university of manitoba faculty of dentistry

8/14/2019 University of Manitoba Faculty of Dentistry

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One university. Many futures.

University of Manitoba Faculty of Dentistry

Anthony M. Iacopino DMD PhD

DeanProfessor, Restorative DentistryDirector,

Centre for Oral-Systemic Health


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Bugs, Biofilm, and Magic Bullets:

Implications for Clinical Practice

Special Event

Thunder Bay

February 12, 2010


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Why should we think more broadly?

EmergingTechnologies

Changing

HealthcareEnvironment

New Science

InterprofessionalAwareness

ImprovedPublic Health


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Periodontal Disease: Gingivitis and Periodontitis

Chronic inflammatory disease one of the most prevalent microbial diseases of mankind

and primarily a gram negative anaerobic oral infection

gingival inflammation

destruction of periodontal supporting tissues

exfoliation of teeth in severe cases

organisms within microbial flora of dental plaque biofilmare the major etiologic agents (Porphyromonas gingivalis,

Tannerella forsythia, and Campylobacter rectus)

microorganisms and endotoxins generate localized host-mediated tissue destructive immune response (cellular,inflammatory cytokines)

(Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)


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Progression of Poor Oral Health

Scottsdale Report, 2007


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Title (32 Myriad Web Pro)


75% of North American population has some formof periodontal disease (~ 15% have severe disease)

recent data indicates gingivitis may be as damaging as

periodontitis (systemic inflammatory burden)

(Moritz and Mealey, Grand Rounds Oral-Sys Med 2:13-20, 2006)


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Traditional Clinical Indices and Diagnostics

plaque index

gingival index (bleeding on probing)

pocket depth

loss of attachment risk factors (i.e., smoking, genetics, systemic disease, age)

Individualized medicine/consideration of biofilm

persistence of orange/red complex

importance of bleeding regardless of pocket depth

epigenetic effects (alteration of host DNA)


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Periodontal Disease: Importance of the Biofilm

Biofilm maturation and characteristics

early colonizers, intermediate (orange), and late (red)

early colonizers create environment for late colonizers(top of the food chain)

biofilm communicates, resists host defense/antibiotics

orange and red (P gingivalis, C rectus) able to evade hostdefenses and have ability for invasion/dissemination

P gingivalisand C rectusare erosive/ulcerative, havetoxins that kill immune cells, and avoid lymphatic system

gingival tissue is highly vascular and total blood volumecirculates through serving as systemic entry portal

(Marsh PD, J Clin Periodontol 6:7-15, 2005)


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Periodontal Disease: Systemic Effects

Transient bacteremia/endotoxemia

linked to disease severity and periods of

progression/exacerbation

organisms invade deep connective tissues and have

been found in vascular endothelium

during progression of gingivitis to periodontitis

pockets gradually deepen and ulcerate

cumulative surface area of ulcerated pockets increases in size

to the palm of a hand creates systemic exposure

tissue destructive responses not limited to oral cavity


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Effects ofsystemic exposure

similar to acute/chronic infection in any other location

of the body

elevation of serum pro-inflammatory cytokines (IL-1,Il-6, TNF-) and acute phase reactants (CRP) hasmany effects on systemic biochemistry/physiology

leads to elevations of serum lipid levels (FFA, LDL/TRG)

destructive influences on cells and tissues

systemic inflammatory state may adversely effect manyorgan systems leading to initiation or exacerbation of systemicdiseases/conditions associated with chronic inflammation


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Effects ofsystemic exposure

epigenetic changes in target tissues (not mutations)

part of environmental stressor category of host alteration

methylation of DNA changes three dimensional conformation

specific effects in each tissue and disease state

decreases transcription and shuts down local defenses andhealing response to allow colonization/dissemination, altershost metabolism to feed bacteria (carbohydrates)

DNA changes are conserved during cell division and the hostis permanently changed

(Barros and Offenbacher, J Dent Res 88:400-408, 2009)


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Adverse pregnancy outcomes

epigenetic changes in target tissues

C rectus causes changes in the developing placenta that impairperfusion causing inflammation and rise in PGE2(contraction of uterine smooth muscle, membrane rupture,

neonatal inflammatory syndrome)

C rectus is abortive bug in veterinary medicine and equineindustry, new data links exposure to 3-fold risk in humans

C rectus shown to reduce IGF-2 growth factor expression in

utero and may be major player in fetal growth restriction

C rectus acts like syphilis and gets into nerve and brain tissueof fetus possibly causing neurologic impairments


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The Oral-Systemic Mechanism: Chronic Inflammation

Untreated oral infection has effects on organ systems

primary inflammatory response enters the system and isprocessed in circulation and liver

secondary and tertiary mediators of chronic inflammation

contributes to overall systemic inflammatory burden

years of elevated systemic inflammation lead todestructive effects on target tissues

Scottsdale Report, 2007


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Relationship Between Periodontitis andSystemic Diseases/Conditions

respiratory disease osteoporosis

arthritis Alzheimers disease

stroke adverse pregnancy outcomes

cardiovascular disease diabetes

gastrointestinal disease

end stage renal disease

Grand Rounds in Oral-Systemic MedicineGapski and Cobb 1(1):14-23, 2006;

Moritz and Mealy 1(2):13-21, 2006;Iacopino 1(3):25-37, 2006;Paquette 1(4):14-25, 2006;

Tae-Ju Oh et al., 2(1):10-21, 2007


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PeriodontitisElevated Serum

Pro-InflammatoryCytokines

Hyperlipidemia

Diabetes

BacteremiaEndotoxemia

InsulinResistance

-CellDestruction

Cardiovascular/Cerebrovascular

Disease

Arthritis

RespiratoryInfection

Aspiration

Dementia

MicrogliaActivation

SynovialInflammation Atherosclerosis

Altered LipidMetabolism

Rheumatoid

Factor

Atherosclerosis

HSP Mimicry and Seeding (Vascular Endothelium)

Linkage Between Periodontitis and Systemic Diseases/ConditionsAdverse

PregnancyOutcome

Seeding (Gut) Gastrointestinal Disease


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Reversibility of Periodontitis-InducedSystemic Inflammation

Periodontitis linked to systemic inflammation andtreatment of periodontitis reduces systemicinflammation

65 healthy subjects (severe generalized periodontitis) blinded randomized control clinical trial

measured CRP, IL-6, LDL cholesterol at baseline andtwo months after treatment (standard therapy) at baseline, inflammatory markers were significantly elevated

after treatment, significant reductions in CRP (p=0.03),IL-6 (p=0.006), and LDL (p=0.002)

reductions independent of age, gender, BMI, ethnicity

(DAiuto et al., J Clin Perio 34:124-129, 2007)


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Reversibility of Periodontitis-InducedEndothelial Dysfunction

Periodontitis linked to endothelial dysfunction (arterial

stiffness/elasticity) and treatment of periodontitisimproves endothelial function

flow-mediated dilatation decreased with severeperiodontitis and corresponding elevations of CRP(Mercanoglu et al., J Periodontol 75:1694-1700, 2004)

treatment of periodontitis and improved periodontalhealth increases flow-mediated dilatation(Tonetti et al., N Engl J Med 356:911-920, 2007)

pulse-wave velocity higher with periodontitis and

corresponding elevations of CRP, IL-6, and TNF-;treatment of periodontitis decreases pulse-wavevelocity and levels of inflammatory biomarkers(Seymour et al., Clin Microbiol Infect 13:3-10, 2007)


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Gastrointestinal

Systemic Inflammation

Genitourinary Respiratory

Diabetes

Smoking

StressObesityDiet

Autoimmune DiseaseGenetics

Environment

Total Burden of Infection

Atherosclerosis

Oral

Linkage Between Infection and Inflammation in CVD and Diabetes

Direct Infection

Molecular Mimicry

- Responsibility of all health professionals to reduce oral infection- Effective health policy must focus on reduction of risk factors- Modest changes in risk can produce significant changes in disease burden


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Periodontal Disease: Treatment Phase I therapy

oral hygiene instruction to reduce microbial burden brushing/flossing mechanical disruption of biofilm

scaling/root planning to remove etiology removes plaque/calculus, polishes tooth surfaces

follow-up care (8 weeks duration, 6-month recall)

adjunctive antimicriobials (antiseptics/antibiotics; i.e., Atridox,Arestin, Periochip, Listerine, Perioguard, Viadent)

modulation of host response (antiinflammatories; i.e., Periostat)

Phase II therapy surgical intervention to restore original architecture

corrects bony defects and establishes cleansible architecture

bone augmentation/grafting and tissue regeneration to restoreadequate tooth support

increased justification to remove epigenetically modified tissue

Prevention is the best treatment available!


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Title (32 Myriad Web Pro)Reduce Oral Inflammation: Good Enough?

Antimicrobials/Host Modulators rinses, toothpastes, chips

adjunctive antibiotics

PERIOSTAT20mg

DoxycyclineHyclate


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Targeted Antibodies: The Holy Grail?

Core Philosophy:

Produce large quantities at pharmacological purity

Rapid and low-cost manufacturing process

Highly specific and effective

No microbial resistance or side effects

Multiple points of intervention (systemic potential)

Perform relevant and convincing clinical trials


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MaternalDental Plaque

Maternal AntibodyResponse to Flora

Low Maternal Antibody

Response Maternal PeriodontitisProgression

Fetal Exposure to

Periodontitis PathogensFetal IgM Response to

Periodontitis Pathogens

Elevated Fetal Inflammatory CytokinesCellular Damage

PTB

(Madianos et al., Ann Periodontol 6:175-182, 2001)

Current Thinking: Individual Responses


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PatientDental Plaque

Patient AntibodyResponse to Flora

Low Patient Immune

Response

Local Inflammation Progression to

Systemic Inflammation;

Periodontal Pathogen Invasion

Chronic End Organ

Exposure to

Inflammatory Burden

Can Begin at8 Years of Age

10-40 YearsIncubation Time

Exacerbation orInitiation of Systemic

Inflammatory Disease

(International Association of Dental Research, Miami 2009)

Current Thinking: Individual Responses


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International Centre for Oral-Systemic Health

ParticipatingFaculties &

Centres


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Comprehensive Patient Care

Hospitals

Long-Term Care Facilities Community Health Settings Urban and Rural Clinics

Interprofessional Teams

Dentist Hygienist

Physician Nurse Pharmacist Dietician Physical Therapist Social Worker Behavioral Psychologist

Interprofessional Education and Research Approaches

Content in oral-systemic science revolving around themes

(inflammation, overall health and wellness)

Biomedical and clinical investigators establish oral-systemicresearch areas in basic biomedical investigation, clinicalintervention/practice models, or epidemiology/public healthleading to systems improvements

Oral-Systemic

Health

HumanEcology

Nursing

Dentistry

Medicine

Pharmacy

Social Work


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ICOSH-IGY Partnership: New Frontier?

Key Assets:

IGY technology to produce antibodies

Broad scope of IGY patents

ICOSH expertise in oral-systemic science

ICOSH infrastructure for clinical trials

ICOSH oral microbial repository

University of Manitoba Technology Transfer Office


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Chicken Egg Yolk Antibody (IgY) Production

inject pathogenic bacteria or specific antigeniccomponents of bacteria into chickens (selected bugsfor caries, periodontal disease, etc.)

chicken makes IgY against the pathogenic bacteriathat is contained in egg yolks

harvest IgY from egg yolks using unique technology

Applications Igy is specific and essentially inert (no cross-reactivity

with human cells/tissues, no side effects)

local use for oral diseases (toothpastes, rinses, gels,microspheres for slow release and substantivity)

systemic use (delivery routes to circulation similar toanti-TNF drugs) to target oral-systemic connections


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Therapeutic Antibodies: State of the Science

Caries most work has involved host protective response fromvaccination (host produces its own antibody)

vaccination approach expensive and difficult

caries vaccine (S mutans) can be effective through

prevention of accumulation ofS mutans in biofilm viacontinuous secretion of salivary IgM but lingeringissues prevent widespread use (mainly hesitancyassociated with vaccines and potential side effects)

IgY approach to S mutans against same bacterial

antigenic component has been effective in animalmodels (administration through drinking water) andin human volunteers using rinses and sprays


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Kou and Zhi, J Stomatol 21:339-41, 2003) most convincing study in animal models rat model using S mutans IgY gargle, IgY lyophilized powder,

egg yolk food containing IgY

significant reduction in caries scores

Human studies are encouraging but preliminary in

nature (more work needs to be done)

Caries:


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Periodontal Disease some work done on systemic anti-TNF to reduce

inflammatory tissue damage (arthritis drugs likeInfleximab and Embrel)

plagued by side effects and complications still doesnt address microbial etiology

approach requires reduction of biofilm (oralmicrobial burden), reduction of red/orange complexbacteria, and possibly systemic intervention toaddress bacteremia related to oral-systemicconnections


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IgY Therapy: Major Concerns

IgY is a protein and might be vulnerable to salivary and

digestive enzymes For biofilm formation, early time points are crtical, so

worry of oral digestion of proteins not as great, IgY

interacts with bugs on contact, daily application should

influence biofilm formation and maturation as bacteria

lose biofilm attachment capability

Oral IgY administration already shown to be effective

for GI applications (longer transit time and greater

potential for digestion, high concentration/purity may

preserve IgY effect)

Need to demonstrate ability to establish circulating IgY

for applications in broader oral-systemic realm


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Title (32 Myriad Web Pro)Basic Oral Care and Medical Spending

Preliminary estimates of medical cost savings for

high-risk populations provided with basicpreventive oral health services

four-year period in the US

$50 per person for diabetes, cardiovascular disease,

and cerebrovascular disease

$700 per mother/child pair for pregnancy

(Albert et al, BMC Health Services Res 6:103-109, 2006;

Ide et al, J Periodontol 78:2120-2126, 2007;Quinonez and Stearns, J Periodontol 79:203-206, 2008)


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Title (32 Myriad Web Pro)Canada: Current Numbers

Canada's population is estimated at 33,143,600

Over 2 million Canadians have diabetes and thatnumber is expected to reach 3 million by 2010

About 2 million Canadians currently living with

some form of heart disease or stroke

Current number of annual Canadian births is 341,048

(Statistics Canada 2008; Canadian Diabetes Assoc 2008;

Heart and Stroke Foundation of Canada, 2008)


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Where Are We Going?

ICOSH partnership with ABY provides linkage oftechnology with clinical research and human resources

New collaboration offers significant potential forchanges to approaches for improving oral-systemichealth, healthcare practice, and overall public health

The shape of things to come?


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O i it M f t

University of Manitoba Faculty of Dentistry

[email protected]

university of manitoba faculty of dentistry

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