulinJP. White blood cell count in generalizedaggressive periodontitis after non-surgical therapy.J Clin Periodontol 2002;29:201–206.29. Mengel R, Bacher M, Flores-De-Jacoby L. Interactionsbetween stress, interleukin-1beta, interleukin-6and cortisol in periodontally diseasedpatients. J Clin Periodontol 2002;29:1012–1022.30. Meyle J. Neutrophil chemotaxis and serum concentrationof tumor-necrosis-factor-alpha (TNF-).J Periodontal Res 1993;28(Pt 2):491–493.31. Paraskevas S, Huizinga JD, Loos BG. A systematicreview and meta-analyses on C-reactive protein inrelation to periodontitis. J Clin Periodontol 2008;35:277–290.32. Kweider M, Lowe GD, Murray GD, Kinane DF,McGowan DA. Dental disease, fibrinogen andwhite cell count; links with myocardial infarction?Scott Med J 1993;38:73–74.33. Scannapieco FA. Position paper of The AmericanAcademy of Periodontology: periodontal disease asa potential risk factor for systemic diseases. J Periodontol 1998;69:841–850.34. Ridker PM, Rifai N, Pfeffer M, Sacks F, Lepage S,Braunwald E. Elevation of tumor necrosis factoralphaand increased risk of recurrent coronaryevents after myocardial infarction. Circulation2000;101:2149–2153.35. Ridker PM, Buring JE, Rifai N. Soluble P-selectinand the risk of future cardiovascular events. Circulation 2001;103:491–495.36. Ridker PM, Cushman M, Stampfer MJ, Tracy RP,Hennekens CH. Inflammation, aspirin, and the riskof cardiovascular disease in apparently healthymen. N Engl J Med 1997;336:973–979.37. Treszl A, Szereday L, Doria A, King GL, Orban T.Elevated C-reactive protein levels do not correspondto autoimmunity in type 1 diabetes. DiabetesCare 2004;27:2769–2770.38. Shoelson SE, Lee J, Goldfine AB. Inflammationand insulin resistance. J Clin Invest 2006;116:1793–1801.39. Serhan CN, Jain A, Marleau S, Clish C, Kantarci A,Behbehani B, Colgan SP, Stahl GL, Merched A,Petasis NA, Chan L, Van Dyke TE. Reduced inflammationand tissue damage in transgenic rabbitsoverexpressing 15-lipoxygenase and endogenousanti-inflammatory lipid mediators. J Immunol2003;171:6856–6865.40. Williams RC, Jeffcoat MK, Howell TH, Reddy MS,Johnson HG, Hall CM, Goldhaber P. Topical flurbiprofentreatment of periodontitis in beagles. JPeriodontal Res 1988;23:166-169.41. Ariel A, Fredman G, Sun YP, Kantarci A, Van DykeTE, Luster AD, Serhan CN. Apoptotic neutrophilsand T cells sequester chemokines during immuneresponse resolution through modulation of CCR5expression. Nat Immunol 2006;7:1209–1216.42. Schwab JM, Chiang N, Arita M, Serhan CN. ResolvinE1 and protectin D1 activate inflammationresolutionprogrammes. Nature 2007;447:869–874.43. Shen J, Herderick E, Cornhill JF, Zsigmond E, KimHS, Kühn H, Guevara NV, Chan L. Macrophagemediated15-lipoxygenase expression protectsagainst atherosclerosis development. J Clin Invest1996;98:2201–2208.44. Hasturk H, Kantarci A, Ohira T, Arita M, EbrahimiN, Chiang N, Petasis NA, Levy BD, Serhan CN,Van Dyke TE. RvE1 protects from local inflammationand osteoclast-mediated bone destruction inperiodontitis. FASEB J 2006;20:401–403.45. Karp CL, Flick LM, Park KW, Softic S, Greer TM,Keledjian R, Yang R, Uddin J, Guggino WB, AtabaniSF, Belkaid Y, Xu Y, Whitsett JA, Accurso FJ,Wills-Karp M, Petasis NA. Defective lipoxinmediatedanti-inflammatory activity in the cysticfibrosis airway. Nat Immunol 2004;5:388–392.46. Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S,Dignass A, Serhan CN, Kang JX. Transgenic micerich in endogenous omega-3 fatty acids are protectedfrom colitis. Proc Natl Acad Sci USA 2006;103:11276–11281.47. Connor KM, SanGiovanni JP, Lofqvist C, AdermanCM, Chen J, Higuchi A, Hong S, Pravda EA,Majchrzak S, Carper D, Hellstrom A, KangJX, Chew EY, Salem N Jr, Serhan CN, SmithLE. Increased dietary intake of omega-3-poly -un saturated fatty acids reduces pathological retinalangiogenesis. Nat Med 2007;13:868–873.48. Levy BD, Bonnans C, Silverman ES, Palmer LJ,Marigowda G, Israel E. Severe Asthma ResearchProgram, National Heart, Lung, and Blood Institute.Diminished lipoxin biosynthesis in severe asthma.Am J Respir Crit Care Med 2005;172:824–830.

CHAPTER 4History of theOral-Systemic RelationshipNoel M. Claffey, Ioannis N. Polyzois, Ray C. WilliamsINTRODUCTIONIn the last decade, the possible associationbetween oral and systemic health has beenhighlighted in numerous reports. The focus ofattention is mainly periodontitis and its impacton certain conditions. Periodontitis is an infec -tious disease associated with a number of pre -dominantly gram-negative bacteria, and it is nowrecognized that for the initiation and progressionof this disease, a susceptible host is also required.It is also well documented that certain systemicconditions can modify the host’s susceptibility toperiodontitis, but it is only recently that evidencesurfaced about the possi bility of a two-way rela -tionship. Speci fically, perio dontitis has been impli -cated as a potential risk factor for cardio vas culardiseases, respiratory diseases, diabetes mellitus,preterm labor, low birth weight, and renal disease.Interest in the relationship of oral health/periodontal disease to general health is not new,but more of a resurgence in the old and dis creditedcon cept of focal infection. Focal infec tion theorybe came popular in the begin ning of the twentiethcentury because it explained a number of con -ditions for which there was no sci entific explana -tion at the time. It eventually fell in to disreputebecause of a lack of scientific evidence.This chapter examines the history of thehypothesis that micro-organisms would localizefrom the source focus to the distant, systemicfocus and follows, step by step, concepts of theoral-systemic relationship that have evolvedover the years.ANCIENT CIVILIZATIONSAND THE MIDDLE AGESThroughout recorded history, manytheories have been put forward to explainhuman illness. One area of the body that hasbeen repeatedly implicated in the origin ofhuman diseases is the oral cavity. Writings asfar back as from the ancient Egyptians (2100BC) mention tooth pain associated withwomen’s reproductive system diseases. 1 InAssyria, the physician of King Ashurbanipal(669–626 BC) wrote about the troubles ofhis king: “The pains in his head, arms, andfeet are caused by his teeth and must beremoved.” 2 In ancient Greece, Hippocrates(400 BC) recorded two cases in which eradicationof the infections of the mouth appearedto relieve patients of rheumatic-liketroubles of the joints. 3 Aristotle, perhaps thefirst dental anatomist—especially from thestandpoint of comparative anatomy—statedthat “those persons who have the most teethare the longest lived.” 4 In his book, On Hygiene,the Roman physician Galen (166–201AD) emphasized the inter-relationship betweenthe oral cavity and other illnesses. 5From the end of the Roman Empireuntil the middle ages, all sciences fell intoabeyance, and had it not been for the Arabs(who had access to the learning and sciencecontained in Greek manuscripts brought totheir country by Nestorian exiles from By -zantium and Greeks who settled in southernItaly), the bulk of science and knowledgeaccumulated to that date might have beenlost. 4 The next notable advance in dentistryprobably occurred in Italy in the 1400s whena physician named Giovanni d’Arcoli beganfilling decayed teeth with gold leaf; anadmirably progressive step for that time. Heis further credited with stating that for casesof severe dental pain, early intervention was

CHAPTER 4 History of the Oral-Systemic Relationship 43advisable because “such violent pains arefollowed by syncope or epilepsy, throughinjury communicated to the heart or brain.” 6In 1548, Ryff wrote a monograph thatdealt exclusively with dental afflictions. Inhis pamphlet titled Useful Instructions onthe Way to Keep Healthy, to Strengthen andRe-invigorate the Eyes and the Sight. WithFurther Instructions of the Way of Keepingthe Mouth Fresh, the Teeth Clean and theGums Firm he wrote, “The eyes and teethhave an extraordinary affinity or reciprocalrelation to one another, by which they easilycommunicate to each other their defects anddiseases, so that one cannot be perfectlyhealthy without the other being so too.” 5In 1768, Berdmore in A Treatise on theDisorders and Deformities of the Teeth andGums described the relationship betweenthe teeth and the entire body as one leading tothe most “excruciating pains and dangerousinflammations and sometimes deep seatedabscesses which destroy neighbouring partsand affect the whole system by sympathy, orby infecting the blood with corrupted matter.” 7In 1818, one of the most famous physicians inAmerica, Benjamin Rush, reported the courseof a disease in which a woman who wassuffering from rheumatism of long standinghad an aching tooth extracted and “she re -covered in just a few days.” 7All of these statements over the courseof history were made without sufficient supportingevidence, yet they were current beliefsat the time. These conclusions wereusually drawn by repeated observation of anumber of patients with similar symptomsand outcomes. Today these ancient theories—especially those related to oral systemicconditions—cannot be considered to be anythingmore than guess work based on simpleobservation. However, it is of great interestto see that historically there existed a sus -picion or hunch that an inter-relationshipexisted between oral disease and systemicconditions.ORAL SEPSIS AS ACAUSE FOR DISEASEThe importance of oral hygiene in relationto bacteriology was first detailed byDutch scientist Antonie von Leeuwenhoek in1683. However, it was with the discoveriesof the late 1800s that the centuries-old debateabout the influence of the mouth on the restof the body began. One of the main reasonsfor interest in the area was due to stridesmade in the study of microbiology. Majorcontributors to advances in microbiology includedPasteur, Lister, and Koch. Koch wasa physician working as a District MedicalOfficer in Wöllstein, a small city in what isnow Germany. During the Franco-Prussianwar, he began to study the disease anthrax,which was prevalent among farm animalsin the community. Earlier, the anthrax bacillushad been discovered by Pollande, Royer,and Davine. Through a series of experiments,Koch demonstrated that pure culturesof the anthrax bacillus could cause theanthrax disease. His work was publishedin 1876 and the “germ theory of diseasecausation” was introduced to the world.Soon, scientists around the globe became interestedin bacteria and their role in diseaseetiology.An American dentist working at Koch’sInstitute for Infectious Diseases, Miller wasconvinced that the bacteria residing in themouth could explain most illnesses. In 1880,to support his theory, Miller published abook with the title The Microorganisms ofthe Human Mouth: The Local and GeneralDiseases Which are Caused by Them. In1891, Miller published a classic article inthe Dental Cosmos journal. 8 The title of thearticle was “The Human Mouth as a Focus ofInfection.” This article aimed to “call attentionto the various local and general diseaseswhich have been found to result from theaction of microorganisms which have collectedin the mouth and to various channelsthrough which these microorganisms or their

44 Periodontal Disease and Overall Health: A Clinician's Guidewaste products may obtain entrance to partsof the body adjacent to or remote from themouth.” It also aimed to “establish the greatimportance of thorough understanding onthe part of the physician, no less than of thedentist, of mouth germs as a factor in theproduction of disease.” The article was presentedunder three headings/sections:• Diseases of the human body which havebeen traced to the action of mouthbacteria• The pathogenic mouth bacteria• Prophylactic measuresThe diseases he felt could be traced tobacteria colonizing the mouth included ostitis,osteomyelitis, septicemia, pyemia meningitis,disturbance of alimentary tract, pneumonia,gangrene of the lungs, Ludwig’sangina, diseases of the maxillary sinus, actinomycosis,noma, diphtheria, tuberculosis,syphilis, and thrush. He described 149 cases,many of which he ascribed to a dental origin,such as fistulae that opened on the neck,shoulder, arm, or breast. Thus was developedthe concept of focus of infection, withorganisms in the oral cavity being implicatedin diseases of the body remote from themouth. Although he did not mandate removalof teeth as a method of eradication offoci of infection, he sometimes suggestedthat the “treatment and filling of root canals”could serve this purpose. In Miller’s opinion,local collection of disease-producing organismscould produce “a metastic abscesswherever a point of diminished resistanceexisted.” Moreover, he postulated that teethwere not the only source of aggregation ofsuch bacteria but that foci in other organs, suchas the tonsils and uterus, could be implicated. 5,8The next important figure in the historyof oral sepsis as a cause of disease wasthe English physician, Hunter. At the time ofMiller’s paper presentation, which Hunterattended, he was the senior assistant physicianat the London Fever Hospital and his attentionwas already drawn to the mouth as apossible source of infection. In 1900, hewrote an article titled “Oral Sepsis as aCause of Disease,” which was published inthe British Medical Journal. 9 Hunter implicatedpoor oral hygiene, together with iatrogenicconservative dentistry, as causes ofthe multitude of diseases attributed to focalinfection. He advocated oral antisepsis measuresto diseased teeth or inflamed gums, theremoval of “tooth stumps,” the boiling ofevery “tooth plate” worn, and the avoidanceof restorations such as bridges, which can’tbe cleanly maintained. 5,9In 1900, Godlee described how thesigns and symptoms of other conditions,such as pleurisy, could be attributed topyorrhea alveolaris, and how all the signsand symptoms disappeared after careful removalof all calculus and regular syringingof the pockets with a hydrogen peroxide solution.5,10 In 1902, Colyer described the resolutionof irregular heart beat, gastric effectsand “general debility” after the treatment ofany oral sepsis present. He also suggested agood maxim with which a dentist should workwas “better no teeth than septic ones.” 5,11In an article published by Wilcox in1903, antral disease was put forward as animportant sequelae of oral sepsis. 12 It wasbelieved that prolonged antral suppurationcould lead to extreme mental depression, oftenending in suicidal tendency. 5,12 Other relationshipsthat were put forward were thosebetween oral sepsis and migraine headaches,laryngeal pain and spasm (which could inducecough, loss of voice, and wasting),blindness, and deafness, all of which Wilcoxhypothesized could be cured with treatmentof the oral sepsis. 5 As the concept of oralsepsis became more popular, theories wereput forward as to which organs were mostsusceptible to different types of oral sepsis,and how the treatment of oral sepsis couldlead to recovery from tonsillitis, tuberculosis,and diabetes. It was also believed that oralsepsis could be transmitted by the licking of

CHAPTER 4 History of the Oral-Systemic Relationship 45envelopes, use of contaminated telephonereceivers, and men with beards.In 1908, Merritt published an article inDental Cosmos with the title “Mouth Infection:the Cause of Systemic Disease.” 13 Inthis article he stated that “there is a generaldisposition on the part of the medical anddental professions to underestimate therelations which exist between an uncleanmouth and many local and systemic disordersof grave nature.” He felt that in many casesof malnutrition, the sole cause was a “filthymouth” and that “no greater good couldcome to humanity than the full recognition ofthe dangers from this insidious, prolific andvirulent infection in the human mouth.” Healso stated that “the adoption of proper oralhygiene practices would result in immediateand marked improvement to general healthand notable increase in the average durationof human life.”On October 3, 1910, Hunter was invitedto McGill University in Montreal, Canada, togive the keynote address at the dedication ofthe Strathcona Medical Building. The titleof his address was “The Role of Sepsis andAntisepsis in Medicine.” In his address, heblamed “oral sepsis” as the cause of a greatmany diseases, and made an attack on conservativedentistry, or as he called it “septicdentistry.” 5 His address was published inThe Lancet, which was the leading Britishmedical journal at the time, as well as in theDental Register. 14,15 Hunter is best rememberedfor the following statement in TheLancet report: “No one has probably hadmore reason than I have had to admire thesheer ingenuity and mechanical skill constantlydisplayed by the dental surgeon. Andno one has had more reason to appreciatethe ghastly tragedies of oral sepsis which hismisplaced ingenuity so often carries in itstrain. Gold fillings, crowns and bridges,fixed dentures, built on and about diseasedtooth roots form a veritable mausoleum ofgold over a mass of sepsis to which there isno parallel in the whole realm of medicine.”He continued with “The worst cases ofanaemia, gastritis, obscure fever, nervousdisturbances of all kinds from mentaldepression to actual lesions of the cord,chronic rheumatic infections, kidney dis -eases, all those which owe their origin to, orare gravely complicated by the oral sepsisproduced by these gold traps of sepsis. Timeand again I have traced the very first onset ofthe whole trouble to the period within amonth or two of their insertion.” It appearsthat Hunter’s condemnation of conservativedentistry was based primarily on its poorstandard. It was fashionable in London at thetime to mimic complicated Americandentistry. However, in many cases the resultswere often of substandard quality. Some wellrespecteddentists at the time, such as EdwardCameron Kirk, the editor of Dental Cosmos,recognized the potential systemic effects oforal sepsis, but felt that Hunter’s criticism ofdentistry was unfair as Hunter’s observationswere primarily based on the disastrous effectsof a very low-standard dentistry. 5In 1911, Billings, the long-servingDean of Medicine at the University ofChicago and head of the focal infection researchteam at Rush Medical College andPresbyterian Hospital, replaced the term“oral sepsis” with “focal infection.” Soonafter that, he was honored with being askedto give the annual Lane Memorial Lectureat Stanford University in 1915. There, hedefined a focus of infection as a “circumscribedarea of tissue infected with pathogenicorganisms” and said that the term focalinfection implied that: (1) such a focus orlesion of infection existed, (2) the infectionwas bacterial in nature, and (3) it was ca pableof dissemination, resulting in systemicinfection of other contiguous or noncontiguousparts. The teeth, tonsils, adenoids,and mastoids were thought to be the usualsources of bacteremia, and certain bacteria,such as streptococcus and pneumococcus,

46 Periodontal Disease and Overall Health: A Clinician's Guidehad special affinities for target organs likethe heart and lungs. 5,16 Billings advocatedthat chronic infectious arthritis was often associatedwith remote foci of streptococcus,gonococcus, or tuberculosis organisms, andsuggested the removal of all foci of infectionand the improvement in patients’ immunityby absolute rest and improvement of population-wideand individual oral hygiene. 17,18One of the first studies measuring the clinicalbenefit of removing focal infection in1917 confirmed his suggestions. The studywas conducted as a retrospective postal survey,and 23% reported a cure for their arthritisfollowing removal of infective foci. Anadditional 46% reported experiencing someimprovement in symptoms. 5,19One of Billings’ research associates wasRosenow. He was a graduate of the RushMedical College where he had been a studentof Billings. He utilized special methods forculturing material from various foci ofinfection. He obtained a number of pathogenicbacteria from patients, including streptococciand gonococci, which he injected in animals.He then tested whether these organisms wouldprovoke lesions similar to the secondarymanifestations noted in the patients fromwhom the foci had been removed. He used theterm “elective localization” to note that certainstrains of pathogenic bacteria (mostlystreptococci) isolated from the oral cavity ofthe patients had localized to the joints, cardiacvalves, or other areas of the animals. 5Physicians like Billings and Rosenowwere prominent and convincing. More and morearticles were published and many other physi -cians, such as Barker and Cecil, embraced theconcept of focal infection. Cecil, best knownfor his textbook of medicine, reported in 1933that “the keystone of the modern treatment ofrheumatoid arthritis is the elimination of theinfected foci.” 20 In an article in 1938, he quotesRosenow who said “the prevention of oralsepsis in the future, with the view to lesseningthe incidence of systemic diseases, shouldhence forth take precedence in dental practiceover the preservation of the teeth almostwholly for mechanical or cos metic pur -poses.” 21 Other leading members of the medicalcommunity, such as Mayo, also advocated thefocal infection theory. He stated that “inchildren the tonsils and mouth probably carryeighty percent of the infective diseases thatcause so much trouble in later life.” He wenton to write “teeth with putrescent pulps mayharbour green-producing streptococci andeven though they show no redness at the gumsthey may be very dangerous to keep in themouth.” 3-5What followed in dentistry as the resultof the “theory of focal infection” was an unprecedentedwave of tooth extractions andthe avoidance of conservative dentistry. 5,22All teeth that were endodontically or periodontallyinvolved were extracted to avoid apossible focus of infection. This approachcame to be known as the “hundred percenter.”The leading spokesperson for thisradical approach was the physiologist Fisher.He regarded a tooth with a root filling as adead organ that needed to be extracted. 5As biomedical research evolved in theearly 1930s, it also started evaluating conceptson a scientific basis. It was then that thestrong belief in the theory of focal infectionbegan to decline. What stimulated this declinewas the work of Holman, who notedthat Rosenow’s work was fraught with contaminationand that his data were incon -sistent. 22,23 Others noted that Rosenowin oculated animals with such high countsof bacteria that it was inevitable that everyorgan or joint would be affected. 24, 25 Grossman,in his book Root Canal Therapy, notedthat Rosenow’s technique “so devastates thelaboratory animal that lesions are sometimesproduced in almost every tissue and organ ofthe body.” The fact that Rosenow’s work inanimal models could not be reproduced byother investigators heavily discredited histheories. 25

CHAPTER 4 History of the Oral-Systemic Relationship 47Cecil, a great proponent of the focal infectiontheory, together with the rest of themedical community, started to re-evaluatehis approach. He and Angevine publishedan article in 1938 that reported a follow-upstudy of 156 patients with rheumatoid arthritiswho had teeth and/or tonsils removed becauseof foci of infection. They concludedthat chronic focal infection was relativelyunimportant in rheumatoid arthritis becauseof the 52 patients who had teeth removed, 47did not get any better and three got worse. Intheir own words they concluded that “focalinfection is a splendid example of a plausiblemedical theory which is in danger of beingconverted by its enthusiastic supportersinto the status of an accepted fact.” 21In 1940, Reiman and Havens wrote acritical review of the theory of focal infectionin the Journal of the American Medical Association.26 They reviewed the literature indetail and ended the report with the followingparagraph. “It may be said, therefore,that: (a) The theory of focal infection, in thesense of the term used here, has not beenproved, (b) the infectious agents involvedare unknown, (c) large groups of personswhose tonsils are present are no worse thanthose whose tonsils are out, (d) patientswhose teeth or tonsils are removed oftencontinue to suffer from the original diseasefor which they were removed, (e) beneficialeffects can seldom be ascribed to surgicalprocedures alone, (f) measures are often outweighedby harmful effects or no effect at all,and (g) many suggestive foci of infectionheal after recovery from systemic disease, orwhen the general health is improved withhygienic and dietary measures.”In 1951, a review by Williams andBurket 27 concluded the following “There isno good scientific evidence to support thetheory that removal of these infected teethwould relieve or cure arthritis, rheumaticheart disease, and kidney, eye, sin, or otherdisorders.” The very strongly worded reviewby Reiman and Havens, as well as overwhelmingnew evidence, brought the “eraof focal infection” to an end. 26 An editorial inthe Journal of the American Medical Associationin 1952 28 stated that this happenedbecause “many patients with diseases presumablycaused by foci of infection havenot been relieved of their symptoms by removalof the foci. Many patients with thesesame systemic diseases have no evident focusof infection, and also foci of infectionare, according to statistical studies, as commonin apparently healthy persons as thosewith disease.” In looking back, the theory offocal infection not only was an easy way toexplain the cause of many diseases, but alsoadvocated treatment that was available tothe patients at the time. 5 According to Gibbons,22 the role of economics in the spreadingof the focal infection theory should notbe underestimated. It is easy to understandthat as the era of focal infection came to anend the lucrative business of extracting teeth,removing tonsils, and treating sinuses as away of treating human diseases graduallydiminished. In his article “Germs, Dr. Billingsand the Theory of Focal Infection,” Gibbonsquotes one bacteriologist of the focal infectionperiod saying “The age of specializationstimulates surgery. Operations carry thebest fees with them, and without intimatingthat economics play a role in the specialist’sdecision, nevertheless it is only reasonable toregard him as human—if he is the proudpossessor of surgical skill, he is more proneto use it.” 22In dentistry, for almost 50 years (1940–1989), there was little interest in the effectof the mouth on the rest of the body. However,throughout the second half of the twentiethcentury, there were dental scientists whocontinued to question whether oral infection(and inflammation) might in some waycontribute to a person’s overall health, butthe reasons given were mostly speculative.They continued to suggest that bacteria and

48 Periodontal Disease and Overall Health: A Clinician's Guidebacterial products found in the mouth couldenter the bloodstream and could in some waybe harmful to the body as a whole. 29 It wasnot until the last decade of the twentieth centurythat dentistry and medicine started againto consider the relationship of oral diseases,such as periodontal disease, as a contributorto risk factors for certain systemic diseases.Oral-Systemic Relationship RevisitedThe late 1980s saw an increasing numberof publications implicating an associationbetween periodontopathogenic bacteria andcertain systemic conditions such as coronaryartery disease, stroke, and preterm/low birthweight babies. Such insinuations had alsobeen made early in the twentieth century, butthis time reports were judged with a moremeasured response. 30 According to Barnett 30this response was a result of several factors:(a) greater analytical and statistical knowledge,and a better understanding of the con -strains of epidemiological research in “estab -lishing disease causalty”; (b) increased aware -ness of the etiology and pathogenesis of oraldiseases; (c) increased awareness of theetiology and pathogenesis of associated systemicdiseases; (d) modern advances in thetreatment of oral conditions; (e) realizationthat bacteria could in some way be implicatedin the development of diseases that asyet have an undetermined etiology.In 1989, Mattila and coworkers 31 inFinland conducted a case-control study on100 patients who had suffered an acute myocardialinfarction. They compared these patientsto 102 control subjects selected fromthe community. A full dental examinationwas performed on all of the subjects studied.Additionally, a dental index was computed.This index computed the sum of scores fromthe number of missing teeth, carious lesions,peri-apical lesions, probing depths, and thepresence or absence of pericoronitis. It wasfound that dental health was significantlyworse in patients with a history of acutemyocardial infarction than in control subjects.This association remained valid evenafter adjustment for age, social class, smoking,serum lipid concentrations, and the presenceof diabetes. It was mainly this studythat renewed the interest of physicians anddentists in the relationship of oral to systemicdisease.In retrospect, it is now clear that theadvent of reports by Mattila and colleagues—followed soon thereafter by DeStefano etal. 32 and Offenbacher et al. 33 —was the beginningof a new era of understanding theimpact of oral health and disease on overallhealth and disease. 25,30 By 1996, the term“periodontal medicine” would emerge asscientists and clinicians in dentistry andmedicine began to appreciate the tremendouseffect that oral disease can have on thebody. 34PERIODONTAL/ORAL DISEASEAS A RISK FACTOR FORSYSTEMIC DISEASEDespite many years of history demonstratingthe influence of oral status on generalhealth, recent decades have seen an acceleratedeffort for the prevention and managementof these conditions through groundbreakingadvances. Specifically, periodontitis,a chronic infectious and inflammatory diseaseof the gums and supporting tissues, hasbeen associated with systemic conditionssuch as coronary heart disease and stroke,higher risk for preterm, low-birth-weightbabies, and certain cancers. It has also beensuggested that it might pose threats to thosewith chronic disease, e.g., diabetes, respiratorydiseases, and osteoporosis. 35-38 Perio -dontal diseases are infections that are causedby micro-organisms that colonize the toothsurface at or below the gingival margin.These infections affect the gingival tissuesand can cause damage to the supportingconnective tissue and bone. Periodontal diseasecan be caused by specific bacteria (such

CHAPTER 4 History of the Oral-Systemic Relationship 49as Porphyromonas gingivalis) from the bio -film within the periodontal pocket. Severaldifferent pathways for the passage of perio -dontal pathogens and their products into thecirculation have been suggested and are currentlythe subject of intensive research.The focal infection theory, as proposedand defended the first time around, wasmainly based on anecdotal evidence and theoccasional case report. In order for the hypothesisnot to fall into disrepute the secondtime around, different levels of evidence mustbe examined in order to establish a relationshipbetween the periodontal condition andsystemic health of the patient. Since not allscientific evidence is given the same weight,the stronger the evidence, the more likelyit is that a true relationship exists betweenthese conditions.Case reports provide us with very weakevidence and can only suggest a link, butnot a relationship. Case-control studies aremainly used to identify factors that may contributeto a medical condition by comparingsubjects who have the condition with patientswho don’t, but are otherwise similar.These studies may lead to cross-sectionalanalyses. Observational studies are used toexamine associations between exposures anddisease. These are relatively inexpensive andfrequently used for epidemiological studies.However, the fact that they are retrospectiveand not randomized limits their validity.Cross-sectional analysis studies the rela -tionship between different variables at a pointin time. These type of data can be used to assessthe prevalence of acute or chronic conditionsin a population. However, since exposure anddisease status are measured at the same pointin time, it may not always be possible todistinguish whether the exposure preceded orfollowed the disease. Stronger evidence isprovided with a longitudinal study, in whichsubject populations are examined over time.A longitudinal study is often undertaken toobtain evidence to try to refute the existenceof a suspected association between causeand disease; failure to refute a hypothesisstrengthens confidence in it. Longitudinalstudies with controls are much stronger thanthe ones without. The same applies for inter -vention trials that provide the strongest form ofevidence. Unfortunately, not only are thesedifficult to conduct, they are expensive andinvolve many ethical considerations.What Is Risk?Risk is the statistical likelihood that certainfactors are associated with the developmentof disease. It can be divided intoabsolute risk, which is the likelihood of acquiringa certain disease, and relative risk,which is the likelihood of acquiring a diseaseif certain factors are modified, compared tothe same likelihood if they are not. It is easyto understand that if true risk factors areidentified, then intervention for those at riskcan be planned and implemented.The strength of association between putativerisk factors and a disease state can beexpressed in odds ratios. An odds ratio of oneindicates an equal chance as to whether ornot an association will occur. An odds ratioof two indicates a two-fold chance of an associationbeing present. Care should be exercisedinferring causation from odds ratios.Association does not, in itself, infer causation.In the interpretation of odds ratios, it isimportant that the confidence interval of theodds ratio not traverse one. If it does, theodds ratio—regardless of magnitude—cannotbe relied upon.There has long been an interest in therole of systemic factors as they affect perio -dontal disease. A series of studies were carriedout looking at systemic risk factors forperio dontal disease and were summarizedby Genco in 1996. 39 In this review, it waspointed out that in addition to pre-existingdis eases, sys temic factors have been identified.These in clude reduced neutrophil function,stress and coping behaviors, osteopenia, age,

50 Periodontal Disease and Overall Health: A Clinician's Guidegender (with more disease seen in males),hereditary factors, infection with periodontalpatho gens, cigarette smoking, and diabetes.It should be noted that these are risk factorscom mon to many chronic, noncommunicablediseases, such as heart disease, stroke,and diabetes, all of which are associated withperiodontitis. 39Periodontitis/Oral Healthas a Risk for Specific Diseases:Evidence for an AssociationCardiovascularThere are at least three possible mechanismsby which oral infections may contributeto cardiovascular disease: 401. Direct effect of infectious agent inatheroma formation2. Indirect or host-mediated responses3. Common genetic predispositionBahekar 35 and colleagues recently conducteda systematic review of the literaturein order to evaluate if such an association exists.This review revealed five prospectivecohort studies involving 86,092 patients forat least six years. The authors consideredthat three out of the five prospective studieswere of good quality, and both the incidenceand prevalence of coronary heart diseasewere increased in subjects with periodontaldisease after adjustments for other variablesknown to increase the risk of coronary heartdisease. Furthermore, five case-control studiesinvolving 1,423 patients and five crosssectionalstudies involving 17,724 patientswere also evaluated. All supported a sig -nificant relationship between periodontaldisease and coronary heart disease. Moreprospective studies are needed, however, toprove the assumption that periodontitis maybe a risk factor for coronary heart disease andto evaluate risk reduction with the treatmentof periodontitis.In planning prospective studies, it isimportant to remember that patients with periodontaldisease share many of the samerisk factors as patients with cardiovasculardisease. These risk factors include age, gender,lower socioeconomic status, stress, andsmoking. 41 Additionally, a large number ofpatients with periodontal disease also exhibitcardiovascular disease; this could bean indication that periodontal disease andatherosclerosis share similar or common etiologicpathways. 42 The literature also suggeststhat a number of pathogens, antigens,endotoxins, and cytokines of periodontitismight be significant contributing factors. 43,44According to Williams et al., 45 controlling forsuch confounding factors when carrying outepidemiological and observational studies requireslarge numbers of subjects to be enrolledand these subjects need to be followedover a long period of time. Common perio -don tal pathogens such as Porphyromonas gingi -valis and Streptococcus sanguis have been foundin arterial plaques from carotid en darterec tomysamples. Furthermore, perio dontal disease hasbeen associated with elevated levels of inflammatorymarkers, such as C-reactive protein.Although there is growing evidence tosupport a role for C-reactive protein as a predictive,pathogenic factor for vascular risk, itis recognized that more research is needed. 35There is a need for large-scale prospectiveintervention studies to assess whether ornot periodontitis can be considered an effec -tive modifiable risk factor in the prevention ofcardiovascular disease.Adverse Pregnancy OutcomesSeveral studies on laboratory animals thattook place in the 1970s and 1980s re vealedthat bacterial endotoxin (a cell wall com ponentisolated from E. coli) is capable of pro ducingspontaneous abortion, low fetal weight, andmalformations. 46 Collins and col leagues suc -cessfully demonstrated that oral anaerobessuch as P. gingivalis had similar effects. 47,48In 1996, Offenbacher and colleaguesconstructed a case-control study with thetitle “Periodontal Infection as a Possible Risk

CHAPTER 4 History of the Oral-Systemic Relationship 51Factor for Preterm Low Birth Weight.” 33 Inthis investigation, they sought to determinewhether or not the prevalence of maternalperiodontal infection could be associatedwith preterm low birth weight, while control -ling for known risk factors such as smokingand poor nutrition. Results observed fromthe 124 pregnant or postpartum mothers whotook part in this study indicated that perio -dontal disease represents a clinically significantrisk factor for preterm low birth weight.This landmark report by Offenbacher andcolleagues was the first of this kind.In the last seven years, there has beenan explosion of data released from casecontrolstudies, cohort studies, and clinicaltrials, as well as from systematic reviews.Many studies have reported a positive association,but it must be concluded that dueto different study designs, heterogeneity inthe way adverse pregnancy outcomes weremeasured, as well as a lack of adequate analysisfor confounders, there is still no consistentevidence for or against this association.There is a need for large-scale prospectiveintervention studies in which adversepregnancy outcomes and the severity ofperiodontal disease can be clearly defined.Diabetes: A Two-Way RelationshipIt is clear from epidemiologic studiesthat diabetes mellitus increases the risk forperiodontal disease. 49,50 The available literaturehighlights the importance of oral healthin subjects with diabetes, and demonstratesan increased prevalence of periodontitisamong patients with poorly controlled diabetes.45 Patients with controlled diabetesshow periodontal conditions similar to thoseof the healthy population.The current literature does not provide uswith conclusive evidence to support a causalrelationship between periodontal disease andrisk for Type 2 diabetes. There is evidencethat there is an increased risk of periodontitisin patients with diabetes, but Taylor andcoworkers also showed that patients with Type2 diabetes who suffer from periodontitis haveworse glycemic control, suggesting that notonly does diabetes affect periodontitis, butonce a diabetic has periodontitis, it leads toworsening diabetes or glycemic control. 51 Thiswas followed by a paper by Grossi and Gencoin which periodontal disease and diabetesmellitus was presented as a two-way relation -ship. 52 This began a long line of investigationin which treatment of periodontal disease indiabetes was found to contribute to glycemiccontrol, with one of the first studies reportedby Grossi and colleagues. 53 Recently, a metaanalysisof nine control studies on the subjectconfirmed that the reduction of glycatedhemoglobin with periodontal therapy can besignificant, comparable to other attempts tocontrol glycated hemoglobin. 45 Researcherstried to evaluate the effects of periodontaltherapy on systemic inflammatory markersand on glycemic control. 54 Several randomizedcontrol trials and a number of longitudinal andobservational studies pro vided some evidenceto support the concept that periodontitis canadversely affect glycemic man agement.Overall though, it is incon clusive thatperiodontal treatment results in improvementof metabolic control and of markers ofsystemic inflammation.There is emerging evidence to suggestthat periodontitis predicts the developmentof overt nephropathy and endstage renal diseasein patients with Type 2 diabetes. 37,55 Aprospective study by Shultis 37 and colleagueswas conducted exclusively in individuals withdiabetes. It also included a proportionallylarge number of individuals with kidney disease.Whether or not treatment of periodontitiswill reduce the risk of diabetic kidneydisease has not yet been determined, but thisstudy provides a rationale for further investigationinto the connections between perio -dontal disease and diabetic progression.There is a need for large-scale prospectiveintervention studies, mainly in specific

52 Periodontal Disease and Overall Health: A Clinician's Guidehigh-risk groups because, according toWilliams 45 and colleagues, these groupscan provide more immediate answers thanstudies with a more heterogeneous diabeticpopulation.Respiratory InfectionsScannapieco 56 describes four possiblemechanisms of the presence of oral bacteriain the pathogenesis of respiratory infections:1. The oral cavity might be a reservoirfor micro-organisms that contaminatesaliva and is then aspirated into thelungs.2. Periodontal disease-associated enzymesin saliva may facilitate theadherence of respiratory pathogensin the mucosal surfaces.3. Periodontal disease-associated enzymesmay destroy protective salivarypellicles, resulting in fewernonspecific host defense mechanismsin high-risk patients.4. Cytokines and other molecules originatingfrom untreated periodontaltissues are continuously released insaliva. Aspiration of these may alterrespiratory epithelium and promoterespiratory pathogen colonization.A systematic review published in 2006by Azarpazhooh and Leake investigated evidencefor a possible etiological associationbetween oral health and pneumonia or otherrespiratory diseases. 57 They concluded thatthere is fair evidence of an association ofpneumonia with oral health, and poor evidenceof an association of chronic obstructivepulmonary disease with oral health.Additionally, there is good evidence thatimplementation of high-quality and frequentoral healthcare decreases the occurrence andprogression of respiratory diseases amongelderly hospitalized or institutionalizedindividuals. 57There is a need for large-scale prospectiveintervention studies targeting high-riskpeople of the community, nursing homes,and intensive care units.OsteoporosisOver the last decade, it has been specu -lated that by decreasing the patient’s alveolarbone mass, osteoporosis makes teeth moresusceptible to resorption by the periodontalinflammatory reaction. Human studies haveaddressed this relationship, and several largescalestudies showed there is an associationbetween osteoporosis and reduced alveolarcrestal height in postmenopausal women. 58In another study, osteoporosis and perio -dontal infection were found to be independentrisk factors for oral bone loss. 59 Otherstudies, especially longitudinal studies, arenecessary to determine the temporal natureof this relationship and to further evaluate it.Some studies investigated the effect ofhormone replacement therapy or vitamin Dintake on tooth loss. 60 In almost all studies,there was a positive correlation between thenumber of teeth retained and medical treatment,but it must be kept in mind that confoundingfactors such as age, smoking, socio -economic status, and many others may haveaffected the results. 40There is a need for large-scale pro s-pec tive studies with as many confoundingfactors as possible to be factored into theseinvestigations.CONCLUSIONSThere is a long-standing and wellacceptedprinciple that good oral health is anintegral component of good general health.In recent years, there has been an attempt totie oral conditions to systemic diseases in acausal relationship, but existing data supportonly an association. Evidence for this relationshipis growing, and a scientifically basedunderstanding of how oral health may posea risk for certain systemic diseases is developing.Certain linkages are stronger thanothers, but until there are a number of well-

CHAPTER 4 History of the Oral-Systemic Relationship 53constructed, controlled intervention studiesproviding “hard” evidence, treatment recommendationsneed to be guarded.Supplemental ReadingsO’Reilly PG, Claffey NM. A history of oral sepsis as acause of disease. Periodontol 2000 2000;23:13–18.Gibbons RV. Germs, Dr. Billings and the theory of focalinfection. Clin Infect Dis 1998;27:629–633.Mattila K, Nieminen M, Valtonen V, Rasi VP, KesäniemiYA, Syrjälä SL, Jungell PS, Isoluoma M, HietaniemiK, Jokinen MJ. Association between dental healthand acute myocardial infarction. Br Med J1989;298:779–782.Offenbacher S, Katz V, Fertik G, Collins J, Boyd D,Maynor G, McKaig R, Beck J. Periodontal infection asa possible risk factor for preterm low birth weight. JPeriodontol 1996;67:1103–1113.Williams RC, Barnett AH, Claffey N, Davis M, GadsbyR, Kellett M, Lip GY, Thackray S. The potential impactof periodontal disease on general health: A consensusview. Curr Med Res Opin 2008;24:1635–1643.REFERENCES1. Gold SI. Periodontics. The past. Part (I) Earlysources. J Clin Periodontol 1985;12:79–97.2. Francke OC. William Hunters’ “oral sepsis” andAmerican odontology. Bull Hist Dent 1973;21:73–79.3. Mayo CH. Focal infection of dental origin. DentalCosmos 1922; 64:1206–1208.4. Lindsay LL. A short history of dentistry. London:John Bale, Sons and Danielsson, Ltd; 1933:14–17.5. O’Reilly PG, Claffey NM. A history of oral sepsisas a cause of disease. Periodontology 2000 2000;23:13–18.6. Arculani J. Comenteria, Venetiis. Cap. XIViii. DeDolore Dentium 1542:192.7. Rush ME. An account of the core of several diseasesby the extraction of decayed teeth.1818:5thed.:197–201.8. Miller WD. The human mouth as a focus of infection.Dental Cosmos 1891;33:689–706.9. Hunter WD. Oral sepsis as a cause of disease. BrMed J 1900;2:215–216.10. Godlee RJ. On some of the medical and surgicalcomplications of pyorrhea alveolaris. Dent Rec1900;20:337–347.11. Colyer S. Oral sepsis: and some of its effects. DentRec 1902;20:200–206.12. Wilcox R. Some immediate and remote effects ofsuppuration in the mouth and jaws. Br Dent J1903;24:733–736.13. Merritt AH. Mouth infection: the cause of systemicdisease. Dental Cosmos 1908;50:344–348.14. Hunter WD. The role of sepsis and antisepsis inmedicine. Lancet 1911;1:79–86.15. Hunter W. The role of sepsis and antisepsis in medicineand the importance of oral sepsis as its chiefcause. Dental Register 1911;44:579–611.16. Billings FA. Focal infection: its broader applicationin the etiology of general disease. JAMA 1914;63:899–903.17. Billings FA. Chronic focal infections and theiretiologic relations to arthritis and nephritis. Arch IntMed 1912;9:484–498.18. Billings FA. Chronic focal infection as a causativefactor in chronic arthritis. JAMA 1913;61:819–823.19. Hughes RA. Focal infection revisited. Br J Rheu -matol 1994;33:370–377.20. Woods AC. Focal infection. Am J Opthalmol 1942;25:1423–1444.21. Cecil RL, Angevine DM. Clinical and experimentalobservations on focal infection with an analysisof 200 cases of rheumatoid arthritis. Ann Int Med1938:12:577–584.22. Gibbons RV. Germs, Dr. Billings and the theory offocal infection. Clin Infect Diseases 1998;27:627–633.23. Holman WL. Focal infection and selective localiza -tion: a critical review. Arch Path Lab Med 1928;5:68–136.24. Beeson PB. Fashions in pathogenetic concepts duringthe present century: autointoxication, focal infection,psychosomatic disease and autoimmunity.Perspect Biol Med 1992;36:13–23.25. Pallasch TJ, Wahl MJ. Focal infection: new age orancient history. Endod Topics 2003;4:32–45.26. Reiman HA, Havens WP. Focal infections andsystemic disease: a critical appraisal. JAMA 1940;114:1–6.27. Williams NB, Burkett LW. Focal infection—areview. Philadelphia Med 1951;46:1509.28. Editorial. JAMA 1952;150:490.29. Thoden van Velzen T, Abraham-Inpijn L, MoorerWR. Plaque and systemic disease: A reappraisal ofthe focal infection concept. J Clin Periodontol1984;11:209–220.30. Barnett ML. The oral systemic disease connection.An update for the practicing dentist. JADA 2006;137:5S–6S.31. Mattila K, Nieminen M, Valtonen V, Rasi VP, KesäniemiYA, Syrjälä SL, Jungell PS, Isoluoma M,Hietaniemi K, Jokinen MJ. Association betweendental health and acute myocardial infarction. BrMed J 1989;298:779–781.

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Renowned clinicians and scientists worldwide have studied therelationship of periodontal disease to overall health and disease.We are fortunate to have assembled such a respected and scholarlybody of contributors who, in eighteen chapters, provide a currentand thoughtful perspective on this relationship.—Robert J. Genco, Ray C. Williams

Periodontal Disease and Overall Health: A Clinician's Guide

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