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 The Oral-Systemic Health Connection: A Guide to Patient Care
Second Edition

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 The
Oral-Systemic
Health Connection SECOND EDITION

A Guide to Patient Care

Edited by
Michael Glick, dmd
Professor, Oral Diagnostic Sciences
University at Buffalo
The State University of New York
Buffalo, New York

Berlin, Barcelona, Chicago, Istanbul, London, Milan, Moscow, New Delhi,

Paris, Prague, São Paulo, Seoul, Singapore, Tokyo, Warsaw
Library of Congress Cataloging-in-Publication Data

Names: Glick, Michael, editor.

Title: The oral-systemic health connection : a guide to patient care /
edited by Michael Glick.
Other titles: Oral-systemic health connection (Glick)
Description: Second edition. | Batavia, IL : Quintessence Publishing Co, Inc., [2019] |
Includes bibliographical references and index. | 
Identifiers: LCCN 2018044816 (print) | LCCN 2018045699 (ebook) |
ISBN 9780867158083  | ISBN 9780867157888 (softcover)
Subjects: | MESH: Oral Health | Periodontal Diseases--complications |
Tooth Diseases--complications | Inflammation | Risk Factors
Classification: LCC RK61 (ebook) | LCC RK61 (print) | NLM WU 113 | DDC 617.6--dc23
LC record available at https://lccn.loc.gov/2018044816

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Printed in the USA

C ONTENTS
Preface  vii
Contributors  viii

1 | Causation: Frameworks, Analyses, and Questions  1

Michael Glick

2 | Essential Statistical and Research Design Elements to Help Critically

Interpret the Literature  24
Barbara L. Greenberg and Michael Glick

3 | The Traveling Oral Microbiome  38

Wenche S. Borgnakke

4 | The Role of Inflammation in Oral-Systemic Interactions  86

Marcelo Freire and Thomas E. Van Dyke

5 | Obesity, Metabolic Syndrome, and Oral Health  102

Ira B. Lamster, Nadia Laniado, and Ilene Fennoy

6 | Associations Between Periodontal Disease and

Hyperglycemia/Diabetes  135
Wenche S. Borgnakke and Robert J. Genco

7 | The Cardiovascular System and Oral Infections  164

Maurizio S. Tonetti and Filippo Graziani

8 | The Association Between Oral Infections and Renal Disease  180

Karren Komitas and Effie Ioannidou

9 | The Association Between Oral Infections and Pulmonary

Disease  193
Karren Komitas and Effie Ioannidou
10 | Periodontal Infections and Adverse Pregnancy Outcomes  210
Yiorgos A. Bobetsis, Wenche S. Borgnakke, and Panos N. Papapanou

11 | Oral Infections and Cancer  231

Dominique S. Michaud

12 | Oral Manifestations of Systemic Diseases  242

Alessandro Villa and Sook-Bin Woo

13 | Oral Complications in the Immunocompromised Patient:

The Oncology Prototype  271 
Douglas E. Peterson

14 | Oral-Systemic Health: The Genomic Connection  292

John R. Shaffer and Robert J. Weyant

15 | Common Risk Factors: The Link Between Oral and

Systemic Disease  311
David M. Williams

16 | Antibiotic Prophylaxis for Patients at Risk for Infective

Endocarditis  329
Peter B. Lockhart

17 | Oral-Systemic Connection: The Salivaomics and

Exosomics Connection  342
˙
Taichiro Nonaka, Karolina Elzbieta Kaczor-Urbanowicz, and David T.W. Wong

18 | The Economic Impact of Periodontal Inflammation  357

Michael C. Alfano

Index  369
PREFA C E
A renewed interest in the oral-systemic health connection has widened the debate on
this fascinating topic, which now ranges from different plausible underlying biologic
principles to potential financial impact and effect on overall health and well-being.
This is not a new topic, but broadened implications for reimbursement models and the
recognition of oral health within the scope of other noncommunicable diseases affect
both clinical practice and health care policies.
The first written mention of the connection between infections in the oral cavity
and systemic health can be traced all the way back to cuneiform tablets from Niniveh
in Assyria circa 700 BC.1 However, since that time, anecdotes and reported cases have
given way to sophisticated research and analyses. Interpreting this research is sometimes
challenging. While distinct study designs and different statistical analyses may generate
different associations between oral infections and systemic diseases, this book provides
clarity and insight, with an ultimate goal of improving our patients’ overall health.
This second edition of The Oral-Systemic Health Connection explores a broad range
of topics that taken together enhance the reader’s appreciation of this still-emerging
association. There are several new chapters in this edition that are included based on
feedback from practitioners, scientists, and policymakers. The first chapter addresses one
of the most critical issues in the debate on the oral-systemic connection: the different
frameworks and models that are or can be used to claim causation. A new chapter on
biostatistical assessment has also been added to assist in the interpretation of the existing
literature. Two additional new chapters discuss the association between oral infections
and cancer as well as the association between oral health and renal disease. Other
chapters include updates on associations with other systemic diseases and conditions,
in addition to updates on what is known today about the role of inflammation and
the microbiome. Other important topics are addressed in new chapters on antibiotic
prophylaxis, the genomic connection, risk factors that are shared with systemic diseases
that are associated with significant morbidity and mortality, and the potential economic
impact of the oral-systemic health connection. Readers will note that there is not always
agreement among the authors about the importance and impact of the oral-systemic
health connection. No attempts have been made to reconcile these differences or reach
a consensus, and it is left to the reader to draw his or her own conclusions. Nonetheless,
similar to a much-appreciated feature in the first edition, specific answers to important
clinical considerations are included in selected chapters throughout the book.
We are inundated with data, statistics, and facts from a variety of outlets, including the
biomedical literature as well as social media and the lay press. It is therefore important
for today’s health care professionals to stay informed and remain reliable sources of
health information. This book will assist readers in understanding and appreciating the
complexity surrounding the oral-systemic health connection and, most importantly, help
to inform others about the impact of this link in order to benefit our patients.

Reference
1. Denton GB. A new interpretation of a well-known Assyrian letter. J Near Eastern Studies 1943;4:314.

vii
 C ONTRIB U T OR S
Michael C. Alfano, dmd, phd
President, Santa Fe Group
Professor, Dean, and Executive Vice
President Emeritus
New York University
New York, New York
Yiorgos A. Bobetsis, dds, phd
Assistant Professor
Department of Periodontology
School of Dentistry
National and Kapodistrian University
of Athens
Athens, Greece
Wenche S. Borgnakke, dds, mph, phd
Senior Research Associate
Adjunct Clinical Assistant Professor
Department of Periodontics and Oral
Medicine
University of Michigan School of
Dentistry
Ann Arbor, Michigan
Ilene Fennoy, md, mph
Professor of Pediatrics
Columbia University Irving Medical
Center
Vagelos College of Physicians and
Surgeons
New York, New York
Marcelo Freire, dds, phd, dmsc
Associate Professor
Genomic Medicine and Infectious
Disease
J. Craig Venter Institute
La Jolla, California
viii
Robert J. Genco, dds, phd
SUNY Distinguished Professor of
Oral Biology and Microbiology and
Immunology
Director, UB Microbiome Center
University at Buffalo
The State University of New York
Buffalo, New York
Michael Glick, dmd
Professor, Oral Diagnostic Sciences
University at Buffalo
The State University of New York
Buffalo, New York
Filippo Graziani, dds, mclindent, phd
Professor of Periodontology
Unit of Dentistry and Oral Surgery
University of Pisa
Pisa, Italy
Barbara L. Greenberg, msc, phd
Adjunct Professor of Dental Medicine
Touro College of Dental Medicine
New York Medical College
Valhalla, New York
Effie Ioannidou, dds, mds
Professor of Periodontology
Director, Dental Clinical Research
Center
School of Dental Medicine
UConn Health
Farmington, Connecticut
Karolina Elzbieta
˙ Kaczor-Urbanowicz,
dmd, phd, msc, msl
Visiting Assistant Project Scientist
Division of Oral Biology and Medicine
Clinical Lecturer
Section of Orthodontics
UCLA School of Dentistry
Los Angeles, California
Karren Komitas, dmd, phd, mdsc
Assistant Professor
Department of Periodontics and Dental
Hygiene
School of Dentistry
University of Texas Health Science
Center at Houston
Houston, Texas
Ira B. Lamster, dds, mmsc
Clinical Professor
School of Dental Medicine
Stony Brook University
Dean Emeritus
Columbia University College of Dental
Medicine
New York, New York
Nadia Laniado, dds, mph
Director of Community Dentistry and
Population Health
Department of Dentistry/OMFS
Jacobi Medical Center
Albert Einstein College of Medicine
New York, New York
Peter B. Lockhart, dds, fds rcsed,
fds rcps
Research Professor
Department of Oral Medicine
Carolinas Medical Center
Charlotte, North Carolina
Dominique S. Michaud, scd
Professor of Public Health and
Community Medicine
School of Medicine
Tufts University
Boston, Massachusetts
Taichiro Nonaka, dds, phd
Assistant Project Scientist
Division of Oral Biology and Medicine
UCLA School of Dentistry
Los Angeles, California
Panos N. Papapanou, dds, phd
Professor of Dental Medicine
Chair, Section of Oral, Diagnostic, and
Rehabilitation Sciences
Director, Division of Periodontics
Columbia University College of Dental
Medicine
New York, New York
Douglas E. Peterson, dmd, phd, fds rcsed
Professor of Oral Medicine
School of Dental Medicine
Co-Chair, Program in Head and Neck
Cancer and Oral Oncology
Neag Comprehensive Cancer Center
UConn Health
Farmington, Connecticut
John R. Shaffer, phd
Assistant Professor
Department of Human Genetics
Graduate School of Public Health
Assistant Professor
Department of Oral Biology
School of Dental Medicine
University of Pittsburgh
Pittsburgh, Pennsylvania
ix
 Maurizio S. Tonetti, dmd, phd, mmsc
Executive Director
European Research Group on
Periodontology
Clinical Professor in Periodontology
Prince Philip Dental Hospital
The University of Hong Kong
Sai Ying Pun, Hong Kong
Thomas E. Van Dyke, dds, phd
Vice President and Senior Member of
Staff
The Forsyth Institute
Professor of Oral Medicine, Infection,
and Immunity
Harvard School of Dental Medicine
Cambridge, Massachusetts
Alessandro Villa, dds, phd, mph
Assistant Professor
Department of Oral Medicine,
Infection, and Immunity
Harvard School of Dental Medicine
Associate Surgeon
Division of Oral Medicine and
Dentistry
Brigham and Women’s Hospital
Boston, Massachusetts
Robert J. Weyant, ms, dmd, drph
Professor and Chair
Department of Dental Public Health
School of Dental Medicine
University of Pittsburgh
Pittsburgh, Pennsylvania
x
David M. Williams, bds, msc, phd, frcpath,
fds rcs (engl)
Professor of Global Oral Health
Bart’s and The London School of
Medicine and Dentistry
Queen Mary University of London
London, England
David T.W. Wong, dmd, dmsc
Felix and Mildred Yip Endowed Chair
in Dentistry
Associate Dean for Research
Professor of Oral Biology
Director, UCLA Center for Oral/Head
& Neck Oncology Research
UCLA School of Dentistry
Los Angeles, California
Sook-Bin Woo, dmd, mmsc
Associate Professor
Department of Oral Medicine,
Infection, and Immunity
Harvard School of Dental Medicine
Attending Surgeon
Division of Oral Medicine and
Dentistry
Brigham and Women’s Hospital
Boston, Massachusetts

Causation: Frameworks,
Analyses, and Questions
Michael Glick, dmd
Why Do We Care About
Causation?
The desire to ascertain causality is one we
encounter in everyday life. Most of us have
difficulty accepting uncertainty, and we want
to discern patterns and reasons to explain why
things occur. This is nothing new; such quests
can be found in ancient texts on philosophy,
science, and even religion. The word cause or
causal wording is often found in the biomed-
ical literature, in nonscientific publications,
and in social and other media. However, it is
not always clear how a claim could have been
made.
My hope is that after reading this chapter,
a reader who encounters a claim of causation
will ask what framework, analysis, or crite-
rion was used to make such a claim. To even
ask such a question, a frame of reference to
compare claims of causation will need to be
established. This chapter provides an overview
of causal constructs that provide a founda-
tion for a discourse on causal relationships.
Throughout this chapter, periodontal disease
is used as a proxy for oral infections, but other
chapters in this book specifically address other
diseases, conditions, and circumstances as a
focus of discussion. In this chapter, we will spe-
cifically examine how proposed frameworks,
CHAPTER 1
analyses, and criteria can be used to claim that
periodontal disease affects systemic health.
Awareness of causal relationships will lead to
benefits such as the ability to explain and pre-
dict outcomes that are important to patients.
However, data generation alone cannot answer
questions about causal relationships. Knowl-
edge about how the data were acquired and
how those data fit into causal constructs are
necessary to assess and use those data to claim
causal relationships.
One challenge is how to interpret results
from observational data and intervention
trials. The conventional use of observational
studies is to find associations that can explain
connections between different exposures and
outcomes.1 Appropriately designed and per-
formed randomized controlled trials (RCTs)
have traditionally been considered one of the
most suitable methods to establish evidence
for causal inferences and claims. But where an
RCT is impossible to carry out, observational
data from cross-sectional, case control, and
cohort studies may still be used to approximate
causal inferences.2
RCTs were initially designed to reduce bias
and have long been labeled the gold standard
for evidence-based medicine, but this concept
has been challenged.3,4 The limitations of RCTs
lie not with the randomization or the control
but with, for example, the use of surrogate
1
1 Causation: Frameworks, Analyses, and Questions
endpoints rather than clinical outcomes, or
inappropriate extrapolation, or generalization
of findings. Furthermore, RCTs do not lend
themselves to all research questions. Research
questions about harm, etiology, prognosis, and
diagnosis may be better answered by obser-
vational studies. Although outcomes from
properly designed and performed RCTs of an
appropriate size lead to an inference, such an
inference is based on a probabilistic estimate
of a clinical prediction. Even when valid, such
a prediction cannot ensure an expected out-
come. Yet RCTs still hold many advantages
over observational studies.
The vast majority of research on the oral
infection–systemic health relationship consists
of observational studies. Many oral diseases,
such as periodontal diseases and caries, are
complex and chronic and are probably asso-
ciated with multifactorial determinants or
risk factors. The same holds true for systemic
illnesses. Except in rare circumstances, it is
difficult to determine the onset of a systemic
condition before signs and symptoms appear
(with the possible exception of pregnancy).
Thus, one of the hallmarks of a causal rela-
tionship—temporality (a directional sequence
of events where a causal event [exposure]
happens before the effect [outcome])—may
be practically impossible to establish. Estab-
lishing whether an oral infection truly occurred
prior to a systemic illness, with our present
research armamentarium and knowledge,
may not always be possible. Furthermore, a
cause-and-effect relationship is not symmetric.
For example, stopping sugar consumption may
reduce the incidence of caries, but treating car-
ies lesions is not in itself a strategy for stopping
sugar consumption.
Statistical analyses can infer associations
among variables and estimate measures of
associations under static conditions, but
they fall short when dealing with changing
conditions. There is no universally accepted
technique or statistical analysis to measure
causal effects, although several methods have
been proposed.5,6
2
As discussed in this chapter, there is no right
way to determine causal relationships, nor
are there any universally agreed upon causal
frameworks, models, methods, algorithms,
criteria, or measures. The advantage of a uni-
versal language and framework for causation is
that it enables a dialogue about consequences
and actions, which is needed to benefit our
patients.7 To quote Voltaire, “If you wish to
converse with me, first define your terms.”
A Brief History of the
Oral Infection–Systemic
Health Link
Observations of a putative link between sys-
temic conditions and oral health were described
on cuneiform tablets from Assyria more than
2,700 years ago.8 Since that time, many prom-
inent figures in the history of medicine have
written about this possible association, includ-
ing Hippocrates (460–370 BCE), who is often
portrayed as the paragon of ancient physicians
and allegedly claimed that it was possible to
cure arthritis by the removal of teeth, and
Galen (131–201 CE), another dominant Greek
physician and the most famous and influential
physician of ancient Rome.
The term focus of infection was coined by
Willoughby Dayton Miller, a leading microbi-
ologist and dentist who published a series of
articles titled “The human mouth as a focus of
infection” in Dental Cosmos and in The Lancet
in 1891.9,10
Most observational reports in the medical
and dental literature in the late 1800s and
early 1900s described how infected teeth
could influence systemic conditions, even sug-
gesting that extraction of infected teeth could
cure systemic illness. This approach to treat-
ing and curing illnesses, for example arthritis,
was later challenged by researchers. Instead
of describing single observations, researchers
conducted retrospective studies that included

multiple patients. In their seminal article on
the association between extracted teeth and
relief of signs and symptoms of rheumatoid
arthritis, Cecil and Angevine famously stated
that “Focal infection is a splendid example of
a plausible medical theory which is in danger
of being converted by its too enthusiastic sup-
porters into the status of an accepted fact.”11
With better appreciation of scientific evidence,
better research design, and better diagnostic
techniques and treatments, a movement away
from the focal infection theory and against
teeth extraction was emerging.12,13
One of the first mentions of periodontal
infection as a possible source of systemic illness
appeared in the first edition of Oral Medicine by
Lester W. Burket in 1946, where he stated that
“the frequent occurrence of bacteremias which
may arise from diseased periodontal tissue,
might be of more importance in the causation
of joint lesions.”13 In 1951, an entire issue of
The Journal of the American Dental Associa-
tion was published as a “report, prepared under
the general direction of the Council on Dental
Health of the American Dental Association,
[that] constitutes a summary and an evaluation
of modern scientific information about the role
of dental foci of infection in body disease.”14
In the late 1980s and the early 1990s, obser-
vational studies from Finland highlighted an
association between dental health (dental car-
ies, periodontal disease, or both) and acute
myocardial infarction, while similar studies
in the United States continued to establish a
bidirectional association between periodontal
health and diabetes.15–17 Apart from observa-
tional studies, experimental animal studies
revealed an association between oral pathogens
and adverse pregnancy outcomes, an associa-
tion that was later observed in humans.18–20
The discussion about the relationship between
oral disease and systemic illness was rapidly
shifting from an association between diseases
to the influence of the oral microbiome (see
chapter 3). Although a proliferation of stud-
ies have investigated the association between
periodontal disease and systemic health, 21
Definitions of Cause and Causation
oral manifestations of systemic illnesses, the
increased susceptibility of the immune-deficient
or immune-dysfunctional host to develop
adverse systemic outcomes due to oral infec-
tion, genetic determinants associated with
oral health, and the association between oral
infection and infectious endocarditis are well
known and should be included in such a dis-
cussion (see chapters 4, 11, 12, 13, and 15).
Definitions of Cause
and Causation
The scientific literature is replete with words
implying causation: affect, cause, contribute,
determine, effect, enhance, impact, influence,
lead to, produce, responsible for, result from,
and so on. It is important to recognize the mis-
use of causal terminology, as authors may at
times employ these causal words to infer effects
beyond study findings.
Common meanings of the word cause
can be found in most dictionaries; it is more
difficult to find a common definition of
causation. However, we need an agreed upon
definition of cause before we can start a dis-
cussion about causation. According to the
Free Dictionary, cause can be defined as “the
producer of an effect, result, or consequence.”
Merriam-Webster similarly defines cause as
“something that brings about an effect or a
result” but elaborates as “a reason for an action
or condition: motive.”22,23 Within the biomed-
ical field, cause is often used synonymously
with etiology. These common definitions
immediately invoke teleology—the study of
origin—one of the core contributors to con-
fusion in what cause is intended to mean in
biomedical contexts.
A more representational depiction of cause
could be described as follows: Variable A is a
cause of variable B if B in any way depends
on A for its value. This rather rudimentary
explanation can help outline different causal
relationships:
3
1 Causation: Frameworks, Analyses, and Questions
• A causes B (direct causal relationship). For
example, sugar is associated with the devel-
opment of caries. Caries cannot develop
without the presence of sugar. Therefore,
sugar causes caries. In this scenario, sugar is
a necessary cause (see Box 1-3).
• A and B are consequences of a common
cause. Let’s assume smoking causes periodon-
tal disease and smoking causes cardiovascular
disease. Such an assumption may suggest a
common cause (smoking) but not necessar-
ily a causal relationship between periodontal
disease and cardiovascular disease. In this
example of considering whether A (periodon-
tal disease) is a cause of B (cardiovascular
disease), smoking may be a confounder, a
third variable affecting both periodontal
disease and cardiovascular disease and poten-
tially fully explaining the putative causal
relationship between A and B. Thus, although
there may be an association between peri-
odontal disease and cardiovascular disease,
there is, in this example, no causation.
• A causes B, and B causes A (bidirectional,
reciprocal, or cyclic causal relationship).
Oral conditions have been claimed to cause
systemic inflammation, and systemic inflam-
matory conditions have been implicated in
the etiology of oral conditions. This recipro-
cal relationship has been used to claim that
as diabetes will exacerbate periodontal con-
ditions and vice versa, there is a bidirectional
claim of causality between these conditions.
The interrelationships between periodontitis
and diabetes provide an example of systemic
disease predisposing to oral infection. Once
the oral infection is established, it exacer-
bates systemic disease. In this case, it may
also be possible for the oral infection to pre-
dispose to systemic disease.24
• B causes A (reverse causal relationship). A
cross-sectional study finds an association
between the presence of periodontal disease
and the presence of cardiovascular disease.
Did periodontal disease cause cardiovascu-
lar disease, or did cardiovascular disease
cause periodontal disease? A variation of
4
this relationship is a logical fallacy known
as fallacy of affirming the consequent: We
know that if X is true, Y must be true. We
know that Y is true, so therefore X must be
true. If I have periodontal disease, I will have
cardiovascular disease. I have cardiovascular
disease, and therefore I have periodontal dis-
ease. Unfortunately, this fallacy is used often
by scientists and laypeople in interpreting
data.
• Both A and B cause C. Both early childhood
caries and periodontal disease can result in
full-mouth extraction. As both conditions
result in the same outcome, a claim may
be made of an association between these
conditions. However, childhood caries and
periodontal disease do not necessarily have
a causal relationship.
• A causes C, which causes B (indirect causal
relationship). Periodontal disease (A) is asso-
ciated with tooth loss (C). Tooth loss (C) is
associated with nutritional deficiencies (B). Is
it therefore possible to claim that periodontal
disease (A) causes nutritional deficiencies (B)?
• There is no connection between A and B; the
correlation is coincidental. For example, we
found that nearsighted individuals are more
likely to have periodontal disease than indi-
viduals who are not nearsighted. Using this
example to infer cause and effect is spurious.
The above examples highlight why causation
is such an elusive concept. Yet it is a concept
that has been discussed and written about at
least since the time of Aristotle (384–322 BCE).
Numerous theories of causation have been
proposed, in philosophy and in biomedical disci-
plines, and this chapter highlights those theories
that could be applied to the association between
oral infection and systemic health. However, an
exhaustive historical literature review of this
topic will not be undertaken. Although defining
causation is important, such an endeavor often
digresses into philosophical and metaphysical
dialogues. In this chapter, we will shy away from
a discourse on definitions and instead highlight
frameworks and methods that describe causal
 Frameworks, Classifications, Criteria, and Analyses to Describe and Infer Causation

Box 1-1  |  Henle-Koch postulates26

1. The microorganism must be observed in all cases of the disease.

2. The microorganism must be isolated and grown in pure culture.
3. Microorganisms from the pure culture, when inoculated into a susceptible animal,
must reproduce the disease.
4. The microorganism must be observed in and recovered from the experimentally
diseased animal.

relationships. The intent of this chapter is not
to promote a specific framework of causation
or engage in an epistemologic discourse on
causation but to provide different frameworks
that can be used to judge claims of causation.
Frameworks, Classifications,
Criteria, and Analyses to
microorganism and a disease. This gold stan-
dard, which was used to establish evidence for
a single infectious agent as a cause for a specific
disease, has been challenged by the discovery
of viruses and other microbes, the recognition
of multiple causes, and its not being adaptable
to experimentation. However, the postulates
did provide a conceptual framework for sub-
sequent models of causation, including the one
proposed by Sir Austin Bradford Hill.

Describe and Infer Causation

Frameworks of causation are generated as an
attempt to explain connections between events.
It is not possible in this chapter to cover all
such proposed frameworks, but a couple of
pertinent conceptual frameworks are high-
lighted below.25 All of them can be used to
some degree when discussing the connection
between oral infections and systemic health.
Many recent proposed frameworks of
causation use a common terminology to delin-
eate nuances that need to be addressed, and
familiarity with this terminology will help the
reader to understand the theoretical arguments
supporting causal frameworks (see glossary).
Henle-Koch postulates
The Henle-Koch postulates (Box 1-1),26 for-
mulated in the late 19th century, were a
scheme to establish a causative link between a
Bradford Hill criteria
One of the most influential and revered
medical statisticians of his time, Sir Aus-
tin Bradford Hill is recognized as one of the
pioneers of RCTs.27,28As a statistician and
an epidemiologist, Hill was concerned with
how the medical community interpreted and
subsequently implemented results from obser-
vation and intervention trials. A method and
framework was needed to distinguish correla-
tions that are true signs of cause-and-effect
relationships from those that are not. In his
president’s address to the Section on Occu-
pational Medicine within the Royal Society
of Medicine in 1965, Hill asked, “What cir-
cumstances can we pass from this [respiratory
illness and dust in the environment] observed
association to a verdict of causation?”25 Hill
put forth nine “aspects of association” (criteria,
or causal components), based on epidemiologic
data, that might be used to assess causation

5
1 Causation: Frameworks, Analyses, and Questions

Box 1-2  |  The Bradford Hill criteria27

Strength (of an association). A small or weak association (effect size, odds ratios, relative risks,
etc) does not mean that there is not a causal effect. However, the larger or stronger the association,
the more likely that it is causal.
Consistency. Consistent findings observed by different researchers, across different study designs,
in different populations, among different locations, and with different samples strengthen the like-
lihood of a causal relationship.
Specificity. The more specific an association between a factor (a causative agent) and a specific
outcome (disease) is, the higher the probability of a causal relationship. This is similar to Henle-Koch
postulates 1 and 2.
Temporality. The exposure must precede the outcome.
Biologic gradient. If greater exposure (dose, level, duration) generally leads to greater incidence
of the effect, a stronger causal relationship is assumed.
Plausibility. A known biologic pathway may explain the pathophysiologic link between a risk factor
and the disease in question.
Coherence. The relationships should not conflict with what we know of the disease (consistency
between epidemiologic and laboratory findings). This is similar to Henle-Koch postulate 3.
Experiment. Experimental results from different experimental methods and by different investigators
are useful evidence toward a causal relationship.
Analogy. After finding a relationship between, for example, human papillomavirus (HPV) and cervical
cancer, we may more readily accept that HPV could cause another type of cancer.

(Box 1-2).29 Five of Hill’s proposed criteria
(strength, consistency, specificity, temporality,
and coherence) had already been used in the
1964 Surgeon General’s report on the dangers
of smoking.30 Although this was not Hill’s
intent, his proposed criteria, often referred to as
the Bradford Hill criteria, have since been used
by researchers to “prove” causal associations
between numerous observational associations.
Hill was very careful not to claim that his nine
criteria served as sufficient proof of causation,
instead stating that they could be used as
“evidence toward a causal relationship.” The
increasing complexity of and advancements in
science since the publication of the Bradford
Hill criteria in 1965 have challenged his ini-
tial understanding of causality.31 The Bradford
Hill criteria should, maybe at best, be used as
a screening test to determine whether further
consideration and examination are warranted
to ascertain a causal relationship. Any student
of causation should be familiar with these crite-
ria as they are still frequently called on to make
causal claims, yet the fallibility of the Bradford
Hill criteria has been discussed at length.32 The
Bradford Hill criteria have been mentioned
when discussing a causal link between peri-
odontal disease and systemic illnesses.33–35
Using the Bradford Hill criteria may be a spe-
cious proposition in an attempt to simplify a
complex process and an unattainable goal.
Necessary and sufficient condition
framework
In science, in medicine, and even in the legal
realm, necessary and sufficient conditions are
used to describe a causal relationship between
events (Fig 1-1 and Box 1-3). A necessary con-
dition is a condition that is required for the
occurrence of the effect (outcome or disease),

6
 Frameworks, Classifications, Criteria, and Analyses to Describe and Infer Causation

Constellations of components*

I II III IV V

ID 2 ID 3 8 4 1 4
ID
1 4 1 6 1 3 5 7
5 7 6 6
Causal scenarios Outcomes
PD Possible Possible Possible Never Never
ID is a necessary
A
condition.
Oalt Possible Possible Possible Never Never

PD Always Always Always Possible Possible

ID is a sufficient
B
condition. Oalt Never Never Never Possible Possible

PD Always Always Always Never Never

ID is a necessary and
C
sufficient condition.
Oalt Never Never Never Always Always

ID is a necessary PD Possible Possible Possible Never Never

D but not a sufficient
condition. Oalt Possible Possible Possible Possible Possible

ID is a sufficient PD Always Always Always Possible Possible

E but not a necessary
condition. Oalt Never Never Never Possible Possible

ID is neither a PD Possible Possible Possible Possible Possible

F necessary nor a
sufficient condition. Oalt Possible Possible Possible Possible Possible

See Box 1-3 for more detailed explanations. *Constellations of components:

• I is only composed of one component, ID.
In this example, immune dysfunction (ID) is inves-
• II is a constellation of components (ID, 1, 2, 4, and 5).
tigated as a causative condition for the outcomes
• III is a constellation of components (ID, 1, 3, 6, and 7).
periodontal disease (PD) or an alternative or nonPD
• IV is a constellation of components (1, 3, 4, 6, and 8),
outcome (Oalt).
where in scenario F 8 is a contributory condition.
Scenarios A to F depict how a necessary and
• V is a constellation of components (1, 4, 5, 6, and 7).
sufficient condition framework changes the impact
on outcomes.

Fig 1-1  |  Necessary and sufficient conditions, and combinations of necessary and sufficient conditions.

but a necessary condition can be present with-
out the occurrence of the effect. For example,
sugar must be present for caries to develop
(necessary condition), but sugar can be con-
sumed without the accompanying development
of caries (see Fig 1-1A). A sufficient condition
is a condition that is always followed by the
occurrence of the outcome, but the outcome
can occur without the presence of a sufficient
condition. For example, exposure of a vital
pulp (sufficient condition) will always produce
tooth pain, but tooth pain can also occur by
other means (see Fig 1-1B).

7
1 Causation: Frameworks, Analyses, and Questions

Box 1-3  |  Necessary, sufficient, and combinations of necessary and sufficient conditions

Necessary condition. If component X (CX) is a necessary condition for outcome Y (OY), CX must always be present
for OY. But the presence of CX doesn’t always result in OY, and an alternative outcome (Oalt) may be present. However,
OY can never be present without CX.
See Fig 1-1A. If immune dysfunction (ID) is a necessary condition for periodontal disease (PD), ID must be present
for PD to be present (constellations I, II, and III). The presence of ID does not always result in PD (constellations I, II,
and III). However, PD can never be present without ID (constellations IV and V).
Another example: Mycobacterium tuberculosis (MTB) (CX) must be present for the development of tuberculosis
(TB) (OY). But MTB can be present without the development of TB. However, TB can never develop without the
presence of MTB.

Sufficient condition. If CX is a sufficient condition for OY, CX will always result in OY, but OY can also occur with
alternative conditions (Calt). However, Oalt can never be present in the presence of CX.
See Fig 1-1B. If ID is a sufficient condition for PD, PD will always be present in the presence of ID (constellations
I, II, and III), but other conditions can also cause PD (constellations IV and V). However, ID can never be present
without the presence of PD.
Another example: 38% silver diamine fluoride (CX) will always cause black staining of teeth (OY), but black staining
of teeth can also occur due to other causes.

Both necessary and sufficient. If CX is both a necessary and a sufficient condition for OY, OY cannot happen
without CX, and OY will always happen with the presence of CX. OY never happens without CX, and CX always leads
to OY.
See Fig 1-1C. If ID is both a necessary and a sufficient condition for PD, PD will never happen without ID (con-
stellations IV and V), and PD will always happen as a result of ID (constellations I, II, and III). ID always leads to PD,
and PD never happens without ID.
Another example: The presence of a third chromosome (CX) is a necessary and sufficient condition for the
development of Down syndrome (OY). There is no alternative condition (no Calt) or any alternative outcome
(no Oalt).

The concept of necessary and sufficient con-
ditions is sometimes invoked when describing
deterministic causality models, which are based
on the notion that every event is caused by an
antecedent event and in accordance with the
laws of nature. Expressions of these conditions,
separately and in combination, are also used to
describe specific conditions.
A third type of condition, known as a con-
tributory cause, is neither a necessary nor a
sufficient condition by itself. A contributory
cause needs to fulfill two criteria: “(1) the attri-
bute referred to as the cause has been shown to
precede the effect; (2) altering only the cause
has been shown to alter the effect.”36
The use of the necessary and sufficient con-
dition framework considers each cause either
a necessary condition or a sufficient condition.
This limits a causal relationship to a one-to-one
association between an observed condition or
cause and an outcome.37 A one-to-one causal
model is of course highly unlikely in the bio-
medical arena, and this framework needs to be
extended to allow multiple or constellations
of conditions to explain observed outcomes.
A simple example that is often used when dis-
cussing this concept is the appearance of light
after flipping a light switch from off to on. If
I had little (or no) knowledge of the under-
lying mechanism necessary for the light to
appear (presence of electricity, complete and

8
 Frameworks, Classifications, Criteria, and Analyses to Describe and Infer Causation

Necessary but not sufficient. If CX is a necessary but not sufficient condition for OY, CX is always present for OY
but can also be present without OY; CX by itself does not always result in OY.
See Fig 1-1D. If ID is necessary but not sufficient for PD, ID is required for the presence of PD (constellations I, II,
and III but never IV or V) but can be present without PD (constellations I, II, and III). ID by itself does not always result in
the presence of PD but can result in PD together with other components (constellations I, II, and III).
Another example: HIV (CX) must be present to develop AIDS (OY), but HIV can be present without a person developing
AIDS; the presence of HIV by itself is not enough for the development of AIDS. An alternative constellation of conditions
(Calt) that includes HIV could have brought about AIDS, but HIV by itself could also result in an alternative outcome (Oalt).

Sufficient but not necessary. If CX is a sufficient but not necessary condition for OY, CX will always result in OY, but
CX is not necessary for OY and OY can happen without CX.
See Fig 1-1E. If ID is sufficient but not necessary for PD, ID will always result in PD (constellations I, II, and III), but
PD can happen without ID (constellations IV and V).
Another example: Full-mouth extraction (CX) will always cause edentulism (OY), but full-mouth extraction is not the
only reason for edentulism, and edentulism can happen in the absence of full-mouth extraction under alternative con-
ditions (Calt). However, there is no alternative outcome (no Oalt) (nonedentulism) when full-mouth extraction is present.

Neither necessary nor sufficient. If CX is neither a necessary nor a sufficient condition for OY, then when CX occurs
OY will sometimes happen. However, OY can also occur without CX. The condition sometimes leads to the outcome, and
sometimes the outcome can occur without the condition. There may be another unknown or alternative condition (Calt)
(contributory condition) that is neither necessary nor sufficient for OY.
See Fig 1-1F. If ID is neither necessary nor sufficient for PD, then sometimes when ID is present PD is present.
However, PD can also occur without ID. ID sometimes leads to PD, and sometimes PD can be present without ID
(constellations I, II, III, IV, and V). There may be another or alternative component (contributory condition) (component
8 in constellation IV) that is neither necessary nor sufficient for PD.
Another example: Although there is an association between low socioeconomic status (SES) and periodontal disease,
low SES (CX) on its own is not required for the development of periodontal disease (OY), and periodontal disease may
occur in the absence of low SES due to a different condition that is neither necessary nor sufficient (Calt).

fully functioning wiring, intact lightbulb, etc), I
might be warranted in claiming that flipping the
switch caused the light to appear. More knowl-
edge makes a causal claim much more complex.
Furthermore, this example also highlights that
a mechanistic requirement, or a biologic path-
way, which was discussed by Hill, has to be
considered.
Sufficient-component framework
In the sufficient-component framework, suffi-
cient cause is used to indicate a complete causal
mechanism that includes a minimal set of com-
ponents (conditions and events) that together
are sufficient for the effect or outcome to occur38
(see Fig 1-2). Each component must be present
or must have occurred for the outcome to hap-
pen. This framework allows for different causal
mechanisms. As highlighted in the hypothetical
example in Fig 1-2, different combinations of
single component causes provide a sufficient
causal mechanism. When considering the cause
of a disease, many of the sufficient components
may be unknown, and it is therefore wise to
include one component cause, labeled U, to
represent unknown determinants38 (see Fig
1-2). In the sufficient-component model, all
the components are essential, and blocking
the contribution of one prevents the onset of
the disease.

9
1 Causation: Frameworks, Analyses, and Questions
I II
A A
U B U B U G
D C F E
A hypothetical example: What causes coronary
artery disease (CAD)?
Single component causes:
A = genetic susceptibility to develop CAD
B = oral inflammation
C = presence of atheroma
D = immune dysfunction
E = p resence of a specific oral bacteria
(eg, Porphyromonas gingivalis)
F = metastasis of oral bacteria
G = metastasis of toxin from oral bacteria
H = bacteremia
I = presence of biofilm
U = unspecified events
Fig 1-2  |  Sufficient-component model of causation. (Adapted from Rothman and Greenland32 and Rothman.38)
Counterfactual framework
When flying out of Buffalo, New York, to
attend a meeting in San Francisco, I decided
to travel via Newark rather than through Chi-
cago. Unfortunately, due to delays of incoming
flights to Newark, my onward flight from New-
ark to San Francisco was severely delayed and I
missed my meeting in San Francisco. I lamented
that if I had taken the Chicago connection, I
would have been on time for my meeting.
A binary outcome event is an outcome event
(attending a meeting on time in San Francisco)
that always occurs after one exposure but not
after the other (arriving on time for my meeting
in San Francisco after traveling either through
Newark or Chicago). Therefore, a causal effect
(my travel route) of a binary event is not neces-
sarily a sufficient cause (the outcome can occur
10
III
Each “pie” is composed of multiple single component
A causes that together represent a sufficient cause of
disease. I, II, and III each depict a causal mechanism.
This model depicts a multicausal framework rather
I H
than a single cause of disease.
The causal mechanisms for CAD are proposed to be the
joint presence of multiple single components:
I. Genetic susceptibility to develop CAD, oral
inflammation, presence of atheroma, immune
dysfunction, and unspecified events
II. Genetic susceptibility to develop CAD, oral inflam-
mation, presence of P gingivalis, metastasis of oral
bacteria, and unspecified events
III. Genetic susceptibility to develop CAD, metastasis
of toxin from oral bacteria, bacteremia, presence
of biofilm, and unspecified events
A component cause (eg, genetic susceptibility to
develop CAD [A]) that appears in all sufficient causes
is a necessary cause of the outcome. An unspecified
event (U) component should always be considered.
by two events, flying via Newark or via Chi-
cago) but has to be a necessary cause (the one
route that took me to San Francisco) without
which the event (attending the meeting on time)
would not have occurred. As only one outcome
will actually occur (in this case, I missed my
meeting in San Francisco), the other outcome is
not observed (I would have arrived in time for
my meeting in San Francisco if I had traveled
via Chicago) and is known as the counterfac-
tual or potential outcome. Events that can be
considered by an “if” statement are known
as counterfactuals, where the “if” portion of
the counterfactual is called the hypothetical
condition (or antecedent) that may lead to the
unobserved or the counterfactual (unrealized,
potential, or maybe untrue) outcome.
We often use counterfactual arguments in
dentistry. For example, “if he had brushed his
 Frameworks, Classifications, Criteria, and Analyses to Describe and Infer Causation
teeth, he wouldn’t have developed gingivi-
tis.” In essence, this counterfactual argument
implies that brushing his teeth would have pre-
vented the development of gingivitis. Or stated
differently, not brushing his teeth caused the
development of gingivitis.
It would be difficult to apply a counterfactual
cause scenario to the oral infection–systemic
health connection. Using the example of peri-
odontal disease and diabetes: If poor metabolic
control was observed in individuals not treated
for periodontal disease and good metabolic
control was observed in individuals treated for
periodontal disease, can we claim that peri-
odontal disease affected metabolic control?
The shortcoming of this argument is that good
metabolic control cases cannot be tested twice,
with and without periodontal treatment. For
example, if we measure equal proportions of
poor metabolic control in the treatment and
control groups, we cannot tell how many cases
of poor metabolic control are actually attribut-
able to the lack of periodontal treatment itself.
It is quite possible that many of those patients
with good metabolic control who underwent
periodontal treatment would, if left untreated,
have had good metabolic control, and, simul-
taneously, many of those with good metabolic
control who did not receive periodontal treat-
ment would have developed poor metabolic
control if treated. Thus, we cannot use the
argument that as lack of periodontal treatment
resulted in poor metabolic control, periodontal
treatment will cause good metabolic control.
Although it has been argued that causal
relationships can be elucidated from experi-
mental studies, the example above suggests
that this is not always true. One reason for this
conundrum is that experimental studies cannot
always affirm or separate the effect of attribu-
tion (what portion/percentage of cases of good
metabolic control could be attributed to a spe-
cific exposure, such as periodontal therapy) and
the effect of susceptibility (what portion/per-
centage of cases with good metabolic control
who did not undergo periodontal treatment
would have developed poor metabolic control
even if they had been treated for periodontal
disease) on experimental data.
Probabilistic framework
A probabilistic cause framework explains the
relationship between cause and effect using
the tools of probability theory. Contrary to
the deterministic cause model, the probabilis-
tic cause framework provides an estimate—a
probability rather than certainty—of an event
occurring. This model is sometimes used to esti-
mate the effect of dose-dependent relationships.
For example, as was mentioned previously,
sugar is a necessary cause for the development
of caries. But could there be a daily consump-
tion threshold for sugar where caries will
always develop (a sufficient cause)? In this theo-
retical example, sugar consumption is not static
but is associated with an action (increasing the
amount of sugar) and can thus be perceived in
accordance with a probabilistic causal frame-
work, as it might be possible to estimate the
probability of such an event occurring.
The probabilistic model may be useful to
estimate the probability that oral infections
may cause a systemic illness. In other words,
if oral infections have consistently and with a
high degree of probability been shown to be
associated with a systemic outcome, we may be
able to claim that the oral infections probably
caused such an outcome, with a caveat that
such a claim can only be made after random-
ized controlled experiments.
Spurious relationships
The presence of spurious (false or bogus) cor-
relations has been recognized for more than
100 years.39 There are several tongue-in-cheek
examples published in even very prestigious
journals. One example is the claim that choc-
olate consumption will increase cognitive
function. The author showed that “there was a
close, significant linear correlation (r = 0.791,
11
1 Causation: Frameworks, Analyses, and Questions
P < .0001) between chocolate consumption
per capita and the number of Nobel laure-
ates per 10 million persons in a total of 23
countries.”40 The author points out that “it
seems most likely that in a dose-dependent
way, chocolate intake provides the abundant
fertile ground needed for the sprouting of
Nobel laureates. Obviously, these findings are
hypothesis-generating only and will have to be
tested in a prospective, randomized trial,” but
“a second hypothesis, reverse causation—that
is, that enhanced cognitive performance could
stimulate countrywide chocolate consump-
tion—must also be considered.”
Unfortunately, spurious correlations are often
espoused as scientifically valid cause-and-effect
relationships both in the lay press and on social
media, where they are propagated by mech-
anisms such as Facebook “likes.” Fallacies
such as post hoc ergo propter hoc and cum
hoc ergo propter hoc (see glossary) can also
sometimes be viewed as spurious relationships.
An inability to differentiate between spurious
relationships and valid causal relationships
may have dire consequences, which has been
amply demonstrated by the efficacy of snake
oil and other fraudulent claims.
Does Periodontal Disease
Cause Systemic Illnesses?
Let’s consider periodontal disease a surrogate
for oral infections and ask whether we can
actually claim that periodontal disease causes
systemic conditions according to the proposed
frameworks above.
Bradford Hill criteria
If we apply each criterion suggested by Brad-
ford Hill, we will discover many inconsistencies
that would make it difficult to use these crite-
ria to ascertain a causal relationship between
periodontal disease and systemic illness. Some
12
of the challenges with using the Bradford Hill
criteria are delineated here.
Strength: Strong associations are more likely
to be causal than weak associations.
Specific bacteria may be strongly associated
with periodontal disease and may therefore
be considered a cause of periodontal disease.
However, an immune dysfunctional environ-
ment may also be a risk factor for periodontal
disease. Immune dysfunction is a confounder
as it is associated with both the exposure
(enabling the growth of specific bacteria) and
the outcome (clinical manifestations of peri-
odontal disease). Confounders can make what
appears to be a strong association seem causal
when it is not. However, consistent findings of
greater magnitudes of association would bol-
ster claims for a causative relationship.
Consistency: Repeated observations of an
association are made under different circum-
stances and in different populations.
As most systemic illnesses are associated with
multiple causes, a single association, such
as periodontal disease, may be statistically
significant and consistent across different pop-
ulations and circumstances but still may not be
enough to explain the entire causal mechanism.
We need to recognize that periodontal disease
by itself may be neither a necessary condition
nor a sufficient one.
Specificity: A cause leads to a single effect.
It is not possible to claim that periodontal dis-
ease will only cause a single systemic illness.
Furthermore, if the Bradford Hill criteria are
essential to establish periodontal disease as a
cause, the specificity criterion would negate
the possibility that periodontal disease may
be the cause of several very different systemic
outcomes. A very influential epidemiology
textbook published many years ago even
stated that “specificity does not confer greater

validity to any causal influence regarding the
exposure effect … the criterion is useless and
misleading.”41
Temporality: The cause needs to precede the
effect.
It is very difficult to determine the onset of
periodontal disease or most systemic illnesses
among cohorts in observational studies. Deter-
mining the onset of oral infections may be
more straightforward.
Biologic gradient: Greater exposure leads to
greater incidence of the effect.
Although we use a grading system to describe
the level of severity of periodontal disease,
the factors responsible for increased severity
may not be the same factors responsible for a
potential causal relationship with a systemic
condition.
Plausibility: A biologic rationale exists for an
association.
Several plausible biologic mechanisms, for
example inflammation, can explain a causal
relationship between periodontal disease and
systemic conditions.
Coherence: A cause-and-effect interpretation
of an association should not conflict with what
is known about the biology and pathogenesis
of the disease.
Periodontal pathogens have been found in
atheromas in individuals with coronary artery
disease (CAD). They have also been shown to
induce platelet aggregation, which is a stage in
the pathogenesis of CAD. Similar findings have
been made in individuals with other systemic
consequences, such as adverse pregnancy out-
comes. The question that needs to be asked is
this: If the periodontal pathogens were removed,
would we still have the same outcomes?
Does Periodontal Disease Cause Systemic Illnesses?
Experiment: Experimental evidence may iden-
tify a factor as a potential cause when removal
of the factor or a change in its frequency will
prevent the outcome.
As periodontal disease has never been shown to
be a necessary or a sufficient condition for the
development of a systemic condition, a change
in a systemic outcome may be associated with
confounders or effect modifiers and not the
removal of periodontal disease (Box 1-4).
However, randomized controlled intervention
trials, comparing individuals with successfully
treated periodontal disease with individuals
with unsuccessful periodontal care, where all
other potential determinants or prognostic fac-
tors are kept the same between the two groups,
may provide evidence of a causal relationship.
Analogy: Identifying a causative factor in
one disease may strengthen the assertion of
observing similar outcomes with the same
causative factor.
Knowing that periodontal disease is an
inflammatory condition strengthens claims
for periodontal disease as a causative factor
for systemic conditions that are known to be
inflammatory in nature, but many other anal-
ogies could also be proposed.
Overall, if we apply the Bradford Hill cri-
teria to other causal frameworks, it is unclear
whether a given criterion is a necessary condi-
tion, a sufficient condition, or a combination
of necessary and sufficient conditions, or
how it can be viewed in a counterfactual or a
sufficient-component causal mechanism model.
However, as highlighted above, several of the
Bradford Hill criteria (strength, consistency,
temporality, biologic gradient, and plausi-
bility) can be used as norms when assessing
the impact of periodontal disease on systemic
conditions.
13
1 Causation: Frameworks, Analyses, and Questions

Box 1-4  |  An example to determine the difference between a confounder and an effect modifier

In a hypothetical cohort study, we measured the association between the treatment of periodontal disease (TxPD+)
versus no treatment for periodontal disease (TxPD−) (exposures) with the risk of having a myocardial infarction
(MI+) (outcome). We found that TxPD− increased the risk of MI+, with a relative risk (RR) of 2.7 (95% confidence
interval [CI]: 2.2–2.9).

Initial study
MI+ MI− Risk of MI+ RR of MI+

TxPD− a b a/(a + b) a / (a + b)

= 2.7
TxPD+ c d c/(c + d) c / (c + d)

However, other cross-sectional studies have shown that smoking is also a risk factor for MI+. We now wanted
to know if smoking was responsible for our result. So we divided our study participants into two subgroups—
smokers and nonsmokers.

Scenario 1
We found that among the subgroup of smokers TxPD− increased the risk for MI+ with an RR of 3.0 (95% CI:
2.6–3.2), but among the nonsmoking subgroup TxPD− increased the risk for MI+ with an RR of only 1.3 (95%
CI: 0.9–1.6). There must have been a modification of the causal pathway of TxPD− to MI+ by smoking, as the
exposure had a different effect among different subgroups. Smoking must have been the risk factor that modified
the effect of TxPD+ to achieve the result in our original study.

Smokers
MI+ MI− Risk of MI+ RR of MI+
TxPD − a b a/(a + b) a / (a + b)
= 3.0
TxPD + c d c/(c + d) c / (c + d)

Nonsmokers
MI+ MI− Risk of MI+ RR of MI
TxPD − a b a/(a + b) a / (a + b)
= 1.3
TxPD+ c d c/(c + d) c / (c + d)

Necessary and sufficient condition
framework
Periodontal disease is not a necessary condi-
tion, as the systemic conditions that have been
linked to periodontal disease have been asso-
ciated with other causes without the presence
of periodontal disease. Periodontal disease is
not a sufficient condition, as the presence of
periodontal disease does not always cause a
specific outcome (systemic condition). Accord-
ingly, periodontal disease is neither a necessary
nor a sufficient condition.
Although periodontal disease, specifically
the presence of periodontal pathogens, has
been suggested as a contributory cause of
cardiovascular disease,42 no study has ever
been published that fulfills the two criteria

14
 Does Periodontal Disease Cause Systemic Illnesses?

Scenario 2
We found that among the subgroup of smokers TxPD− decreased the risk for MI+ with an RR of 0.9 (95% CI:
0.7–1.1), and among the subgroup of nonsmokers TxPD− decreased the risk for MI+ with an RR of 0.7 (95% CI:
0.6–1.1). Thus, our original finding that TxPD− increased the risk for MI+ (RR of 2.7 [95% CI: 2.2–2.9]) must be
incorrect. In scenario 2, the RR for MI+ with TxPD− did not change in either subgroup of smokers or nonsmokers,
and a factor that was associated with both the exposure and the outcome but does not lie in the causative
pathway—a confounder (smoking)—must have been present.

Smokers
MI+ MI− Risk of MI+ RR of MI+
TxPD − a b a/(a + b) a / (a + b)
= 0.9
TxPD+ c d c/(c + d) c / (c + d)

Nonsmokers
MI+ MI− Risk of MI+ RR of MI+
TxPD− a b a/(a + b) a / (a + b)
= 0.7
TxPD + c d c/(c + d) c / (c + d)

Scenario 3
Among the subgroup of smokers the RR with TxPD− is 2.2 (95% CI: 2.0–2.4), while among the subgroup of
nonsmokers the RR with TxPD− is 2.7 (95% CI: 2.5–2.9). This means that the smoking is neither a confounder
nor an effect modifier.

Smokers
MI+ MI− Risk of MI+ RR of MI+
TxPD− a b a/(a + b) a / (a + b)
= 2.2
TxPD + c d c/(c + d) c / (c + d)

Nonsmokers
MI+ MI− Risk of MI+ RR of MI+
TxPD − a b a/(a + b) a / (a + b)
= 2.7
TxPD+ c d c/(c + d) c / (c + d)

If, in a subgroup analysis, which is based on a suspected confounder or a suspected effect modifier, the orig-
inal association holds up in one subgroup but not in another, the factor is an effect modifier. But if the original
association between the exposure and outcome does not hold up in both subgroups, the factor is a confounder.

15
1 Causation: Frameworks, Analyses, and Questions
(temporality and treatment effect) necessary
to make such a claim.
Sufficient-component framework
In the sufficient-component causal mechanism
model, each and every component is necessary.
As far as we know, there are no systemic condi-
tions that cannot occur without the presence of
periodontal disease. Thus, periodontal disease
cannot be a single-component cause.
Counterfactual framework
The definition of periodontal disease and the
parameters used to assess periodontal disease
vary greatly.43 Thus, it would be very difficult
to assess the effect of periodontal disease on
systemic outcomes using a counterfactual
framework, as the effect on a systemic outcome
may be directly determined by how periodontal
disease is defined. On the other hand, because
periodontal pathogens may affect systemic con-
ditions such as coronary heart disease (CHD),
it may be possible to infer that the absence of
periodontal pathogens would prevent or miti-
gate the development of such conditions. RCTs
may be able to test this hypothesis.
A comprehensive causal mechanism may be
considered a binary outcome event scenario
because a set of factors, when considered
together, cause a binary outcome event. Thus,
omission of just one factor would change the
outcome. Because many of the systemic ill-
nesses linked to oral infections can be caused
by a multitude of mechanisms, it would not
be possible to single out oral infections as a
cause using a counterfactual cause model. The
same argument was put forth when discussing
the shortcomings of the Bradford Hill criteria.
For example, if the strength of an association is
weak, we cannot conclude that a strong associa-
tion might have resulted in a different outcome.
16
Probabilistic framework
Numerous observational studies have found
strong measures of association, such as
absolute risk, relative risk, odds ratio, mean dif-
ference, and standardized mean difference, that
can be used to claim causal inference. There is
no universal agreement on what is considered
a strong or weak association, as there are no
absolute numbers that could apply to all study
designs, populations, or circumstances. How-
ever, there is little disagreement that extremely
high and consistent measures of associations
(eg, odds ratios in the range of 10 to 15 or
more) can be used to make causal inferences.
For example, the odds ratio associated with
developing lung cancer in male smokers ranges
from a low of 9 to more than 50 depending
on the number of cigarettes smoked per day.44
But measures of association of this magnitude
or even close to those found in smokers that
develop lung cancer have never been seen in the
literature for the periodontal-systemic link. It
is unclear what the lowest number to make a
causal inference might be.
It may be possible to claim that strong
measures of association are enough to infer
causality and that there is no need to ascertain
a true causative effect using existing criteria or
frameworks. This may be the case when ethical
concerns prohibit conducting RCTs. For exam-
ple, it would be unethical to conduct a RCT to
ascertain whether smoking causes lung cancer.
Additional Strategies to
Assess Causation
The difficulties associated with conduct-
ing RCTs have spurred the search for better
methods to determine causal inference from
observational studies. Two of these methods
are discussed in the sections that follow.

Z (the instrumental variable [IV]) is associated
with the exposure (effect) X; X is associated
with the outcome (disease) Y; Z is indirectly
associated with Y through X; U, the unknown
or unmeasured confounder, is associated with
both X and Y.
1. Z (the IV genotype, single nucleotide poly­
morphisms, or allele) must not associate with
(is independent of) U (confounders [eg, age,
sex, smoking status, education level]).
2. Z must reliably associate with X (obesity).
3. Z must not associate with (independent of)
Y (periodontal disease), given X and U; or,
there is no pathway from Z to Y without going
through the exposure of interest, X.
Observational studies have found an association
between obesity and periodontal disease. As most of
these are cross-sectional studies, a causative relationship
cannot be established. An RCT where the risk for devel-
oping periodontal disease is compared between two
groups, one where obesity is “assigned” to a treatment
group and no obesity to a control group, obviously cannot
be conducted to establish a causative relationship.
It is known that specific genotypes (Z) are associated
with obesity (X), and these genotypes are not associated
with other risk factors for obesity (U) or for periodontal
disease (Y). It is possible to determine the presence of
periodontal disease in two groups of individuals with
Fig 1-3  |  Instrumental variable method to generate a causal estimate.
Instrumental variable
Instrumental variables (IVs) can be used
as a nonconfounded proxy and control for
threats to internal validity in observational
studies, such as confounding variables, mea-
surement error, and reverse causality. When
used correctly, IVs allow for the possibility of
making causal inferences from the analysis of
(cross-sectional) observational data even in the
presence of unmeasurable confounders.45
An instrument within the IV framework is
the Z variable that (1) has a causal effect on
X (the actual exposure or intervention), (2)
affects the outcome (Y), and (3) only affects
Additional Strategies to Assess Causation
Z is not associated with Unmeasured
(is independent of) U confounders
U
Z X Y
Genotype Obesity Periodontal
disease
Z is not associated with (is independent of) Y
the same risk for developing periodontal disease (the
same prognostic characteristics), where one group has
a genetic propensity to develop obesity and the other
group does not. If obesity is not a causal risk factor for
periodontal disease, we would expect similar findings of
periodontal disease in individuals with a genetic predis-
position to obesity and in individuals without a genetic
disposition to obesity. In other words, the pathway to
periodontal disease in those with a genotype for obesity
and those without did not have to pass through obesity.
See Shungin et al48 for more specifics about how it was
determined that obesity was not a causal risk factor for
periodontal disease.
the outcome Y through X, yet (4) there also
exists an unknown confounder (U) that directly
affects both X and Y but is not affected by
Z46,47 (Fig 1-3). For example, if smoking (X)
affects periodontal disease (Y), will encourag-
ing or not encouraging smoking cessation (Z,
something that will directly affect only smok-
ing and not the presence of periodontal disease)
explain the changes in the outcome (presence
of periodontal disease)? If Z can explain the
observed effect on Y, is it possible to argue for
a causal relationship even if the confounder U
cannot be measured or corrected for?
For example, a recent study used IVs to
test the popular saying, “gain a child, lose a
17
1 Causation: Frameworks, Analyses, and Questions
tooth.” The authors exploited random natu-
ral variation in family size resulting from (1)
the birth of multiples vs singletons, and (2)
the sex composition of the two firstborn chil-
dren (increased likelihood of a third child if
the two firstborn children are the same sex).
The findings suggest that an additional birth
might indeed be detrimental to the mother’s
oral health but not the father’s.49
The IV method is similar to the counter-
factual model of causation but differs in that
Z is an actual intervention and not part of a
thought experiment.47 In purely observational
studies (in which neither the instrument Z nor
the treatment X has been subject to experimen-
tal manipulation), a major limitation of all IV
methods is their strong reliance on the assump-
tion that Z is truly independent of U and Y.
Mendelian randomization, an
instrumental variable construct
As Gregor Mendel discovered during his exper-
iments with genes for pod colors in pea plants,
different forms of a specific gene—alleles—were
associated with altered observable phenotypes.
An allele is one of a pair or series of genes
that appears at a specific location (locus) on a
particular chromosome and controls the same
characteristic, such as eye color. A change in
allele at a specific genetic loci is called a genetic
variant and is responsible for observable phe-
notypical traits. Humans have two alleles at
each genetic position, one inherited from each
parent. Mendel’s law of segregation states that
alleles for a trait separate when gametes (cells
that carry half of the genetic information of
the parent from which they are inherited) are
formed through meiosis. These allele pairs are
then randomly united at fertilization. Thus,
alleles are produced randomly. Alleles are not
associated with subsequent behavioral, social,
or environmental influences, and subsequent
behavioral, social, or environmental exposures
cannot change the fixed genotypes as these are
determined at the time of conception. These
18
specific characteristics of alleles—randomiza-
tion, lack of effect of subsequent exposures,
and lack of effect of subsequent exposures
on the fixed genotype—can be exploited to
discover the effects of confounders in obser-
vational studies.
There are several limitations of epidemio-
logic studies that thwart attempts at making
causal inferences. Some of these limitations can
be mitigated with properly and appropriately
conducted RCTs. The presence of confound-
ers and reverse causation are acknowledged as
some of the main reasons for the discrepancy
between an inference of causal relationships
obtained from observational data analysis and
study outcomes from RCTs. A novel type of
investigation, the Mendelian randomized (MR)
method, involves finding alleles that are asso-
ciated with a specific exposure and examining
the association between these genetic variants
and the outcome. The randomization of alleles
makes MR akin to an RCT (Fig 1-4).50
The basic premise of MR is that genotypes
are generally not susceptible to the confound-
ing found in observational studies.51,52 The
underlying concept of MR is to take advan-
tage of situations where genotypic differences
produce effects similar to environmental fac-
tors (and vice versa) and use genetic variants
as proxies for environmental exposures rather
than measure the exposures themselves. This
is similar to IV analysis where the allele is the
IV (see Fig 1-4).
This methodology has already been used
to determine how confounders may affect the
association between biomarkers and clinical
outcomes, such as C-reactive protein (CRP) and
incident coronary events. Observational studies
have suggested an association between the pres-
ence of CRP and an elevated risk for CHD, but
when the MR method (using genetic proxies for
CRP concentration) was employed it failed to
confirm that CRP is a risk factor for CHD.53,54
In other studies using MR, a causal relationship
could be confirmed between individuals who
were homozygote for an allele associated with
higher plasma homocysteine and stroke.55

Mendelian randomization
Random segregation of alleles
Exposure: Exposure:
alleleEa1 alleleEa2
All prognostic
characteristics are
the same
between groups
Compare results
Fig 1-4  |  Comparison of Mendelian randomization with RCTs. (Adapted from Smith and Ebrahim.50)
MR was performed to assess the associa-
tion between obesity (measured by body mass
index) and periodontal disease (clinically
assessed and self-reported) in a multicentered
cohort of more than 49,000 individuals.48 This
study could not support a causal relationship
between absolute adiposity and periodontitis.
Using MR to investigate a causal relation-
ship between oral infections and systemic
health would provide important information
to help ascertain the veracity of such an asso-
ciation. However, as with other frameworks
used to assess causality, MR is not a panacea to
determine causal relationships, and challenges
remain to interpreting MR analyses.52
Conclusion
RCT
Randomized method
Exposure: Exposure:
interventionEi1 interventionEi2
All prognostic
characteristics are
the same
between groups
Compare results
Conclusion
This chapter does not provide an exhaustive list
of methods and concepts used in the context of
causal inference. Some constructs and frame-
works not mentioned in this chapter include
directed acyclic graphs, regression-discontinuity
design, difference-in-difference analysis, and
propensity score matching.2,56,57
Furthermore, the frameworks, methods, and
criteria discussed in this chapter cannot account
for all possible ways cause operates. Awareness
of the difficulties in establishing causality and
recognition that many different concepts are
used in the scientific literature will enhance the
discussion on this important topic. However,
when a claim of causal inference is made, it is
important to know which framework, method,
19
1 Causation: Frameworks, Analyses, and Questions
or analysis was used to reach that conclusion.
How else can a claim be judged?
The benefits of establishing a true caus-
ative relationship between oral infections and
systemic outcomes are clear—improved pre-
vention strategies, better prognostic assessment
of disease development, better treatment strate-
gies, and overall improved patient benefits, just
to mention a few. But what would be the down-
side of claiming a causative relationship where
none exists? Resources that could be spent on
beneficial health strategies would be wasted;
patient expectations, such as reducing adverse
pregnancy outcomes by periodontal therapy or
preventing heart attacks and strokes, would not
be met; and there may be legal ramifications
from arguing that expenditures should be made
to achieve an outcome that cannot be realized.
The inability to determine causal infer-
ences should not deter us from recognizing
the associations that have already been estab-
lished between oral infections and systemic
health. These associations should serve as an
important springboard to improve interpro-
fessional education, practice, and research and
to provide better and more science-based pre-
vention, interventions, and reimbursement in
a value-based health care model. But we must
be careful not to overstate the impact of these
associations. In the end, it might be worthwhile
to take note of (but not necessarily agree with)
Bertrand Russell’s claim that “the law of cau-
sality, I believe, like much that passes muster
among philosophers, is a relic of a bygone age,
surviving, like the monarchy, only because it is
erroneously supposed to do no harm.”
Glossary
antecedent  The “if” portion of a counterfac-
tual or hypothetical condition.
antecedent event  “Going before,” or an
event preceding another event.
association  A relationship between an expo-
sure or characteristic and an outcome, such
20
as a disease, that is statistically dependent;
that is, the presence of one alters the proba-
bility of observing the presence of the other.
causal inference  Use of a measurement of
an effect.
causative chain with component cause  Mul-
tiple, joint causes for the occurrence of the
outcome.
component cause  An event required for an
outcome to develop.
confounder  A factor that is associated with
both the exposure and the outcome but
does not lie in the causative pathway. Con-
founders should be eliminated to prevent
misrepresentation of research findings. Con-
founders differ from effect modifiers (see
effect modifier).
confounding  More than one possible indepen-
dent variable (cause) acting at the same time.
correlation  A statistical measure of an asso-
ciation; linear association between two
continuous or ordinal variables. A correla-
tion is not sufficient to claim causation.
counterfactual  Nonexistent or false. An out-
come, after exposure to a determinant or an
agent of change, is compared in a thought
experiment with the same outcome but with-
out a determinant or an agent of change. For
example, suppose you examine a patient and
discover she has a 6-mm pocket depth on
the mesial side of the mandibular right first
molar, so you decide to insert a biodegrad-
able chip containing a new pharmaceutical
agent in the pocket. After 1 month, her
pocket depth is only 3 mm. Did this outcome
occur because of the chip? You compare the
outcome—reduced pocket depth—which
you observed, with the counterfactual out-
come, which you would have observed if
you had chosen not to insert the chip in the
pocket (a thought experiment). If you think
the outcome would have been different—no
reduction in pocket depth—if a chip had not
been inserted, you will conclude that the chip
caused the reduction in pocket depth.
cum hoc ergo propter hoc  Latin for “with
this, therefore because of this.” This fallacy

is commonly used to infer a causal relation-
ship when two events occurring together are
taken to have a cause-and-effect relationship.
However, such a temporal relationship does
not by itself imply a causative relationship.
As an example, we can infer that wearing
bathing suits causes consumption of ice
cream as there is an observed association
between the presence of wearing bathing
suits and ice cream consumption.
effect modifier  An exposure that has a differ-
ent effect among different subgroups and lies
in the causal pathway. Effect modifiers are
not associated with the exposure but with
the outcome. An effect modifier (a third fac-
tor) can be used to change the magnitude of
the effect. Effect modifiers differ from con-
founders (see confounder).
event  Any assignment of a value or set of val-
ues to a variable or a set of variables; specific
occurrence.
external validity  Refers to how well data and
theories from one setting apply to another;
also known as generalizability or the exten-
sion of research findings and conclusions
from a study conducted on a sample or study
population to the population at large.
necessary condition  If X is necessary for Y
(necessary condition), it means that X must
be present for Y to happen. In other words,
a necessary condition (X) means that the
outcome (Y) can never happen without the
condition (X). However, the condition can
occur without the outcome. (For examples,
see Fig 1-1.)
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23

Essential Statistical and Research
Design Elements to Help Critically
Interpret the Literature
Barbara L. Greenberg, msc, phd
Michael Glick, dmd
Clinical researchers, translational researchers,
and consumers of scientific literature strive
to inform and guide clinical care and health
policy development to optimize the health and
well-being of patients and populations. An
overwhelming amount of scientific literature is
published every day on the connection between
oral and systemic disease. For example, a
search of the literature on the link between
periodontal disease, diabetes, and cardiovas-
cular disease suggests that, on average, one new
article has been indexed in PubMed every day
for the past 10 years (Fig 2-1). Unfortunately,
many of these articles report studies with dif-
ferent and even dichotomous results. Yet oral
health care professionals have a responsibility
to interpret and use this scientific information
to inform the practice of dentistry and affect
the overall health of patients.
The clinical literature produced is unfortu-
nately not of equal quality, and merely being
published does not ensure quality. Producers
of scientific literature have a responsibility
to appropriately and thoroughly report and
interpret results, while consumers of scientific
literature have a responsibility to critically read
and understand the literature. Thorough assess-
ment of the research quality of the literature
is a complex, multifaceted endeavor that in its
entirety is beyond the scope of this chapter.
Instead, this chapter focuses on several critical
24
CHAPTER 2
elements used to assess the literature on the
link between oral and systemic health, includ-
ing determination of the clinical importance
of study results.
There is a misconception that if something
is statistically significant it is also clinically
important, and if something is not statistically
significant it is not clinically important. This
is not necessarily true. This chapter presents
the basic concepts that are essential for under-
standing and determining statistical significance
and clinical importance. The terms clinically
meaningful, clinically important, and clinically
relevant are often used synonymously; in this
chapter these terms are collectively referred to
as clinically important. Clinical importance
is distinct from clinical significance, which is
defined later in the chapter.
A discussion of statistical and clinical
importance first assumes that the study (1) is
answering an important question, (2) is well
designed, (3) is well implemented, and (4) is
properly analyzed. However, the discussion
must also include, among other things, P val-
ues, α level, confidence intervals (CIs), minimal
clinically important differences (MCIDs), and
effect size. The purpose of this chapter is to
facilitate the interpretation of these fundamen-
tal elements for understanding and determining
statistical and clinical importance when con-
suming scientific literature.
 Overview of Statistical Significance

400

350

Number of publications indexed on PubMed

50% since
2008
300

250

200

150

100

50

0
49

53

58

62

66

70

74

78

82

86

90

94

98

02

06

10

14

18
19

19

19

19

19

19

19

19

19

19

19

19

19

20

20

20

20

20
50% 50%
Year

Fig 2-1  |  Periodontal disease, diabetes, and cardiovascular disease in humans: number of PubMed citations
by publication year as of March 15, 2018 (N = 6,343). For the past 10 years, one publication has been indexed
in PubMed almost every day on the links between periodontal disease and diabetes and between periodontal
disease and cardiovascular disease, with 50% of the total published in 2008 or later.

Overview of Statistical submission for publication, there is a growing

Significance
The purpose of research is to make inferences
from a study sample that can be applied to
the total population, whether it is to determine
if there is an association between a risk fac-
tor or characteristic and the development of
disease, to determine treatment efficacy, or to
derive appropriate inferences about a causal
relationship. Statistical significance testing
is the process of reaching conclusions about
characteristics of a larger population using
data from a subset, or sample, of that pop-
ulation, and it is the fundamental approach
for making such inferences. Although statis-
tical significance testing is commonly used
and is sometimes required for acceptance of a
sentiment among biostatisticians that research
should move away from reporting only statisti-
cal significance and P values and instead focus
on CIs and effect size to assess precision and
clinical importance.1,2
Most research is hypothesis driven, with
a null hypothesis (H0) that states there is no
statistically significant association between
a factor and an outcome and an alternate
hypothesis (H1) that states there is a statistically
significant association. The alternate hypothesis
is what the researcher is predicting or expect-
ing. The null hypothesis is what the researcher
tries to disprove; statistics test the null hypoth-
esis of no association. Although this may sound
counterintuitive, it is similar to the approach
used in the United States judicial system when
someone is accused of a crime. The accused is

25
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature
presumed innocent, and the jury is asked to
reject or not reject this “hypothesis.”
Based on the outcome of the statistical test,
the null hypothesis is rejected or not rejected.
When a statistical test result for a given study
is significant, the null hypothesis is rejected;
when the test result is not significant, the null
hypothesis is not rejected. The null hypothesis
is not the opposite of the research hypothesis;
the null hypothesis is “no association.” A test
of statistical significance answers the following
question: If the null hypothesis were true, what
is the probability that a difference (or an asso-
ciation) at least as big (or as strong) as the one
observed would occur, assuming that chance is
operating alone?
A statistically significant result suggests that
the observed association is not likely assum-
ing chance alone is operating and is evidence
to infer a real association between a predictor
and an outcome. Remember, we are studying
a sample drawn from a larger population and
we are interested in whether what we observe
in the study sample is also happening in the
population the sample is supposed to represent.
Statistical significance provides a measure to
help us make that decision.
In summary, significance testing addresses
only the yes/no question of whether there is
a statistically significant association that is
unlikely to be due to chance alone. Statistical
testing is a formal process for determining the
probability of obtaining the observed study
results or an outcome more extreme given that
the null hypothesis is true; it is not an indica-
tion of the probability of a real association. But
it is important to keep in mind that study out-
comes, even when determined to be statistically
significant, may not confer any clinical impor-
tance or may not be scientifically meaningful.3
26
How Do We Determine
Statistical Significance?
Hypothesis testing is based on the α level and
P value. The α level is the level of statistical sig-
nificance that is set a priori by the investigator.
By convention, for epidemiologic observational
and clinical trials, the α level is typically set
at .05. However, there may be circumstances
where multiple null hypotheses are being tested
and one wants to minimize type I errors, for
example in genome-wide association studies
(GWASs). In such instances, the α level may be
set at much smaller values depending on what
is being investigated. In the case of GWASs, the
α level may be 10−8 or even smaller.4 A type I
error is the incorrect rejection of a true null
hypothesis, also known as a false positive find-
ing. A type II error is the incorrect failure to
reject the null hypothesis when it is false, also
known as a false negative finding (Fig 2-2).
The α level can be defined as the probability
of rejecting the null hypothesis when in fact
it is true or the risk of concluding there is an
association when none exists. An α level of
.05 means there is a 5% probability that one
will incorrectly reject the null hypothesis of no
association and conclude there is an association
when in fact there is none. In other words, by
predetermining an α level of .05, we accept
that there is a 5% probability of reaching a
false positive result. When testing the efficacy
of two drugs or treatments, the P value is used
to determine if the difference is statistically sig-
nificant. In this instance, a P value that is not
significant (P ≥ α) indicates that for the given
study data, the difference in the two drugs or
treatments is not statistically significant. That
should not be interpreted to mean that the two
drugs or treatments are the same; the correct
interpretation is that there is insufficient evi-
dence to conclude that the drugs or treatments
are different. Studies designed specifically to
assess if two drugs or treatments are the same
often require very large sample sizes.
 How Do We Determine Statistical Significance?

Study on the impact of periodontal treatment (TxPD) on adverse pregnancy outcomes (APO)
Hypothesis (H1) = TxPD will result in fewer APO
Hypothesis (H0) = TXPD will not affect APO

True difference
Study outcome after
providing periodontal treatment No impact
Fewer APO;
on APO;
H0 “false”
H0 “true”

Reject H0 Correct Type I error

Not reject H0 Type II error Correct

Fig 2-2  |  Example of hypothesis testing with type I and type II errors.

The P value is the probability that the
observed result, or one that is more extreme,
differs from the null hypothesis (no association),
assuming chance is operating alone and the null
hypothesis is true. The P value evaluates how
well the study data support the null hypothe-
sis and answers the question of how likely the
observed effect is in the given study sample data
if the null hypothesis is true. There are many
reasons for a difference between the observed
data and the null hypothesis if the null hypoth-
esis is true. As it is not known why a difference
may exist, the P value is the computed proba-
bility assuming chance was operating alone or
merely the probability that the observed out-
come is due to chance.5 To determine statistical
significance, the calculated P value is assessed
relative to the a priori set α level. A P value
less than the α level (P < α) indicates that the
observed study results are not likely to be due
to chance alone and suggests that the study
data provide sufficient evidence to reject the
null hypothesis; the study results are considered
statistically significant. A P value greater than
or equal to the α level (P ≥ α) indicates that the
study data are likely under the null hypothesis
and there is insufficient evidence to reject the
null hypothesis; the study results are considered
not statistically significant. With a significant P
value, the null hypothesis is rejected; with a P
value that is not statistically significant, the null
hypothesis is not rejected.
While statistical significance based on the P
value is a ubiquitous concept in the literature,
there are a number of pitfalls and limitations
of the P value, and incorrect interpretations
of it are very common.5 The P value is not a
measure of support for the alternate hypothe-
sis that there is an association or difference; a
statistically significant finding does not mean
that the alternate hypothesis is accepted, nor is
it the probability of mistakenly rejecting a true
null hypothesis. The P value addresses only the
question of how likely the study data are given
the null hypothesis.
In summary, the P value is a point estimate
that assesses how well the data support the null
hypothesis of no association; it is not a measure
of support for the alternate hypothesis. The P
value does not provide information about how

27
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature
TABLE 2-1  |  Questions answered by P value versus CI
Description
P value A calculated probability
CI A calculated parameter ± a margin of errora
The margin of error determines the width of the CI.
a
well the study was designed or conducted, nor
does it provide a measure of the strength of
an association or difference. The P value alone
should not be the primary influence for clinical
interpretation or application of study results to
clinical decision making.
How Do We Evaluate Clinical
Importance?
As noted earlier, a study outcome can be statis-
tically significant but not clinically important
or meaningful. Likewise, a study outcome that
is not statistically significant can be clinically
important or meaningful. The concepts used
beyond the P value include CI, MCID, and
effect size.
Confidence interval
The CI is used to obtain information beyond
the statistical significance of a result and to
begin to assess clinical importance. The CI
represents the magnitude of the association
or difference observed and the precision of
the estimate of the association or difference,
or how much uncertainty is associated with
the point estimate from the given study data.
This is in contrast to the P value, which only
answers the yes/no question of whether the
observed association or treatment difference
is statistically significant (Table 2-1).
28
Questions answered
• How well do the study sample data support the null hypothesis? Do
we reject or not reject the null hypothesis?
• Is there a statistical association? How likely are the observed results or
a more extreme result assuming chance is operating alone?
• What is the size of the association or treatment difference?
• How precisely did the given study or trial estimate the association or
treatment effect?
• Is there a statistical association?
The CI is a range of values that attempts
to quantify the level of uncertainty that this
range will include the desired true population
value as determined by a specific parameter.
Examples of a parameter include an arithmetic
mean, a difference, an odds ratio, or a relative
risk, each of which will have a certain calcu-
lated value. The desired true parameter for a
population is what we try to infer from the
result of a sample from the population. Thus,
CIs are based on sample data and give ranges
of plausible values for the true parameter. The
CI consists of the point estimate ± a margin
of error (level of precision, which is depicted
as the width of the CI) that provides a lower
and an upper confidence limit around the point
estimate. The lower and upper confidence lim-
its delineate the range for the estimate, and
the difference between the lower and the upper
limit indicates the width of the CI. The width
of the CI depicts the magnitude of the effect. A
wide interval has more uncertainty (usually due
to a small sample size or a high degree of mea-
surement variability), but the results may still
be statistically significant though not always
clinically important. The wider the interval, the
less precise the estimate and the more difficult it
is to make a clinical interpretation. Figures 2-3
and 2-4 show graphic representations of CIs.
Typically, the CI calculated is the 95% CI.
This means that if a study is repeated indef-
initely and a 95% CI is placed around each
sample parameter, 95% of the intervals will
contain the true (population) parameter. In

Clinical assessment of marginal bone loss and gain after the use of an experimental bone
augmentation material used in six different studies
Harmful
Probably harmful
Almost certainly
harmful
–1.0 –0.8 –0.6 –0.4
Bone loss
The box is the point estimate of the CI. The CI has a lower and an upper limit, represented by the vertical lines at the end of each horizontal line.
The distance between the lower and upper limit represents the width of the CI. The determination of what is harmful, trivial, or beneficial is based
on prior clinical knowledge.
Fig 2-3  |  Example of CI and effect. (Adapted from Page.6)
other words, the 95% CI contains the true
value in 95 of 100 studies performed. Thus,
with the 95% CI there is a 95% probability
that an interval calculated from the sample data
contains the true population value; it does not
mean that there is a 95% chance that the true
population value lies within the calculated CI
for any given study. To provide more certainty
that the interval contains the true population
value, the 99% CI could be calculated; how-
ever, this interval is wider but less precise than
the 95% CI. For any calculated CI (eg, 95% or
99%), the wider the interval is, the less precise
it is; a wider CI implies poorer precision.
For any given parameter of interest, there is a
“no effect” or “null value,” the value indicating
there is no association, no effect, or no differ-
ence. For a ratio the null value is 1, and for a
difference the null value is 0 (see Table 2-2).
For example, a study is performed to determine
the risk of developing an adverse pregnancy
How Do We Evaluate Clinical Importance?
Unclear Beneficial
Almost certainly beneficial
Probably beneficial
Very likely trivial
Unclear
–0.2 0 0.2 0.4 0.6 0.8 1.0
Bone gain
No change
outcome from data comparing a group of
pregnant women who received periodontal
treatment with a group of pregnant women
who did not receive periodontal treatment. If
the quotient of the estimated risk of developing
an adverse pregnancy outcome in the group
of pregnant women who received periodontal
treatment divided by the estimated risk in the
group of pregnant women who did not receive
periodontal treatment equals 1 (the risk ratio
equals 1), we can determine that there is no
difference (1, in this case, is the null value).
A CI that does not contain the null value is
considered statistically significant and will cor-
respond to a significant P value (P < .05); a CI
that contains the null value is considered not
statistically significant and will correspond to a
calculated P value that is not statistically signif-
icant (P ≥ .05). A CI that does contain the null
value indicates that the true population param-
eter could indeed be equal to the null value so
29
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature

Marginal bone loss and gain after the use of an experimental bone
augmentation material used in five different studies (A–E)

A
Not statistically significant; not clinically important
B
Statistically significant; clinically important
C
Statistically significant; probably clinically important
D
Not statistically significant; not clinically important
E
Not statistically significant; potentially clinically important

Difference
–0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0 in mm

Relevance limit (MCID)

Lines represent lower and upper limits of CI and mean differences.
Guidelines for determining level of clinical importance:
• While the “0” difference will aid in determining the statistical difference (if the CI crosses the 0, we state that there is no statistical significance),
the MCID will aid in determining clinical importance.
• Definitely not clinically important: study A—the MCID lies within the CI but is larger than the study point estimate; study D—the MCID lies outside
the upper limit of the CI and is larger than the study point estimate.
• Probably clinically important: study C—the MCID lies within the interval of the CI and is smaller than the study point estimate.
• Potentially clinically important: study E—the MCID lies within the interval of the CI and is smaller than the study point estimate, but the wide CI
also suggests potentially no clinical importance. (The difference between study C and study E is the width of the CI, and calling one “probable”
and one “potential” is a semantic difference where “probable” denotes more certainty than “potential.”)
• Definitely clinically important: study B—the MCID lies outside the lower limit of the CI and is smaller than the study point estimate.

Fig 2-4  |  Example of CI, significance, and MCID.

TABLE 2-2  |  Assessing statistical significance using CIs and P values

Null Assessing significance using Assessing significance using

Parameter value the CI the corresponding P value
Difference: mean difference, CI contains 0 = not significant P ≥ .05
standardized mean difference, 0
risk difference, rate difference CI does not contain 0 = significant P < .05

Ratio: relative risk, odds ratio, CI contains 1 = not significant P ≥ .05

1
rate ratio CI does not contain 1 = significant P < .05

that one cannot reject the null hypothesis of no
association. Table 2-2 shows the null value for
a given parameter and guidelines for assessing
statistical significance with the CI and P value.
Overlapping CIs do not necessarily mean there
is no statistical significance.
In addition to the calculated CI, there are
key clinical indicators set by the investigator or
accepted among clinicians that help determine

30

the clinical importance of study results. These
include MCID and effect size.
MCID and effect size
The MCID is the smallest change considered
meaningful by a practitioner or patient and/
or that would result in a change in patient
management. There are no standards for deter-
mining the MCID other than clinical judgment
or widely accepted clinical standards for a
given outcome of interest.
The effect size is the magnitude of the desired
difference between groups or the magnitude of
the desired observed association that is consid-
ered clinically important. There are different
measures of effect, including means, standard-
ized means, relative risks, odds ratios, and
absolute risks. The desired or expected effect
size should be established at the outset of the
study, reported in the manuscript, and when
appropriate (ie, in comparing results with dif-
ferent measurement units), standardized across
the different units of measurement. The larger
the effect size, the easier it is to find statistical
significance. The determination of the desired
effect size is based on previous literature and/
or clinical knowledge. When setting the desired
effect size, important considerations include a
change that is of interest to patients or clini-
cians, a change in an important outcome (eg,
any outcome that may alter treatment deci-
sions), and the associated risk-benefit ratio.
Assessing clinical importance
using the CI and effect size or MCID
The CI indicates the magnitude and direction
of the effect. In addition to statistical signifi-
cance, the CI in conjunction with the a priori
effect size can be used to assess whether the
given study results are trivial, beneficial, or
harmful. A CI that is greater than the null
value and includes or exceeds a desired positive
effect size would be considered beneficial; a CI
that is less than the null value and includes a
How Do We Evaluate Clinical Importance?
harmful effect size would be considered harm-
ful or potentially harmful. A CI that includes
the null value and crosses the threshold for a
beneficial and harmful effect would be con-
sidered unclear. Figure 2-3 presents a graphic
representation of CI and effect size.
Similarly, if the CI contains or is less than
the MCID, the results would not be clinically
important because the true population param-
eter could be less that the MCID. If the CI is
greater than the relevance limit or MCID, the
result is considered clinically important because
this indicates the true population parameter is
greater than the MCID. A graphic represen-
tation of the CI and the MCID is shown in
Fig 2-4.
As an example, a randomized controlled
trial (RCT) that assessed the effect of non-
surgical periodontal treatment reported a
statistically significant improvement in the
metabolic control (P = .019) between indi-
viduals with type 2 diabetes receiving therapy
compared with individuals not receiving the
therapy.7 Using available data provided in the
article, 95% CIs placed around the reported
sample means could be calculated. After 6
months, the treatment group had a reported
mean fasting plasma glucose of 150.02 mg/dL
(standard deviation [SD] 49.54; n = 42) com-
pared with 167.95 mg/dL (SD 41.90; n = 48)
for the control group. The calculated 95% CI
was 135.04 to 165.00 in the treatment group
and 156.10 to 179.80 in the control group.
How should these results be interpreted? For
the purpose of this study question and given
these data, the CIs are considered sufficiently
narrow. This would suggest that the data are
sufficiently precise. However, the difference
between the resulting CIs does not seem to be
clinically important, as neither group achieved
metabolic control (< 126 mg/dL); there is an
overlap between the two CIs, and the differ-
ences between the lower limits and between the
upper limits do not seem clinically important
at this level of poor metabolic control. Further-
more, the authors did not mention an MCID.
Thus, the clinical impact of the observed data
31
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature

Did investigator
assign exposure?

YES NO
Experimental study Observational study
Random allocation? Comparison group?

YES NO YES NO

Randomized Nonrandomized Analytical study Descriptive study

controlled controlled
trial trial Direction?

Exposure   Outcome Exposure   Outcome Exposure   Outcome

Cohort Case- Cross-

study control sectional
study study

Cohort study: Study groups are defined by an exposure, and the exposure is tracked forward in time to an outcome.
Case-control study: Study groups are defined by an outcome, and the outcome is traced backward to an exposure.
Cross-sectional study: The exposure and the outcome are assessed in the study group at the same time (a snapshot in time).

Fig 2-5  |  Classification of study designs. (Adapted from Grimes and Schulz.10)

for this particular patient population within
this particular clinical setting is unclear, as it
is unclear if the difference in outcomes would
have changed any therapeutic interventions,
had any impact on the quality of life of
patients, or affected potential complications
and comorbidities.
The width of the CI indicates the precision
of the data. There is no set range that is consid-
ered wide; this is based on clinical knowledge
and judgment and the characteristics of the
chosen measurement tool, such as measure-
ment error. A wide CI could also be a function
of a poorly implemented study.
CIs are not always reported, and the data
provided in a study do not always enable
calculation of a CI.8 This is unfortunate, as a
P value does not provide enough information
to inform clinical practice.
In addition to considering an outcome clini-
cally important as previously described, there is
also the concept of clinical significance, which
encompasses the additional element of statisti-
cal significance. For a finding to be considered
clinically significant, it should incorporate three
features: (1) the difference or change in the
outcome observed between the experimental
group and the control group is of interest to
someone (clinician or patient); (2) this differ-
ence or change is observed in what is defined as
an important outcome; and (3) the difference
or change reached statistical significance.9

32
 Study Designs

SR

Critically
Filtered
appraised
information
topics

Critically appraised
individual articles
e
enc
vid

Bia
of e

Randomized controlled trials

s
lity
Qua

Unfiltered
Cohort studies
information

Case-control studies/
Case reports/Case series

Cross-sectional epidemiologic studies/

Narrative reviews/Expert opinions

Fig 2-6  |  Quality of evidence and level of bias in different study designs. The quality of evidence increases from
the base toward the top of the pyramid as the rigor of the study design increases. The bias increases going from
the top toward the base of the pyramid. SR, systematic reviews.

Study Designs exposure, also called observational studies (Fig

A major goal of epidemiologic research is to
explain patterns of disease occurrence and
to make causal inferences. There are several
measures to quantify associations, such as odds
ratios and relative risks, and there are different
study designs that can answer particular ques-
tions. The specific question being asked and
the available data, together with matters such
as ethical concerns and resources, will dictate
the suitable study design. This section provides
a brief overview of different study designs and
highlights the appropriateness and inappropri-
ateness of specific research designs.
Applied epidemiologic and clinical research
is typically divided into two major types of
investigations: (1) studies where an exposure
is being assigned, also called experimental
studies, and (2) studies without assigning an
2-5). As the rigor of the study design increases,
the potential bias decreases and the quality of
the evidence increases (Fig 2-6).
Experimental trials
RCTs, considered the gold standard for clinical
epidemiologic and translational research, are
the most rigorous study design, are typically
used to assess the effectiveness of a treatment
or an intervention, and provide the strongest
epidemiologic evidence for making causal
inferences on the relationship between an expo-
sure or treatment and an outcome. The terms
randomized trials, randomized clinical trials,
randomized controlled trials, and randomized
placebo-controlled trials are often used inter-
changeably in the literature. The hallmark of
a randomized trial is the random allocation

33
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature
or assignment of study participants to treat-
ment, intervention, or exposure groups. The
main purpose of randomization is to minimize
selection bias on the part of the investigator.
In addition, randomization often increases
comparability of the treatment groups for
variables we can measure as well as those we
are not aware of or cannot measure, thus min-
imizing the impact of potential confounders.
(A confounder is a factor that is associated
with both the exposure and the outcome but
does not lie in the causative pathway; see page
20.) However, to ensure that frandomization
produces comparable groups, investigators
should always assess similarity of the study
groups at baseline for relevant known clini-
cal and demographic characteristics and other
potential prognostic characteristics. In other
words, the chance of achieving the study out-
come should be the same in the intervention
(treatment, exposure) group and the noninter-
vention group (also referred to as the control
group or placebo group if a placebo is being
used) if an intervention had not been assigned.
Another important design element of RCTs that
reduces the potential for bias is blinding; in sin-
gle blinding or masking, the study participants
are unaware of what treatment group they are
assigned to; in double blinding, both the inves-
tigator and the study participants are unaware
of the group assignment. A well-designed and
implemented RCT can therefore minimize
selection bias, information bias (blinding of
both participants and research personnel), and
confounding (the intervention group and the
control group are potentially exposed to the
same confounders). Another advantage of an
RCT is the certainty of the temporal relation-
ship (which comes first) between an exposure
(in this case, treatment or intervention) and
an outcome.
However, there are drawbacks associated
with RCTs. The inclusion criteria for partic-
ipant selection is often restrictive, as RCTs
usually address a very specific condition among
a very select demographic that is healthy other
than the condition of interest. Therefore,
34
results from an RCT may be difficult to gen-
eralize (external validity) because a “normal”
population may have many characteristics or
other conditions that differ from those of the
study population. For example, it would not be
possible to generalize the results from a study
that looked at the success rate of immediate
versus delayed placement of dental implants
if the exclusion criteria for the study popula-
tion included factors that could have affected
the outcome (eg, success rate) and are com-
monly found in the general population, such
as smoking, systemic diseases, medications,
or periodontal disease. Furthermore, individ-
uals that volunteer to participate in medical
research are often healthier than the general
population.
Another issue with RCTs is a potential eth-
ical concern, as randomization is not always
ethical.11 It would obviously be unethical to
assign a known harmful exposure to individuals
to compare the outcome to a group that was
not exposed to the harmful exposure. Another
example of an ethical concern is when indi-
viduals suffering from a disease with a dire
outcome, such as cancer, are randomized to an
intervention group that receives a new drug that
may potentially be beneficial and another group
is given a placebo when there is a known ther-
apy available with some degree of effectiveness.
However, this is no longer common practice.
Measures of association for RCTs include
relative risks and odds ratios, with the relative
risk being the preferred measure. The known
temporal relationship between the exposure
and the outcome allows for calculation of the
incidence or risk of developing the outcome
of interest, and the relative risk is the ratio of
the incidence of the outcome in the exposed
group to the incidence of the outcome in the
nonexposed group. Relative risk is discussed
further in the next section.
One way to assess the rigor of an RCT is
to ascertain whether the reporting of the RCT
follows the Consolidation of Standards for
Reporting Trials (CONSORT) guidelines.12
Other resources are websites where trials are

supposed to be registered prior to their initia-
tion,13 such as clinicaltrials.gov, administered by
the US National Library of Medicine.14
Observational studies
Analytical observational studies (studies that,
contrary to descriptive studies, include a
comparison or control group) include cohort
studies, where a group of individuals free
of the disease/outcome of interest with and
without the exposure of interest are followed
prospectively forward in time; case-control
studies, where individuals with (cases) or
without (controls) the outcome of interest are
traced backward in time to determine possible
exposure; and cross-sectional studies, where
exposure and outcome are measured at the
same time (see Fig 2-5).
As mentioned previously, unlike with RCTs,
the exposure in observational studies is not
assigned but observed in groups of interest.
Cohort studies are prospective in nature and
compare outcomes in groups (cohorts) of par-
ticipants with an exposure to a similar group of
participants without an exposure (but having
the same risk for developing the outcome). In
short, participants in the exposed and unex-
posed groups need to be similar in all aspects
except for their exposure; all prognostic charac-
teristics must be the same. In this study design,
it is important to establish that the study par-
ticipants are free of disease at the start of the
study and to have a clear, measurable definition
of exposure and outcome. For example, two
groups (cohorts) of adults shown to be free of
periodontal disease, one group that smokes cig-
arettes (the exposure) and one group that does
not use tobacco at all, are followed forward in
time for the development of periodontal disease.
The two groups should be similar, with similar
risk factors for the development of periodon-
tal disease, except for the fact that participants
in the exposure group smoke cigarettes and
participants in the control group do not. The
outcome of interest, the development of peri-
odontal disease, will be assessed after 2 years.
Study Designs
Because participants are free of the outcome
(periodontal disease) at the onset of the study,
this type of study design can determine whether
the development of the outcome is associated
with the exposure based on the difference in
incidence (the development of the disease over
a specific time period) between the two groups.
Overall, cohort studies always move forward,
but the data collection might not. For example,
investigators can use existing dental records to
identify individuals at risk for and not at risk
for developing periodontitis according to a
defined past exposure (eg, flossing), as long as
they can determine that at the time of expo-
sure the individuals were free of disease. The
identified individuals are then tracked forward
in time to determine who developed periodon-
titis. In other words, the study uses historical
data to determine disease-free status and still
looks forward from exposure to outcome. This
is referred to as a retrospective cohort study.
Given that individuals are disease free at
the study outset, cohort studies can determine
incidence rates in the exposed and nonexposed
groups. Also, it is possible to determine tempo-
rality when conducting cohort studies because
the exposure always occurs before the outcome.
However, cohort studies may suffer from selec-
tion bias if baseline prognostic characteristics
are not adequately accounted for with similar
distribution in each cohort, and there is always
a risk of losing study participants during the
progression of the study such that the final study
sample is a biased sample. The relative risk, the
measure of disease association in cohort stud-
ies, is the proportion of participants who will
develop the outcome in the cohort with expo-
sure as a ratio of (divided by) the proportion of
participants who will develop the outcome in
the cohort without the exposure. Relative risk
is the incidence of the outcome in the exposed
group relative to the incidence of the outcome in
the nonexposed group and provides a measure
of the risk of developing disease if exposed.
Information to pay attention to when
interpreting cohort studies includes concerns
with information bias, loss to follow-up, and
35
2 Essential Statistical and Research Design Elements to Help Critically Interpret the Literature
whether potential confounders were controlled
for.
In case-control studies, researchers begin
with an observed outcome and then try to ret-
rospectively determine the presence of exposure.
Cases used in this study design are those with
the outcome of interest, and the controls are a
comparable group (with the same prognostic
characteristics except for the presence of the
outcome of interest) based on a well-defined
definition of the outcome. The selection and
source of cases and appropriate controls are
critical in case-control studies, but it is beyond
the scope of this chapter to discuss this concern
in more detail. In brief, cases should be rep-
resentative of all cases in the population and
controls should be representative of all controls
in the population from which they were drawn.
For example, cases of adults with periodontal
disease are compared to adults without peri-
odontal disease to determine if an exposure,
such as smoking cigarettes, is associated with
the presence of periodontal disease. In this study
design, the investigator can only assess the prev-
alence of disease, as there is no way to ensure
that the exposure happened before the disease
process began. If a greater proportion of cases
(adults with periodontal disease) have a history
of smoking cigarettes compared to the controls,
smoking cigarettes may be associated with the
presence of periodontal disease.
As case-control studies do not have a true
denominator of at-risk individuals, and because
the temporal relationship of exposure and out-
come is not clearly established, case-control
studies cannot use the relative risk as a measure
of association and instead use the odds ratio
(the odds of exposure among the cases as a ratio
of [divided by] the odds of exposure among
the controls) as a measure of association. In a
case-control study, the odds ratio assesses the
odds of exposure if disease is present. The odds
ratio can be used as a measure of disease associ-
ation in a cohort study, and in that study design
the odds ratio assesses the odds of developing
disease given exposure, but it is not as strong a
measure of association as the relative risk. It is
36
always important to ascertain that the partic-
ipants in the control group have the same risk
of developing the outcome (same prognostic
characteristics) as do the cases.
When reading studies using a case-control
design, the appropriateness of the control
group should be ascertained by determining
whether all potential biases that could influence
the outcome were controlled for and whether
the controls represent the population at risk
of becoming cases. It is often difficult to make
this determination, as the needed data are not
always available.
A cross-sectional study assesses the presence
or absence of an exposure and the presence
or absence of an outcome at a particular time
(prevalence of the exposure and prevalence
of the outcome). Researchers may determine,
at a particular time, the presence of children
with or without caries that consume or do not
consume sugar-containing beverages. As this
determination represents a snapshot in time, it
is not possible to know if the consumption of
the sugar-containing beverages occurred prior
to the development of caries (a temporal rela-
tionship), and accordingly, if consumption of
sugar-containing beverages is associated with
the development of caries. Cross-sectional
studies cannot be used to claim causative rela-
tionships and are typically used for prevalence
studies or to develop a hypothesis to be tested
in more rigorously designed studies.
Case reports and case series are purely
descriptive and may, similar to other observa-
tional studies, help generate hypotheses about
exposure and outcomes that need to be tested
with higher-quality study designs. Descriptive
studies are also used to monitor the health of
populations and assess trends over time. With-
out comparison groups and consideration of
temporality, inferences about causality are not
appropriate. One concern with descriptive
studies is that sometimes the case definition
is not clearly specified or the study cannot be
reproduced. This is true of any type of study
that requires a clearly defined case definition or
a clearly defined diagnostic outcome.

The nature of the question being asked and
the data and financial resources available will
dictate the most appropriate study design.
Questions about the effectiveness or harm-
fulness of a therapy or intervention are best
answered by RCTs. Cohort and case-control
studies are the most appropriate study designs
to begin to answer questions about etiology
and risk factors. In some instances, ethical con-
siderations will preclude RCTs being conducted
with human volunteers (eg, studies of smoking
and lung cancer). In these instances, data from
cohort and case-control studies may provide
the necessary information if there is consistency
across outcomes and strong enough measures
of association.15 For questions about prognosis,
cohort studies may be the most appropriate;
questions about diagnosis may be answered by
cross-sectional and case-control studies.
Conclusion
Given the large volume of literature on the
oral-systemic disease connection and the
varying conclusions and quality of what is
published, it is incumbent upon clinicians to
critically interpret what they read. This chapter
provides a basic overview of fundamental sta-
tistical concepts and research design elements
to facilitate interpretation and application of
research findings into clinical decision making.
References
1. Rothman KJ. Disengaging from statistical significance.
Eur J Epidemiol 2016;31:443–444.
2. Poole C. Low P-values or narrow confidence intervals:
Which are more durable? Epidemiology 2001; 12:
291–294.
3. Berry DA. P-values are not what they are cracked up
to be. The American Statistician Online Discussion.
https: //amstat.tandfonline.com/doi/suppl/10.1080/00
031305.2016.1154108/suppl_file/utas_a_1154108_
sm5342.pdf. Accessed 27 February 2018.
Further Reading
4. Ioannidis JP. Preventing tooth loss with biannual dental
visits and genetic testing: Does it work? J Am Dent
Assoc 2015;146:141–143.
5. Greenland S, Senn SJ, Rothman KJ, et al. Statistical
tests, P-values, confidence intervals, and power: A
guide to misinterpretations. Eur J Epidemiol 2016; 31:
337–350.
6. Page P. Beyond statistical significance: Clinical inter-
pretation of rehabilitation research literature. Int J Sports
Phys Ther 2014;9:726–736.
7. Mauri-Obradors E, Merlos A, Estrugo-Devesa A, Jané-
Salas E, López-López J, Viñas M. Benefits of non-
surgical periodontal treatment in patients with type 2
diabetes mellitus and chronic periodontitis: A random-
ized controlled trial. J Clin Periodontol 2018; 45:
345–353.
8. Teeuw WJ, Kosho MX, Poland DC, Gerdes VE, Loos
BG. Periodontitis as a possible early sign of diabetes
mellitus. BMJ Open Diabetes Res Care 2017; 5:
e000326.
9. Brignardello-Peterson R, Carrasco-Labra A, Shah P,
Azarpazhooh A. A practitioner’s guide to developing
critical appraisal skills: What is the difference between
clinical and statistical significance? J Am Dent Assoc
2013;144:780–786.
10. Grimes DA, Schulz KF. An overview of clinical research:
The lay of the land. Lancet 2002;359:57–61.
11. Nardini C. The ethics of clinical trials. Ecancermedical-
science 2014;8:387.
12. The CONSORT Statement website. http://www.consort-
statement.org/. Accessed 20 February 2018.
13. Kotsakis GA. Mandatory trial registration in oral health
research. Long overdue? J Am Dent Assoc 2017;148:
353–356.
14. ClinicalTrials.gov website. https: //clinicaltrials.gov.
Accessed 20 February 2018.
15. United States Department of Health, Education and
Welfare. Smoking and Health: Report of the Advisory
Committee to the Surgeon General of the Public Health
Service. Public Health Service Publication No. 1103.
Washington, DC: United States Public Health Service,
1964.
Further Reading
Gordis L. Epidemiology, ed 5. Philadelphia: Elsevier Saun-
ders, 2014.
Modulsky H. Intuitive Biostatistics: A Nonmathematical
Guide to Statistical Thinking, ed 4. New York: Oxford
University, 2017.
Guyatt G, Rennie M, Meade MO, Cook DJ. Users’ Guides
to the Medical Literature: A Manual for Evidence-Based
Clinical Practice, ed 3. New York: McGraw-Hill Edu-
cation, 2015.
37

The Traveling
Chapter Title Oral
The Traveling
Chapter Title Oral Microbiome
Microbiome
Michael Glick,
Wenche S. Borgnakke,
dmd dds, mph, phd
Microbes are everywhere. Each time we breathe
in, we inhale a million microbes or more,
depending on where we are. Many remain
trapped in our nostrils, but countless continue
into our bodies; fortunately, the overwhelming
majority cause no harm.
Science is now focused on identifying
microbes and all other living organisms, thanks
to novel technologies and computer capabilities
of formerly unthinkable power. Collectively, the
microorganisms in the oral cavity—bacteria,
archaea (one-celled, nucleus-free organisms
formerly classified as archaebacteria), fungi,
viruses, and protozoa—have been referred to as
the oral microflora, oral microbiota, and more
recently, the oral microbiome. While the term
microbiome refers strictly to the total pool of
genetic material in a particular environment,
whereas microbiota encompasses the entirety
of the microbes, these terms are used synon-
ymously to refer to all nonhuman organisms
that inhabit the human body inside and out.
Our understanding of the human oral micro-
biome is currently in a groundbreaking phase
of development in which science has to rethink
and rewrite large parts of what was hitherto
known. High-throughput genetic-based assays,
powerful and novel bioinformatics tools, and
superfast computers recently have made it
possible to comprehensively survey the human
oral microbiome to identify and determine the
38
CHAPTER 3X
prevalence of previously unknown or not cul-
turable organisms.
The ability to fully describe the microbiome
that inhabits the human body, including the
oral microbiome, suggests a need to reexamine
these microbes and their relationship to health
and disease. The use of these methods sheds
new light on the role of the oral microbiome
in periodontal disease and other oral diseases
as well as in systemic diseases and conditions.
This new insight will lead to novel therapeutic
advances that will initiate future changes in
clinical practice. We have yet seen only the very
tip of the iceberg. The sky is the limit.
“I” Am Really “We”
Perhaps it is time for each of us to think of
ourselves and our commensal microbes (usu-
ally present and living in or on our bodies) as
constituting a “we” rather than an “I.” That
is, each of us can be considered a collective
microbiome–human body “superorganism.”
The rough estimate that the number of micro-
bial cells (1014) outnumbers our roughly 100
trillion human cells (1013) in the human body
by a ratio of 10:1 is due to only two papers
from the 1970s.1,2 However, recent estimates of
3.8 × 1013 (one-celled) bacteria and 3.0 × 1013

human cells put this ratio at about 1.3:1, with
an uncertainty of 25% and a population varia-
tion of 53% for a standard male of 70 kg/154.3
lb.3,4 In other words, there are almost equal
numbers of microbial and human cells in the
human superorganism. As an aside, red blood
cells constitute the overwhelming majority of
human cells, namely about 84%.3,4 Whereas
muscle and fat cells represent the vast majority
of the weight of the superorganism, bacteria
have a total mass of about 0.2 kg/0.44 lb.4
Further knowledge regarding the human
microbiomes that inhabit various body loca-
tions (eg, nose, oral cavity, intestines, female
reproductive tract, outer part of the urinary
system, and skin) may in the future be used in
combination with metagenomic information
to identify individuals at high risk for specific
diseases and thereby enable individualized
preventive and therapeutic care, referred to as
precision medicine, in which the oral microbi-
ome plays a pivotal role. Researchers are just
now beginning to understand some aspects of
this role.
Unlearn the Learned
Concepts
Concept 1: “Periodontal pathogen” no more?
Old knowledge. Specific periodontal pathogens
(bacteria and possibly other microbes living in
the periodontal sulcus or pocket) are especially
“virulent” and cause periodontal disease.
New knowledge. Depending on the microbe-
host environment interaction and the technique
used for their detection, disease severity will
vary, and different members of the oral micro-
biome will be identified in varying proportions
in subgingival plaque.
Subgingival plaque from 15 smokers and 15
nonsmokers was studied using three different
methods to identify the presence of bacteria.5
With two of the methods, the researchers found
Unlearn the Learned
no differences between smokers and nonsmok-
ers in the proportions of the members of the
microbiomes. In contrast, sequencing of the
16S ribosomal RNA (rRNA) revealed that
some genera were more abundant in nonsmok-
ers and others in smokers. This third method
also showed that participants with more severe
periodontal disease, particularly smokers, had
fewer varieties of microbes. Considering find-
ings from previous studies as well as their own,
Bizzarro et al wrote that “the ‘pathogenic role’
of few specific species is questionable. Thus,
we consider now the identification of a few
targeted species for diagnostic purposes to be
an out-of-date procedure.”5
Concept 2: Could periodontal bacteria actually
be a consequence, and not the cause, of
periodontal breakdown?
Old knowledge. Specific periodontal pathogens
cause periodontal tissue breakdown. Mainly
gram-negative, anaerobic bacteria cause peri-
odontal disease. Clusters of microbes live in the
plaque in the periodontal sulcus. They develop
into a more mature ecosystem that eventually
morphs into the most mature, complex, patho-
genic biofilm that causes further breakdown of
periodontal tissues.
New knowledge. Periodontal breakdown in
susceptible individuals creates an environ-
ment suitable for particular oral microbes,
which then flourish. Deep periodontal pockets
provide an environment deprived of oxygen
that enhances habitation by certain anaerobic
bacteria.
Bartold and Van Dyke6 questioned whether
the so-called periodontal pathogenic bacteria
really are the cause or may be a consequence of
the chronic inflammation known as periodon-
titis. They agreed with Löe et al7 who more
than 50 years ago showed that host-parasite
interactions cause gingivitis. The oral microbi-
omes form an ecosystem that maintains health
when in equilibrium. Bartold and Van Dyke6
39
3 The Traveling Oral Microbiome
contend that the host is largely responsible for
the complex alterations in the local periodontal
environment that disturb this healthy homeosta-
sis and facilitate the switch of commensal flora
to an opportunistic pathogenic flora. Therefore,
the authors concluded that such changes are
caused mostly by the host, not by the bacteria.
Emerging evidence supports the major role
of host responses modulated through genetic,
immunologic, and inflammatory responses;
stress; smoking; diet; social determinants; and
general health—which have been identified as
risk indicators for periodontitis8–10—as being
the major determinants of the outcomes of
periodontitis. Therefore, the overgrowth of
periodontal microbes may well be a result of
the periodontal tissue breakdown and not the
cause of periodontitis.
This concept is supported by the fact that
currently there is no scientific evidence that
identifies any particular bacteria as a cause
of periodontitis. Only associations have been
observed; that is, deep periodontal probing
depths and an abundance of certain bacteria
are detected simultaneously.
Concept 3: Could bacteria inhabiting the peri-
implant space actually be a consequence, and
not the cause, of breakdown of peri-implant
tissues—and are they the same bacteria as
those associated with periodontitis?
Old knowledge. The microbes in the
peri-implant space in peri-implantitis are sim-
ilar to those found in periodontitis. Specific
periodontal pathogens cause periodontal tissue
breakdown, and these bacteria are suspected
of also leading to breakdown of tissues sur-
rounding dental implants. Clusters of microbes
live in the plaque in the periodontal sulcus.
They develop into a more mature ecosystem
that eventually morphs into the most mature,
complex, pathogenic biofilm that causes further
breakdown of peri-implant tissues.
New knowledge. Breakdown of peri-implant
tissues in susceptible individuals creates an
40
environment suitable for particular oral
microbes, which then flourish. Deepened
peri-implant pockets provide an environment
deprived of oxygen that enhances habitation
by certain anaerobic bacteria. The types of
microbes and their relative abundance iden-
tified in peri-implantitis are to a great degree
different from those found in periodontitis.11–14
Peri-implantitis is found to be prosthetically and
surgically triggered,15 and peri-implant predic-
tors, different from those in periodontitis, are
identified, including female sex, malposition-
ing, overloading, and bone reconstruction.15
Furthermore, the connection area between the
implant and its restoration has been shown to
act as a reservoir for bacteria associated with
peri-implant diseases.16 Also, the breakdown
of peri-implant tissues is partially due to nor-
mal inflammatory responses, either solely or
predominantly or in addition to the microbial
insults. Albrektsson et al on behalf of a con-
sensus meeting in Rome in 2016 suggested that
the marginal tissue breakdown around dental
implants is mostly due to immune-osteolytic
reactions, aided by complicating factors such
as “patient genetic disorders, patient smoking,
cement or impression material remnants in the
peri-implant sulcus, bacterial contamination of
the implant components and technical issues
such as loose screws, mobile components or
fractured materials.”17
Concept 4: Dental implants may not be a
treatment option in all patients with diabetes.
Old knowledge. Implants represent an accept-
able treatment option for people with diabetes.
New knowledge. People with prediabetes and
well-controlled diabetes might be at about
the same risk for peri-implant mucositis and
peri-implantitis as those with normal blood
glucose levels. However, patients with poor
glycemic control are more prone to develop
peri-implantitis.18,19 Evidence to support offer-
ing dental implants to patients with diabetes

often does not specify the importance or level
of glycemic control. Furthermore, studies often
cite implant failure or survival of relatively
short duration instead of long-term implant
success, defined as healthy peri-implant tissues,
as an outcome.20
Concept 5: All bodily fluids contain a
microbiome, also in health.
Old knowledge. Human bodily fluids and most
surfaces, including mucosa, are sterile in health,
such as blood and nasal and pulmonary fluids.
New knowledge. In health, all human bodily
fluids and mucosal surfaces harbor distinct
microbiomes that are changing constantly in
response to environmental influences from
within and external to the body. Even blood21,22
and breast milk,23,24 synovia (fluids in synovial
joints),25 the vagina,26 nonmalignant pancre-
atic cysts,27 amniotic fluid,28 as well as mucosal
surfaces like the ocular surface that consists of
the cornea and conjunctiva29,30 harbor bacteria,
fungi, and possibly viruses in health and may
contain microbes that travel from elsewhere in
the body, including the oral cavity. The latter
was shown for bacterial communities in amni-
otic fluid.31,32
Concept 6: Tobacco smoking may also directly
affect the oral microbiome.
Old knowledge. The adverse effects of tobacco
use, such as smoking cigarettes or chewing
betel nuts, are due to irritation of the mucosa
and the toxic ingredients in the tobacco and
its smoke.
New knowledge. It may also be the case that
use of tobacco products has a direct effect on
the microbiota in the buccal mucosa, where
the diversity of microbes (number of different
microbes) is less than in nonsmokers,33 hence
disturbing the normal ecosystem in health in
which homeostasis (balance) prevails.
Unlearn the Learned
Concept 7: Infections with bacteria are also
found inside cells.
Old knowledge. Bacterial infections are con-
tained in the intercellular spaces.
New knowledge. Some bacteria actually are
able to invade cells, including vascular cells
in arteries, and the white blood cells that are
supposed to kill them. Some bacteria that are
usually part of the oral microbiome, such as
strains of Porphyromonas gingivalis, have
developed sophisticated methods to not only
migrate between layers of cells into tissues but
also penetrate cell walls and enter host cells,
where they can both survive and multiply, and
eventually exit and infect other cells.34 Think
“Trojan horse.” This is important because
while located intracellularly, neither the host’s
immune system nor antibiotics can identify and
annihilate these bacteria if the host has a T-cell
immune deficiency that allows intracellular
bacteria to flourish.
What does this new knowledge
mean for the dental practitioner?
Concepts 1 and 2 express the current beliefs
and synthesize sentiments that have been devel-
oping over the last few years5,6 They actually
make perfect sense. For many years, the search
to identify the culprit bacteria that cause peri-
odontal disease used methods that depended on
growth and observation of bacteria in a labo-
ratory. Now the members and communities of
the oral microbiome in health and in disease
can be explored without culturing the bacte-
ria. They can now be detected from even small
pieces of genetic material, so it is not necessary
to examine the entire organism, let alone live
ones that can be kept alive and cultured in the
laboratory. The precision with which microbes
can be identified is unprecedented and has
largely necessitated relearning most of what
we thought we knew about microbiology.
Detailed genetic analysis of bacteria, which
is increasingly available and economically
41
3 The Traveling Oral Microbiome
feasible, has demonstrated an unanticipated
genetic diversity within species. This knowl-
edge guides future prevention and treatment
protocols, which seem to point in the direction
of precision medical and dental care tailored
to the individual based on personal genetic,
environmental, and clinical profiles.35 The
increasingly sophisticated molecular-level ana-
lytical tools and exploration of inflammatory
responses and other host factors have shown
that factors within the host may be at least as
important as the potential pathogen.
For now, however, these new viewpoints
on mechanisms will not change the need to
keep the oral cavity as healthy and free of
dental plaque as possible. Nevertheless, these
perspectives suggest that dental professionals
must constantly be vigilant and consider the
possible existence of systemic health conditions
and diseases in need of attention, especially in
patients with severe periodontitis.36
What Is an Infection?
The term infection has various definitions.
The main difference among definitions is that
some include the reaction of host tissues to the
infectious organisms and the toxins they pro-
duce while others regard merely the presence
of the infectious agent in unusual amounts or
places to be sufficient for application of the
term, even in the absence of pronounced host
responses. The latter state is what the former
definition would regard as carriage; that is, the
host acts as a carrier who does not necessarily
show signs or symptoms of an infection but
may do so if the host’s resistance to infection
is decreased, as during psychologic stress, for
instance. Still others regard an infectious agent
as one that is not normally found in the body.
These distinctions are important for how we
think about infection in conjunction with peri-
odontal disease and the identification of oral
microbes in the rest of the body.
42
In this chapter, increased levels of oral
microbes in the oral cavity are regarded as
overgrowth of commensal microbes in envi-
ronmental conditions conducive to their
multiplication. Therefore, the terms infection
and pathogen are not used in conjunction with
organisms usually inhabiting the biofilm in
the periodontium. Hajishengallis and Lamont
described in 2016 how “pathogens” originally
are commensal microbes that due to changes
in their environment take advantage of their
enhanced conditions and multiply and thrive
(“overgrow”), without any intrinsic features.37
They introduce the term keystone patho-
gen (alpha-bug or bacterial driver) for such
microbes, of which the periodontal bacterium
P gingivalis is a prime example. In 2015, Han
used the expression commensal-turned patho-
gen for this notion regarding another such
bacterium, namely Fusobacterium nucleatum.31
The term microbe refers to both live and
dead bacteria and their byproducts, as well as
archaea, viruses, and fungi, unless specifically
noted. In the human body, fungi can appear
in three forms, namely as hyphae (filaments),
pseudohyphae, and yeast. Yeast is unicellular
whereas the other two types are multicellular.
Fungal cell walls consist predominantly of chi-
tin, a derivative of glucose.
Gram-positive versus
gram-negative bacteria
Gram refers to a staining method of bacteria
that uses crystal violet stain. The cell walls
of gram-positive bacteria take up this stain
and therefore appear violet when observed
in a microscope, even after decolorization
washing that includes alcohol. In contrast,
gram-negative bacteria are not able to retain
the purple color upon washing. In order to be
able to see these gram-negative bacteria in a
microscope, a counterstain is used to color
them. For example, they will appear pink or
red due to taking up eosin in the commonly
used hematoxylin and eosin stain.

Gram-positive bacteria have a thick cell wall
predominantly consisting of a mesh composed
mostly of sugars and amino acids called peptido-
glycan (polysaccharide and peptide chains), also
known as murein or mucopeptide, that provides
strength and rigidity. In contrast, gram-negative
bacteria are defined by a cell envelope composed
of a thin peptidoglycan cell wall sandwiched
between a bacterial outer membrane and an
inner cytoplasmic cell membrane.
Antibiotics work on gram-positive bacteria
whose thick cell wall disintegrates, whereas the
outer cell membrane protects gram-negative
bacteria from several antibiotics, such as
penicillin, so other antibiotics must be used.
Importantly, the lipopolysaccharides in the
outer membrane of gram-negative bacteria exert
a strong proinflammatory effect seen in some
of the most abundant periodontitis-associated
bacteria, such as P gingivalis.38–40
The Human Genome
Genomes and DNA  material and uses sequence-based methods
The term genome was adopted in 1920 and is a
blend of the two words gene and chromosome.
A genome consists of all the genetic material of
a living entity and can be considered the “Book
of Life” comprising two volumes, namely one
from each parent (https://ghr.nlm.nih.gov/
primer/basics/gene). This Book can be likened
to a cookbook that contains recipes for the
actions of genes. A gene is a distinct sequence
of nucleotides (DNA or RNA) that codes for
the production of proteins. Such protein-coding
genes are interspersed between noncoding
genes and together form a chromosome.
Humans possess 23 pairs of chromosomes
that are all located in the nucleus of all cells,
except red blood cells that do not contain any
nucleus. Because not all genes need to be active
at all times, they turn on and off according to
demand. DNA is made up of pairs of nucle-
otides in various sequences. The nucleotides
are adenine (A), thymine (T), cytosine (C),
The Human Genome
and guanine (G). The nucleotides A and T are
always bonded together as a pair, as are C and
G, hence the expression base pair. The nucleic
acid RNA uses uracil (U) instead of thymine,
so its base pairs are A + U and C + G.
The Human Genome Project
The Human Genome Project was declared com-
pleted with the final mapping and sequencing
of the human genome on April 14, 2003, which
was 2 years ahead of the 15-year-long sched-
ule.41 For the first time, all 20,500 human genes
were cataloged after sequencing of the 3 billion
chemical base pairs that make up human DNA.
This human genome is a “reference genome”
from a combination of anonymous donors, but
each human being has a unique gene sequence.
Knowledge about the human genome is piv-
otal to understanding how our bodies function
so that preventive and curative measures can
be devised to improve our patients’ health and
quality of life.
Metagenomics is the study of genetic
that permit the genetic material from all the
microbes harvested from a biologic sample to
be analyzed simultaneously without the need
for cultivating the microorganisms in a lab-
oratory. Metagenomics provides vastly more
information than the analysis of single, isolated
microbes. It is possible not only to determine
which organisms are present but also to deduce
the relative abundance of the different species.
Furthermore, it may be possible to discover
which metabolic pathways are encoded by
the organisms so that information can be
obtained about their functions in the body.
Metagenomics is used to analyze the human
oral microbiome in unprecedented detail.
Sequencing of the 16S rRNA gene
The 16S rRNA gene has been sequenced to
detect the order (sequence) in which the four
RNA nucleotides (A + U, C + G) appear.
The entire length of the 16S gene of RNA
43
3 The Traveling Oral Microbiome
from ribosomes has been sequenced, and this
information is stored in the publicly accessi-
ble Human Microbiome Project database as a
reference.42 Scientists can now compare their
findings to the reference RNA for identification.
The bacterial 16S rRNA gene is the molecular
marker most widely used to identify microbes
to study the diversity of microbial communities.
The 16S rRNA gene is used as a reference for
sequencing for a number of reasons:
• It is present in almost all bacteria.
• It is a highly conserved gene, preserved in its
original form through various manipulations
such as cell death and freezing.
• Its function has not changed over time, sug-
gesting that random sequence changes are a
more accurate measure of time (evolution).
• It is sufficiently long (1,500 base pairs) for
informatics purposes involving identification
for comparisons to detect similarities and
differences between genetic samples.
Importantly, as in metagenomics, the
microbes do not have to be whole or alive for
this method to be used. The DNA can stem from
dead organisms or from only pieces thereof.
Consequently, even bits of the cell walls (endo-
toxins) are sufficient for determining the identity
of a certain microbe. A brief overview of this
so-called next-generation workflow for health
care professionals is provided by Kilian et al.43
The Human Microbiome
A microbiome is the totality of microorganisms
(microbes), their genetic elements (genomes),
and environmental interactions in a particular
environment. The term was coined in 2001,
which indicates the novelty of this concept.
Some consider the microbiome a “newly dis-
covered organ,” because its existence was not
generally recognized until the late 1990s.
Researchers are only beginning to under-
stand its vast impact on human existence,
44
health, and disease. The human microbiome
consists of all the microbes that inhabit the
inside and outside of the human body. As
mentioned earlier, it contains about 38 tril-
lion (3.8 × 1013) bacteria alone,3,4 but it also
contains more than 8 million protein-coding
genes, outnumbering human genes by 360:1
(8 million:20,500).44 The human microbiome
normally consists of beneficial, harmless, non-
pathogenic organisms that in health exist in
homeostasis in which there is a relatively stable
equilibrium, as opposed to dysbiosis, a micro-
bial imbalance or derangement that is often
associated with disease.
Because of their small size, microorganisms
make up only a minute fraction of the weight
of a human. Sender, Fuchs, and Milo pointed
out4 that although initial reports suggested that
1.5 to 4.5 lb (0.7 to 2.0 kg) of microbes live in
and on a 150-lb (68 kg) person, the estimated
mass of the bacteria may actually be only 0.2
kg (200 g, about 0.5 lb), representing about
0.3% of the overall body weight.4
The microbiome is necessary for human
survival. Its components digest food, synthe-
size essential nutrients and vitamins, educate
and maintain the innate (inborn) and adaptive
(acquired) immune system while maintaining
self-tolerance to avoid autoimmunity, regulate
immune homeostasis, fight off infections, and
maintain homeostasis and healthy equilibrium.
The Human Microbiome Project
The Human Microbiome Project was launched
by the US National Institutes of Health to
characterize the human microbiome and
subsequently analyze its role in health and
disease.45 The Human Microbiome Project
is the largest-ever 5-year project aimed at
identifying and cataloging the human micro-
biome. Researchers sampled 300 healthy 18- to
40-year-old individuals from two US cities.
Even the presence of minor “gum disease” was
enough to exclude a subject from the study.46
The study was focused on identifying the
microbes residing in five body areas (Fig 3-1).

Fig 3-1  |  Body sites for sampling microbiomes for the
Human Microbiome Project.
Researchers sampled 15 body sites in each man
and 18 sites in each woman.47
Nine of the 15 or 18 sites sampled were
located in the oral cavity, which is a testament
to the immensely important role the oral micro-
biome plays in human health and disease.
The Human Oral Microbiome
Currently, about 700 different bacterial species
have been identified in the human oral cavity,
but estimates suggest that the actual number
may be as many as 1,200.48 The oral cavity
differs from all other human microbial habitats
by the simultaneous presence of two types of
surface for microbial colonization: shedding
surfaces (mucosa) and solid surfaces (teeth and
different fixed and removable oral appliances).
This intrinsic property of the oral cavity pro-
vides immense possibilities for a diverse range
of microbiota. Saliva contains around 100 mil-
lion bacteria and archaea per milliliter, by far
the two most common types of microbe in the
mouth.49
Currently, only about half of the microor-
ganisms detected in the mouth are officially
named, and only about three-quarters of those
are indisputably oral commensals. The rest may
The Human Oral Microbiome
Nasal
Oral
Skin
Gastrointestinal
Urogenital
represent transient colonization, but some may
turn out to inhabit the mouth on a regular
basis. Knowing which microbes live in the oral
cavity is important for targeting measures to
improve or attain oral health.
The Human Oral Microbiome
Database
The human oral microbiome is the most
studied human microflora. The Human Oral
Microbiome Database was created to provide
the scientific community with a comprehensive
database of the oral bacterial species.42 It is
basically a ledger that provides information on
the genomes of oral bacteria.
An example follows of the classification hier-
archy of subgroups, namely for P gingivalis,
formerly known as Bacteroides gingivalis. As
displayed in Box 3-1 and Fig 3-2, the genomes
of a total of 19 different strains or subspecies
have been identified.50 This was the result of
testing 27 strains that turned out to be clus-
tered into two groups of shared proteins.50
Such development of strains or subspecies
demonstrates the capability of P gingivalis to
adapt to new environments.
The same order of classification hierarchy for
Streptococcus mutans is Bacteria, Firmicutes,
45
3 The Traveling Oral Microbiome
Box 3-1  |  Tree of life classification of P gingivalis
Hierarchy Bacterium
Domain Bacteria
Phylum Bacteroidetes
Class Bacteroides
Order Bacteroidales
Family Porphyromonadaceae
Genus Porphyromonas
Species gingivalis
# Strains >19
Bacilli, Lactobacillales, Streptococcaceae,
Streptococcus, and mutans.
Does a core oral microbiome exist?
Bacteria
Researchers have wondered about the existence
of a core set of oral microorganisms that are
common to most humans. Only with recently
developed novel techniques that are still being
refined is it possible to begin to look for pos-
sible answers to this question. When three
healthy, unrelated individuals were studied,
samples originating from shedding surfaces
(mucosa of the tongue, cheek, and palate)
were clearly distinguishable from samples that
were obtained from solid surfaces (teeth).51 The
three people had only one-quarter (26%) of
the 6,315 unique bacterial gene sequences in
common, but the abundance of the families of
bacteria to which these belonged were almost
identical (99.8%) in the three persons. This
supports the concept of a core microbiome in
health, but only at the bacterial family level.
However, the proportions of even the com-
mon microbes vary widely among individuals,
46
Fig 3-2  |  P gingivalis, a keystone periodontal bacte-
rium and community activist.
as shown for the three individuals in Fig 3-3.51
Moreover, the distribution and abundance of
bacteria at the phylum level in the different
oral sites sampled varied substantially among
three individuals51 (Fig 3-4). Interestingly, bac-
teria formerly regarded as causing periodontitis
were harbored in the three subjects as well as in
multiple participants in a larger study52 but typ-
ically only as minor components of the plaque.
Distinguishing oral microbiomes in health
and in periodontitis is difficult because up to
95% of microbe genera are present in both
health and disease, and periodontal prob-
ing measures cannot attest to whether a site
is in the process of breaking down or is on
the mend. Therefore, a group of researchers
calculated the ratio of bacterial dysbiosis as
an expression of the periodontal breakdown
activity.53 Such dysbiosis ratios turned out to
be correlated with the severity of periodontitis
assessed by pocket depth and might hence be
useful for both risk prediction and monitoring
of healing pockets.
A study of 66 healthy Han Chinese subjects
spanning in age from neonatal (3 to 4 days) to
elderly (62 to 76 years) clearly demonstrated
that the oral cavity is a highly diversified space
 The Human Oral Microbiome

20

S1
S2
S3
15

10

0
Streptococcus; 803
Streptococcus; 165
Corynebacterium; 280
Neisseria; 637
Rothia; 513
Streptococcus; 230
Veilfonellaceae; 110
Actinomyces; 419
Granulicatella; 335
Streptococcus; 262
Porphyromonas; 475
Firmicutes; 592
Streptococcus; 452
Corynebacterium; 145
Actinomyces; 374
Fusobacterium; 202
Rothia; 64
Corynebacterium; 610
Haemophilus; 697
Prevotella; 181
Neisseria; 591
Actinomyces; 752
Streptococcus; 669
Fusobacterium; 758
Gampytobacter; 316
Neisseriaceae; 683
Streptococcus; 679
Actinomyces; 382
Neisseriaceae; 508
Rothia; 721
Haemophilus; 210
Streptococcus; 676
Fusobacterium; 608
Streptococcus; 109
Haemophilus; 5
Actinomyces; 500
Leptotrichia; 9
TM7; 40
Neisseriaceae; 42
Capnocytophaga; 517
Haemophilus; 16
Fusobacterium; 375
Granulicatella ; 23
Capnocytophaga; 345
Derxia; 321
Acidovorax; 797
Haemophilus; 182
Actinomyces; 578
Capnocytophaga; 18
Moryella; 350
Cardiobacterium; 192
Fig 3-3  |  Shared abundant phylotypes in three oral microbiomes (S1, S2, and S3) and their relative abundance.
Only abundant phylotypes that contributed to at least 0.1% of the individual microbiome are shown. The most
abundant phylotypes (0.5% or more of the microbiome) are grouped separately in the left panel. Phylotypes were
defined as operational taxonomic units (OTUs) clustering sequences at a 3% genetic difference. The highest
taxon (in most cases, genus) at which the OTU was identified is shown together with the cluster identification
number. Different colors indicate three different microbiomes. (Reprinted from Zaura et al51 with permission.)

100%

80%
Actinobacteria

Bacteroidetes
60%
Firmicutes

Fusobacteria

Proteobacteria 40%

Spirochaetes

TM7 20%
Unclassified
bacteria

0%
B_incisor
L_incisor
Appr_incisor
B_molar
L_molar
Appr_molar
Palate
Cheek
Tongue
Saliva
Average

B_incisor
L_incisor
Appr_incisor
B_molar
L_molar
Appr_molar
Palate
Cheek
Tongue
Saliva
Average

B_incisor
L_incisor
Appr_incisor
B_molar
L_molar
Appr_molar
Palate
Cheek
Tongue
Saliva
Average

S1 S2 S3

Fig 3-4  |  Average and site-specific relative distribution of bacterial phyla in three individuals (S1, S2, and S3).
Unclassified bacteria were reads without a recognizable match in the full 16S rRNA reference database. B, buccal;
L, lingual; Appr, approximal surface of either an incisor or a molar. (Reprinted from Zaura et al51 with permission.)

47
3 The Traveling Oral Microbiome
Saliva
11,171
3,193 3,427
3,619
Supragingival Buccal
dental plaque 806 mucosa
13,333 6,302
with highly different microbiomes according
to dentition stage (age) and location within the
mouth and that any core oral microbiome must
be specific for the respective age/dentition status
and oral niche/location/medium (dental plaque,
saliva, and buccal swabs).54 Figure 3-5 illus-
trates the small subset of microbes measured as
operational taxonomic units (OTUs) that are
common for all three as well as pairwise.
Several microorganisms that are common
elsewhere in the body inhabit or are frequent
guests in the oral cavity. For example, Staphylo-
coccus aureus is frequently detected, although
it is not a bacterium normally considered a reg-
ular member of the oral microbiome. In people
with cleft lip and palate, transmission to the
mouth can easily occur from the nasal micro-
biota. In a study of young children with cleft lip
and palate, those with fistulas had significantly
more S aureus in the oral cavity than did those
without fistulas, and those with larger fistulas
had greater counts of S aureus than those with
smaller fistulas.55
As in the total human microbiome, the
abundance and diversity of the oral micro-
biome presents homeostasis in health but
dysbiosis in disease.56,57 Therefore, it is likely
48
Fig 3-5  |  Venn diagram of shared and differ-
ent OTUs of the oral bacterial communities. A
large number of OTUs could be detected only
in saliva (11,171), supragingival dental plaque
(13,333), and buccal mucosa (6,302), whereas
only 3,619 OTUs were shared among all three
niches. (Reprinted from Xu et al54 with permis-
sion.)
that the overall function of the complex oral
microbiome is more important than any of its
individual components in understanding oral
health and disease, which could serve as the
basis for potentially exploring novel therapeu-
tic targets.56
Fungi
In 2010, a group of researchers characterized
for the first time the “basal” fungal microbi-
ome (mycobiome) of the oral cavity in healthy
individuals. Figure 3-6 shows the fungus genera
present in each of the 20 subjects examined,
illustrating the great diversity and individual
differences in the composition of their myco-
biomes.58 The number of different genera of
fungi among the healthy subjects ranged from
3 to 16. While the commensal oral fungal com-
munity plays an important, even critical, role
in health and disease in humans, nonetheless
it has largely been ignored.59
Saliva
It is estimated that human saliva contains
108 to 109 bacteria per milliliter.60 However,
 The Human Oral Microbiome

Zygosaccharomyces Wallemia
100– Verticillium Trichaptum
Tremel/ales Torulaspora
– Subulispora Stemphy/ium
Sebacina Rhizopogon
90– Pyrenophora Pueraria
Pongo
– Phaeosphaeria
Peziza Orpinomyces
80– Ophiostoma Nectria
Macrophomina Lecania
– Lasiodiplodia lssatchenkia
Guignardia Gigaspora
70– Flammulina Filobasidiales
– Epicoccum
Frequency (%)

Davidiella
Cystofilobasidium Corynespora
60– Conoplea Clavispora
Claviceps Chaetomium
– Bagnisiella Avena
50– Amanfta Acremonium
Campylobacter Xylariales
– Trichosporon Sordariomycete
Schizosaccharomyces Pleosporaceae
40– Pichia Phoma
Paecilomyces Ochroconis
–
Nigrospora Lewia
30– Hypocreales Hormonema
Emericella Atractylodes
– Ascomycete Trichocomaceae
Stachybotrys Schizophyllum
20– Penicillium Dothideomycete
– Gibberella Cryptococcus
Glomus Eurotium
10– Saccharomyces Fusarium
Aspergillus Alternaria
– Teratosphaeria Dothioraceae
Saccharomycetales Aureobasidium
0– Cladosporium Candida
Non-culturable
A1 A2 A3 B1 B2 B3 C1 C2 C3 D1 D2 E1 E2 E3 F1 F2 G1 G2 G3 H2
Sample
Fig 3-6  |  Overall distribution of fungi in oral rinse samples obtained from 20 healthy individuals. Δ, sample con-
taining 16 fungal genera; *, sample containing 3 fungal genera. (Reprinted from Ghannoum et al58 with permission.)

the bacterial composition of saliva samples
is representative of neither supragingival nor
subgingival plaque nor or of any other oral
biofilm. Furthermore, the different methods
used to sample the saliva—including collecting
saliva upon passive drooling or after stimulat-
ing salivary production by chewing paraffin,
active swishing with a liquid (mouthrinse or
mouthwash), insertion of paper points, or
buccal or tongue swabs—may affect the rep-
resentativeness of the oral microbiome.
However, it was demonstrated that no or very
little variation occurs in the microbial profiles
over a 24-hour period and after 1 week in stim-
ulated saliva, which means the diurnal timing
is not crucial when obtaining salivary samples
for analysis.61 Furthermore, the same research-
ers showed that bacterial profiles in stimulated
saliva are sufficiently similar to unstimulated
saliva and hence can be used for analysis.62 This
is important because collection of unstimulated
saliva samples from passive drooling at rest
takes much longer than collecting samples of
stimulated saliva by chewing for 1 minute on
paraffin, for instance.
After studying a large extended Ashkenazi
Jewish family whose members lived in dif-
ferent locations, Shaw et al63 concluded that
the human salivary microbiome is more a
result of environmental factors like shared
households rather than due to genetics. Such
a household-shaped salivary microbiome can
persist for several years after leaving the ini-
tial environment. Time will tell whether a core
universal human salivary microbiome in health
will emerge.64
Distribution of oral microbes
Intraoral diversity
Within the oral cavity, groups of microbial spe-
cies arrange themselves into surface-localized
communities that vary considerably in compo-
sition according to their exact location. Even
adjacent oral sites “only millimeters or less”

49
3 The Traveling Oral Microbiome

Second
layer

Basal
layer

Tooth side
Fig 3-7  |  Localization of the most abundant species in supragingival biofilms. Streptococcus species (yellow)
form a thin band on top of the biofilm, almost engulf the biofilm, or present as small cells scattered through the top
layer of the biofilm. (B) Cells from the CFB cluster of bacteria in the top layer of the biofilm, without defined struc-
ture. (C) Lactobacillus species (red) forming long strings through the top layer. (D) Actinomyces species (yellow)
plaque attached to the tooth. (E) Actinomyces species (green) and cocci forming initial plaque. (F) Multispecies
initial plaque composed of Streptococcus species (yellow), yeast cells (green), and unidentified bacteria (red). (G)
Streptococcus species (green) and Lactobacillus species (red) forming initial plaque. Black holes might be chan-
nels through the biofilm. Panels A, B, C, E, and F are double-stained with probe EUB338 labeled with FITC or Cy3.
Scale bars are 10 μm. CFB cluster, Cytophaga-Flavobacterium-Bacteroides cluster, including Parvimonas micra, P
gingivalis, Prevotella intermedia, Porphyromonas endodontalis, and Prevotella nigrescens. (Reprinted from Zijnge
et al65 with permission.)

apart exhibited “strikingly different” microbial
community compositions.65 The dorsum of the
tongue specifically can harbor several bacte-
rial species detected in ventilator-associated
pneumonia.
Tooth surfaces and periodontal pockets. There
are considerable differences in bacterial com-
position among teeth at different intraoral
locations and even among different surfaces
of the same tooth.66 Pronounced differences
were observed in incisors and canines, where
Streptococcus species were found on 40% to
70% of the vestibular surfaces but were almost
absent on the lingual surfaces.
There are considerably more differences
between the microbiomes in supragingival and
subgingival dental plaque for various reasons,
such as the availability of oxygen. Until rather
recently, our knowledge regarding the bacte-
rial composition of plaque was largely based
on studies conducted in the 1970s that used
culture and electron microscopic techniques.67
Zijnge et al used the novel Fluorescence In
Situ Hybridization (FISH) technique for the
first time to provide visualization of the most
abundant bacterial phyla and species as well
as the composition and structure of the supra-
and subgingival biofilm from extracted human
teeth.65 Figures 3-7 to 3-10 visualize the most

50
 The Human Oral Microbiome

Fig 3-8  |  Localization of the most abundant species in subgingival biofilms. (A) Overview of the subgingival
biofilm with Actinomyces species (green), bacteria (red), and eukaryotic cells (large green cells on top). (B) Spiro-
chaetes (yellow) outside the biofilm. (C) Detail of Synergistes (yellow) in the top layer in close proximity to eukary-
otic cells (green). (D) CFB cluster (yellow) in the top and intermediate layer. (E) F nucleatum in the intermediate
layer. (F) Tannerella species (yellow) in the intermediate layer. Each panel is double-stained with probe EUB338
labeled with FITC or Cy3. The yellow color results from the simultaneous staining with FITC and Cy3-labeled
probes. Scale bars are 10 μm. CFB cluster, Cytophaga-Flavobacterium-Bacteroides cluster, including P micra,
P gingivalis, P intermedia, P endodontalis, and P nigrescens. (Reprinted from Zijnge et al65 with permission.)

abundant species in supragingival (see Fig
3-7) and subgingival biofilm (see Fig 3-8), the
bacteria most abundant in periodontitis (see
Fig 3-9), and various aggregations of bacteria
located within the biofilm (see Fig 3-10).65
Combining the FISH technique with confocal
scanning fluorescent microscopy and histology
shed new light on these features.67 Mark Welch
et al introduced the notion of “biogeography”
to describe the complex multispecies microbi-
omes like the human oral microbiome at the
micron scale, suggesting interpretation of the
so-called “hedgehog,” “corncob,” and “cauli-
flower” structures that are briefly illustrated
in the following pages, beginning with a sche-
matic representation (Fig 3-11).68
Figures 3-12 to 3-1468 show bacteria made
visible by 10 fluorescent probes by the com-
plex Combinatorial Labeling and Spectral
Imaging Fluorescence In Situ Hybridization
(CLASI-FISH) technique developed by the
Valm and Welch team,69 a major scientific
breakthrough that for the first time enabled
visualization of the biogeography of 15 differ-
ent taxa simultaneously to further explore the
various components of a microbiome as well
as its architectural structure.70

51
3 The Traveling Oral Microbiome

Fig 3-9  |  Localization of species associated with periodontitis. (A) Overview of the subgingival biofilm with
CFB-cluster species (red) and Prevotella species (yellow). Because Prevotella species are part of the CFB cluster
of bacteria, cells appear in yellow. (B) Top of the biofilm with a microcolony of P micra (yellow). (C) Microcolonies
of P gingivalis (yellow) in the top layer. (D) Microcolonies of P endodontalis (yellow) in the top layer. (E) Microcol-
onies of P intermedia in the top layer. Panels B, C, D, and E are double-stained with probe EUB338 labeled with
FITC or Cy3. Scale bars are 10 μm. CFB cluster, Cytophaga-Flavobacterium-Bacteroides cluster, including P mi­
cra, P gingivalis, P intermedia, P endodontalis, and P nigrescens. (Reprinted from Zijnge et al65 with permission.)

Fig 3-10  |  Bacterial aggregates in oral

plaque. (A) Transversal view of a test-tube
brush found in subgingival plaque com-
posed of filamentous cells from the CFB
cluster. (B) Tannerella species (yellow) in a
test-tube brush. (C) Longitudinal view of
a test-tube brush with Lactobacillus spe-
cies (red rods) as central structures. F nu­
cleatum (green) and CFB-cluster filaments
radiating from the central structures. (D)
Longitudinal and transversal view of a
test tube brush stained with the eubac-
terial probe. (E) Transversal view of the
test-tube brush in panel D, composed of
Synergistetes group A species. (F) Trans-
versal view of Streptococcus species
(green) aggregation around a central cell
(not stained) in supragingival plaque. (G)
Transversal view of supragingival plaque
with Streptococcus species (green coc-
ci) and C albicans (green hyphae) in the
top layer of the biofilm and forming corn
cob structures growing outwards. Bars
are 10 μm. CFB cluster, Cytophaga-
Flavobacterium-Bacteroides cluster, in-
cluding P micra, P gingivalis, P intermedia,
P endodontalis, and P nigrescens. (Re-
printed from Zijnge et al65 with permission.)

52
 The Human Oral Microbiome

Fig 3-11  |  Summary hypothesis for inter-

pretation of hedgehog structures. Coryne­
bacterium filaments bind to an existing biofilm
02, saliva, sugars
containing Streptococcus and Actinomyces.
At the distal tips of the Corynebacterium fila-
ments, corncob structures form in which the CO2, lactate,
filaments are surrounded by cocci, including acetate, H2O2
Streptococcus and Porphyromonas, in direct
contact with the Corynebacterium filament Anoxic
Tooth
as well as Haemophilus/Aggregatibacter in
contact with Streptococcus. Clusters of Neis­
seriaceae also occupy the periphery of the
hedgehog. The Streptococcus cells create
a microenvironment rich in CO2, lactate, and
acetate, containing peroxide, and low in ox-
ygen. Elongated filaments of Fusobacterium Base Annulus Perimeter
and Leptotrichia proliferate in this low-oxygen,
high-CO2 environment in an annulus just Crevicular fluid
proximal to the corncob-containing peripher-
al shell of the hedgehog. The CO2-requiring Corynebacterium Porphyromonas Fusobacterium Other
Capnocytophaga also proliferates abundantly Streptococcus Neisseriaceae Leptotrichia
Haemophilus/ Capnocytophaga Actinomyces
in and around this annulus. The base of the Aggregatibacter
hedgehog is dominated by Corynebacterium
filaments and thinly populated by additional
rods, filaments, and/or cocci. (Reprinted from
Mark Welch et al68 with permission.)

Fig 3-12  |  Corncob structures formed by Cory­
nebacterium and cocci in plaque. Corynebacterium
cells (magenta) are visible as long filaments, with coc-
ci (green) bound to the tips of the filaments. Partially
disrupted plaque was hybridized with a probe for Co­
rynebacterium and a universal bacterial probe. Scale
bar is 20 μm. (Reprinted from Mark Welch et al68 with
permission.)
Fig 3-13  |  A cauliflower structure in plaque com-
posed of Lautropia, Streptococcus, Haemophilus/
Aggregatibacter, and Veillonella. Scattered cells of
Prevotella, Rothia, and Capnocytophaga are also
visible. (Reprinted from Mark Welch et al68 with per-
mission.)

53
3 The Traveling Oral Microbiome
10 um
a b
Corynebacterium Fusobacterium
Streptococcus Leptotrichia
Porphyromonas Capnocytophaga
Haemophilus/Aggregatibacter Neisseriaceae
c sentative images showing types of corncobs frequently
Periapical periodontitis. Biofilm adhering to
gutta-percha from a purulent infection around
the apex of an endodontically treated tooth
was compared to biofilm from similarly treated
teeth with apparently healthy periapical tissues,
using the FISH technique.71 Whereas the lat-
ter contained few to no bacteria, the former
revealed dense bacterial aggregates of varying
composition (Fig 3-15).
Studying bacterial diversity in 10 root canals
with acute apical abscesses demonstrated that
a multitude of different bacteria were involved,
but none were present in all specimens, indicat-
ing great differences between the participants.72
The bacteria most frequently encountered were
anaerobic gram-negative bacteria of the phylum
Firmicutes, followed by Bacteroidetes. Another
study found Candida to be more frequently
isolated from people with hyperglycemia/
diabetes than in normoglycemic patients with
endodontically treated teeth.73 In conclusion,
endodontics-related microbial overgrowth is
54
Fig 3-14  |  Complex corncob structures in supra­
gingival plaque. (a and b) Clusters of corncobs at
the perimeter of hedgehog structures. (a) Whole
mount of plaque hybridized with probes for Coryne­
bacterium, Fusobacterium, Streptococcus, Porphyro­
monas, and Haemophilus/Aggregatibacter. (b) Meth-
acrylate-embedded section hybridized with probes for
Corynebacterium, Streptococcus, Porphyromonas,
and Haemophilus/Aggregatibacter. (c) Gallery of repre-
observed. Scale bar in c is 5 μm. (Reprinted from Mark
Welch et al68 with permission.)
not caused by any specific bacterium; rather
it is associated with a heterogeneous group of
organisms consisting of at least fungi, viruses,
and bacteria, including several currently uncul-
tured bacteria.
Microbes from both primary and posttreat-
ment apical periodontitis have easy access
into the neighboring tissues and blood vessels,
which may be important because of their high
prevalence. A 2017 review found a worldwide
prevalence of 7% to 86% for primary apical
periodontitis and 10% to 62% for apical peri-
odontitis after endodontic treatment.74
Dental implants. Compared to patients with
healthy peri-implant tissues, P gingivalis,
Prevotella intermedia, Tannerella forsythia, and
F nucleatum were found to be more abundant
in patients with peri-implantitis, whereas no
important roles seemed to be played by Aggre-
gatibacter actinomycetemcomitans (previously
called Actinobacillus actinomycetemcomitans)

Fig 3-15  |  FISH staining of biofilm fractions detected
in the transport media of the retrieved gutta-percha
fractions, as detected by epifluorescence microscopy.
A selection of the taxa is presented in the correspond-
ing subfigures. The FISH probes used for the staining
are provided in parentheses. Scale bars are 10 μm. (Re-
printed from Zehnder et al71 with permission.)
and Staphylococcus species.11 The first system-
atic review and meta-analysis, based on 12
studies exploring the effect of hyperglycemia
on peri-implant tissue health, concluded that
whereas there was no significant difference
regarding peri-mucositis, peri-implantitis was
significantly more frequently present in peo-
ple with diabetes.18 Meta-analysis of data from
seven sufficiently similar studies calculated that
people with diabetes had almost a 50% greater
risk (RR = 1.46; 95% CI: 1.21–1.77) and 90%
greater odds (OR = 1.89; 95% CI: 1.31–2.46)
for peri-implantitis than normoglycemic
implant recipients. Meta-analysis of the three
studies that included only nonsmokers (247
hyperglycemic and 74 normoglycemic partici-
pants with a total of 706 implants) calculated
a three-fold greater risk for peri-implantitis
among those with hyperglycemia (RR = 3.39,
95% CI: 1.06–10.81).18 The latter results cir-
cumvent the confounding effect of smoking.
The Human Oral Microbiome
A: Prevotella sp. et rel. (PRV392-Cy3) B: Fusobacteria sp. (FUS664-Cy3)
C: Treponemes Cluster 1 (TrepG1-679-Cy3) D: Synergistes Cluster A (SYN-A1409-FAM)
E: Selenomonas sp. et rel. (SEL1150-FAM) F: Parvimonas micra (Pmic 740-Cy3)
G: Aggregatibacter actinomycetemcomitans (Aact639-Cy3)
H: Actinomyces naeslundii, A. oris et rel. (L-Act476-2-Cy3)
I: Campylobacter rectus et rel. (CAMP655-Cy3)
J: Porphyromonas gingivalis (L-Pgin1005-2-Cy3) L: Prevotella nigrescens (Pnig657-Cy3)
K: Tannerella forsythia Cluster 1 (Tfor127-Cy3) M: Prevotella denticola (Pdent654-FAM)
Helicobacter pylori was found to be cor-
related with the level of hyperglycemia assessed
by glycated hemoglobin (HbA1c), which reflects
long-term blood sugar levels, in a dose-response
manner.75 It can be debated whether H pylori
is a commensal or a frequently encountered
transient member of the oral microbiome.75
Orthodontic appliances. Based on 13 stud-
ies, a 2017 systematic review concluded that
placement of orthodontic brackets leads to an
increase in the abundance of certain bacteria in
the dental plaque.76 However, several months
after the removal of the orthodontic appliances,
the bacterial abundance seemed to return to
pretreatment levels. Nonetheless, a prospec-
tive cohort study monitoring four periodontal
bacteria concluded that local factors related to
the orthodontic appliances influenced the alter-
ations in the subgingival plaque that resulted in
increases in inflammation and gingival bleed-
ing.77 Also, both fixed and removable space
55
3 The Traveling Oral Microbiome
retainers are shown to cause an increase in the
abundance of both bacteria and yeast (mostly
Candida) colonization.78 Conversely, a study
among women free of periodontitis receiving
clear aligners showed decreased diversity in
the subgingival microbiome with changes in
the bacterial communities but no development
of periodontitis after the first 3 months upon
aligner placement.79
Removable dentures. Removable dentures can
function as a reservoir and lead to an increase
in the microbial load consisting of both bac-
teria and fungi.80 Biofilm from such dentures
is shown to contain a high number of oral
bacteria that are usually associated with oral
diseases and are resistant to several antibiotics
and other antimicrobial drugs.81 The micro-
biome of denture wearers is demonstrated to
differ from that of individuals with only nat-
ural teeth in both diversity and composition
and is influenced by the presence or absence
of natural teeth as well as the location of the
denture.82 It was also illustrated that the devel-
opment of denture stomatitis is much more
complex than a simple overgrowth of C albi-
cans because bacteria also play a role.
Oral epithelial cells: Hostels for traveling
microbes from elsewhere. A variety of visit-
ing (transient) bacterial species are harbored
in oral epithelial cells, which together could
be considered a reservoir for these bacteria.
In one study, Enterococcus faecalis was the
most prevalent visiting species found in oral
epithelial cells (20.6%) but was identified only
in people with deep periodontal pockets.83 No
correlation was found with age, sex, bleeding
on probing (BOP), or supragingival biofilm.
Half of those with great attachment loss also
harbored Pseudomonas aeruginosa.
Another study found that subgingival plaque
samples contained DNA from these two
bacteria as well as from two more non-oral
pathogenic bacteria (Escherichia coli and S
aureus). DNA from these four bacteria was
found—alone or together with DNA from
56
bacteria usually associated with periodontitis—
to be strongly associated with periodontitis.84
The finding that the prevalence of the oppor-
tunistic bacteria E coli, E faecalis, S aureus, and
P aeruginosa is correlated with the presence
and severity of periodontal disease could be
regarded as confirmation that host factors are
important in invasion by common inhabitants
of other body sites that multiply in the mouth
under certain favorable conditions. This dis-
covery further supports the concepts that, in
periodontitis, (1) bacteria (and viruses) interact
with microbes that do not normally inhabit the
mouth and (2) groups of several microbes, not
only one bacterium, are found in periodontitis.
Intraindividual and interpersonal diversity
Saliva. The composition of the salivary micro-
biome varies both within and among persons
and over time. Figure 3-16 presents the relative
proportions of the most frequently identified
bacterial phyla for each of five individuals at
different time points. The salivary microbial
community appeared to be stable over at least
583 to 7 days.61 However, samples taken up to
29 days after baseline showed that the compo-
sitions of microbiome samples taken at closer
time intervals were not necessarily more similar
than those obtained over longer intervals in
any individual. The saliva samples were dom-
inated by the seven major groups (phyla), but
only five groups were found in all participants
at all times (see Fig 3-16). The remaining two
were also found in all participants but not at
every time point.
Stimulated saliva samples from 30 partici-
pants (10 with periodontitis, 10 with caries,
and 10 orally healthy) were analyzed with a
novel technique called HOMINGS (Human
Oral Microbe Identification using Next Gen-
eration Sequencing) and did indeed contain
bacterial profiles that differed among the
three groups as seen in Fig 3-17.85 These pro-
files were further confirmed by metagenomic
and metatranscriptomic analysis that support
a hypothesized genetic expression.86
 The Human Oral Microbiome

100–

80–

–
Unclassified bacteria
60– Spirochaetes
Fusobacteria
– TM7
Bacteroidetes
40–
Actinobacteria
– Proteobacteria
Firmicutes
20–

0–
29

15

15

1
4
1
4

5
4–

5–
5–
4–
4–
1
5

1
7

1
5

l
5–

Al
1–

2–

3–
1–
1–

2–
2–

3–
3–

Fig 3-16  |  Relative abundance of predominant phyla across 15 salivary microbiomes, namely three from each
of five individuals on three different days. Sample numbers include subject ID and the follow-up day after the first
sampling time point (day 1). The days are indicated by the number after the hyphen (-) on the horizontal axis. For
instance, the saliva samples from the leftmost participant were taken on days 1, 5, and 29. Bacterial phyla are
indicated by color. The rightmost column, designated as All, displays the average phyla proportions when the
individual samples were pooled. Both Streptococcus and Staphylococcus species belong to the order Bacilli,
which are part of the phylum Firmicutes (dark blue). (Reprinted from Lazarevic et al64 with permission.)

A periodontal intervention study reported Geographic diversity. Several research teams

a strong correlation between reduction in
abundance of bacteria in the subgingival
and salivary microbiomes.87 Furthermore,
the effect of smoking is sufficiently strong
to enable distinction between the salivary
microbiomes in smokers and in nonsmokers
receiving single-tooth implants in the posterior
mandible.88 Smokers harbor oral microbiomes
containing lower richness and diversity than
nonsmokers but with certain bacteria occurring
more frequently. Specifically, the abundance
of P gingivalis was significantly greater in
smokers, which was related to greater sever-
ity of peri-implant marginal bone loss during
the 3-month bone healing period following
implant placement.88 Consequently, smoking
might directly affect the microbiomes as man-
ifested in both dental plaque and saliva.
have explored whether various populations
in different countries and of different racial
backgrounds indeed share a core oral micro-
biome despite their individual variation. There
is scant evidence that some evolutionary lin-
eages of bacteria have adapted to particular
ethnic groups.89 With the limited informa-
tion available, few of these differences can be
directly related to differences in prevalence
of periodontal disease. Asian populations are
regularly colonized with A actinomycetemcom-
itans serotype C with questionable pathogenic
potential. On the contrary, the JP2 clone of A
actinomycetemcomitans causes significantly
higher prevalence of aggressive periodontitis in
adolescents whose descent can be traced back
to the Mediterranean region and western parts
of Africa.89

57
3 The Traveling Oral Microbiome

45
40 Prevotella veroralis Veillonella atypica
Campylobacter concisus Porphyromonas sp oral taxon
35 Streptococcus sanguinis Prevotella pallens
Gemella sanguinis Veillonella atypica
30
Megasphaera micronuciformis Prevotella salivae
25 Oribacterium sinus Prevotella histicola
Neisseria pharyngis Fusobacterium periodonticum
20 Veillonella rogosae Rothia mucilaginosa
15 Neisseria flavescens Haemophilus parainfluenzae
Leptotrichia sp oral taxon 417 Prevotella melaninogenica
10
5
0
a Periodontitis Oral health Dental caries

25 Veillonella genus probe 1

Actinomyces genus probe 4

20 Streptococcus genus probe 1

Leptotrichia genus probe 1
Prevotella genus probe 1
15
Fusobacterium genus probe 4
Granulicatella genus probe
10 Veillonella genus probe 2
Neisseria genus probe 2

5 Streptococcus genus probe 4

0
b Periodontitis Oral health Dental caries

Fig 3-17  |  Relative abundance of predominant species-level and genus-level probe targets in saliva. (a) Relative
abundance of the 20 most predominant species-level probe targets in each group. (b) Relative abundance of the
10 most predominant genus-level probe targets in each group. (Reprinted from Belstrøm et al85 with permission.)

In Korean adults with advanced periodonti- subgroups (genera) with non-Amerindians

tis, all diseased sites harbored Fusobacterium
species, while P gingivalis, Treponema spe-
cies, and T forsythia were detected in more
than 96% of the sites.90 Even in periodontally
healthy subjects, Fusobacterium species were
present in the highest proportion (58%) of
sites, while Treponema species, P gingivalis,
and T forsythia were each detected in about
one-fifth of healthy sites.
The oral mucosa microbiota in cheek swabs
from six Amazon Amerindians of Guahibo
ethnicity living in Venezuela was highly dom-
inated by four bacterial groups (phyla).91
These Amerindians shared only 23% of the
from previous studies and had a lower rich-
ness of genera (51 versus 177 genera reported
in non-Amerindians). In addition, their micro-
biota included some bacteria common in soil.
In another study, saliva samples were
obtained from 10 individuals from each of 12
worldwide locations.92 Overall, approximately
13.5% of the total variance in the composition
of genera was due to differences among indi-
viduals. Investigation of some environmental
variables revealed a significant association
between the genetic distances among loca-
tions and the distance of each location from
the equator.

58

There is high diversity in the salivary micro-
biome within and among individuals, indicative
of an enormous geographic diversity in the
human salivary microbiome. Microbial com-
munity diversity in the Echuya Batwa, a former
hunter-gatherer group from Uganda, is signifi-
cantly higher than that in agricultural groups
from Sierra Leone and the Democratic Republic
of the Congo.93 Forty microbial genera previ-
ously not described in the human oral cavity
were identified in the Batwa. Their distinctive
composition of the salivary microbiome may
have been influenced by recent changes in life-
style and diet.
Knowledge regarding geographic variations
in the oral microbiome and their relationship to
periodontal disease and other oral conditions
could be clinically important for considering
precision periodontal treatment in the future.
The dynamic oral microbiome
The teeth are unique in that they do not con-
stantly renew their outer layer, shedding the
old, as other human tissues do. Therefore,
they allow a subgingival biofilm, consisting of
a highly variable and complex community of
microbes, to colonize, organize, and develop for
extended periods. Bacteria within dental plaque
biofilms are in a dynamic state and interact with
each other, embedded within a self-produced
matrix of extracellular polymeric substance
that consists of polysaccharides, lipids, proteins,
and nucleic acids. In the subgingival plaque
matrix, there is also abundant extracellular
DNA (eDNA) located outside the microbes but
emanating from them. In addition to carriage of
DNA, this eDNA may play an important role
in early biofilm formation and possibly in hori-
zontal transfer of DNA between oral bacteria,94
as well as in protection against desiccation or
radiation and avoiding overcrowding.95
Various organizational patterns of cohabita-
tion by different microbial species living in the
same biofilm (dental plaque) that could contain
bacteria, fungi, and possibly viruses are illus-
trated schematically in Fig 3-18 (Panel A), and
The Human Oral Microbiome
their categorical interactions are exemplified in
Panel B, showing strong and weak cooperation,
exploitation, and competition.96
Figure 3-19 illustrates four ways in which
two oral bacteria that coexist in a symbiotic
relationship within a biofilm can cooperate,
resulting in one species enhancing the virulence
of the other.97
In contrast to microorganisms growing in
a planktonic (freely floating) state, the inhab-
itants of communities within this densely
structured biofilm are effectively protected
from host defense mechanisms and from ther-
apeutic agents, including antimicrobial agents.
For example, enterococci were harvested by
inserting paper points into the periodontal
pocket of patients with periodontitis and
showed a strong association with biofilm
formation.98 These bacteria turned out to
be resistant to vancomycin, erythromycin,
ciprofloxacin, teicoplanin, amoxicillin, and
gentamicin and confirmed the role of the sub-
gingival dental plaque as a reservoir for such
antibiotic-resistant bacteria.
Like human microbiomes in other body loca-
tions, such a microcosm includes organisms of
varying types and proportions, depending on
whether its environment is in homeostasis.
Once the milieu is altered, this delicate balance
is interrupted to the benefit of certain com-
mensal microbes, which subsequently exhibit
opportunistic overgrowth to the detriment of
other members of this biofilm community;
the latter organisms then diminish in amount,
possibly even to rates below detection. The
oral microbiome formation and the virulence
of its various components are influenced by
environmental factors such as acidity (pH),
temperature, cytokines, hormones, and oxida-
tive stress.99
Babies are exposed to a multitude of micro-
organisms both in utero and upon delivery. The
oral microbiome of a newborn infant changes
quickly and is influenced by many factors,
among them the feeding mode.100 This means
that the abundance and composition of the
bacterial oral microbiome in newborns differ
59
3 The Traveling Oral Microbiome

Fig 3-18  |  Interspecies bacterial interac-

tions in multispecies biofilm spatial organi-
zation. (a) Spatial organization of bacteria in
1 2
biofilms: (1) intermixinga; (2) layered struc-
ture without patchy patterninga; (3, 5b) in-
terspecific segregationa; (4) layered struc-
Strong cooperation
ture with patchy patterninga,c; (6) patchy
patterning structureb,c; increased biomass
3 of one or all member species in mixed spe-
ciesb; decreased biomass of one or all mem-
ber species in mixed species; one species
Weak cooperation
is dom­inanta,c; (b) Interspecies interactions:
cooperation, exploitation and competition.
4
Cooperation and exploitation lead to in-
creased biomass of one or all member spe-
cies in mixed-species biofilms compared to
Exploitation
single-species biofilms (a1 to a4), whereas
competition results in decreased biomass
5 6
of all member species in mixed-species bio-
films compared to single-species biofilms (a5
and a6). Arrows and vertical bars represent
Competition
growth facilitation and inhibition, respectively.
(Reprinted from Liu et al96 with permission.)
a b

Fig 3-19  |  Ways that a microbe can pro-

Symbiosis
mote the virulence of another in a mixed bio-
film: (A) subvert host defenses by limiting/
A. Subverting immunity killing by phagocytosis or complement
activity; (B) provide novel carbon sources
or nutrients; (C) inhibit the growth of com-
B. Providing nutrients peting microbes, allowing overgrowth; (D)
provide novel terminal electron acceptors,
allowing more efficient energy production.
C. Inhibiting competing microbes (Reprinted from Selleck and Gilmore97 with
permission.)

D. Enabling aerobic respiration

between breastfed and formula-fed babies.100 In
addition, changes in the microbiome compo-
sition within both groups were observed over
time, especially for Streptococcus species whose
abundance increased markedly between ages 4
through 8 weeks.
A longitudinal study comparing buccal
swabs from 65 adult farmworkers to 52 adults
who did not work on farms found significant
seasonal changes in the oral microbiome rep-
resented by seven commensal bacterial taxa in
the former.101 The organophosphate insecticide
azinphos-methyl was detected in the blood
of 30 of the farmworkers, and 27 of them
showed a significantly altered composition of
the buccal microbiome, including a decrease
in the abundance of the genus Streptococcus
and with extinction suggested of entire taxa
in some individuals. Any long-term health
consequences of such pesticide exposure and
subsequent changes in the buccal microbiome
are currently unexplored.101

60
 The Human Oral Microbiome

100% –
Other
90% – TM7
80% – Gammaproteobacteria
Relative abundance of reads

70% – Betaproteobacteria
60% – Coriobacteria
50% – Actinobacteria
40% – Erysipelotrichi
30% – Clostridia
20% – Bacilli
10% – Flavobacteria
0% – Bacteroidia
Fusobacteria

Low Candida load High

Fig 3-20  |  Relative abundance of bacterial taxa in saliva samples at the class level. The sample order corre-
sponds to the increase in C albicans load in the samples. The Candida load was measured as the proportion
of internal transcribed gene (Candida) over 16S gene (bacteria) abundance by quantitative polymerase chain
reaction. The increase in Candida load was statistically significantly, positively correlated with reads classified as
Bacilli (includes streptococci), while the Candida load correlated negatively with the classes Bacteroidia, Flavo-
bacteria, and Fusobacteria. (Reprinted from Kraneveld et al102 with permission.)

Numerous short- and long-lasting changes salivary microbiome decreased significantly,

in a human’s life cause more or less divergence
from “normal” status in the oral cavity, buccal
mucosa, gingival and periodontal tissues, gin-
gival crevicular fluid (GCF), and saliva. Many
of their effects on the subgingival microcom-
munity are unknown, but emerging research
reports some known effects.
Modifiable changes
Because the healthy state is so delicate, it can be
questioned whether ardent use of bacteriostatic
mouthrinse in the absence of periodontitis or
gingivitis may actually do some harm and dis-
turb the balance, especially due to the common
alcohol content that also is a desiccant.
To enable researchers to explore the inter-
actions between fungi and bacteria, 82 older
Dutch community dwellers delivered unstim-
ulated saliva samples (passive drooling into
a sterile cup) first thing on awakening in the
morning.102 The bacterial diversity of the
with increasing load of the yeast C albicans.
Not only were there fewer kinds of bacteria
present in persons with more C albicans, but
their salivary bacteria composition also shifted
markedly to being dominated by sugar-loving
and acid-producing bacteria, namely strepto-
cocci (Fig 3-20). Such a synergistic relationship
between C albicans and streptococci has been
hypothesized to be an important mechanism
for maintaining good oral health.103
This leads to the question of whether con-
trolling the oral environment to become less
acidic may be a potential preventive measure
for overgrowth of Candida as well as for pre-
vention of caries, especially on the roots.
One way of changing the abundance of bac-
teria and the composition of the supra- and
subgingival87 microbiomes, at least tempo-
rarily, is by periodontal therapy that leads to
a decrease in the abundance of certain peri-
odontal bacteria, especially those most closely
associated with periodontitis.104,105 Home oral

61
3 The Traveling Oral Microbiome
hygiene may also alter the oral microbiome,
such as brushing with a toothpaste that con-
tains enzymes and proteins that enhance the
natural defense mechanisms of saliva and shifts
the ecologic balance of the oral bacterial micro-
biome community toward health.106
Another way is to decrease or cease tobacco
smoking107 and betel nut chewing.108 Even
subtle changes to some aspects of cigarette
smoking, for instance degree of mentholation,
show temporal changes in the oral microbi-
ome after 14 days.109 Al-Hebshi et al examined
491 species-level taxa belonging to 178 genera
and 11 phyla in the bacteriome of smokeless
tobacco users.110 Richness and diversity of
the species were greatest in users of Swedish
snus and lowest in users of Yemeni shammah;
the effects of smokeless tobacco on the oral
microbiome were found to be qualitative and
quantitative as well as functional. A study of
oral microbes in oral wash from 1,204 US
adults confirmed that the compositions of the
microbiomes in current and noncurrent (former
and never) smokers were different, with those
in smokers harboring less diversity.33 Further-
more, the microbiomes depleted by smoking
lead to shifts in functionality that potentially
could impact smoking-related diseases. While a
lower diversity in the buccal mucosal microbi-
ome was found in smokers when comparing 23
current smokers with 20 never-smokers, there
also were oral sites whose microbiome com-
position did not differ by smoking status.111
A third way to change the abundance of bac-
teria is to decrease the level of hyperglycemia,
as high levels of blood glucose enhance the
growth of certain oral bacteria, even to such a
degree that the microbiomes actually exhibit
distinct clustering by various blood glucose lev-
els.112 Importantly, hyperglycemia and smoking
affect the oral microbiome in different ways,
and when both occur their synergistic effect
on the microbiome is greater than the sum of
their respective effects.112 Hyposalivation can
be a consequence of long-term hyperglyce-
mia that damages the nerves of the salivary
glands, which leads to decreased salivary
62
output and hence a decrease in the abundance
of the microbial defense substances contained
in saliva.113 An example of such a substance
is the family of histatins that contains natural
defense properties against oral microbes such
as bacteria and fungi and, when present in
diminished concentration, may predispose to
candidal overgrowth.114
Systemic illness also causes changes in the
oral microbiome, especially ailments that affect
the immune system, such as psychologic stress,
HIV, or the use of immune-suppressive medi-
cation in conjunction with transplants.115 Even
the progression of gingivitis to periodontitis
leads to interspecies interactions resulting in
microbiome transitions.116
A definitive way to change the oral micro-
biome is to become pregnant and give birth or
otherwise terminate the pregnancy. A Japanese
study following 132 healthy pregnant women
and 51 similar but nonpregnant women exam-
ined seven microbial species three times from
weeks 7 through 39 of pregnancy and found
the total abundance to be greater in pregnancy.
The incident proliferation of P gingivalis and A
actinomycetemcomitans was especially signif-
icant, whereas P intermedia and F nucleatum
did not change over time.117 Another Japanese
study comparing similar pregnant (n = 30)
and nonpregnant women (n = 30) found no
difference in salivary flow, but the prevalence
of oral yeast (likely mostly Candida species) in
pregnant women was double that of nonpreg-
nant women.118 Moreover, during the 6-month
study, the abundance of yeast increased sta-
tistically significantly in the pregnant women
from the first to the third trimester but not
in the nonpregnant women, likely due to the
measured greater salivary acidity in pregnancy.
Traveling Oral Microbes
The effects of oral microbes on the rest of
the body may be categorized as indirect and
direct. The indirect effects consist of the body’s

general cascade of inflammatory reactions to
those microbes and bacterial endotoxins. The
direct effect is observed as the consequences of
specific oral organisms traveling to and colo-
nizing body locations outside the oral cavity.
Therefore, the particular microbes need to be
identified via detection of the microorganism
itself or specific antibodies to it. The rest of
this chapter focuses on the direct effect of oral
microbes venturing outside the oral cavity and
emphasizes the logistics of their travels.
Travel destinations
In addition to the oral cavity and connected
spaces, oral microbes have been identified in
the following body sites:
• Oropharynx
• Pathologic heart valves
• Heart valve prostheses
• Surfaces of intracardiac devices (pacemakers
and implantable cardioverter-defibrillators)
• Atherosclerotic plaque in the cardiovascular
system (coronary arteries, carotid arteries, and
coronary thrombi in myocardial infarction)
• Brain (atherosclerotic thrombi in ischemic
stroke, brain tissue, and meninges)
• Respiratory tract (lungs)
• Liver
• Gastrointestinal system
• Pancreas
• Joints (synovial fluid)
• Vertebrae
• Vertebral disc
• Mother-infant unit in pregnancy (fetal brain
tissue, amnion, chorion, amniotic fluid,
umbilical cord, and placenta)
• Breast milk
• Vagina, cervix
• Voice prostheses
Travel options
Dissemination of oral microbes occurs in var-
ious ways. First, travel within a human body
via different avenues and by various vehicles
Traveling Oral Microbes
is described. This is considered intrapersonal
travel. In the next section, interpersonal travel
between humans is addressed.
Intrapersonal
By air: Aspiration. Pulmonary aspiration refers
to the entry of material from the oropharynx
(upper respiratory tract) or gastrointestinal
tract into the lungs via the larynx and lower
respiratory tract, which is the part of the respi-
ratory system from the trachea to the lungs.
When food or drink is aspirated, people use
the expression that the particle or liquid “went
down the wrong (wind) pipe.”
By cell invasion: Attachment, entry/internal-
ization, trafficking, persistence, and exit. P
gingivalis is able to transfer from one cell to
another, even when the cells are of different
types and when the cells are not in cell-to-cell
contact, although that speeds up the transit.34
Usually, autophagy is intended to and succeeds
in enclosing and devouring its target, such as
a microbe that can cause harm. However, Fig
3-21 illustrates conceptually how P gingivalis
makes use of the autophagic pathway in the
case of human coronary artery endothelial cells
(HCAEC) by the following:
• Adhesion: attaching to the outside of the cell
• Internalization: entering into the cell
• Trafficking: moving inside the attacking ves-
icle (autophagosome) inside the cell
• Persistence: staying alive and multiply-
ing inside the autophagosome, to which P
gingivalis signals not to cause the final dis-
integration of its contents
• Exit: leaving the autophagosome still viable
and in great numbers able to infect other
cells34,119
An important feature of the virulence of P
gingivalis is that this bacterium can not only
enter and stay viable inside cells but even
multiply within cardiovascular cells and ath-
erosclerotic plaques in humans and eventually
63
3 The Traveling Oral Microbiome

Fig 3-21  |  Proposed entry, trafficking, and

persistence of strains of P gingivalis that
Adhesion (0–15 m)
utilize the autophagic pathway in human
carotid artery endothelial cells. m, minutes.
Signaling
(Reprinted from Olsen and Progulske-Fox34
Rough with permission.)
Internalization endoplasmic
(15–16 m) reticulum
Early phagosome
(Rab5)

Late phagosome
(Rap1)
Early autophagosome
(Atg7 and BiP)

Trafficking (60–240 m)

Late autophagosome
(BiP and Lamp1)

Phagolysosome Replicating vacuole (2)

(Lamp1 and cathepsin L)

Autolysosome Persistence
(Lamp1 and cathepsin L) (> 240 m)

exit.34 This technique is often referred to as
a “Trojan horse” mechanism. There are dif-
ferences in virulence between the different P
gingivalis strains, among which the invasion
and exit mechanisms vary and also depend
on the type of host cell.34 P gingivalis is
also able to adhere to and eventually invade
human fibroblasts, the most abundant cell in
the periodontium, which induces expression
of proinflammatory mediators that contribute
to the breakdown of periodontal tissues and
chronic inflammation.120 Other oral plaque
bacteria, such as S mutans, are also able to use
this pathway with HCAEC, and still others can
stimulate P gingivalis to use this mechanism,
such as F nucleatum and Filifactor alocis.34 A
2018 review also describes emerging research
of the influence of P gingivalis on adult den-
tal stem cells isolated from dental pupal and
periodontal ligament cells as well as exfoliated
primary teeth.120
Figure 3-22 illustrates schematically two pro-
posed mechanisms for microbial involvement
in atherogenesis, namely bacteremia-mediated
delivery to the left and phagocyte-mediated
delivery to the right.119 Note the release of
bacteria upon the death of the host cell, illus-
trated to the right in Fig 3-22. This idea is not
just speculation, as shown in a human study
in which DNA from periodontal bacteria
was found in 78% of carotid atherosclerotic
plaques with internal hemorrhage.121 Older
Japanese men with hypertension had highly
elevated levels of the periodontal bacteria A
actinomycetemcomitans and P intermedia in
the subgingival plaque compared to normo-
tensive men, whereas there was no difference
in women.122 This could be interpreted to be
a clinical manifestation of periodontal bacte-
ria–associated atherosclerosis, which would
be in line with a 2016 systematic review
and meta-analysis based on 12 studies that

64
 Traveling Oral Microbes

Bacterial component of atheromas

Blood flow
Bacteremia MCP-1 Vascular lumen
Blood MN
MΦ
Apoptotic EC
Leukocyte
Intima
transmigration
Spreading (EC layer)
infection

Growth Spreading
SMC factors infection
proliferation
Media
Tissue MΦ (SMCs)

Fig 3-22  |  Conceptual model of two avenues for systemic dissemination and delivery to the site of inflamma-
tion of the microbial component of atherogenesis. Bacteremia-delivered bacteria invade the endothelial layer
and further spread into deeper tissue (left). Activation of infected endothelia are represented with the release of
proinflammatory chemokines (such as MCP-1) in the lumen, activating blood monocytes (MN) and macrophages
(MΦ) and promoting their adhesion and diapedesis. Phagocyte-delivered viable bacteria internalized in transmi-
grating leukocytes (center) that can switch them into an uncultivable state (red into green), while their internal-
ization by phagocytes can reactivate them (from green to red). Atheromas can grow due to smooth muscle cell
proliferation mediated by macrophage-secreted growth factors. Bacteria are also released upon host cell death
(right). EC, endothelial cell releasing intracellular bacteria; MΦ, macrophage with internalized bacteria; MCP-1,
monocyte chemotactic protein (a proinflammatory chemokine). (Reprinted from Reyes et al119 with permission.)

calculated an increased odds of 50% (OR: 1.50;
95% CI: 1.27–1.78) for those with moderate/
severe periodontitis to suffer from hyperten-
sion.123 Another study demonstrated for the
first time in 2017 that intensive periodontal
therapy leads to a significant decrease in blood
pressure and endothelial microparticles up to 6
months posttreatment, without the aid of any
antihypertensive medication.124
Intriguingly, not only can periodontal bacte-
ria invade gingival cells in periodontitis; they
can even form a complex biofilm inside the gin-
giva that seems to differ in composition from
that in the subgingival plaque from which they
originated.125 The virulence of the keystone P
gingivalis depends partly on its ability to invade
cells, and its different strains/subspecies pos-
sess different levels of invasive capabilities
that again are associated with the severity of
periodontitis.126
By direct transfer: Genetic material. In the
human superorganism, the bacteria are in
frequent, intimate contact with human cells.
Bacterial DNA, including DNA from bacteria
that are often part of the oral microbiome, inte-
grates into the human somatic genome. This is
often referred to as lateral gene transfer. Figure
3-23 shows the integration of genetic material
from the human papillomavirus (HPV) into
human chromosome 8.127 Note the connection
from the eighth chromosome to the HPV. The

65
3 The Traveling Oral Microbiome
connections from chromosome 8 to the viral
oncogenes E6 and E7 expressions are also indi-
cated.127 Such transfer occurs more frequently
in cancer and is thought to promote or possibly
contribute to oncogenesis.127
By blood: Bacteremia. Whenever the integrity
of the oral cavity is compromised, it presents an
opportunity for bacteremia, which is the pres-
ence of bacteria in the blood. Oral bacteria slip
into the bloodstream during most professional
dental procedures. However, such bacteremias
are short lived and transient, and the highest
intensity is limited to the first 30 minutes after
a triggering episode.128 This is the conclusion of
a review of 50 pertinent reports. Yet some indi-
viduals are not able to clear the bacteria before
they lodge themselves in new garages on their
journey, such as arterial walls and organs. The
current consensus is that bacteremia involving
oral bacteria is caused by everyday activities to
a much greater extent than occasional proce-
dures by dental professionals. For instance, a
systematic review and meta-analysis based on
12 reports concluded that the accumulation
of dental plaque and gingival inflammation
66
Fig 3-23  |  Identification of HPV integration
into the HeLa genome. The integration of hu-
man papillomavirus genome HPV NC_001357
(red) into chromosome 8 in the HeLa cell ge-
nome represented by human genome version
19 (blue) is supported by read pairs with one
read mapping to HPV and the other mapping to
the human genome (purple lines). The log-
transformed coverage of the reads supporting
integration (purple histogram: axis minimum
= 0, axis maximum = 4) is consistent with the
known integration of the HPV E6 and E7 genes
shown in yellow on the HPV genome. The log-
transformed coverage of the viral mate pairs is
also shown (red histogram). bp, base pair. (Re-
printed from Riley et al127 with permission.)
significantly increased the risk for bacteremia
after tooth brushing two- to three-fold.129
Blood tests 30 seconds and 10 minutes,
respectively, after full-mouth flossing and scal-
ing and root planing (SRP) in one quadrant
in patients with chronic periodontitis demon-
strated the development of total bacteremia in
30% of the former versus 43.3% of the latter,
a nonstatistical difference.130 Furthermore, the
incidence of bacteremia with viridans strep-
tococci that include several species and are
often associated with infective endocarditis
was 26.7% after both activities, involving
11.4% of the total bacteremia in flossers ver-
sus 7.6% of those undergoing SRP. Whereas
gingival inflammation was correlated with the
incidence of both total bacteremia and viridans
streptococci, there was no difference between
the two groups in either of the two types of
bacteremia.130
Similarly, a systematic review of nine studies
found 49.4% of patients receiving periodon-
tal therapy to develop bacteremia, with the
species Streptococcus and Actinomyces being
most abundant and Streptococcus viridans,
A actinomycetemcomitans, P gingivalis, and

Parvimonas micra (formerly Peptostreptococ-
cus micros and Micromonas micros) occurring
most frequently.131 However, no conclusions
could be drawn regarding the magnitude or
duration of the bacteremia.
By blood: Fungemia. Fungemia is the term
used to describe the situation in which fungi
are present in the blood. The yeast C albicans
has been implicated in some cases of infective
endocarditis. However, the C albicans organ-
isms that invade the bloodstream do not seem
to originate in the oral cavity.132 A Brazilian
team simultaneously examined the palatal
mucosa, the palatal surface of the maxillary
denture, and the blood of patients with denture
stomatitis for the presence of C albicans.133 The
researchers found a strong relationship between
denture stomatitis and Candida species from
the palatal mucosa and maxillary denture.
Despite abundant amounts of the yeast in these
two locations, however, use of a novel DNA
identification method detected no C albicans
in the blood. Conversely, fungemia caused
by Candida (C albicans and C parapsilosis),
named candidemia, as well as invasive candidi-
asis are serious and may cause life-threatening
complications in neonates.134,135
By bloody entryways and access roads. Routes
of possible entry of oral microorganisms into
the systemic circulation include the following:
• Root canal: periapical and lateral lesions
into the alveolar and adjacent blood vessels,
including those in the maxillary sinus
• Periodontium: into capillaries and other
small blood vessels in junctional epithelium
and gingival connective tissues or into the
alveolar blood vessels
• Mucosal lesions with injury to capillaries in
the oral cavity: injuries caused by mastica-
tion of hard food items or biting of tongue
or cheek; denture-related ulcers; candidiasis;
and pierced tissue (with jewelry): tongue, lip,
and maybe face via saliva
Traveling Oral Microbes
By bloody travel vehicles. Various mechanisms
for the systemic dissemination of oral microbes
via the circulating blood have been suggested.
These include flowing freely in the bloodstream;
catching a ride with a “raft” of lipoproteins,
sometimes along with medium-sized choles-
terol molecules; adhering to red blood cells;
and hiding intracellularly. The last mechanism
is an especially effective mode of transport
that can be likened to the Trojan horse model.
The microbes are engulfed or cloaked in a
phagocytosis-like fashion, thereby not only
being transported but also evading discovery
and attacks by the host defense system (circu-
lating phagocytes) and antibiotics. P gingivalis,
the “atherogenic bacterium,” especially uses
this method. Bacteria internalized in white
blood cells (phagocytes) can persist in the cir-
culation for extended periods.
By nerves: Following nerve pathways. Viruses
and bacteria, as well as fungi, seem to be able
to travel along nerve corridors once trans-
ported to the nerve tissue via bacteremia.
Viruses. Herpes simplex virus (HSV) lies dor-
mant in the nervous system throughout the
life course of the host,136 and the virus seems
to travel along neural networks. Emerging
evidence explores the role of infection and
inflammation in the neuropathology of Alz-
heimer’s disease, especially in its late-onset
form, and neurotropic viruses from the Her-
pesviridae family, especially cytomegalovirus
(CMV) and human herpesvirus (HHV)-1 and
-2.137 A first study of its kind to explore the
potential role of HSV and CMV during a
lifetime as opposed to focusing on the older
age groups, analyses of data from the third
National Health and Nutrition Examination
survey (NHANES) regarding seropositivity to
HSV-1and CMV found that such seropositiv-
ity was associated with cognitive impairment
at all ages over 6 years.136 HSV-1 seropositivity
was associated with lower reading and spa-
tial reasoning test scores in children ages 6 to
16 years and was linked to impaired coding
67
3 The Traveling Oral Microbiome
speed. CMV seropositivity was associated
with impaired learning and recall in those
aged 20 to 59 years, and HSV-1 seropositiv-
ity was associated with immediate memory
impairment in the oldest group (> 60 years).136
In addition to HSV and CMV, hepatitis C
virus may also be associated with Alzheimer’s
disease.137
Bacteria. Bacterial infection and its subse-
quent inflammatory responses are increasingly
accepted as potential risk factors for Alzheimer’s
disease, as shown in cadavers.138 It seems that
periodontitis is increasingly recognized as a risk
factor contributing to Alzheimer’s disease.139
Some of the bacteria often found in periodontitis,
for example P gingivalis and some spirochetes,
have developed sophisticated survival mecha-
nisms to avoid detection by the immune system
and therefore may reach the brain tissue by
traveling along the nerves leading thereto,
in addition to the dissemination by blood. In
especially susceptible individuals, they can acti-
vate and perpetuate a series of inflammatory
reactions, aided by the chronicity of periodon-
titis and its responding incessant inflammatory
reactions.139,140 A study attempted to shed light
on this association by creating and relating two
scales, namely the “Cognitive and periodontal
impairment state,” including measures of the
mental state and BOP, and the “Inflammatory
state” that measured levels of cytokines.141
Whether any causal links exist between the two
scales or whether this association simply rep-
resents co-occurrence, as inflammation is part
of the pathology of both BOP and Alzheimer’s
disease, needs further exploration.
Fungi. The same travel mode along nerve cor-
ridors is suggested to also involve fungi such as
C albicans, which is suspected to be involved
in late-onset Alzheimer’s disease.140
Associated conditions
Alzheimer’s disease. The potential involve-
ment of viruses, bacteria, and fungi that are
68
commonly encountered in the oral cavity
with or without oral diseases is potentially
important due to the aging of the world’s pop-
ulation and to the fact that Alzheimer’s disease
accounts for 60% to 80% of dementia cases.142
Any infection and its subsequent sys-
temic inflammation can lead to formation
of amyloid-beta (Aß or Abeta) that consists
of peptides of 36 to 43 amino acids. Aß is
deposited as senile plaques, a hallmark of Alz-
heimer’s disease together with synaptic loss
and neurofibrillary tangles consisting of hyper-
phosphorylated tau protein. Aß is a protective
substance against oxidative stress and has anti-
microbial properties.37 Neuroinflammation is
suggested to contribute to aggravation and
possibly to initiation of Alzheimer’s disease.143
Emerging evidence explores the role of infec-
tion and inflammation in Alzheimer’s disease,
especially its late-onset form, and neurotropic
viruses from the family Herpesviridae, espe-
cially HHV-1, HHV-2, and CMV, are suggested
to be associated within Alzheimer’s disease neu-
ropathology.137 However, the degree to which
these viruses actually originate in the oral
cavity and contribute to general inflammatory
cascades or actually migrate to the brain needs
further exploration.
P gingivalis infection has been reported to
cause sleep pattern disturbances by changing
molecular clock activity in glial cells register-
ing light and darkness, and this in turn can
affect the clearance via the lymphatic system
of potentially disease-associated substances,
such as Aß.144 This possibility has led authors
to wonder whether improved management of
commensal periodontal bacteria may delay or
prevent the onset or progression or Alzheimer’s
disease.144 This idea is intriguing as sleep dis-
turbances and circadian rhythm disruption are
also risk factors for periodontitis,9 but they
may turn out to simply be comorbidities with-
out any causal links.
A large population study reported that
people with periodontitis or gingivitis had an
adjusted hazard ratio (HR) for having Alzhei-
mer’s disease of more than twice that of those

periodontally healthy (aHR: 2.54; 95% CI:
1.30–3.35).145 In a 5-year study, those with
levels of serum antibodies to periodontal
bacteria associated with moderate or severe
periodontitis were at twice the risk for devel-
oping incident Alzheimer’s disease as those
without.146 In 2015, periodontitis was shown
for the first time in humans to be associated
with the load of Aß in the brain.147
As with any other evidence linking oral
microbes/periodontitis and general health,
there exists a possibility that periodontitis
merely co-occurs with systemic diseases and
conditions. Common inflammatory-based
chronic diseases, especially in susceptible indi-
viduals, generally increase and become more
severe with age when the immune responses
deteriorate. As Bartold reminds us, while at
the same time pointing out that the only solid
evidence for the oral-systemic health connec-
tion is between periodontitis and diabetes/
hyperglycemia, “The increasing number of
periodontal-systemic associations corrupts
the ability of dentists to distinguish which of
the associations are spurious and which are
valid.”148 That is, any biologic, causal relation-
ship may not exist despite evidence for strong
associations. Reporting on genetic findings,
Carter et al also noted the importance of the
simultaneous occurrence of several chronic
inflammation- and age-related diseases:
“genes related to cognitive disorders, Alzhei-
mer’s disease, and dementia, and its co-morbid
conditions type 2 diabetes, obesity, and cardio-
vascular disease.”149
Diseases of the eye: Glaucoma and uveitis.
The oral microbiome has been associated
with the neurodegenerative disease glaucoma
that affects the retina and optic nerve, as illus-
trated by the significantly greater load of oral
bacteria in mouthwash from people with (n
= 58) glaucoma compared to glaucoma-free
but otherwise similar individuals (n = 45).150
Exploring this association in the opposite direc-
tion, those with the highest quartile of bacterial
loads had more than three times greater chance
Traveling Oral Microbes
of suffering from primary open angle glaucoma
(POAG) than the first quartile (OR: 3.25; 95%
CI: 1.20–10.55). This study also included an
animal model as a proof of concept in which
mice with glaucoma were injected with bac-
terial material (lipopolysaccharide), which
caused deterioration in the retinal and optical
nerves.150
A study among 21 patients with idiopathic
uveitis, an infection of the interior of the eye,
and 22 healthy people assessed 11 bacterial
species in oral plaque samples and inflamma-
tory markers in the GCF, serum, and saliva.151
The abundance of five of the bacterial species,
including A actinomycetemcomitans and F
nucleatum, was greater in the patients than in
their healthy counterparts and were accom-
panied by altered inflammatory biomarkers
observed both locally and systemically.
Interpersonal
By direct transfer: Direct contact between
humans. Speculation abounds regarding
whether mode of delivery would lead to dif-
ferences in the composition of the neonatal oral
microbiome. A study of maternal and newborn
microbiomes found only minor differences in
the oral gingival microbiome immediately
after birth in infants delivered vaginally and
by cesarean section. At the age of 6 weeks,
the microbiomes at various body sites of the
baby did not show any correlation with deliv-
ery method.152 On the contrary, a 2017 review
reported such a difference in the first 6 months
of a baby’s life, while noting that development
of accurate, DNA-based methods for fungus
identification are still lacking.153 This review
concluded that the most frequently studied
fungus in vertical transmission from mother
to child is C albicans.153
By indirect transfer: Via saliva. Oral microbes
are transmitted via kissing, sharing of utensils,
parents licking or cleaning a pacifier or pre-
chewing food for their babies, oral sex, biting,
and so on.
69
3 The Traveling Oral Microbiome
Cariogenic bacteria are transmitted from
parents or other caregivers to the child, whose
oral cavity is sterile at birth. There is limited
contemporary evidence for parent-to-child
transmission of bacteria usually associated
with periodontal disease. A study genetically
identifying A actinomycetemcomitans and P
gingivalis in subgingival plaque in families with
periodontitis revealed interspousal transmis-
sion of A actinomycetemcomitans in 4 of 11
married couples (36%) and of P gingivalis in 2
of 10 married couples (20%).154 Parent-to-child
transmission of A actinomycetemcomitans was
seen in 6 of 19 families (32%), whereas P gingi-
valis was not transmitted from parent to child
in any of the study families.
When salivary DNA in edentulous infants
and their mothers was compared, it became
clear that even the young, predental baby
hosted a wide variety of bacteria.155 A total of
397 bacterial genera were identified. Only 28
were different between the adult and the child,
27 of them seen in the adults. Streptococcus
was the predominant genus in infant saliva,
significantly more abundant than in the moth-
ers (62.2% in infants versus 20.4% in adults).
This study demonstrated that a diverse bac-
terial community exists in the oral cavity of
infants even before tooth eruption. It remains
to be seen which environmental factors affect
the further colonization and subsequent risks
for oral and gastrointestinal disease.
Growing evidence supports an oral origin
of bacteria that cause chorioamnionitis, an
inflammation of the fetal membranes (amnion
and chorion), as well as the placenta156,157 and
umbilical cord.158 While bacteremia is the main
suspected travel mode,159,160 receptive oral sex
from a partner with periodontal disease can
also be the cause.159 Interestingly, a compre-
hensive review concluded in 2017 that “The
composition of the placental microbiome is
distinct from that of the vagina and has been
reported to resemble the oral microbiome.”160
Bite marks in humans by humans are mostly
seen in violent crimes, especially in rape attacks
and child abuse. The use of morphology of the
70
bite mark has been abandoned, and instead
identification via the culture-independent DNA
analysis is generally accepted as hard evidence
in court. A research team found that strepto-
coccal DNA from bite mark samples aligned
significantly more closely with profiles gen-
erated from the teeth responsible for the bite
than with those from other teeth in the same
individual. Hence, streptococcal DNA can be
used directly from bite marks.161
Another team examined three genomic
regions of streptococcal DNA to discriminate
between swabs from bite marks and teeth from
16 participants.162 Using three different tech-
niques, the researchers found probabilities of
92%, 99%, and 100%, respectively, for correct
identification of the tooth whose plaque was
found in the bite mark.
Bacterial DNA is preserved for a longer time
in bite marks than in, for instance, decompos-
ing human cells in a corpse and may therefore
be useful if collected after longer time spans
after the bite occurred. Bacterial DNA is more
convenient in such cases because it could be
difficult to distinguish human DNA between
the biter and the bitten. Consequently, oral bac-
terial DNA may be used in forensic dentistry
to provide documenting information on the
identification of the biter.
Pacifiers. Many parents clean their infant’s pac-
ifier with their own saliva by sucking it. In so
doing, parents transfer their oral microbes to
the child.163 Based on a study of 184 infants,
pediatricians concluded that vaginal delivery
and parents’ cleaning of pacifiers with their
saliva generated independent and additive, sig-
nificant protective effects against development
of asthma (88% decrease) as well as eczema
and sensitization (63% decrease for each) at
18 months old. The authors speculated that
the child’s immune system is stimulated by
microbes in the mother’s birth canal and the
parents’ saliva.
However, various professional dental organi-
zations have strongly opposed recommending
this practice because of the risk of transfer of

oral organisms that contribute to the develop-
ment of caries and periodontal disease.
By indirect transfer: Layover in dental labora-
tory or hospital equipment. Removable dentures
are often in need of adjustment and repair due
to resorption of the edentulous alveolar ridges
after tooth extraction. Bacteria that inhabit the
oral microbiome and can turn into opportunis-
tic pathogens in a favorable milieu have been
found in pumice samples from dental labora-
tories. Additionally, studies have shown that
the pumicing procedure produces splatter and
aerosols, through which the bacteria can spread.
By indirect transfer: Contaminated gloves and
other protective gear. A
 study of health care
personnel at four hospitals and one medical
center used fluorescent lotion and disclosed
that contamination of the skin and clothing of
health care personnel occurs frequently during
removal of contaminated personal protective
equipment (PPE), such as gloves and gowns,
on average in 80% of the cases with incorrect
PPE removal and even in one-third of the cases
following correct PPE removal.164 It should be
mentioned that 1 and 3 months after educa-
tional intervention, the contamination rate
dropped to a stable 12%.
By air: Sneeze propelled. Although periodontal
bacteria are reported to be part of atmospheric
air high above the ocean, it is not known
whether such high flyers actually can infect
a new host on landing and multiply in the
adopted environment. Moreover, the literature
currently seems devoid of confirmed coloniza-
tion through human-to-human transmission
of oral microbes after sneezing or coughing.
However, such transmission may be possible.
By water: Sink drain. A first report of its kind
was published in April 2013 where DNA from
P gingivalis was identified in the complex
biofilm in the drain of a sink in a hospital bath-
room. Applying a novel technique of generating
genomic DNA from single cells, the researchers
Traveling Oral Microbes
recovered a nearly complete genome represent-
ing a new strain of a periodontal bacterium,
namely P gingivalis JCVI SC001.165
Travelers’ qualifications, methods,
and frequencies
Oral bacteria easily enter the bloodstream
when the periodontium is inflamed due to
infection. The ease with which this occurs
seems to depend on the severity and extent of
the periodontal infection and inflammation and
is greater in people with poor oral hygiene.
That is, the worse the periodontal disease, the
more easily will bacteria penetrate the blood
vessel wall and enter the bloodstream. Once in
the blood, the microbes from the periodontal
biofilm and their byproducts—such as live or
dead microbes and pieces of bacterial cell walls
(lipopolysaccharides)—will travel to various
destinations in the body. Lipopolysaccharides
are large molecules that are known also as
endotoxins. They are a major constituent of
the outer cell membrane of gram-negative bac-
teria, for instance those often associated with
periodontal destruction.
Endotoxins can elicit strong immune
responses. Humans are much more sensitive
to them than are other mammals, such as mice.
A dose of 1 µg/kg induces shock in humans,
but mice will tolerate a dose up to 1,000 times
higher.166 This is a major reason why findings
from research conducted in mice with exper-
imental periodontal disease should be viewed
with caution, as the results may not transfer
directly to humans.
Travel qualifications
Through the use of powerful novel techniques,
an unexpected genetic diversity within the
bacterial species has recently come to light. In
many cases, the evolution of specific species
and their subspecies is disproportionately asso-
ciated with infection or overgrowth.89 Only
71
3 The Traveling Oral Microbiome
a limited number of species and strains are
detected in bacteremias so far. It may be that
certain microbial attributes play a role in the
ability of specific bacterial species to penetrate
and survive in the bloodstream, invade distant
tissues and organs, and ultimately multiply
there. Reportedly, some species exhibit innate
attributes that enhance such activities, includ-
ing the ability to do the following:
• Adhere to multiple different surfaces
(microbes, tissues, immune cells, and sali-
vary molecules)
• Decrease the phagocytic activity of cells that
would engulf them
• Penetrate between cells in tissue and into
host cells
• Initiate, maintain, and ensure long-term
survival of an intracellular localization for
transportation, defense, and multiplication
(Trojan horse model)
Because only certain subspecies (strains) of
bacteria seem to travel systemically, it is nec-
essary to identify exactly which strains cause
harm in order to target those organisms in
future therapy and prevention.167
Travel share: The mouth, the gut, and
atherosclerosis
A landmark study was designed to test the
hypothesis that bacteria from the mouth and/or
the gut could end up in atherosclerotic plaque
and thus contribute to the development of car-
diovascular disease.168 Using 16S rRNA genes
to survey and compare the bacterial diversity
of oral, gut, and atherosclerotic plaque samples
from 15 individuals with atherosclerosis and
15 healthy controls, Koren et al168 found the
following:
• Bacterial DNA was present in atherosclerotic
plaque.
• Veillonella and Streptococcus species were
detected in the majority of the atheroscle-
rotic plaque samples.
72
• The combined abundances of Veillonella
and Streptococcus species in atherosclerotic
plaques correlated with their abundance in
the oral cavity.
• DNA from several additional bacteria was
common to the atherosclerotic plaque and
oral or gut samples within the same individual.
In the year 2000, Haraszthy et al identified
DNA from periodontal bacteria in 80% of
50 atheromatous plaque specimens obtained
from patients undergoing carotid endarterec-
tomy,169 and several studies have confirmed
these findings in specimens in, for example,
coronary bypass graft surgery.170 A 2016 sys-
tematic review included 63 studies with a total
of 1,791 patients and reported the presence of
23 oral commensal bacteria within atheroscle-
rotic plaques in patients undergoing carotid
endarterectomy, catheter-based atherectomy,
or similar procedures.171 A study of specimens
from atherosclerotic plaque from the carotid
arteries found DNA from periodontal bacteria
to not only be present in between 24% and
68% of the samples but also to be associated
with intraplaque hemorrhage, which is a risk
factor for ischemic stroke.121
Overall, these findings strongly support
the hypothesis that the oral cavity can be a
source for atherosclerotic plaque–associated
bacteria. These bacteria may contribute to
further inflammation and eventual destabili-
zation and rupture of the plaque, ultimately
causing a heart attack or ischemic stroke. For
example, bacterial DNA from various bacterial
oral species and Chlamydia pneumoniae was
identified in thrombus aspirates and arterial
blood from patients with ST-segment-elevation
myocardial infarction undergoing primary
percutaneous coronary intervention (n = 101;
76% male; mean age: 63.3 years).172 Interest-
ingly, the concentration of bacterial DNA was
16 times greater in the thrombi than in the
blood samples. About four of five (78.2%) of
the thrombi contained DNA from oral viridans
streptococci mostly associated with endodontic
infection, and DNA from periodontal bacteria

was identified in one-third (34.7%) of the
thrombi. Importantly, the 30 participants with
panoramic radiographs had significant dental
restorations and pathology, including end-
odontic treatment in two-thirds (66.7%) and
periapical abscesses in almost half (46.6%), of
which one-third occurred in conjunction with
endodontically treated teeth.172 In the thrombi,
the odds of finding streptococci were 13.2 times
greater in those with periapical abscesses than
in those with healthy periapical tissues (OR:
13.2; 95% CI: 2.11–82.5). In patients under-
going extracorporeal circulation auxiliary to
open-heart surgeries, those with periapical
abscesses were more likely to develop infec-
tious complications, such as septicemia, than
those with healthy periapical tissues.173
Frequent traveler: Human papillomavirus
Unquestionably, the most important microbe
transmitted easily by direct contact between
people is HPV. HPV might not be thought of
as part of the normal human oral microbiome,
and no significant association was identified
between the presence of periodontitis and HPV
in oral rinse specimens by adjusted analyses of
the NHANES 2009–2012 data.174 However,
a pilot study demonstrated the potential for
periodontal pockets to be reservoirs for HPV
by scraping such pockets and identifying mes-
senger RNA from HPV in study participants
with chronic generalized periodontitis in 50%
of the eight participants who showed no signs
of HPV-related diseases.175
As HPV is the most common sexually
transmitted virus, the US Centers for Disease
Control and Prevention (CDC) estimates that
up to 80% of the US population will harbor
HPV at some time during their lifetime.176 Most
affected persons do not realize they are carriers
and are passing the virus on to a sex partner,
and the vast majority of cases go unnoticed.
No HPV test for men has been approved by
the CDC.176 The majority of HPV infections
(many would regard this as carriage, not infec-
tion) are undetectable after 1 year, and about
Traveling Oral Microbes
90% will resolve within 2 years, except in
some immunocompromised individuals, such
as those infected with HIV. For example, an
Italian study among 305 HIV-positive men
found 265 (86.9%) to have HPV detected in
either oral rinse or anal swabs.177
Importantly, HPV does not multiply in saliva
or blood. It establishes productive infections
only in keratinocytes of the skin or mucous
membranes. More than 40 HPV types can
infect the mouth and throat as well as the gen-
ital areas of both males and females. HPV is
not disseminated via bacteremia but is easily
transferred by direct contact, most often during
vaginal and anal sex; it may also be passed on
during oral sex. HPV may also be transmitted
via kissing. Whether the exact means of trans-
mission is direct contact or via saliva remains
to be determined. There is as yet no evidence
that saliva acts as an HPV transmission vehicle
for oral or genital contamination. However,
given the presence of shed epithelial cells in
oral fluids, this route is quite possible.
In addition to causing cancer, HPV infections
can cause other health problems, including
100% of genital warts; recurrent respiratory
papillomatosis, a rare condition in which warts
grow in the throat; and juvenile-onset recur-
rent respiratory papillomatosis seen in babies
infected by their mothers during delivery. The
types of HPV that can cause genital warts are
not the same as the types of HPV that can
cause cancers. Warts can appear from weeks
to months after HPV is contracted,178 and the
patient might be unaware of carrying the virus
until symptoms occur.
World traveler: Prevalence of HPV. There are
more than 100 different kinds of HPV, but not
all of them cause health problems. According
to the World Health Organization (WHO), the
two most prevalent HPV types are HPV-16
(3.2%) and HPV-18 (1.4%).179 The global
prevalence of infection with HPV in women
without cervical abnormalities is 11% to 12%;
rates are higher in sub-Saharan Africa (24%),
Eastern Europe (21%), and Latin America
73
3 The Traveling Oral Microbiome
(16%). Particularly high HPV prevalence is
seen in Eastern Africa and the Caribbean,
where rates exceed 30%. In general, higher
rates are observed in less developed regions
of the world.179 For instance, 75.3% of the
population in a study in India was infected by
HPV.180
HPV was detected in 4.0% of oral rinse spec-
imens obtained from 1,688 healthy men, aged
18 to 74 years (median 31 years), from the
United States, Mexico, and Brazil. The HPV
types were similar in the three countries, except
that HPV-55 was seen more often in Mexico.181
The strongest predictor for the presence of oral
HPV was smoking. However, the prevalence of
oral HPV in these men was only one-tenth that
of infection at genital sites (4% versus approx-
imately 40%). The reason for this discrepancy
is not clear, but the authors speculated that the
mouth may be more resistant to infection than
the anogenital area. Over 12 months, 4.4% of
these men acquired new oral HPV. However,
most were cleared within 1 year, after a median
infection period of less than 7 months.182
A large population study in China came to
a similar conclusion upon following 3,289
healthy, rural men and women aged 25 to 69
years for a mean of 18.3 months with oral
swab specimens,183 namely that the majority
of these new oral HPV infections were cleared
within 1 year, with 89.7% cleared after only 3
months. Recent oral sex was associated with
greater incidence of mucosal HPV infection
with an adjusted hazard ratio of more than
10-fold (aHR: 10.13; 95% CI: 2.14–48.06).
A much greater prevalence of oral (measured
in saliva) HPV infections (24%) was reported
among 100 women aged 22 to 52 years with
known HPV genital infections compared to 8%
in 25 women aged 20 to 49 years without such
genital lesions.184
Based on nine reports involving 3,762
individuals, a systematic review and meta-
regression concluded that worldwide and
among people without HIV or cancer, 7.5%
had oral infections with any type of HPV, and
the annual cumulative incidence (new cases)
74
was 4.8% (95% CI: 3.2–7.3%).185 The overall
oral HPV clearance was reported to be 0% to
80% between studies, and the median time to
clearance varied from 6.5 to 18 months.
In the United States, almost 80 million indi-
viduals are currently infected with HPV, which
amounts to almost a full quarter of the entire
US population of 327 million of all ages. About
14 million people will contract the infection
each year, and about 360,000 men and women
will develop genital warts.176 Around 7% of the
US adult population, namely 10.1% of males
and 3.6% of females, have one or more of 37
types of oral HPV, detected in purified DNA
from oral exfoliated cells obtained from oral
rinse.186,187 Publication in 2017 of analyses of
data from 2011 to 2014 reported that the prev-
alence of any oral HPV was 7.3% among US
adults aged 18 to 69 years, with 11.5% of men
and 3.3% of women.188
Vaccination and testing for HPV. The CDC
now recommends two (down from three) doses
of HPV vaccine for all girls and boys aged 11
or 12 years, as well as for older unvaccinated
individuals, with the second dose given 6 to 12
months after the first.189 In addition to prevent-
ing genital HPV infection, it is shown that HPV
vaccination induces neutralizing antibodies in
oral fluids in both humans190 and mice; the
latter were subjected to different vaccination
modes that all completely prevented oral infec-
tion with HPV-16.191
As an aside, a study conducted among 10%
of Danish dentists showed that they had no
increased risk of being infected with HPV.192
Dental practitioners are in an eminent posi-
tion to be alert to any signs of epithelial
changes in the oral mucosa. As partners of
the patient-centered health care team, den-
tal professionals can also contribute to their
patients’ general health care by educating and
encouraging them to obtain HPV vaccination
as part of overall health. However, it seems
dentists may need to increase their literacy on
this topic193 and overcome some perceived bar-
riers to patient education.194

Intermittent traveler: Herpes simplex virus
Several types of viruses inhabit the oral cavity
and are more often associated with periodontal
pockets than gingivitis. The role of these viruses
as causative agents for periodontitis has been
questioned. Nevertheless, HSV merits mention
as a frequent, although intermittently dormant,
member of the oral microbiome.
After infecting an individual, HSV takes up
permanent residence in the host. HSV spreads
easily between humans, mostly via direct con-
tact such as kissing and caressing but also
through shared utensils and towels, lip balm,
and razors as well as via sexual contact. The
carrier from whom the virus is transferred
needs not have signs or symptoms of the infec-
tion, such as cold sores. Such transmission is
termed asymptomatic viral shedding.
HSV-1 is usually acquired in childhood,
whereas type 2 (HSV-2) typically spreads
through sexual contact. However, HSV-1 can
also be transmitted via oral sex and cause
genital cold sores. In 2015–2016, the over-
all prevalence of HSV-1 in the US population
aged 14 to 49 years was about half (48.1%),
with significantly more females (50.9%) than
males (45.2%) infected.195 HSV-1 is seen in 6
in 10 of the age group 40 to 49 years. More
than one-tenth (12.1%) of that same popu-
lation is infected with HSV-2, ranging from
0.8% of the youngest (14 to 19 years) to 1
in 5 (21.2%) of the 40- to 49-year-olds.195
While whites have a prevalence of 8.1%, 1 in
3 (34.6%) non-Hispanic blacks have HSV-2
infection.
About 50 million US adults experience
between one and three symptomatic episodes
every year. After the first outbreak of a her-
petic lesion, the virus moves from the skin to
the central nervous system. There it will stay
dormant until a triggering event, such as stress,
illness, fever, sun exposure, menstrual period,
or surgery, interrupts the host’s homeostasis
and decreases resistance. The outbreaks may
occur in the buccal and gingival mucosa or on
the tonsils, as well as on the lips.
Traveling Oral Microbes
Many dental professionals refrain from
treating a patient during the active phase of an
outbreak. This is due to concern about poten-
tial viral transmission either via direct contact
between dental personnel and a patient’s cold
sores or via a virus-containing aerosol created
by air blown into the mouth and bounced back
over the lips of an infected patient.
Lifelong lurking traveler: Epstein-Barr virus
The Epstein-Barr virus (EBV), also known as
human herpesvirus 4, is a common member
of the human herpesvirus family and as such
lingers in the human body for life.196 Ironically,
the EBV infects not only epithelial cells but
also the B cells of the immune system that are
supposed to combat this virus. It stays dormant
in the B cells until a triggering event causes it
to proliferate. Worldwide, more than 90% of
adults are EBV seropositive.
EBV is usually acquired in early childhood or
adolescence. Children are susceptible as soon
as the antibodies inherited from their mother
wear off, and about half of 5-year-olds in the
United States have been exposed to the virus. If
infection instead occurs during adolescence or
during the teen years, infectious mononucleo-
sis will manifest itself in one-third to one-half
of the cases in the United States. Because the
virus is transferred via saliva (and genital secre-
tions), infectious mononucleosis is known as
the kissing disease (or mono). EBV has also
been identified in oral diseases such as oral
lichen planus and oral hairy leukoplakia.
Reverse traveler: Helicobacter pylori bacterium
Although not discovered until 1984,197 H pylori
is the bacterium responsible for stomach and
duodenal ulcers. H pylori is one of the most
common pathogenic infective agents; about half
the world’s population is affected. Its preva-
lence correlates closely with socioeconomic and
hygienic conditions. Developing countries have
a prevalence of 80% to 90%, whereas that of
developed countries is usually less than 40%.198
75
3 The Traveling Oral Microbiome
After pooling results from different stud-
ies, a meta-analysis concluded that there is a
close relation between infection with H pylori
in the oral cavity and in the stomach; 45.0%
of gastrically infected individuals and 23.9%
of individuals without stomach infection have
oral H pylori.199 Initial infection with H pylori
usually occurs in childhood and has been
observed in live, cultivable form in primary
endodontic infections.200
Even in the absence of gastritis, H pylori is
frequently detected in the oral cavity, especially
in people with periodontitis; in dental plaque
in up to 88% of people; in benign laryngeal
lesions; on the surface of oral cancer lesions;
and in salivary gland secretions. Additionally,
the same type of H pylori was identified in the
mouth (saliva and plaque) and in the stom-
ach, and in one study none of the participants
had oral H pylori infection without gastric
infection.198
There is no consensus whether H pylori
should be regarded as a transient or a resident
member of the oral biofilm. The mechanism
by which H pylori reaches the oral cavity is
unknown. It is possible that occasional reflux
or vomit from the gastric (juice) reservoir
allows colonization of the oral cavity. It is also
possible that the reverse is true. In addition,
oral presence of H pylori could even present a
mode of interpersonal transmission, including
transmission from mother to child.198
Pooling of findings from 26 studies showed
that aggressive systemic antibiotic therapy
resolved the presence of H pylori in the stom-
ach in about 90% of individuals but in the
mouth in only 6%.199 That is, 94% still har-
bored the bacterium in the mouth (tongue
dorsum, supragingival and subgingival plaque,
and the saliva) after the intensive antibiotics
course. The oral cavity may act as a perma-
nent or transient reservoir or sanctuary for H
pylori and may be the source of reinfection
of the stomach, as confirmed by a systematic
review.201 It has been suggested that profes-
sional removal of plaque and calculus as well
as home oral hygiene procedures be performed
76
along with the systemic multi-antibiotic treat-
ment of H pylori. Close collaboration between
the patient’s dental professionals and gastro-
enterologist or other medical care provider is
pivotal.
Because a large proportion of adults harbor
H pylori in the oral cavity, dental treatment
could result in frequent exposure of the den-
tal care providers via aerosols. Some studies
have found dental personnel to be at greater
risk, whereas others have not. Polish dentists
who had practiced longer than 15 years had a
much elevated rate of infection in their gingi-
val sulci, and male dentists were much more
often infected than female dentists.202 More-
over, a serologic study at a dental school in
Japan showed that clinical dental professionals
were at 2.7 times greater risk for contracting H
pylori infection over a 6-year period than were
nonclinical employee controls.203
Fatal dead ends, road blocks, and tourist traps:
Antibiotics
Usually the white blood cells, of which 40%
to 70% are neutrophils, a type of granulocyte
and phagocyte, defend our bodies by attack-
ing, ingesting, and poisoning with enzymes,
thereby killing dangerous, infectious microbes.
However, the 2004 discovery of such defense
systems gone awry pertains to “neutrophil
extracellular traps” (NETs) released from
hyperactive or overly reactive neutrophils that
might conduct their entrapment and microbial
killing to the detriment of the host as it can
result in destruction of tissues, such as the peri-
odontium, assisted by enzymes released by P
gingivalis.204
Antibiotics are used against bacteria, but in
the interest of limiting further development
of resistant bacteria, myriad other substances
with antimicrobial properties are currently
being investigated for their potential role in
controlling the dissemination of oral bacteria
to the rest of the body as well as for prevent-
ing further breakdown of periodontal tissues.
The following examples have a focused range
 Future Travels

A broadly distributed ‘supercore’ pathway: coenzyme A biosynthesis (COA-PWY) Major contributors

Bm
An

Sp
Td

Pf
–1

S
Streptococcus
–2 Lactobacillus
Bacteroides

28 pathways
–3 Haemophilus
Corynebacterium
–4 Propionibacterium
Prevotella
–5 Other
a –6 Unclassified
6 body sites
A human microbiome-enriched pathway: adenosylcobalamin salvage from cobinamide (PWY-6269)
Bm
An

Sp
Td

Pf
–1
S
Bacteroides
Porphyromonas
–2 Parabacteroides
17 pathways

–3 Streptococcus
Prevotella
–4 Escherichia
Klebsiella
–5
b –6
Other
Unclassified

A body area (oral)-enriched pathway: nitrate reduction (DENITRIFICATION-PWY)

Bm
An

Sp
Td

Pf
S

–1 Neisseria
Actinomyces
–2 Lautropia
21 pathways

–3 Capnocytophaga
Kingella
–4 Cardiobacterium
Pseudomonas
–5
c –6
Other
Unclassified
log10(rel. abund.)
–6 –5 –4 –3 –2 Anterior nares Buccal mucosa Supragingival plaque Tongue dorsum Stool Posterior fornix
Skin | n = 157 Oral | n = 183 Oral | n = 191 Oral | n = 210 Gut | n = 249 Vaginal | n = 97

Fig 3-24  |  Core and distinguishing functions of human body site microbiomes: (a) 28 metabolic pathways were
core at all 6 major body sites (“supercore” pathways); (b) 2 supercore pathways and 17 additional pathways
were core in multiple body areas and enriched among human-associated taxa (“human microbiome–enriched”
pathways); (c) 21 pathways were considerably more abundant at 1 body site than at sites from all other body
areas (“body site–enriched” pathways). Heat map values reflect the first quartile of relative abundance. In path-
way bar plots, total (community) abundance is log-scaled, and the contributions of the top seven genera are
proportionally scaled within the total. The six major body sites: An, anterior nares; Bm, buccal mucosa; Sp, su-
pragingival plaque; Td, tongue dorsum; S, stool; Pf, posterior fornix. Major contributors: “Other” encompasses
contributions from additional, known genera; “unclassified” encompasses contributions of unknown taxonomy.
(Reprinted from Lloyd-Price207 et al with permission.)

of action, namely wild blueberry polyphe- individual microbial communities can be iden-
nols that target F nucleatum205 and highbush tified. For example, in 2017 the second wave
blueberry proanthocyanidins targeting A of the National Institutes of Health Human
actinomycetemcomitans.206 Microbiome Project provided 1,631 new
metagenomes from 265 healthy individuals,
bringing the project total to 2,355 genomes
and hence contributing twice the number of
Future Travels hitherto known genomes (Fig 3-24).207 Note
the important, prominent role of the 9 oral
The oral microbiome in humans is extraordi- microbiome sites of the total of 15 in males
narily complex. This community of microbes, and 18 in females.
along with that of the gut, contains the great- By the time of this study, several of the 265
est diversity and abundance of all human healthy adults had provided data from up to
microbiomes. Now that more rapid, reli- three time points, allowing temporal variation
able, and affordable molecular techniques to be observed and classified into rapidly vari-
are available—and many more are in speedy able, moderately variable, and stable subsets.207
development or refinement—the genomes of This is a major step toward understanding the

77
3 The Traveling Oral Microbiome
function and dynamics of microbiomes at a
personal level on the path to personalized or
precision medicine, which has been dubbed
“the way forward.”208
In addition to studying individual micro-
bial communities, researchers must study the
interaction, organization, and communication
(eg, cell-to-cell signaling) of these commu-
nities. There are still many microbes in the
human mouth and the rest of the body whose
identity and function are largely or com-
pletely unknown. These longtime or transient
members of the human microbiomes and the
interactions between them must be studied over
time and under myriad internal conditions and
external influences within the host and from
the greater surrounding environment to learn
about their function, flexibility, and reactions
to conditions and stimuli such as diseases and
antibiotics present in the host. Not until these
and other mechanisms are better understood
will it be possible to successfully manipulate
individual human microbiomes in the quest for
improved oral health.
Exciting and exotic travels continue to clear
new paths on which to walk—or run—wher-
ever they lead into the unexplored lands of
the microbes inhabiting the human body. This
journey will be bursting with new discoveries
that help improve the future understanding
of interactions among the host genome, epig-
enome, and oral microbiome. Medical and
dental professionals have the duty and priv-
ilege to skillfully apply these discoveries in a
personalized manner to promote the health,
including oral health, of each individual human
being.209,210
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189. Meites E, Kempe A, Markowitz LE. Use of a 2-dose
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191. Ahn J, Peng S, Hung CF, Roden RBS, Best SR. Prophy-
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192. Genner J, Scheutz F, Ebbesen P, Melbye M. Antibody
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193. Vazquez-Otero C, Vamos CA, Thompson EL, et al.
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199. Zou QH, Li RQ. Helicobacter pylori in the oral cavity and
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200. Hirsch C, Tegtmeyer N, Rohde M, Rowland M,
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85

The Role of Inflammation in
Oral-Systemic Interactions
Marcelo Freire, dds, phd, dmsc
Thomas E. Van Dyke, dds, phd
A localized inflammatory response to an injury
or infection is a spatially defined and tempo-
rally regulated condition that is self-limited.
If the lesion does not resolve and becomes
chronic, the acquired immune system is
stimulated, including broad activation of
lymphocytic pathways and cell-mediated and
humoral immunity. The inflammatory and
immune system can be a contributing factor
in the pathology of many chronic diseases,
including cardiovascular diseases (CVDs),
type 2 diabetes, rheumatoid arthritis, and
periodontal diseases. Local persistent inflam-
matory lesions lead to systemic dysregulation
of homeostasis, an extended response that goes
beyond confined localization to one tissue. The
chronicity of the lesion alters molecular, cel-
lular, and overall tissue responses in remote
regions of the body, having a transient or per-
manent effect on overall health. The ability of
scientists to better understand the underlying
pathology and to identify groups of patients
susceptible to inflammatory disease through
precision medicine could potentially lead to
new, innovative treatments.
Oral conditions can significantly influence
or be influenced by local and systemic events.
Periodontal diseases, periodontic-endodontic
lesions, traumatic lesions, reactionary oral
lesions (chronic irritation), premalignant
lesions, oral cancer, and other conditions are
86
CHAPTER 4
distinct in etiology and mechanisms but have
in common a programmed immune response
that modulates disease progression, prognosis,
and treatment. Periodontal tissues in particular
have an anatomical and multitissue origin, are
hypervascularized, and have a unique interface
with commensal microorganisms, maintaining
a controlled homeostatic response in health.
Infectious and inflammatory diseases of the
oral cavity, such as periodontitis, result from an
imbalance of the commensal-host relationship
that results in or may be caused by excessive
inflammation and overgrowth of commensal
pathogens. It is becoming clear that chronic
oral infections and inflammation have a sys-
temic impact. It is relevant to the fields of
biology, medicine, and dentistry to understand
the mechanisms of the intricate molecular
interactions that underlie the relationship
between oral conditions that arise locally and
their long-term systemic consequences.
Historically, the first descriptions of localized
tissue response to injury and infection were
recorded by the ancient Egyptian and Greek
cultures. Hippocrates, in the 5th century bce,
introduced terms such as edema that are still
used to describe the local response—inflam-
mation.1 He referred to inflammation as an
early component of the healing process after
tissue injury. The invention of the compound
microscope by Janssen in the 1500s and the

subsequent improvement of its optical reso-
lution by Leeuwenhoek gave rise to the early
descriptions of the tissue response to injury.
The initial concepts related to inflammation
came from intuition (and clinical observations)
rather than careful scientific investigation. The
controversial observations described by ancient
cultures provided the framework for critical
experimentation in later centuries, when it
became clear that it was necessary to elucidate
the relationship between local responses and
systemic health.
Still, until the middle of the 20th century,
scientific and medical theory was based on
observation and intuition rather than exper-
imentation and application of the scientific
method. One example is the concept that focal
infection or injury is the basis of systemic dis-
ease. The focal infection theory, introduced in
1891 by Miller, proposed a relationship between
oral and systemic infection.2 A prevailing theory
of medicine around this time was that miasmas,
or bad smells, caused disease, in spite of Koch’s
discovery of the infectious nature of disease.
Miller emphasized that oral microorganisms
or their products were the etiologic factors of a
variety of diseases in sites far removed from the
oral cavity, including arthritis, brain abscesses,
pulmonary diseases, cardiovascular and gastric
problems, and even stupidity.
The role of oral sepsis as a cause of systemic
disease was described by William Hunter, a
prominent British physician, who emphasized
that dental restorations “built in, on, and
around diseased teeth which form a veritable
mausoleum of gold over a mass of sepsis to
which there is no parallel in the whole realm
of medicine, and it is unique to oral tissues.”3
In 1919, Rosenow published a series of animal
experiments and human case reports support-
ing the concept of focal infection. He suggested
cooperation between dentists and physicians to
ensure that the focus of oral infection would
be eliminated completely. It became com-
mon practice to extract all endodontically or
periodontally involved teeth to eliminate any
possible foci of infection, with the expectation
The Role of Inflammation in Oral-Systemic Interactions
that this would prevent or cure a plethora of
local or systemic problems.3
The lack of scientific foundation for the
concept of focal infection eventually led to its
rejection because there was no clear basis for
ascribing most systemic diseases to bad teeth
and gums. The practice of dentistry changed,
and practitioners and the community redirected
their focus to restorative procedures. However,
as a more scientific approach was applied to
investigating clinical problems, it became clear
that there are in fact situations in which oral
bacteria can affect distant structures, partic-
ularly in the case of bacterial endocarditis in
susceptible people.
In the late 1980s, research evidence
demonstrated a direct association between
periodontitis and systemic conditions, includ-
ing coronary heart disease (CHD), stroke,
and the association of preterm birth and low–
birth weight babies in mothers with severe
periodontitis. However, the response of the
dental and medical professions this time was
considerably more measured than in the early
part of the 20th century. There was no sugges-
tion that elimination of oral infection would
cure/improve cardiovascular or other systemic
inflammatory diseases. The relationship of oral
disease to systemic disease was thought of in
terms of modifiable risk factors.
In recent years, substantial additions to the
scientific literature recognize that inflammation
is a hallmark response to bacteria or bacte-
remia that, as an evolutionarily programmed
reaction to injury and infection, is a significant
link between oral and systemic diseases.4–6 The
investigation of oral-systemic disease connec-
tions is a rapidly advancing area of research.
Considering the existing data, it is essential
to reflect on all the plausible relationships.
Oral and systemic conditions may coexist, but
they may be disorders of different origin that
affect the outcomes of one another. Various
infectious or inflammatory conditions of the
oral cavity, including periodontal diseases, are
directly or indirectly associated with systemic
diseases, increase the risk of development of
87
4 The Role of Inflammation in Oral-Systemic Interactions
other diseases, or vice versa. The relationship
might also be causal. This chapter examines the
mechanisms linking oral and systemic diseases,
emphasizing unresolved inflammation as the
key to pathogenesis.
Inflammation
Innate immunity, characterized by the local
inflammatory response, is the early host
response. Its purpose is to identify and elim-
inate infectious agents or damaged tissues.
As an initial and protective response to chal-
lenges presented to host tissues, inflammation
is characterized by vascular dilation, enhanced
permeability of capillaries, increased blood
flow, and leukocyte recruitment. Together,
these result in the five cardinal signs of inflam-
mation: heat, redness, swelling, pain, and
loss of function. Cells control the magnitude
of the inflammatory response. Polymorpho-
nuclear leukocytes (PMNs) or neutrophils
(named for their staining characteristics
with hematoxylin-eosin) are the first line of
defense. PMNs are professional phagocytes
with potent oxidative and nonoxidative kill-
ing mechanisms to combat bacteria. After
PMN infiltration, mononuclear cells (mono-
nuclear phagocytes and macrophages) enter
the site and clear cellular debris, bacteria, and
apoptotic PMNs by phagocytosis without
prolonging inflammation. The degree of inflam-
mation activation is dependent on the nature
of the inflammatory trigger, the response, its
localization, and its persistence.7
The major sensors for the inflammatory
response are innate immune cells that migrate
to the injured site and resident stromal cells.
Together, they trigger production of media-
tors that modulate the fate of inflammation.
Neutrophils, macrophages, dendritic cells,
and mast cells produce low–molecular weight
proteins called cytokines that control the ini-
tiation of inflammation, the maintenance and
regulation of its amplitude, and the duration
88
of the response. Regulation of transcription
factors, genes, their translation, and secretion
of proinflammatory cytokines from a variety
of cells is generally dependent on nuclear fac-
tor κB (NFκB) nuclear protein activation of
transcription. The NFκB-regulated pathways
are activated by pattern-recognition receptors
such as toll-like receptors (TLRs) that bind
bacterial lipopolysaccharide (LPS) and other
molecules. Both inflammatory cytokines and
chemoattractant cytokines, or chemo­­kines,
are produced for autocrine, endocrine, and
paracrine functions. 4,8 The cytokines are
low–molecular weight proteins that modu-
late inflammation positively or negatively.
Cytokines produced by resident cells, such
as epithelial cells and fibroblasts, as well as
phagocytes in the acute and early chronic
phases of inflammation modulate immune
cells in adaptive immunity.
After microbial recognition, cytokines of the
innate response, including tumor necrosis fac-
tor α (TNF-α), interleukin (IL) 1β, and IL-6,
are the first secreted and are collectively known
as the signature innate cytokines. TNF-α is a
pleiotropic cytokine that has many func-
tions, from signaling cell migration to tissue
destruction. TNF-α upregulates the production
of IL-1β and IL-6. TNF-α is also correlated
with extracellular matrix degradation and
bone resorption through actions promoting
the secretion of matrix metalloproteinases
(MMPs) and receptor activator of NFκB ligand
(RANKL) and coupled bone formation.9
Chemokines are cytokines with chemoattrac-
tant functions that induce cell migration to the
site of infection or injury. Once blood leuko-
cytes exit a blood vessel, they are attracted by
functional gradients of chemotactic factors.
Multiple cell types, including leukocytes and
endothelial, epithelial, and stromal cells, pro-
duce chemokines. Beyond their chemotactic
role, chemokines function as messengers of
distinct biologic processes, including cell pro-
liferation, cell death, angiogenesis, and tumor
metastasis. Bacterial peptides are also chemo-
tactic for inflammatory cells.10

The innate immune recognition of dif-
ferent microorganisms is complex. Viral
infections induce the production of inter-
ferons (IFN-α, IFN-β) and the activation of
cytotoxic lymphocytes (natural killer [NK]
cells); bacterial pathogens are recognized by
pattern-recognition receptors such as TLRs,
which are expressed by tissue-resident macro-
phages and other host cells. Binding of TLRs
induces the production of inflammatory cyto-
kines, chemokines, and proinflammatory lipid
mediators such as prostaglandins. These inflam-
matory mediators are the major players in
establishing an effective inflammatory response
and clearance of bacteria. Proinflammatory
mediators, such as IL-1β, IL-6, TNF-α, and
prostaglandin E2 (PGE2) are produced locally
in inflamed tissues. Proinflammatory cytokines
in circulation induce systemic actions, includ-
ing leukocytosis and acute-phase proteins in
the liver. On the other hand, parasites lead to
the production of a different set of cytokines
and cellular responses. These include IL-4, IL-5,
and IL-13 by mast cells and basophils. With
continued exposure, soluble antigens react by
circulating a specific antibody to form immune
complexes that further amplify inflammation
at sites of deposition.5
Locally produced lipid mediators, such as
prostaglandins and leukotrienes, are proinflam-
matory signals that trigger the nervous system
to promote fever and fatigue.10 Prostaglandins
and leukotrienes are derived from membrane
lipids, particularly arachidonic acid. Two major
enzyme pathways, cyclooxygenases (COXs)
and lipoxygenases (LOs), metabolize arachi-
donic acid. COX-1 (constitutively expressed
COX) and COX-2 (inducible COX) catalyze
the conversion of arachidonic acid into pros-
taglandins, prostacyclins, and thromboxanes.
Prostaglandins have 10 subclasses, of which
D, E, F, G, H, and I are the most important in
inflammation.
Three LOs are important in inflammation: 5-,
12-, and 15-LO. LOs catalyze the formation of
hydroxyeicosatetraenoic acids (HETEs) from
arachidonic acid, leading to the formation of
Inflammation
leukotrienes. Excessive production of inflam-
matory mediators and an exacerbated sensing
response to inflammatory triggers positively
correlate with progression from acute inflamma-
tion to chronic inflammation in many diseases.
Microorganisms that gain access to the
blood circulation are usually eliminated by
the reticuloendothelial system within min-
utes (transient bacteremia) with no clinical
symptoms. Local bacterial antigens that are
systemically dispersed trigger significant sys-
temic inflammation. Leukocytes, endothelial
cells, and hepatocytes respond to bacteria and
their virulence factors with the secretion of
proinflammatory immune mediators called
acute-phase proteins, such as C-reactive protein
(CRP), which is secreted by the liver. Persistence
of infection, with continuous exposure of the
host to new antigens, results in the activation of
humoral immunity and antibody production.
Circulating specific antibodies form immune
complexes with respective target antigens,
which in turn activate the complement system
and Fc receptors on phagocytes to amplify
inflammation at sites of deposition. Likewise,
proinflammatory mediators, such as IL-1β,
IL-6, TNF-α, and PGE2, produced locally in the
inflamed tissues, may spill into the circulation
and have a systemic impact, such as induction
of endothelial dysfunction.9,11
Although the inflammatory response is pro-
tective, failure to remove noxious materials
produced by neutrophils via phagocytosis,
failure of clearance of apoptotic inflamma-
tory cells, or delay of apoptosis characterize
the chronic and pathologic lesion. The incom-
plete elimination of leukocytes from a lesion
is observed in susceptible individuals; acute
inflammation fails to resolve, and chronic
disease and fibrosis develop. Accordingly, loss
of resolution and failure to return tissue to
homeostasis results in neutrophil-mediated
destruction and chronic inflammation with
accumulation of proinflammatory macro-
phages, which is directly related to human
inflammatory pathologies, cancers, type 2 dia-
betes, CVDs, and periodontal diseases.
89
4 The Role of Inflammation in Oral-Systemic Interactions
The natural resolution of inflammation after
an acute inflammatory response results from
well-coordinated biochemical pathways that
are activated by a class switch of enzymes. LO
pathways active in the acute phase eventually
result in the action of two different LOs on
the same substrate arachidonic acid molecule.
The double substitution leads to the forma-
tion of lipoxins, a new series of eicosanoids
that share the same backbone structure of the
proinflammatory leukotrienes and HETEs
but bind to distinct receptors. The active,
receptor-mediated regulation halts neutrophil
function, promotes neutrophil apoptosis, and
promotes the nonphlogistic (noninflammatory)
accumulation of macrophages that efficiently
clear the lesion of remaining bacteria and apop-
totic cells.
There are a number of resolution pathways,
depending on the fatty acid substrate. Omega-3
fatty acids in the diet are metabolized by the
same enzyme pathways as arachidonic acid to
produce molecules called resolvins of the D and
E series (from docosahexaenoic acid and eicos-
apentaenoic acid, respectively), protectins, and
maresins. All of these factors drive resolution
of inflammation through different receptors
on inflammatory cells. Chronic inflammation
results from a combination of excessive pro-
duction of proinflammatory mediators and
a failure to produce sufficient proresolution
mediators (for review, see Serhan et al6).
Periodontal Diseases
The local acute periodontal inflammatory
response is a reaction to the local micro-
bial biofilm. The commensal flora and host
inflammatory response evolved to maintain
a relationship that is symbiotic and healthy,
as observed in periodontal tissues and other
mucosal surfaces, including the oropharynx
and the gut. Disturbances of homeostasis,
characterized by increased inflammation and
90
overgrowth of pathologic organisms, initiates
chronic inflammation, which is followed by an
acquired immune response and tissue destruc-
tion, or periodontitis.
Failure to remove both the trigger (patho-
genic bacteria) and inflammatory cells,
mainly neutrophils, characterizes the chronic,
pathologic lesion. The rapid and complete
elimination of leukocytes from an acute inflam-
matory lesion is the ideal outcome following
insult. In susceptible individuals, periodontal
inflammation fails to resolve, and chronic
inflammation becomes periodontal pathology.
Accordingly, reduced resolution and failure to
return the tissues to homeostasis results ini-
tially in neutrophil-mediated destruction and
chronic inflammation followed by a complex
immune lesion with destruction of the extra-
cellular matrix and bone, scarring, and the loss
of periodontal tissue function.12,13
The presence of bacterial plaque and gin-
givitis is prevalent in humans, affecting more
than 90% of the adult dentate population. The
same direct correlation cannot be said for peri-
odontitis; despite abundant plaque deposits in
most people, the prevalence of moderate peri-
odontitis (attachment loss greater than 5 mm)
is around 40% of the population.14 However,
this prevalence of periodontitis is not uniformly
distributed across races, ethnicities, and socio-
economic groups. This being the case, despite
the universal presence of plaque, bacteria do
not appear to be the primary determinants of
the progression of gingivitis to periodontitis.
Although the popular dogma has been to accept
that periodontitis arises from a specific subgin-
gival infection, the concept that periodontitis
occurs when the periodontal tissues provide an
adequate ecologic environment for opportunis-
tic bacteria to flourish has been presented, for
some time, by eminent oral microbiologists as
an alternative mechanism.15–17
The host-parasite interaction is responsi-
ble for the initiation of the gingivitis lesion,
but what happens next is less clear. There is
no definitive evidence that specific bacteria

are responsible for the progression and mani-
festation of advanced periodontitis; however,
specific pathogens are associated with deep
periodontal pockets. It can be argued that the
specific bacteria are present as a result of the
disease but do not cause the disease. This is
no different than most mucosal biofilm–associ-
ated pathologies where the complicating issue,
which still remains unresolved, is which comes
first—the host response or the change in the
biofilm?18
Several biologic pathways linking peri-
odontal disease to induction of systemic
inflammation have been identified. 17–19 In
health, the gingival sulcular epithelium and
local innate immune cells act as a natural
barrier preventing bacterial penetration. In gin-
gival health, only a small number of bacteria,
mostly facultative anaerobes, are found in the
gingival crevice and bloodstream. However, in
periodontal disease, inflamed tissue and ulcer-
ated subgingival pocket epithelium is ulcerated
and permeable, providing bacteria a port of
entry to the circulation.
Periodontal Inflammation in
Oral Cancer
A higher incidence of cancer development is
found in individuals with chronic inflammatory
conditions; this insight has driven suggestions
of a possible link with periodontal inflamma-
tion.20,21 Associations between periodontal
disease and the risk for precancerous lesions
relate to chronic inflammation. A possible link
between periodontal disease and oral neoplasm
has been described. In fact, recent evidence
from the National Health and Nutrition
Examination Survey (NHANES) III indicated
that periodontitis was significantly related to
tumors.22 The stratified analysis found that
this association was only present in current
smokers. Also, a stronger relationship between
periodontitis and human papillomavirus (HPV)
Periodontal Inflammation in Oral Cancer
status in patients with oropharyngeal cancer
has been reported.23
The risk of cancer increases with periodon-
titis, and the risk of death is higher when
periodontitis is present. In a follow-up of sub-
jects from NHANES I,20,24 patients diagnosed
with periodontitis had a 55% (95% confidence
interval [CI]: 25%–92%) increase in risk of
death from any cancer. There was a signifi-
cantly increased risk for lung cancer; however,
this was not evident in individuals who had
never smoked.
The incidence of cancer consistently increased
in patients with periodontitis. A larger study
with a 17.7-year follow-up identified 5,720
incident cancers in 48,375 men enrolled. Men
who reported periodontal disease had a slightly
increased total cancer incidence of 14% (95%
CI: 7%–22%), which remained significant
when the analysis was limited to those who had
never been smokers.25 There was a significantly
increased risk of lung, kidney, pancreatic, and
hematologic cancers after adjustment. The risk
for lung cancer was the only association when
the number of teeth was used as the exposure.25
Similar genetic risk factors for periodontal
disease and cancers were found in a prospec-
tive study in Sweden. The study identified more
than 4,000 incident cancers after a median
follow-up of 27 years.26 At baseline, the par-
ticipants were classified as having periodontal
disease if they reported that at least half their
teeth had loosened or fallen out on their own.
Periodontal disease was associated with a 15%
(95% CI: 1%–32%) increased risk for all can-
cers. Periodontal infection was also associated
with increased risk of colorectal, pancreatic,
and prostate cancers.
In twin analyses, monozygotic twins with
baseline periodontal disease showed a 50%
increase in total cancer risk, but in dizygotic
twins this association was markedly attenu-
ated. Similar patterns emerged for digestive
tract cancers, suggesting that shared genetic
risk factors may partially explain associations
between periodontal disease and cancers.20,26
91
4 The Role of Inflammation in Oral-Systemic Interactions

Proresolution signals Proinflammatory signals

TGF-β TNF-α
IL1-Ra IL-1

Chronic inflammation
IL-4 IL-6
Health

IL-10 CCL2
GM-CSF CXCL8
Local tissue
Immunoresolvents: CRP
inflammation
Resolvins Histamine
Lipoxins Prostaglandins
Protectins
Maresins

Fig 4-1  |  Tissue-inflammatory processes link to systemic homeostasis. The nature of challenge and balance
between the response from sensors and mediators leads to distinct fates in acute inflammation. Proinflamma-
tory mediators such as IL-1β, TNF-α, and others listed are important molecules that initiate the tissue response
to injury and infection. The termination of acute processes is modulated by immunoresolvents and consequent
upregulation of anti-inflammatory cytokines. An unresolved inflammatory process is the primary step leading
to development of chronic inflammation and loss of local and systemic function. CCL2, chemokine (C-C motif)
ligand 2; CXCL8, interleukin 8; TGF-β, transforming growth factor β; IL1-Ra, interleukin 1 receptor antagonist;
GM-CSF, granulocyte-macrophage colony-stimulating factor.

Link Between Periodontal tissue destruction and osteoclast-mediated bone

Disease and Systemic
Conditions
Uncontrolled (chronic) inflammation is a hall-
mark of various human conditions, including
periodontitis, diabetes, CVDs, and premature
labor.23–25 Despite advances in knowledge of
causes and risk factors associated with chronic
periodontitis, there are no signs of decline in
prevalence. According to the US Centers for Dis-
ease Control and Prevention (CDC), 647 million
adults worldwide had periodontal diseases as
of 2012.14 Periodontal diseases, including gin-
givitis and periodontitis, are leukocyte-driven
inflammatory diseases characterized by soft
loss. The etiology of periodontitis is recognized
to be primarily bacterial but multifactorial, and
some behavioral, environmental, systemic, and
genetic risk factors influence host susceptibil-
ity and disease progression. The impact of a
dysregulated inflammatory response has the
potential to harm the systemic health of indi-
viduals (Fig 4-1).
Periodontitis and diabetes
Among many diseases that impact the popula-
tion globally, type 2 diabetes is a major public
health problem. Worldwide, about 347 million
adults suffer from type 2 diabetes.28 According
to the World Health Organization (WHO), the
prevalence may double by the year 2030, and

92
 Link Between Periodontal Disease and Systemic Conditions
health care expenditures related to diabetes will
increase significantly.29
Inflammatory diseases such as type 2 diabetes
and chronic periodontal diseases have a recipro-
cal relationship. Among people diagnosed with
type 2 diabetes, one-third present with severe
periodontal disease, and adult diabetic patients
with severe periodontitis have a higher risk of
poor glycemic control, increasing the risk of
oral and systemic complications.28 Hyperglyce-
mia resulting from type 2 diabetes can impact
PMNs and monocytes through various mecha-
nisms, including the accumulation of advanced
glycation end products (AGEs) that leads to an
increase in extracellular production of super-
oxide by leukocytes and increased secretion
of proinflammatory cytokines, such as IL-1β,
insulin-like growth factor, TNF-α, and MMPs.30
Increased inflammation in periodontitis leads to
prolonged activation of PMNs and monocytes
and results in ineffective clearance of bacte-
ria and prolonged inflammation, aggravating
systemic diabetes regulation. Systemic inflam-
mation in type 2 diabetes, defined by increased
circulating TNF-α, is associated with obesity
and periodontitis and has been proposed as a
mechanism for the connection between these
conditions. A case-control study demonstrated
that periodontitis is associated with elevated
plasma triglycerides and total cholesterol.31
A relationship between inflammatory path-
ways and metabolic diseases, such as type 2
diabetes or insulin resistance, is one line of
active investigation.32 Attempts to understand
the molecular pathways that regulate diabe-
tes and insulin resistance require the study of
adipose tissue. For example, adipose tissue is
now recognized as a biologically active endo-
crine organ and not simply a site of inert lipid
storage. Adipocytes, like any stromal cells,
secrete cytokines, now collectively known
as adipokines, into the circulation, including
adiponectin, TNF-α, plasminogen activator
inhibitor type 1, and resistin.33 The realization
that adipocytes have a molecular influence on
the entire system helps explain why obesity
is frequently associated with inflammatory
disease, type 2 diabetes, and atherosclerosis.
Evidence suggests that inflammatory cells may
be found within adipose tissue; perhaps the
fat itself is actively involved in inflammatory
processes, contributing to the release of proin-
flammatory mediators.
Fat tissue adipokines have many actions in
sites away from their origin, including the liver,
blood vessel walls, and muscles. They regulate
metabolic functions, including glucose lev-
els, insulin, and lipid metabolism. Although
adipose tissue may release a host of proin-
flammatory cytokines, adiponectin is of interest
because it seems to be anti-inflammatory and
therefore protective. For example, studies have
shown that lower levels of plasma adiponectin
are found in patients with both diabetes and
CHD than in patients with diabetes without
CHD, suggesting that adiponectin may be anti-
atherogenic.18,31,33 Humans in insulin-resistant
states also have lower levels of adiponectin; this
was reversed by the administration of thiazoli-
dinedione, an insulin-sensitizing compound.30,31
There also seems to be a negative relationship
between adiponectin and CRP, again suggesting
that adiponectin has an anti-inflammatory role.
Diabetic patients have a higher risk for
developing chronic periodontitis, and those
with elevated hemoglobin A1c (HbA1c) levels
have a significantly higher prevalence of peri-
odontitis and experience more tooth loss than
do those with better metabolic control. Acute
and chronic infections may adversely influence
glycemic control.28 Thus, the concept of HbA1c
being adversely affected by systemic inflam-
mation is well accepted by medical and dental
communities.
It is now clear that a biologically plausible
link between periodontitis and metabolic con-
trol has been determined. If adequate treatment
of periodontitis can modify glycemic control,
as suggested in some studies,28 periodontal
therapy may be an essential contribution to
a patient-management program that incorpo-
rates lifestyle changes and medications.
Periodontal therapy has shown uniform
outcomes across studies. While periodontal
93
4 The Role of Inflammation in Oral-Systemic Interactions
conditions have shown consistent results when
treated, the effects of the therapy in diabetic
patients are not consistent. The standard treat-
ment outcome for diabetic patients has been
reductions in HbA1c, because reducing HbA1c
has been shown to delay the development of
diabetic complications. Although there have
been efforts to reduce HbA1c levels through
periodontal therapy, the ideal level to be
reached is not clear.28,33–35 It is possible that
periodontal treatment can improve HbA1c lev-
els by 0.4% to 0.5%35; this beneficial systemic
action of periodontal therapy demonstrates the
importance of controlling local inflammatory
conditions as part of diabetes management.
Periodontitis and cardiovascular
disease
Periodontal disease has been linked to
CVD in cross-sectional and cohort stud-
ies. 31,36,37 Studies report that elevated
cell- and cytokine-mediated markers of inflam-
mation, including CRP, fibrinogen, and various
cytokines, are associated with periodontal dis-
ease.18,30 The same proinflammatory markers
in periodontal disease have also been linked
with atherothrombogenesis.18,19,38 When the
progression of periodontal disease is reduced,
levels of inflammatory markers common
to both diseases (ie, IL-6, TNF-α, and CRP)
decrease, which might in turn decrease the risk
of vascular disease. It is still unknown whether
inhibiting or reducing inflammation in general
or CRP in particular will lower the rate of vas-
cular effects.39
In several atherosclerosis studies using ani-
mal models, periodontal disease was shown
to be a contributing factor.18,19,40 Activated
immune cells in the atherogenic plaque pro-
duce proinflammatory cytokines (IFN, IL-1,
and TNF-α), which induce the production
of substantial amounts of IL-6. These cyto-
kines are also produced in various tissues in
response to infection and in the adipose tis-
sue of patients with metabolic syndrome. IL-6
94
acts as a stimulant of acute-phase reactants,
including CRP, serum amyloid A, and fibrino-
gen, especially in the liver.
Although cytokines at all steps have import-
ant biologic actions, their amplification at each
step of the cascade makes the measurement of
downstream mediators such as CRP partic-
ularly useful for clinical diagnosis. Increased
high-sensitivity CRP plasma levels in patients
with prehypertension or established hyper-
tension may link these two conditions. Major
depression, physical inactivity, family histories
of CVD, advancing age, and male sex are other
risk factors for atherosclerotic CVD that are
commonly found in patients with periodontitis
and may serve as confounders.36
Risk factors common to CVD and peri-
odontitis are thought to be related to increased
systemic inflammation.31 Diet, genetics, medi-
cations, and environmental factors influence
the course of periodontal disease, and when
periodontal disease combines with these ele-
ments, they influence cardiovascular health
status. In CVD studies, periodontal disease
has been shown to be a contributing factor.37,41
Low-density lipoproteins (LDLs) are known
to initiate and propagate an inflammatory
response.38 Once the migration of leukocytes
has occurred, monocytes differentiate into mac-
rophages and proliferate. Fatty streaks develop;
these consist of lipid-laden monocytes and
macrophages as well as T lymphocytes, which
are eventually joined by migrating smooth
muscle cells from the vessel wall. If the cas-
cade of events goes unchecked, the fatty streaks
develop into advanced lesions, whereby macro-
phages accumulate, a necrotic core is produced,
and a fibrous cap is formed that blocks the
lesion from the lumen.
The fibrous cap, which is characteristic of
late-stage atherosclerosis, is of concern; rupture
of this fibrous cap is believed to underlie the
vast majority of myocardial infarctions that
may derive from these inflammatory processes.
Cytokines, such as IFN-γ, are involved in the
destabilization of the plaque because they
lead to a decrease in matrix synthesis as well
 Link Between Periodontal Disease and Systemic Conditions
as matrix degradation. In addition to these
cytokines, MMPs are involved in controlling
degradation; macrophages express MMPs, fur-
ther contributing to degradation.31
Periodontal inflammation causes a local
and systemic cytokine response. Several
studies have reported that elevated cell- and
cytokine-mediated markers of inflammation are
relevant to periodontal diseases.36,37,40 Proin-
flammatory cytokines induce an acute-phase
response in the liver characterized by elevated
levels of CRP and fibrinogen, which in turn
promote atherogenesis. Also, gingival ulcer-
ation in periodontitis allows the migration of
bacteria into the blood (bacteremia), which
could provide a second inflammatory stimulus
leading to atheroma formation.42
CVD, once characterized as a lipid disease
because of the end-stage pathology, is now
known to have a significant inflammatory com-
ponent. In recent years, epidemiologic studies
have ascertained an association between CVD
and other inflammatory diseases, particularly
periodontal diseases.4,36 Given the prolonged
nature of the pathogenesis of CVD, it has been
difficult to demonstrate cause and effect in
this association. To that end, the relationship
between CVD and periodontitis was investi-
gated longitudinally in an animal model. New
Zealand white rabbits were fed a 0.5% cho-
lesterol diet for 13 weeks. This protocol causes
atheromatous changes in the large arteries of
the animals.40 Periodontitis was induced with a
ligature and Porphyromonas gingivalis in half
the animals, while the other half maintained a
normal periodontium; all animals were fed the
atherogenic diet. Animals that had periodon-
titis exhibited twice the atheroma formation
of the control animals. These data provide
direct longitudinal evidence that periodontal
inflammation can affect the progression of
CVD. Further investigation was unable to iso-
late bacteria from the arterial lesions; however,
it was demonstrated that local inflammation
was able to induce upregulation of the systemic
inflammation. Increased levels of circulating
CRP and IL-1 were detected in periodontitis
animals.31,40 These data suggest that the impact
of infection is not at the level of bacteremia
and direct stimulation of arterial endothelium
but rather the result of the local inflammation
inducing systemic stimulation.31
Patients with periodontitis who have two
or more known risk factors for atherosclero-
sis should be referred by the dental team for
evaluation of atherosclerotic risk, which should
include physical examination and annual mea-
surement of blood pressure and blood lipid
profile.31 Patients with periodontitis and abnor-
mal serum lipid values, elevated levels of plasma
CRP (as measured by high-sensitivity CRP), or
both are recommended to follow a multifaceted
lifestyle-modification program to reduce the
risk of CVD. Cessation of cigarette smoking is
recommended for all patients with periodonti-
tis. Furthermore, all patients with periodontitis
who have elevated blood pressure (> 130/80
mmHg) should be treated according to stan-
dard hypertension-management protocols and
should undertake lifestyle changes, including
reduction of weight and dietary sodium intake,
as appropriate. Periodontal evaluation should
be considered in patients with CVD who have
signs or symptoms of a gingival disease or
unexplained tooth loss. Moreover, when peri-
odontitis is newly diagnosed in patients with
CVD, dentists and physicians should closely
collaborate to optimize CVD risk reduction
and periodontal care.43
Atherogenesis leading to atherosclerosis
involves highly specific cellular and molecular
responses that are described as an inflamma-
tory disease. Cardiovascular risk factors can
be viewed as an injury or insult to which the
body adapts, setting in motion a decades-long
response. Regardless of the cause, the ear-
liest changes in atherosclerosis occur in the
endothelium, leading to increased tissue per-
meability and cell adhesiveness, particularly of
leukocytes, as well as increased procoagulation
properties that result in activation of vasoactive
molecules, cytokines, and growth factors.9
In the pathogenesis of atherosclerosis, mono-
cytes and T cells mediated by endothelial
95
4 The Role of Inflammation in Oral-Systemic Interactions
expression of adhesion molecules accumulate
at the injury site. Activated lymphocytes release
mediators such as cytokines and chemokines.
Through a cascade of signals, the process lead-
ing to entry of leukocytes into the endothelium
involves the rolling, activation, and adherence
of leukocytes. One particular adhesion mole-
cule, vascular cell adhesion molecule 1, is of
importance in the adherence process because
it binds precisely with monocytes and T lym-
phocytes. Once adherent to the endothelium,
monocytes transmigrate into the intima. 9
During inflammation, selective recruitment of
leukocytes to the injured tissue regulates spe-
cific cell population migration to the tissues.
Early proinflammatory cytokines, such as IL-1
and TNF-α, stimulate chemokine production.
Another cytokine, IFN-γ, is secreted by T lym-
phocytes (specifically T helper cell type 1); this
induces chemokine production directly and by
acting with IL-1 and TNF-α.
Two groups of chemokines associated
with IFN-γ are CC and CXC. CC chemok-
ines induce the migration of monocytes. For
example, monocyte chemoattractant protein
1 is responsible for monocyte migration from
the bloodstream into the surrounding tissue
by binding to and activating CC chemokine
receptors, in this case CC chemokine recep-
tor 2. Depending on their receptor structural
characteristics, CXC chemokines can induce
migration of neutrophils or attract lympho-
cytes. Atheroma-associated cells have been
found to play a role in the movement and
maintenance of activated T lymphocytes in
vascular wall lesions during atherogenesis.16
The same study also found increased expres-
sion of the receptor for these chemokines, CXC
chemokine receptor 3, by T lymphocytes in
human atherosclerotic lesions.
When the progression of periodontal disease
is low, levels of inflammatory markers com-
mon to both diseases (IL-6, TNF-α, and CRP)
also decrease. This might, in turn, decrease
the risk of vascular disease.36 When adjusted
for risk factors, such as smoking, diabetes,
alcohol intake, obesity, and blood pressure,
96
subjects with periodontal disease had a 1.14- to
1.59-fold greater risk of developing CVD than
did those without periodontal disease.36,37,42
Although inflammatory response to injury
and infection is essential to health, the response
causes problems when inflammatory processes
are maladaptive, leading to chronic diseases
such as diabetes and CVD. New pathways by
which local chronic inflammation can affect
large vessels need further investigation.
Periodontitis and pregnancy
Periodontal diseases are inflammatory responses
to infectious pathogens that, although distant
from many organs, can affect the fetoplacental
unit.44 Host cells activate a local inflammatory
response against bacteria and their numerous
virulence factors (eg, LPS) to contain the lesion.
However, several studies have reported that
inflammatory cytokines, periodontal bacteria,
and their virulence factors can enter the blood
circulation to disseminate throughout the body.
Such an event triggers systemic inflammatory
responses and ectopic infections.36
Not surprisingly, local inflammation can
interfere with the homeostasis of healthy
pregnancy and labor. While a large number of
epidemiologic studies have shown a positive
association between periodontal disease and
pathologic outcomes of pregnancy, the results
have not always been confirmed.44
In a healthy pregnancy, the mother and the
fetus exchange nutrients and waste through the
umbilical cord that connects the placenta of the
mother to the fetus. In amniotic fluid, levels
of inflammatory mediators, including PGE2,
TNF-α, and IL-1β, increase incrementally
throughout pregnancy, reach a threshold, and
promote uterine contraction, cervical dilation,
and delivery.45 It is of extreme importance that
average levels of inflammatory mediators and
hormones be tightly regulated to maintain a
regular course of pregnancy.44
Evidence suggests that periodontal patho-
gens interfere with homeostatic control of
pregnancy. Through DNA identification
 Resolution of Inflammation and the Periodontal Disease–Systemic Disease Link
and immunodetection, both P gingivalis and
Aggregatibacter actinomycetemcomitans
have been detected in biopsy specimens taken
from the placentas of women diagnosed with
preeclampsia.46 Most commonly in amniotic
fluids, Fusobacterium nucleatum was identified
in patients suffering from premature labor or
giving birth to babies with low birth weight.47
Although there is clear evidence that bac-
terial presence in diverse tissues establishes
pathologic conditions during pregnancy, the
mechanisms by which the pathogens arise
in the local tissues remain unclear.44 Recent
evidence indicates that pathogens can gain
access to the amniotic cavity by ascending
from the vagina and the cervix, by hematog-
enous dissemination through the placenta, by
accidental introduction at the time of invasive
procedures (amniocentesis), and by retrograde
spread through the uterine tubes.44,48 Besides
the pathogens themselves, their virulent fac-
tors, including LPS, have been associated with
triggering the same type of pathologic actions
to the placenta and fetus.
Localized elevated levels of maternal IL-1β,
IL-6, PGE2, and TNF-α in the amniotic fluid
have been associated with pregnancy alterations,
including premature birth. Other biomark-
ers, such as MMPs, estriol, elastase, protease,
phospholipase, prolactin myeloperoxidase,
and tissue inhibitor of MMP 1 (TIMP-1) have
been evaluated48 but with inconclusive results.
CRP, an acute-phase molecule synthesized by
the liver, activates systemic inflammation and
proinflammatory cytokines; it is also associated
with premature birth.42 Other pregnancy com-
plications have been associated with elevated
levels of CRP, including intrauterine growth
restriction and preeclampsia.44
Finally, a combination of local complications
places the host at risk for poor pregnancy out-
comes. For example, women with gestational
diabetes mellitus have a high risk of present-
ing elevated serum levels of CRP, IL-6, and
TNF-α. Through inflammatory pathways,
these cytokines interfere with insulin-signaling
homeostasis. Therefore, carbohydrate metab-
olism, hormonal control, and inflammatory
mediators together influence health during
pregnancy and the outcome of labor.44 For
more information on periodontal infections
and pregnancy outcomes, see chapter 10.
Resolution of Inflammation
and the Periodontal Disease–
Systemic Disease Link
Periodontitis is an inflammatory disease that
is initiated by the oral microbial biofilm and
modulated by the host immune response
and metabolism.15 This distinction implies
that it is the host response to the biofilm
that destroys the periodontium in the patho-
genesis of the disease. As the understanding
of inflammation pathways has matured, a
better understanding of the molecular basis
of resolution of inflammation has emerged.
Resolution of inflammation involves an
active, agonist-mediated, well-orchestrated
return of tissue homeostasis.49 Table 4-1 details
the actions of immunoresolvents in acute
inflammatory disease models.
The distinction between anti-inflammation
and resolution has biologic and clinical
relevance. Anti-inflammation involves phar-
macologic blocking of specific inflammatory
pathways; resolution is mediated by physi-
ologic pathways that restore homeostasis.6
Research suggests that chronic inflammatory
periodontal disease consists of both failures of
resolution pathways to restore homeostasis and
excessive response leading to the development
of the chronic lesion.6,11 Proof-of-concept stud-
ies published in the 1980s demonstrated that
pharmacologic anti-inflammatory measures
reduced periodontal disease progression in ani-
mals and humans.71 However, such therapies
induce side effects related to the nonsteroi-
dal anti-inflammatory drugs or other enzyme
inhibitors or receptor antagonists in periodon-
tal treatment.
97
4 The Role of Inflammation in Oral-Systemic Interactions

TABLE 4-1  |  Local and systemic actions of tissue inflammation

Inflammatory
disease models Immunoresolvents and their actions Reference(s)
Periodontitis/Rabbit Lipoxin A4/ATL
Prevents connective tissue and bone loss Serhan et al50
Accelerates healing of inflamed tissues Serhan et al50
Ceases infiltration of neutrophils Serhan et al50
Resolvin E1
Reduces bone loss Hasturk et al51
Regenerates lost soft tissue and bone tissue Hasturk et al52

Peritonitis/Mouse Lipoxin A4/ATL

Stops neutrophil recruitment Bannenberg et al53
Promotes lymphatic removal of phagocytes Schwab et al,54 Arita et al55
Resolvin E1
Decreases PMN infiltration Schwab et al54
Regulates chemokine and cytokine production Bannenberg et al53
Promotes lymphatic removal of phagocytes Spite et al56
Resolvin D1
Shortens resolution interval Recchiuti et al57
Regulates miRNAs Krishnamoorthy et al58
Reduces concentrations of LTB4, PGD2, PGF2, and TXA2 in exudates Norling et al59
Lowers antibiotic requirement Chiang et al60
Increases animal survival Chiang et al60
Reduces bacterial titers Chiang et al60
Protectin D1
Promotes local clearance of apoptotic cells Bannenberg et al53
Regulates lymphatic removal of phagocytes Ariel et al61,62
Modulates T-cell migration Schwab et al54
Maresin-1
Blocks infiltration of PMNs into the peritoneum Serhan et al63

Colitis/Mouse Lipoxin A4/ATL

Reduces severe colitis Aliberti et al64
Attenuates proinflammatory mediators’ gene expression Gewirtz et al65
Inhibits weight loss Gewirtz et al65
Reduces immune dysfunction Wallace and Fiorucci66
Resolvin E1
Improves animal survival rate Arita et al55
Reduces weight loss Arita et al55
Promotes LPS detoxification Campbell et al67
Stops neutrophil recruitment Ishida et al68
AT-Resolvin D1
Reduces disease’s activity index Bento et al69
Attenuates proinflammatory mediators’ gene expression Bento et al69
Attenuates neutrophil recruitment Bento et al69
Resolvin D2
Improves disease’s activity index Bento et al69
Reduces colonic PMN infiltration Bento et al69

Retinopathy/Mouse Resolvin E1/Resolvin D1/Protectin D1

Protects against neovascularization Connor et al70

ATL, aspirin-triggered 15-epi-lipoxin A4; LTB4, leukotriene B4; PGD2, prostaglandin D2; PGF2, prostaglandin F2; TXA2, thromboxane A2.
(Adapted from Freire and Van Dyke.73)

The isolation and characterization of biologic area of research into the use of endogenous lipid
agonist molecules, such as lipoxins, resolvins, mediators of resolution as potential therapeutic
protectins, and maresins, have opened a new agents for the management of inflammatory

98

periodontitis. Animal models of periodontitis
have revealed the potential of this therapeutic
approach for prevention and treatment and
forced reconsideration of the understanding
of the pathogenesis of human periodontal dis-
eases72 (see Table 4-1; for review, see Freire and
Van Dyke73).
The importance of agonists of resolution in
eliminating inflammation has been confirmed
in demonstrations of control of systemic
inflammatory disease by exogenous addition
of excess lipoxins or resolvins.74 These findings
are observed in concert with the resolution of
periodontitis in the same animal, suggesting that
control of inflammation is central to the associa-
tion between periodontitis and systemic disease.
The report provided support and a rationale for
the mechanism of the observed connections as
well as a basis for the clinical concern that peri-
odontitis increases the risk for many important
systemic inflammatory diseases.51,52
Conclusion
The link between oral and systemic inflamma-
tory processes and its consequences are directly
related to the tissue response to challenge,
usually microbial, and inflammation. This
biologic process is controlled by the balance
between mediators and sensors that amplify the
inflammatory process and those that regulate
the return to homeostasis. Diseases associated
with uncontrolled acute inflammation are char-
acterized by insufficient actions of resolution
programs and inappropriate release and main-
tenance of high levels of toxic substances and
proinflammatory mediators that may result
in damage to host tissues and prolong the
inflammatory response. In experimental ani-
mal models, compelling evidence demonstrates
the actions of proresolution mediators in the
regulation of local and systemic inflammatory
responses, elucidating the role of endogenous
mediators in systemic inflammatory processes
and disease regulation. A clearer picture of
References
the central role of inflammation as the driving
mechanism in the association between peri-
odontitis and a number of systemic diseases
and conditions is emerging. A more precise
picture is also emerging of the central role of
inflammation in association with metabolism
and microbiome in the local and systemic
compartments. The target of periodontal ther-
apy, whether control of the biofilm or control
of local inflammation, is control of systemic
inflammation associated with chronic systemic
diseases.
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review and meta-analyses on C-reactive protein in
relation to periodontitis. J Clin Periodontol 2008; 35:
277–290.
43. Devchand PR, Arita M, Hong S, et al. Human ALX recep-
tor regulates neutrophil recruitment in transgenic mice:
Roles in inflammation and host defense. FASEB J 2003;
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44. Madianos PN, Bobetsis YA, Offenbacher S. Adverse
pregnancy outcomes (APOs) and periodontal disease:
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40(suppl 14):S170–S180.
45. Haram K, Mortensen JH, Wollen AL. Preterm delivery:
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46. Gonzales-Marin C, Spratt DA, Millar MR, Simmonds M,
Kempley ST, Allaker RP. Levels of periodontal pathogens
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47. Han YW, Redline RW, Li M, Yin L, Hill GB, McCormick
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2272–2279.
48. Gürsoy M, Könönen E, Gürsoy UK, Tervahartiala T,
Pajukanta R, Sorsa T. Periodontal status and neutrophilic
enzyme levels in gingival crevicular fluid during preg-
nancy and postpartum. J Periodontol 2010; 81:
1790–1796.
49. Van Dyke TE, Serhan CN. Resolution of inflammation:
A new paradigm for the pathogenesis of periodontal
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50. Serhan CN, Jain A, Marleau S, et al. Reduced inflam-
mation and tissue damage in transgenic rabbits
overexpressing 15-lipoxygenase and endogenous
anti-inflammatory lipid mediators. J Immunol 2003; 171:
6856–6865.
51. Hasturk H, Kantarci A, Ohira T, et al. RvE1 protects from
local inflammation and osteoclast-mediated bone
destruction in periodontitis. FASEB J 2006;20:401–403.
52. Hasturk H, Kantarci A, Goguet-Surmenian E, et al.
Resolvin E1 regulates inflammation at the cellular and
tissue level and restores tissue homeostasis in vivo. J
Immunol 2007;179:7021–7029.
53. Bannenberg GL, Chiang N, Ariel A, et al. Molecular
circuits of resolution: Formation and actions of resolvins
and protectins. J Immunol 2005;174:4345–4355.
54. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin
E1 and protectin D1 activate inflammation-resolution
programmes. Nature 2007;447:869–874.
55. Arita M, Yoshida M, Hong S, et al. Resolvin E1, an
endogenous lipid mediator derived from omega-3 eicos-
apentaenoic acid, protects against 2,4,6-trinitrobenzene
sulfonic acid-induced colitis. Proc Natl Acad Sci U S A
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56. Spite M, Summers L, Porter TF, Srivastava S, Bhatnagar
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58. Krishnamoorthy S, Recchiuti A, Chiang N, Fredman G,
Serhan CN. Resolvin D1 receptor stereoselectivity and
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JB. Omega-3 fatty acid-derived mediators 17(R)-
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101

Obesity, Metabolic Syndrome,
and Oral Health
Ira B. Lamster, dds, mmsc
Nadia Laniado, dds, mph
Ilene Fennoy, md, mph
Obesity has been identified as a major health
problem across the globe.1–3 It has been linked
to the initiation and acceleration of a variety
of disorders, including cardiovascular disease
(CVD) and associated hypertension, diabe-
tes and metabolic syndrome,4,5 obstructive
sleep apnea,6 osteoarthritis,7 and nonalco-
holic fatty liver disease8 and is associated with
increased all-cause morbidity and mortality.9
Globally, obesity continues to increase in pedi-
atric and adult age groups.10,11 The prevalence
of obesity is greater in adult women than in
adult men (Fig 5-1). In the United States, it
has been estimated that state-specific medical
expenditures would be 6.9% to 10% lower in
the absence of obesity,12 demonstrating a signifi-
cant economic impact in addition to the impact
on health and well-being. Given the negative
effects of obesity on health and an expanding
literature on the relationship between obesity
and oral disease, all oral health care profession-
als must consider the impact of obesity on the
provision of oral health care services.
Assessment of Obesity
Obesity is defined as an increase in total body
fat. Multiple methods exist for the measure-
ment of body fat, including anthropometry
102
CHAPTER 5
(skinfold thickness), magnetic resonance imag-
ing (MRI), hydrodensitometry (underwater
weighing), air plethysmography, bioelectric
impedance, and dual-energy x-ray absorpti-
ometry (DXA).13,14 Anthropometry is difficult
to standardize in practice and therefore is not
a useful clinical tool, though it has been used
frequently in population-based research studies
and has been demonstrated to have validity
against the more technologic methods men-
tioned above.15 Many of the other methods
are not practical for routine clinical use due
to cost, radiation exposure, and time but have
been used to validate body mass index (BMI),
a measure calculated as weight in kilograms
divided by height in meters squared (or pounds
divided by height in inches squared, multiplied
by 703).15,16
Classification of weight status by BMI is
established in adults as follows: BMI < 18.5
= underweight, ≥ 18.5 to 24.9 = normal
weight, ≥ 25 to 29.9 = overweight, and ≥ 30
= obese17 (Table 5-1). The obesity group has
been further classified by severity, with Class 1
obesity defined as BMI ≥ 30 and < 35, Class 2
as BMI ≥ 35 and < 40, and Class 3 as BMI ≥
40.17,18 In adults, these criteria are independent
of height, age, and sex. However, in children,
BMI requires adjustment for developmental
status and sex and is therefore plotted on sex-
and age-specific growth charts with percentile
 Assessment of Obesity

Fig 5-1 |  Age-standardized prevalence of obesity (BMI ≥ 30) worldwide in men (a) aged ≥ 20 years and
women (b) as of 2013. (Reprinted from Ng et al11 with permission.)

rankings.19 To further relate pediatric classifica-
tion with that of the adult, severe obesity (Class
2) in childhood has been identified as ≥ 120%
of the 95th percentile, and very severe obesity
(Class 3) as ≥ 140% of the 95th percentile.20
Distribution of fat between visceral depots
and subcutaneous areas has been associated
with variation in risk for comorbidities.21,22
BMI fails to provide information on this aspect
of obesity and as a result must be augmented

103
5 Obesity, Metabolic Syndrome, and Oral Health
TABLE 5-1  |  BMI-for-age weight status
Weight status category Percentile range
Underweight < 5th
Healthy weight 5th to < 85th
Overweight 85th to < 95th
Obese ≥ 95th
by other measures. Measurement of waist cir-
cumference (WC) is used clinically to determine
visceral adipose tissue23 and has been correlated
with adverse cardiovascular outcomes.
WC, waist-hip ratio, and waist-height ratio
have all been shown to correlate with cardio-
vascular comorbidities reflective of increased
visceral body fat and increased cardiovascular
risk.21 In addition, WC and waist-height ratio
have been associated with periodontal pockets,
albeit weakly.24
Prevalence of Obesity
Recent (2015–2016) estimates of obesity in
the United States indicate a prevalence of
39.8% among adults, with younger adults
having a lower incidence than adults aged
20 to 60 years.25 Overall, there were no sig-
nificant differences by age group between
men and women.25 Ethnicity, however, pro-
vided a significant difference in prevalence,
with non-Hispanic Asians demonstrating an
incidence of 12.7%, non-Hispanic whites
37.9%, non-Hispanic blacks 46.8%, and His-
panics 47%.25 Within the ethnic groups, Asian,
Hispanic, and black women demonstrated sig-
nificantly more obesity than men of the same
ethnic group, while white men and women had
a similar prevalence.25
For children in the United States, the
prevalence of obesity from 2 to 19 years
was 18% for the years 2015 to 2016, with
104
BMI
< 18.5
18.5–24.9
25–29.9
≥ 30
12- to 19-year-olds demonstrating the high-
est prevalence (20.9%) and 2- to 5-year-olds
demonstrating the lowest (13.9%).25 Overall,
there was no significant sex-specific difference.
By ethnicity, black (22%) and Hispanic (25%)
children had the highest prevalence of obesity,
with non-Hispanic whites having a 14.1%
prevalence and Asians having 11%.25 For both
adults and children, there has been a slow but
steady rise in the prevalence of obesity from a
30.5% in adults and 13.9% in youth in 1999
to 2000 to the current measures of 39.8% in
adults and 18.5% in children.25
Worldwide, the number of men categorized
as overweight increased from 28.8% in 1980
to 36.9% in 2013, accompanied by an increase
for women from 29.8% to 38.0%.11 Both
developing and developed countries demon-
strate this trend, with women showing more
rapidly increasing obesity than men. Children
demonstrate these same trends in overweight
and obesity, with increases from 16.9% to 23%
in boys and 16.2% to 22% in girls from devel-
oped countries between 1980 and 2013, while
increases in developing countries rose from
8.1% to 12.9% in boys and 8.4% to 13.4%
in girls over this same time period. Prevalence
was higher at all ages in developed countries
compared to developing countries. However,
there are distinct geographic patterns for the
prevalence of overweight and obesity, with the
Middle East, North Africa, and Oceania and
Micronesia demonstrating some of the highest
numbers for children and adults. Globally, 62%
of all persons with obesity live in developing

countries, though the United States accounts
for 13% of all persons with obesity. Obesity
is clearly a global problem that is increasing
worldwide.
Etiology of Obesity
Obesity represents a disorder with multifac-
torial causes. At a basic level, it represents a
mismatch between energy in and energy out.
However, the etiology of that imbalance has
been shown to be at least 50% genetic,26,27
while the remainder involves environmental,
psychologic, socioeconomic, and physiologic
factors.28,29 These factors can be seen to be
operational, beginning prenatally with ges-
tational obesity30 and diabetes,31 associated
with increased risk of childhood obesity, or
in animal studies exposure to bisphenol A
and S,32 associated with fetal adipogenesis. In
cases of maternal diabetes, fetal exposure is
linked to multigenerational effects,30 hypoth-
esized to be transmitted through epigenetic
mechanisms33—that is, through mechanisms
affecting DNA expression but not the genes
themselves. Additionally, the prenatal problem
of intrauterine growth restriction is associated
with childhood obesity and insulin resis-
tance.34 Thus, the prenatal environmental
experience is a contributor to both childhood
obesity and adult cardiovascular and meta-
bolic disease.35
Dietary composition represents another
contributor to the obesity epidemic. High-fat
diets have been hypothesized as responsi-
ble for the increasing obesity of populations
based on their contribution to increased energy
density.36,37 Nevertheless, epidemiologically a
reduction in fat content in US diets has been
associated with a continued rise in the prev-
alence of obesity in the overall population.38
This apparent paradox has been clarified by
the recognition that despite a decrease in fat
content, there has been an increase in total
caloric intake and an increase in carbohydrate
Etiology of Obesity
content.38 Reduced-calorie diets have been
shown to result in equal weight loss regard-
less of the specific macronutrient emphasized.39
Thus, low-fat and low-carbohydrate diets at the
same caloric level provide equal effectiveness
in inducing weight loss. Certain dietary com-
ponents, however, have been identified as more
commonly associated with weight gain. These
include sugar-sweetened beverages (SSBs) and
processed foods such as potato chips and pro-
cessed meats.40 Individual dietary components
have been particularly identified as problem-
atic for key obesity-related disorders, such as
saturated fats for hypercholesterolemia41 and
sugar for diabetes.42,43
In general, the effect of dietary macronu-
trients on CVD represents a composite effect,
reflecting the relationship between nutrients
rather than a single nutrient alone,44 as well as
the role of the individual’s genetic contribution.
Dietary patterns are the areas of concern, not
isolated macronutrients.45 Hence, saturated
fat alone is not the culprit but the extent to
which those saturated fats are replaced by
unsaturated fats versus simple carbohydrates.46
The increase in SSBs, therefore, is a particu-
lar adverse dietary change associated with an
increase in cardiometabolic disease.47
SSB intake has been associated with
metabolic, cardiovascular, and oral health dis-
orders.48,49 From 1965 to 2004, SSBs increased
dramatically as a proportion of the Ameri-
can diet.50,51 More recent data indicate some
decline, but more than 50% of the US popu-
lation still consumes at least one SSB per day,
with 25% consuming at least 200 kcal/day
from SSBs.52 Variations in consumption differ
by age, race/ethnicity, and sex. Non-Hispanic
black persons consume the greatest amount as
a percent of total calories ingested, both chil-
dren (8.5% of kcal) and adults (8.6% of total
kcal), while non-Hispanic white adults ingest
the least (5.3% of total kcal).52
Genetic predisposition may contribute
to sensitivity to weight gain from SSBs, as
demonstrated by Qi et al.53 However, pro-
spective cohort studies and a meta-analysis of
105
5 Obesity, Metabolic Syndrome, and Oral Health
randomized controlled trials (RCTs) both docu-
ment increased weight gain in association with
increased intake of SSBs,54 suggesting that this
is a general phenomenon. Furthermore, efforts
to limit SSB intake in children and adolescents
have been associated with decreased weight
gain.55,56
Physical activity
Physical activity patterns are inversely cor-
related with rates of obesity.57 Spontaneous
physical activity or nonexercise activity (ie,
activity of a fidgeting, restless nature, not
motivated by a reward-seeking goal, such
as food-seeking behavior) has been shown
to help prevent weight gain.58 Furthermore,
intervention data demonstrate that increases
in physical activity to at least 150 minutes
per week are effective in achieving weight loss
in those with appropriate diets compared to
those on the same diet without the exercise.59
In short, both spontaneous and exercise activ-
ity contribute to total energy expenditure,
with low energy expenditure associated with
increased weight gain.60
The importance of physical activity is also
demonstrated from a financial perspective,
with 11.1% of health expenditures associated
with individuals who have inadequate physi-
cal activity, defined as less than 150 minutes
per week.61 Only 50% of adults in the United
States met these guidelines for aerobic activ-
ity in 2012.62 For children aged 6 to 11 years
in 2003–2006, 71% performed more than 60
minutes per day of moderate physical activity,
but only 9.9% of 12- to 17-year-olds engaged
in at least 60 minutes per day of moderate
physical activity.63 Overall, youth activity has
declined from 1971 to 2012 while electron-
ics use and computer time have increased.64
Among adults in Australia, a trend toward
increases in physical activity has occurred along
with an increase in sedentary behavior associ-
ated with an increase in obesity.65 These results
highlight the fact that an increase in physical
activity is not synonymous with a decrease
106
in sedentary behavior. The independent con-
tributions of physical activity and sedentary
behaviors to obesity have been demonstrated
by Stamatakis et al66 in adults and Loprinzi
et al63,64 in children. Efforts to modify lifestyle
behaviors for prevention or treatment of obe-
sity must address both sedentary behavior and
physical activity. Emphasis on the importance
of a healthy lifestyle, which is a potential new
practice activity for oral health care providers
and is discussed later in this chapter, includes
increased physical activity.
Pathophysiology of Obesity
Obesity, inflammation, and insulin
resistance
Adipose tissue is a vibrant, active tissue
involved in physiologic and immune regula-
tion.67 It is a multicellular organ composed of
fat cells (adipocytes and preadipocytes) and
a network of connective tissue, vascular, and
immune system cells.68,69 Adipocytes make up
25% of the cell population, while the other cell
types, referred to as the stromal-vascular com-
ponent, make up the remaining 75%.70 Cells
of the adipose tissue organ can be categorized
as follows: (1) by function (white fat used
primarily as a storage organ for fuel reserves
and brown fat used for heat generation), (2)
by localization (subcutaneous versus visceral
fat), and (3) by cell types (adipocytes versus
the stromal-vascular component).70,71 Excessive
adipose tissue, particularly visceral adiposity, is
associated with increased cardiovascular risk,
type 2 diabetes, and periodontal disease, all of
which have an inflammatory component.72–74
Indeed, excessive adiposity or obesity is itself
recognized as an inflammatory condition,75
characterized by macrophage recruitment76 and
increased production of tumor necrosis factor
alpha (TNF-α),77 C-reactive protein (CRP),78
interleukin 6 (IL-6),79 and a host of other cyto-
kines (Fig 5-2).
 Pathophysiology of Obesity

Adipose tissue and inflammation

Leptin Cytokines
Adiponectin Interleukins
IL-12 TNF-α
IFN-γ IL-6
IL-1βRa VEGF
Cathepsin S LPS
CCR2 HIF-1α
Integrin αvβ3
PAI-1
Leptin
HIF-1α
VEGF
Endothelial cell Preadipocyte

Th1 cell
Cytokines, chemokines

Adipocyte M1 macrophage Lymphocyte Th1 cell

Fig 5-2 |  Factors contributing to immunity and inflammation in obesity. Adipose tissue demonstrating both
adipocytes, preadipocytes, endothelial cells, and M1 macrophages with their secretory products, which support
inflammation. Adipocytes produce leptin, adiponectin, cytokines, and interleukins. M1 macrophages produce
interleukins (IL-12, IL-6, IL-1βRA), cytokines (interferon gamma [IFN-γ] and TNF-α), proteases such as cathepsin
S, chemokine receptor 2 (CCR2), hypoxia-inducible factor-1α (HIF-1α), and lipopolysaccharide (LPS). Endothe-
lial cells produce cell adhesion molecules like integrin αvβ3, cytokines, chemokines, HIF-1α, and plasminogen
activator inhibitor-1 (PAI-1). Preadipocytes produce growth factors such as vascular endothelial growth factor
(VEGF), leptin, HIF-1α, PAI-1, and cell adhesion molecules like integrin αvβ3.

Macrophage infiltration represents a key tion).81 Interferon gamma (IFN-γ), cytokine

element in the inflammation associated with
obesity.72,76,80 The stromal-vascular cells of
visceral adipose tissue produce increased mac-
rophage mRNA transcripts that correlate with
increased body mass in mice in both genetic
and diet-induced obesity.76 Furthermore, both
adipocyte size and BMI are predictors of the
numbers of macrophages in various fat depots
of mice.76 Considering the importance of the
inflammatory response to the pathogenesis of
periodontal disease, an in-depth discussion of
the role of inflammation in obesity follows.
Macrophages are of two types: proin-
flammatory (M1, classical activation) and
anti-inflammatory (M2, alternative act­iva­
secretion, IL-12, bacterial lipopolysaccharides
(LPSs), and T-cell activation are all media-
tors of the classical activation pathway, while
immunosuppression of T-cell immune reactions
through mediators such as IL-10, IL-13, and
IL-4 is characteristic of the alternative path-
way.81 Obesity alters the macrophage type
distribution toward an increase in the proin-
flammatory M1 macrophages.82 These macro-
phages overexpress genes for factors involved
in macrophage migration and phagocytosis,
such as IL-6 and CC chemokine receptor type
2 (CCR2).79,83 Thus, macrophages in adipose
tissue are a major contributor to the inflam-
matory response seen with obesity.

107
5 Obesity, Metabolic Syndrome, and Oral Health
The adipocyte secretes adipokines, includ-
ing leptin, adiponectin, interleukins, and
cytokines,84 which have effects on the immune
system. Fain et al85 demonstrated that the
contribution by nonadipocyte cells, particu-
larly macrophages, was greater than that of
the adipocyte for a variety of these cytokines,
including cathepsin S, macrophage migratory
inhibiting factor (MIF), and interleukin 1β
receptor antagonist (IL-1βRa).85 However,
leptin not only acts as a cytokine but has
been shown to regulate T-cell production of
additional cytokines such as stimulation of
the Th1 cell type with its proinflammatory
cytokine production over the Th2 cell type
with its immunoregulatory cytokine pro-
duction.86–88 As a cytokine, leptin activates
increased numbers of and increased phagocy-
tosis by macrophages/monocytes, chemotaxis
of neutrophils, and their release of oxygen
radicals.89,90 Adipocyte-derived leptin directly
and indirectly stimulates immune responses,
augmenting the effects of the non–fat cell
component of adipose tissue, resulting in an
increased inflammatory state.
Adiponectin, in contrast, exhibits dual roles
with respect to inflammation. In autoimmune
disorders, locally and systemically increased
adiponectin levels have been noted in the
presence of inflammation.91 Serum levels have
been described as elevated in systemic lupus
erythematosus and rheumatoid arthritis.92 In
rheumatoid arthritis, adiponectin has been
shown to bind to adiponectin receptors (Adi-
poR) on chondrocytes in a dose-dependent
manner and to increase mRNA expression
of matrix metalloproteinases associated with
increased destruction of chondrocytes.93 Both
IL-6 and pro-matrix metalloproteinase-1, the
principal mediators of inflammation in rheuma-
toid arthritis, are upregulated by adiponectin.94
In both osteoarthritis and rheumatoid arthritis,
increased adiponectin has been found in syno-
vial fluid.95
In obesity and metabolic disorders, adi-
ponectin has been well documented to have
anti-inflammatory effects and to negatively
108
correlate with weight gain or obesity.96–98
Adiponectin inhibits colony-forming units
(CFUs) of macrophages and granulocytes and
suppresses mature macrophage functions.99
A reciprocal relationship exists between the
cytokines TNF-α, IL-6, and adiponectin: Pro-
duction of TNF-α and IL-6 is inhibited by
adiponectin,100,101 while TNF-α and IL-6 inhibit
adiponectin gene expression and secretion.102
The low adiponectin levels seen in obesity thus
support the inflammatory state through loss of
suppression of TNF-α and IL-6.91
Obesity and angiogenesis
Endothelial cells contribute to the inflammatory
process by coordinating the recruitment of leu-
kocytes into the adipose mass.103 Activation of
endothelial cells results in the production of cell
adhesion molecules (CAMs), chemokines, cyto-
kines, and ectoenzymes. These products guide
leukocytes into underlying tissues through a
series of steps involving (1) tethering and roll-
ing by adhesion molecules such as selectin, then
(2) firm adhesion and activation by chemoat-
tractants on the endothelium and adhesion
molecules such as integrins on the leukocytes
or CAMs on the endothelium, and finally (3)
diapedesis of leukocytes through cell-to-cell
endothelial junctions involving molecules such
as platelet/endothelial CAMs (PECAMs).103,104
Cytokines associated with inflammation such
as IL-6 and TNF-α are known to induce endo-
thelial activation.105 As a result, the endothelial
cell can function as a regulator of the move-
ment of leukocytes to the underlying tissues.
In addition, substances secreted by micro-
vascular endothelial cells have been shown
to promote proliferation of preadipocytes,
supporting a role of the endothelium as a con-
tributor to fat mass expansion.106,107 Integrin
αvβ3 and plasminogen activator inhibitor 1
(PAI-1), produced by both endothelial cells and
preadipocytes, have been identified as key sub-
stances in the coordinated development of both
endothelial cells and adipose tissue at the same
site,108 while peroxisome proliferator-activated

receptor gamma (PPAR-γ), involved in adipo-
cyte differentiation, can be shown to interfere
with both adipose tissue development and
angiogenesis if overexpressed as a dominant
negative contruct.109 Furthermore, blocking
of angiogenesis by use of vascular endothelial
growth factor receptor 2 (VEGFR2)–blocking
antibody resulted in a similar failure of angio-
genesis and adipose tissue development,109 as
did use of a variety of other angiogenesis inhib-
itors.110 Adipogenesis is therefore dependent on
angiogenesis.
Hypoxia is considered a key initiator of
the endothelial activation associated with
expanding fat tissue.111 As the fat mass
expands with increasing recruitment of leuko-
cytes, the demand on local oxygen supply is
inadequate, causing relative hypoxia. Adipose
tissue in obese mice has been demonstrated
to be in a hypoxic state compared to that of
lean mice.112,113 Hypoxia-inducible factor-1
(HIF-1), a transcription factor activated
under low oxygen conditions, binds to mul-
tiple genes in the cis-acting hypoxic response
elements responsible for glucose metabolism,
angiogenesis, inflammation, cellular stress,
extracellular matrix remodeling, and apop-
tosis.114 Furthermore, an increase in HIF-1α
transcription factor along with an increase in
protein secretion of leptin and VEGF occurs
when human preadipocytes are exposed to
hypoxic conditions.115
Macrophages in the non–fat cell compart-
ment of adipose tissue also demonstrate gene
expression for HIF-1α.113,116 Under hypoxic
conditions, gene expression by macrophages
for TNF-α, IL-6, IL-1, MIF, and VEGF can all
be demonstrated to be increased.113 With both
macrophages and preadipocytes providing evi-
dence of increased cytokine production in the
hypoxic state, it is likely that hypoxia underlies
the inflammatory state seen in obesity.
Insulin resistance represents one of the major
outcomes of this chronic inflammatory state.72
Consequences of Obesity
Consequences of Obesity
Morbidity and mortality
Systematic review of the literature and meta-
analysis has documented increased all-cause
mortality (hazard ratio = 1.18 [95% confi-
dence interval (CI): 1.12–1.25]) in association
with obesity (BMI ≥ 30 kg/m2) compared to
those with normal weight (BMI = 18 to ≤ 25
kg/m2).9 International data spanning 32 coun-
tries, evaluating individuals followed for 5
years or more and excluding those who had
ever smoked or had preexisting chronic condi-
tions, reaches a similar conclusion but with the
rise in mortality beginning with the overweight
category and increasing with severity of obesi-
ty.117 In the United States, quality-adjusted life
expectancy for 18-year-olds of normal weight
(BMI = 18.5 to 24.9 kg/m2) has been shown to
vary from a high of 54 years to a low of 48.2
years for those with Class 2 and Class 3 obe-
sity (BMI ≥ 35 kg/m2).118 Years of life lost are
greatest for younger individuals, from 8.4 years
in men aged 20 to 39 years who are severely
obese compared to normal-weight men versus
0.8 years lost in severely obese men aged 60
to 79 years, with similar results for women.119
Not only is mortality increased with obe-
sity, but so is disability. When disability is
defined as limitations in activities of daily
living (ADL), a gradation of increased disabil-
ity can be shown to occur as obesity severity
increases.120 Cheng et al121 have documented
both functional limitations (ie, limitations in
mobility) and limitations in ADL in associa-
tion with obesity in those aged 60 years and
older.121 From the National Health and Nutri-
tion Examination Survey (NHANES) data for
1988 through 2004, the odds of impairment
increased with increasing obesity. However,
from 2005 to 2012 the odds stabilized for
functional limitations and severe impairment
of ADL with a decline in the odds of mod-
erate impairment of ADL.122 Recent years,
therefore, have demonstrated some improve-
ment in the disability status of obese people.
109
5 Obesity, Metabolic Syndrome, and Oral Health
However, cross-sectional studies in Europe of
those aged between 50 and 75 years document
a decline in the proportion of the population
expressing a sense of having good health from
81% for those at normal BMI to 53% for those
with Class 2 obesity, while the proportion of
people without chronic disease declined from
62% and 65% in normal-weight men and
women to 26% and 32%, respectively, in
men and women with Class 2 obesity.123 This
suggests that although the degree of disability
associated with obesity appears to be stable,
it nevertheless impairs the sense of well-being
and disease-free life expectancy.
Chronic disease in association with obesity
involves multiple organ systems.124 Common
and significant comorbidities have included
CVD and diabetes,125,126 nonalcoholic fatty liver
disease,127–129 focal glomerulosclerosis,130,131
obstructive sleep apnea,6,132 polycystic ovarian
syndrome,133 and gastroesophageal reflux.134
Cancer has also been implicated as a disorder
influenced by the presence of obesity.135,136
Economic impact
Systematic review of international data demon-
strates that obese individuals incur 6% to 43%
higher health care costs than individuals of nor-
mal weight.137 In terms of BMI levels, those
with BMI 30 or above incurred 30% higher
costs than those with BMI 25 and below.137
In the United States and the United Kingdom,
these costs have been estimated to be largely
driven by a rise in prevalence of obesity with
an associated rise in the chronic comorbid con-
ditions of diabetes, heart disease, stroke, and
cancer.1
One health system database, the Geisinger
system, reviewed electronic medical records
and claims from 2004 through 2013, identi-
fying 21 obesity-related chronic conditions in
56,895 individuals.138 The incremental costs for
a single condition varied from $160 per per-
son per year for angina to $1,663 per person
per year for a pulmonary embolus. Population
110
analysis of 100,000 individuals identified
hypertension, dyslipidemia, and osteoarthritis
costs of $18 million or more each per year.138
As of 2010, interventions to prevent obe-
sity through medication or physician/dietician
counseling were estimated to reduce health care
expenditures in the United States by as much as
$2 billion.139 Clearly, a major effort to reduce
obesity is important to health economics.
Metabolic syndrome
Metabolic syndrome, a cluster of risk factors
associated with increased risk of diabetes mel-
litus and CVD, is commonly associated with
many of the disorders described earlier as
consequences of obesity.140 Diagnosis of this
syndrome is somewhat controversial.141–143 In
the United States, the National Cholesterol
Education Program (NCEP) Adult Treatment
Panel III (ATPIII) criteria have been com-
monly used, requiring the presence of three
or more of the following five characteristics:
abdominal obesity, hypertension, elevated
fasting blood sugar, elevated triglycerides, and
low high-density lipoprotein (HDL) choles-
terol.144 Using the NCEP/ATPIII definition, the
prevalence of metabolic syndrome from 2003
to 2012 in the United States was estimated
at 33%, with a higher prevalence in women
than in men.145 Both the International Diabe-
tes Federation and the National Heart, Lung,
and Blood Institute with the American Heart
Association have considered WC a requisite
part of any definition.143 These differences can
be shown to identify different populations,
particularly with respect to ethnic or racial
differences.143,146 Prevalence rates of macrovas-
cular complications, however, increase under
all of these definitions. In addition to the major
criteria listed here, PPAR modulation and pro-
thrombotic and proinflammatory states have
been considered components of the syndrome,
with the presence or absence of insulin resis-
tance affecting morbidity.147 Regardless of these
variations in definition, metabolic syndrome

has been associated with increased left ventric-
ular mass and left ventricular hypertrophy and
an increased risk of having a cardiovascular
event and developing diabetes.146 Hence, the
presence of metabolic syndrome represents a
significant increased health risk.
Obesity and the Oral Cavity
There is interest in the relationship of body
weight and obesity to oral diseases. This inter-
est derives from the recognized association of
obesity and diabetes and the importance of the
relationship between diabetes and oral health
(reviewed in chapter 6). The mechanism that is
central to the relationship between diabetes and
periodontitis is enhanced local and systemic
inflammation and production of inflammatory
mediators by adipocytes and macrophages in
adipose tissue contributing to the inflammatory
burden. In addition, weight gain is often related
to food intake, and the intake of fermentable
carbohydrates can have an effect on the denti-
tion and other tissues in the oral cavity. Obesity
is also associated with sleep apnea, and dental
professionals are expanding their role in treat-
ing this disorder.
The relationship between overweight and
obese status and different oral/dental diseases
and disorders has been studied. The resulting
research strongly suggests the need for dental
professionals to be aware of the association
between oral disease and obesity, understand
the basis of these links, and develop a pre-
ventive approach to reduce and manage the
general health effects associated with being
overweight and obese. Further, oral health care
professionals need to consider a role in obesity
management for their patients. They are well
versed in delivering a nutrition message related
to carbohydrate intake and diet activities and
should consider expanding their responsibility
in regard to weight management for patients
in their care.
Obesity and the Oral Cavity
Periodontal disease and obesity
Obesity and periodontitis are conditions asso-
ciated with local and systemic inflammation.
Based on an understanding of the contribution
of obesity to the systemic inflammatory bur-
den and the importance of the inflammatory
response to the progression of periodontitis,
the relationship of obesity to periodontitis has
been a focus of research.
There is evidence from animal models that
obesity can affect the severity of periodontal
destruction. In a study by Verzeletti et al,148
two groups of Wistar rats were established.
One was fed a regular diet and the other a
diet high in calories. After 90 days, silk lig-
atures were placed in the crevice around the
maxillary second molars, and all animals were
sacrificed 30 days later. More weight gain was
observed in the animals fed the diet high in cal-
ories. Further, there was greater loss of alveolar
bone in the obese group. Similarly, in a study
by Cavagni et al,149 obese Wistar rats demon-
strated significantly greater bone loss than a
control group.
Cross-sectional clinical studies
Systematic reviews and meta-analyses have
supported a positive association between the
prevalence of periodontitis and overweight/
obesity in both children and adults.74,150–152 The
majority of studies have been cross-sectional,
not longitudinal, in design; therefore, cause and
effect could not be determined. In these studies,
risk ratios and odds ratios (ORs) ranged from
1.35 to 1.81, with significant methodologic
heterogeneity among the studies. There were
inconsistencies in research design with regard
to the indices of periodontal disease and cutoffs
for the definitions of adiposity and periodon-
tal disease.153 Furthermore, many studies did
not consider important covariates and con-
founders such as diabetes mellitus, smoking,
socioeconomic status (SES), hypertension, and
oral hygiene.
111
5 Obesity, Metabolic Syndrome, and Oral Health
Association between overweight/obesity and periodontitis in adults.
Study
ID
Buhlin 2003 n = 96
Genco 2005 n = 12,367
Nshida 2005 n = 372
Saito 2005 n = 584
Kushiyama 2009 n = 1,070
Han 2009 (males) n = 96
Han 2009 (females) n = 102
Overall (I-squared = 73.0%; P < .001)
Note: Weights are from random effects analysis
Odds ratio 0.25
0.5 1 2 4 8 16
Fig 5-3  |  Overweight and obesity compared with normal weight (body mass index). (Adapted from Suvan et
al157 with permission.)
Regarding the biologic plausibility of the
association between periodontitis and obesity,
two explanations have been proposed. The first
is an exaggerated inflammatory response. Adi-
pocytes, macrophages, and other cell types in
fat tissue produce a range of proinflammatory
cytokines, and the concentration of acute-phase
proteins and the number of circulating leuko-
cytes is elevated in obesity.154 In support of this
concept, elevated levels of TNF-α in gingival
crevicular fluid (GCF) have been observed
in obese patients.155 The other mechanism is
related to reduced sensitivity to insulin, which
is important to the linkage of obesity and the
development of type 2 diabetes mellitus. With
elevated circulating levels of proinflammatory
cytokines, blood levels of glucose would rise
with increased production and accumulation
of advanced glycation end products, for a
greater systemic inflammatory burden. This
mechanism has been associated with increased
periodontal pathology.156
Chaffee and Weston74 conducted a system-
atic review and meta-analysis of the association
between chronic periodontitis and obesity.
They examined 554 citations and 70 studies
that met specific inclusion criteria. An empha-
sis was placed on reporting of periodontitis by
112
%
OR (95% CI) weight
4.54 (1.59–13.00) 9.58
1.45 (1.13–1.93) 21.18
3.17 (1.79–5.61) 16.31
4.30 (2.10–8.90) 13.97
1.09 (0.77–1.53) 29.09
2.50 (0.85–7.38) 9.27
1.47 (0.52–4.95) 9.70
2.13 (1.40–3.26) 100.00
accepted clinical parameters and indices and
not on other variables such as level of oral
hygiene or number of missing teeth. A total
of 28 studies contributed to the calculation of
the OR of the association between periodontal
disease and obesity, which was 1.35 (95% CI:
1.23–1.47). Stronger associations were found
between obesity and periodontal disease for
younger versus older adults, women versus
men, and those who did not smoke versus
smokers.
A subsequent systematic review and
meta-analysis157 included 33 studies in the
systematic review and 19 in the meta-analysis.
There was a statistically significant associa-
tion between periodontitis and obesity (OR:
1.81; CI: 1.42–2.30), overweight (OR: 1.27;
CI: 1.06–1.151) and when overweight and
obese weight categories were combined (OR:
2.13; CI: 1.40–3.26; Fig 5-3).157 Again, cause
and effect could not be assessed due to the
cross-sectional nature of most studies.
Examining individual studies helps to
demonstrate the heterogeneity of the research
findings. Recognizing that cigarette smoking
is the most important environmental risk fac-
tor for periodontal disease, the relationship
between body weight (assessed by BMI) and

periodontitis in a group of nonsmoking older
adults was examined.158 In a fully adjusted
model, there was no significant association
between BMI and periodontitis. Compared
to individuals with a BMI below 25, the rela-
tive risk (RR) of more advanced periodontitis
for those individuals with a BMI between 25
and 30 was 0.7 (95% CI: 0.6–0.9) and a BMI
of above 30 was 1.1 (95% CI: 0.8–1.4). This
study should be interpreted cautiously because
of the other risk factors that would occur in
this population, including advanced age,158 as
well as a very broad definition of periodontitis.
Longitudinal studies
In a systematic review that analyzed longi-
tudinal studies of obesity and periodontitis,
overweight/obesity, weight gain, and increased
WC were identified as potential risk factors
for the development and/or worsening of
periodontitis.159 In addition, studies with lon-
ger follow-up times (> 20 years) were more
likely to show a direct association between
obesity and periodontitis, perhaps due to the
longer exposure of the periodontium to the
bacterial biofilm with persistence of the inflam-
matory response. Whether fat was distributed
viscerally or generally affected the association;
individuals with visceral fat accumulation had
a stronger association than those with high
BMI. This is consistent with the production
by abdominal adipose tissue of proinflamma-
tory adipocytokines such as TNF-α and IL-6.153
Similar conflicting results were reported for
younger individuals. Using data from a longi-
tudinal study,160 measures of obesity including
BMI, WC, and a history of being identified as
obese or overweight in earlier examinations
were related to measures of periodontal dis-
ease, including bleeding following periodontal
probing, the presence of calculus, and the num-
ber of teeth with a probing depth greater than
or equal to 5 mm. While there was an associa-
tion between gingival bleeding and obesity, this
relationship did not remain in a fully adjusted
model. No association between deeper probing
Obesity and the Oral Cavity
depths and obesity was observed; however, a
relationship was seen between obesity and
dental calculus. Unfortunately, while the larger
parent study was longitudinal in nature, the
periodontal variables were only collected at
one time point.
Longitudinal data are also available from a
study by the Veterans Administration. An anal-
ysis sought to determine whether changes in
body weight could predict the progression of
periodontitis.161 Increases in weight, WC, and
arm fat were related to changes in periodontal
disease over a period of nearly 30 years. Pro-
gression of periodontal disease was defined as
an increase in probing depth greater than 3
mm or tooth loss associated with periodonti-
tis. Men were categorized at baseline as being
normal weight (BMI 18.5–24.9 kg/m2), over-
weight (BMI 25–29.9 kg/m2), or obese (BMI
≥ 30 kg/m2), and weight gain in these groups
was divided into tertiles.
In general, greater weight gain over time
was associated with greater progression of
periodontitis. For men with normal weight
at baseline, both the greatest weight gain and
the greatest increase in WC were associated
with greater progression of periodontitis, as
compared to those with the least weight gain
or a smaller increase in WC (Fig 5-4).161 An
increase in arm fat was associated with greater
progression of periodontal disease in men in
the normal-weight group. Similar trends were
seen for obese men, but differences did not
reach significance for this subgroup because
the number of patients was small. This is an
important contribution to the literature on
oral changes related to excessive weight and
confirms the association of weight gain and
progression of periodontitis. The data suggest
a concurrent increase in weight and severity of
periodontal disease.
Similar findings were reported in a study
of the relationship of BMI at baseline to the
development of periodontal disease during the
following 5 years.162 In a fully adjusted model,
the hazard ratio of developing periodontitis for
men who were overweight (BMI 25.0–29.9)
113
5 Obesity, Metabolic Syndrome, and Oral Health

Tertile of weight change Tertile of waist circumference change Tertile of arm fat area change
18 – 18 – 18 –
16 – 16 – 16 –
Teeth with PPD event (no.)

* * **
14 – 14 – 14 –
12 – 12 – 12 –
10 – 10 – 10 –
8– 8– 8–
6– 6– 6–
≤ –0.05 kg/yr
4– > –0.05 to 0.19 kg/yr 4– ≤ 0.14 cm/yr
4– ≤ 0.25 cm2/yr
> 0.14 to 0.38 cm/yr > 0.25 to 0.5 cm2/yr
2– > 0.19 kg/yr
2– > 0.38 cm/yr 2– > 0.5 cm2/yr
0– 0– 0–
–
–
–
–
–
–
–
–

–
–
–
–
–
–
–
–
2 3 4 5 6 7 8 9

–
–
–
–
–
–
–
–
2 3 4 5 6 7 8 9 2 3 4 5 6 7 8 9
Examination no. Examination no. Examination no.

Fig 5-4 |  Mean cumulative number of teeth with probing pocket events in men who were normal weight at
baseline. (Adapted from Gorman et al161 with permission.)

was 1.30 (P < .001), and for men who were contrary to the generally accepted epidemio-
obese (BMI ≥ 30.0) the risk was 1.44 (P = logic finding that periodontal disease prevalence
.072). The risk for women was 1.70 (P < .01) is greater in men but may be partially explained
and 3.24 (P < .05), respectively. by the limitation of just using BMI as the mea-
It is becoming clear that it is important to surement of obesity, as previously discussed.
distinguish between different patterns of fat For example, males have more muscle mass
distribution. Body weight and BMI alone do and higher BMI, which may account for this
not describe body fat distribution or the RR study’s finding that there was no progression
for adverse effects of obesity. Furthermore, as in periodontitis severity for males.
mentioned by these authors, high BMI in men
is not necessarily indicative of excessive fat.163
Other measurements, such as WC and arm fat, Treatment effects
are more reliable markers for intra-abdominal The evidence of the modifying effect of obe-
visceral fat and upper body subcutaneous adi- sity on the treatment of periodontal disease is
posity. In a population-based cohort study inconclusive. In a study by Suvan et al,167 over-
of adults, investigators looked at the effects weight/obese patients with severe periodontitis
of abdominal and general adiposity on peri- were followed for 2 months after nonsurgical
odontal outcomes after 3 years and found periodontal therapy. Their combined data-
that abdominal obesity was associated with base consisted of 260 individuals ranging in
unfavorable periodontal outcomes.164 Their age from 27 to 77 years. They concluded that
findings corroborate other studies, which show obesity was an independent predictor of worse
that abdominal obesity is associated with met- periodontal treatment outcomes at 2 months,
abolic disturbances and increased risk for other measured by percentage of probing pocket
chronic diseases.165 depth greater than 4 mm (P < .012). How-
With regard to effect modification by sex, ever, they cautioned that interpretation of these
a 5-year population-based prospective study results is limited based on issues with study
found an association between obesity and design and sample size. Further, the magnitude
attachment loss only in women.166 This is of the difference was minimal.

114

In a study that examined the effects of scal-
ing and root planing (SRP) on the clinical
response and serum levels of adipocytokines
in 24 obese patients with periodontitis and a
control group of 24 nonobese patients with
periodontitis, obese patients had lower reduc-
tions in probing depth after 6 months of SRP.
In addition, the treatment did not affect the
circulating levels of leptin and adiponectin in
any group.168
In sum, a systematic review and meta-analysis
that included a total of 15 studies and 867
patients investigated the effect of overweight/
obesity on response to periodontal treatment.
While the evidence was determined to be of low
quality, the authors concluded that there was
no difference in clinical periodontal outcomes
(clinical attachment level and probing depth)
but that there were significant differences in cir-
culating levels of certain inflammatory markers
(adiponectin and leptin) following treatment of
overweight/obese patients and normal-weight
patients.169
Levels of inflammatory mediators
Levels of inflammatory mediators in biologic
fluids from patients with obesity and peri-
odontitis can provide insight into the systemic
and local inflammatory response. Progranulin
(PGN) is a proinflammatory mediator that
has been associated with influx of polymor-
phonuclear leukocytes and macrophages and
neovascularization in wound healing sites.170
CRP levels are closely linked to levels of PGN,
and elevations in BMI are associated with ele-
vations in PGN. In one study, concentration of
PGN and CRP were evaluated in four groups
of patients171: individuals who were not obese
without periodontitis (group 1), obese but
without periodontitis (group 2), not obese with
periodontitis (group 3), and obese with peri-
odontitis (group 4). The concentration of both
mediators was determined in serum and GCF.
The concentrations of both mediators in serum
and GCF were highest in group 4, followed by
group 2, group 3, and then group 1, indicating
Obesity and the Oral Cavity
that both mediators were more closely associ-
ated with obesity than with periodontitis.
A study of a panel of inflammatory mark-
ers/adipocytokines were evaluated in serum
and GCF from individuals in four groups
(with and without obesity, with and without
periodontitis).171 Levels of resistin, adiponec-
tin, leptin, TNF-α, and IL-6 were determined.
Both obesity and periodontal disease appeared
to influence the concentration of the inflam-
matory mediators in serum and GCF. The
levels of adiponectin, which is considered to be
anti-inflammatory, were lower in the serum of
patients with periodontitis and were not influ-
enced by obesity. TNF-α levels were influenced
by both obesity and periodontitis. Higher levels
of TNF-α were seen in obese patients versus
normal-weight patients when periodontitis was
not present. Periodontitis was associated with
higher levels of TNF-α. These data emphasize
that the effect of periodontitis and obesity on
local and systemic levels of inflammatory medi-
ators is complex.171
Treatment effects can also be used to eval-
uate the influence of periodontal diseases on
local and systemic levels of inflammatory medi-
ators. The effect of conservative periodontal
therapy on circulating levels of inflammatory
mediators in obese and normal-weight indi-
viduals with periodontitis has been studied.172
All individuals received a complete periodon-
tal examination, evaluation of the lipid profile,
and assessment of the levels of CRP, blood glu-
cose, insulin, IL-6, TNF-α, and leptin. Insulin
resistance was also determined. All parameters
were recorded prior to treatment and 3 months
after SRP (which included extraction of hope-
less teeth) and a complete-mouth disinfection
protocol that relied on subgingival irrigation
and rinsing with chlorhexidine.
Both groups demonstrated a pronounced
improvement in clinical parameters following
treatment. The obese group demonstrated a
significant reduction in the concentration of
circulating IL-6, TNF-α, and leptin following
treatment, while the normal-weight individuals
demonstrated a reduction in the concentration
115
5 Obesity, Metabolic Syndrome, and Oral Health
of IL-6. Further, insulin resistance decreased
in the obese individuals. This was a small
study, but it suggested that periodontal dis-
ease and periodontal inflammation can both
adversely affect the concentration of inflam-
matory mediators in blood as well as induce
insulin resistance in patients with obesity and
periodontitis.
Examining specific measures of systemic
inflammation has also provided evidence for
the association of periodontitis and obesity.
There is also preliminary evidence to sug-
gest that treatment of periodontal disease in
patients with metabolic syndrome reduces CRP
and white blood cell count and raises the level
of HDL.173 These findings suggest that patients
with metabolic syndrome should have a dental
evaluation, and treatment would be indicated
if periodontitis is present. In addition, patients
presenting to the dental office with periodon-
titis and signs and symptoms of metabolic
syndrome should be referred to a medical pro-
vider for appropriate treatment.
Metabolic syndrome and the risk of
periodontal disease
As noted previously, metabolic syndrome is
a complex of clinical and physiologic alter-
ations that include excessive weight/obesity,
insulin resistance, dyslipidemia, and elevated
blood pressure. Metabolic syndrome places
individuals at risk for development of diabe-
tes mellitus and CVD. Periodontitis has been
linked to a number of criteria that are part
of metabolic syndrome. A systematic review
and meta-analysis including 20 studies exam-
ined the relationship of metabolic syndrome
to periodontitis.174 Most were cross-sectional
in design and yielded an OR of 1.71 (95% CI:
1.42–2.03). The OR increased to 2.09 (95%
CI: 1.28–3.44) when a more precise diag-
nosis of metabolic syndrome was required.
Approximately 40% of patients with metabolic
syndrome also presented with periodontitis.
However, the direction of this association
(metabolic syndrome affecting periodontitis,
116
or periodontitis affecting the metabolic syn-
drome) could not be assessed due to a lack of
longitudinal data. Further, metabolic syndrome
includes a number of criteria that are risk fac-
tors for periodontitis, emphasizing the complex
nature of these associations.
In a review article on metabolic syndrome
and periodontal disease, Lamster and Pagan175
suggest that their association is the result of
systemic oxidative stress and a robust inflam-
matory response. Furthermore, evidence
indicates that of the metabolic syndrome com-
ponents, dysglycemia and obesity are the most
closely related to the risk of periodontitis, with
lipid levels and hypertension playing a lesser
role.
The relationship between metabolic syn-
drome and dental caries is less clear. In a review
of the epidemiologic evidence for an associ-
ation between obesity, metabolic disorders,
and oral diseases, some studies have shown a
positive relationship between metabolic syn-
drome and caries and others have not shown
any association.153 It has been postulated that
hyperglycemia and reduced salivary flow are
factors associated with an increased risk of
dental caries in persons with these conditions.
Dental caries
The expectation that dental caries and weight
should be correlated is based on the assump-
tion, and in many cases the observation, that
overweight individuals consume greater quan-
tities of high-caloric and cariogenic foods.
Dietary patterns such as the frequency of
eating cariogenic foods have been shown to
increase the risk for dental caries.176,177 For
young children in the primary dentition, there
is a link between frequent consumption of
cariogenic foods and severe early childhood
caries (S-ECC).176 In a study that examined
feeding practices and intake of sweets in Bra-
zilian children aged younger than 12 months,
an association was found between caries inci-
dence in early childhood (38 months) and diet
(RR = 1.46–1.55).178 In another cross-sectional

study, it was reported that children with S-ECC
(average age 3.6 years) had significantly higher
BMI scores than their caries-free peers.179
In older children, however, studies of the
relationship between dental caries and BMI
are not conclusive.180,181 A systematic review
of the literature in 2012 examined 49 papers
that were published between 2004 and
2011. The authors reported that the studies
fell into three categories with respect to the
association between BMI and dental caries:
23 studies found no association, 17 found a
positive relationship, and 9 found that caries
decreased with increasing BMI.180 Another
systematic review and meta-analysis, which
included 14 papers, found a significant rela-
tionship between obesity and caries but not
when the permanent and primary dentitions
were analyzed separately. Furthermore, obesity
and caries were positively correlated in children
from developed countries but not in develop-
ing countries, suggesting that socioeconomic
factors confound the association.182
Examining specific studies, there are reports
in the literature that demonstrate a posi-
tive association between obesity and dental
caries. Evaluating a cohort of 1,160 Mexi-
can children aged 4 to 5 years, a significant
association was found between caries in the
primary dentition and being overweight or
at-risk for being overweight (now referred to as
obese and overweight).183 A prospective study
of 403 Swedish 15-year-olds who had been
followed since the age of 1 year found that
snacking habits reported in early childhood
were associated with increased prevalence of
interproximal caries.184 In a German study of
2,071 primary-school pupils, a significant asso-
ciation between caries prevalence and BMI was
found and remained significant after adjusting
for age.185
There are also several well-designed stud-
ies that have shown an inverse relationship
between obesity and caries. In a study of
1,003 Iranian children, a statistically signifi-
cant positive association was found between
increased BMI and being caries free.186 A
Obesity and the Oral Cavity
cross-sectional Kuwaiti study of 8,284 chil-
dren aged 9 to 11 years reported a statistically
significant decrease in the prevalence of caries
in permanent teeth with increasing BMI-for-age
categories.187 A more recent cross-sectional
study of 8,000 fourth- and fifth-grade Kuwaiti
children concluded that the percentage of chil-
dren with decayed or filled teeth was negatively
correlated with BMI.188
Several cross-sectional studies have examined
the association between dental caries and obe-
sity solely in adolescent populations. A study
conducted in India examined 2,000 children
aged 12 to 15 years who were normal weight
(average BMI of 20.8) and overweight (average
BMI of 26.9) and concluded that there was
not a significant difference in the mean num-
ber of decayed, missing or filled teeth (DMFT)
between groups (3.4 versus 3.9).189 Another
study of Indian school children aged 11 to
14 years looked at the relationship between
BMI, caries, and SES. They found that in the
high SES category, there were fewer caries in
overweight children than in normal-weight
children.190
Larger and more detailed studies in the
United States using national surveys have
failed to find an association between body
weight and caries. Analyses of oral health and
body measurement data from the 1999–2002
NHANES indicated that for 6,000 children
aged between 2 and 17 years, there was no
statistically significant association between
caries and BMI-for-age percentile in the
primary or the permanent dentition after
controlling for age, sex, race/ethnicity, and
poverty status. Furthermore, of all children
with caries, those who were overweight had
fewer DMFT than their normal-weight coun-
terparts.191 A later study based on the same
NHANES database examined over 1,500 2- to
6-year-olds and found no significant associ-
ation between overweight and caries.192 A
third study examined data from NHANES III
(1988–1994) for 10,180 children and from
NHANES 1999–2000 for 7,568 children. In
both surveys, for children aged 2 to 5 years
117
5 Obesity, Metabolic Syndrome, and Oral Health
there were no significant differences in caries
prevalence by weight categories. However, in
NHANES III, overweight children aged 6 to
18 years were less likely to have caries than
the normal-weight group.193
Clearly, there are conflicting findings in the
literature with respect to caries and weight sta-
tus, suggesting that this relationship is complex
and affected by a multitude of factors. Diet,
eating patterns and frequency, SES, race/eth-
nicity, and psychosocial factors are important
variables that are examined in the literature.
Systematic reviews note the inconsistencies in
the measures of weight status194 as a possible
cause of the variation in findings.
More research is needed to address the con-
flicting findings in the relationship between
caries and weight status. The factors that
account for weight gain may or may not
account for caries prevalence across different
populations and age groups. For example,
physiologic factors such as a reduced flow of
whole saliva in obese children have been sug-
gested as an explanation for increased caries in
these individuals.195 Identifying common risk
factors associated with increased weight would
suggest approaches to implement health pro-
motion and disease prevention for two chronic
conditions. Further, exploring the reasons for
differences between groups may allow investi-
gators to develop innovative ways to decrease
the negative effects of obesity and caries.
Sugar-sweetened beverages
No discussion of the obesity epidemic, diet,
and oral disease would be complete without
mention of the impact of SSB consumption
on weight gain. SSBs are defined as soda, fruit
drinks, sports and energy drinks, presweetened
coffees and teas, and other sugar-sweetened
drinks. SSBs do not include diet sodas or 100%
fruit juice. Sugar-containing beverages (SCBs)
include both SSBs and 100% fruit juice.
The most recent report from the US Centers
for Disease Control and Prevention on SSB con-
sumption among US youth indicates that almost
118
two-thirds of individuals between the ages of
2 and 19 consume at least one SSB per day,
which is approximately 7% of the total daily
caloric intake.196 Among adults, approximately
50% consume at least one SSB daily, with
young adults having the highest mean intake
and percentage of daily calories from SSBs.197
Several studies have noted that there is an
association between consumption of SSBs and
obesity.54,198–201 Many systematic reviews, includ-
ing most recently a review of the association
between SCBs and weight gain among children
aged younger than 12 years, have shown a sta-
tistically significant positive association between
consumption and adiposity.202,203 However, in
a study based on data from NHANES 1999–
2004, 100% fruit juice intake was not shown to
be associated with early childhood caries, and it
is suggested that parents should encourage other
healthy eating behaviors.204
Despite the link with obesity and the assump-
tion of a relationship between SSB and caries,
there is a paucity of evidence linking SSB con-
sumption and dental disease (eg, caries, tooth
loss, periodontitis). This may be due to the
multitude of modifying factors (eg, saliva flow
and constituents, frequency of sugar intake,
fluoride exposure, oral hygiene practices). A
2001 cross-sectional study of NHANES data
that examined sugared soda consumption and
caries found that there were significant associ-
ations between SSB consumption and DMFT
scores in individuals older than 25 years but
not in younger individuals.205 An in-depth sys-
tematic review in 2014, used to inform World
Health Organization guidelines that recom-
mend restriction of free sugars to less than
10% of energy consumption, concluded that
there was moderate evidence to support a rela-
tionship between amount of sugar consumed
and caries, particularly in children.206
A few research reports have looked at this
longitudinally. In a 4-year prospective study
of the relationship between SSBs and caries
in Finnish adults, it was found that despite
individuals’ sociodemographic characteris-
tics, adults drinking one to two and three or

more SSBs daily had 31% and 33% greater
DMFT than those who did not drink SSBs,
respectively.207 With regard to tooth loss
and SSB consumption, only a limited num-
ber of published studies are available. In a
cross-sectional assessment of young adults
aged 18 to 39 years, a positive association
was found between SSB consumption and
tooth loss. This relationship was observed
even for those who consumed fewer than one
SSB per day.208 Another cross-sectional study
analyzed the relationship between diabetes,
SSBs, and tooth loss. Using self-reported data
from the Behavioral Risk Factor Surveillance
System, the authors concluded that among
adults with diabetes mellitus, consuming two
or more SSBs per day was associated with hav-
ing had six or more teeth extracted (OR: 1.46,
P < .0001).49
In response to the wide availability and
aggressive marketing of SSBs and evidence
suggesting that these beverages contribute to
the obesity epidemic, many countries have
implemented taxes on SSBs, including Den-
mark, France, Hungary, Ireland, Mexico,
Norway, and the United Kingdom. Policy-level
efforts have recently been initiated in several
US cities to tax SSBs as a primary preventive
method to control consumption.209,210 To date,
several US cities, including Berkeley, Philadel-
phia, San Francisco, Oakland, Boulder, and
Seattle, have introduced taxes on SSBs.211 A
systematic review of the effect of taxes on
SSB consumption in middle-income countries
concluded that the taxes will reduce intake
and prevent an increase in obesity prevalence,
but for permanent change to occur other obe-
sity interventions need to be implemented as
well.212 A study of the effect of SSBs on caries
and treatment costs concluded that taxes on
SSBs would reduce caries and dental treatment
costs, especially for younger individuals and
those who have low income.213
Obesity and the Oral Cavity
Tooth eruption and tooth
movement
Evidence suggests that high body fat con-
tent affects hormonal metabolism, skeletal
growth, and onset of puberty. A longitudinal
study demonstrated that higher BMI gain in
childhood is associated with an earlier onset
of puberty.214,215 It appears that although early
puberty and increased height are associated
with obesity, once puberty has been reached,
final adult height is similar to normal-weight
children.215–217
Given obesity’s association with accelerated
skeletal growth, it is possible that hormonal
changes produced by obesity could mod-
ify the timing of tooth eruption.218 Many
cross-sectional studies have shown that over-
weight or obese children have accelerated dental
development, which can have implications
for caries risk and orthodontic treatment.219
For example, in a longitudinal study of 110
Mexican schoolchildren, overweight children
had fewer carious teeth and more erupted per-
manent teeth than normal-weight children (at
aged 11 years, the children in the overweight
group had an average of five more permanent
teeth than normal-weight children).220
In a study by Hilgers et al221 on childhood
obesity and dental development, the dental ages
for 104 children were determined by subtract-
ing each subject’s chronologic age from the
calculated dental age such that a positive value
reflected accelerated dental development and a
negative value reflected delayed development.
When analyzed by BMI-for-age percentile, the
mean difference in dental age was 0.63 ± 1.31
years for normal-weight subjects, 1.51 ± 1.22
years for overweight subjects, and 1.53 ± 1.28
years for obese subjects. After adjusting for
age and sex, the authors concluded that dental
development was associated with higher BMI
percentile.221
In a cross-sectional study of 100 children
aged 8 to 12 years, Zangouei-Booshehri et
al222 studied the relationship between BMI
and dental age. Using the international BMI
119
5 Obesity, Metabolic Syndrome, and Oral Health

standards and collapsing the categories into

normal and above-normal weight groups, 30 –

Median number of permanent teeth erupted

they found that the mean eruptive age was 9.5
25 –
years for the children in the normal BMI group
and 10.0 years for the 15% of children in the 20 –
above-normal BMI group. They concluded that
15 –
increased BMI is associated with increased den-
tal eruptive age.222 10 –
In a study of 540 adolescent orthodontic
patients aged 8 to 17 years, BMI percentile, 5–
Nonobese
skeletal maturation, and dental age were Obese
0–
assessed via retrospective chart review.223 Lin-

–
–
–
–
–
–
–
–
–
ear and logistic regression models assessed

5–
6–
7–
8–
9–
10
11 .9
12 .9
13 2.9
–1
–1
–1
–1
5.9
6.9
7.9
8.9
9.9
the effect of weight on dental age and cervical

0
1

vertebral stage (used to assess skeletal matu-
ration). The results demonstrated that cervical
vertebral stage and dental age were slightly but
significantly greater in subjects with higher BMI
percentiles. The coefficient for the BMI percen-
tile was 0.005 year per one unit increase in
dental age (P < .001), and the OR for the effect
of the BMI percentile on the cervical vertebral
method was 1.02 (P < .0001). The impact of
obesity on the accuracy of determining dental
age has significant clinical implications for the
timing of orthodontic treatment.
Looking at percent body fat as another
measure of obesity, a study calculated BMI
percentile, used DXA to determine body
fat analysis, and assessed skeletal and den-
tal age for 107 children. The difference
between chronologic and skeletal-dental age
was statistically significant for preobese and
obese children but not for underweight and
normal-weight children. The results demon-
strated that, in addition to BMI percentile,
there is an association between accelerated
skeletal-dental age and percentage of body fat
as measured by DXA.224
The aforementioned studies were carried
out on convenience samples, opening the pos-
sibility of biased or nongeneralizable findings.
However, a study based on data from three
NHANES databases from 2001 to 2006 also
found that obesity was significantly associated
with tooth eruption in children. In this national
proportional probability sample designed to
3.9
Age (y)
Fig 5-5 |  Median number of teeth erupted by age
category and obesity status. (Reprinted from Must et
al225 with permission.)
reflect the US population, obese children aged
5 to 14 years had a higher average number of
erupted teeth during the mixed dentition period
than normal-weight peers. Analyses of 5,434
participants found that, on average, obese chil-
dren had 1.44 more erupted permanent teeth
than nonobese children after adjusting for age,
sex, and race/ethnicity225 (Fig 5-5). The acceler-
ation of tooth eruption in obese children may
also affect the sequence of tooth emergence,
with implications for orthodontic treatment.
The correlation between BMI-for-age percen-
tile and the sequence of tooth eruption was
examined in a cross-sectional sample of 8,292
Kuwaiti children aged 9 to 11 years. Using
the BMI percentiles, 29% of the children
were obese and 18% were overweight. When
compared to the 53% normal/underweight
children, the obese and overweight children
had significantly more permanent teeth, adjust-
ing for age and sex. The overweight and obese
groups had an average of 1.2 and 2.7 more
erupted teeth than the normal-weight group,
respectively. Moreover, this study demonstrated
that there was a statistically significant differ-
ence in mean number of erupted teeth between
each discrete BMI category.187

120

Mechanisms to explain accelerated skele-
tal maturation (and early puberty) in obese
children appear to involve control of skeletal
maturation and turnover. In the literature, it
has been suggested that leptin, a hormone
produced by adipose tissue, can stimulate
skeletal growth and accelerate pubertal devel-
opment.226,227 Alternatively, leptin might act
directly on the skeletal growth centers. Leptin
receptors have been found in the cartilaginous
growth centers involved in skeletal matura-
tion. Therefore, an obese subject may have a
mechanism of central resistance to leptin and
an increased sensitivity to leptin peripherally,
causing increased differentiation and prolifer-
ation of chondrocytes, resulting in precocious
skeletal maturation.228 Leptin was strongly
associated with fat mass as well as loss of eat-
ing control in a study of 7- to 18-year-olds.229
The concentration of leptin in saliva was sig-
nificantly higher in obese children compared
to nonobese children.187
Early tooth eruption and skeletal matura-
tion are important considerations for pediatric
dentists and orthodontists. When considering
orthodontic therapy, knowledge of the stage
of skeletal development is essential because
treatment is often initiated during the early
mixed dentition to redirect growth in a more
favorable manner.218 A prospective cohort
study found that the number of paired teeth
at 15 months was correlated with obesity at
17 years, suggesting that early primary tooth
eruption may be an unrecognized indicator for
the development of obesity.230 Furthermore,
obese orthodontic patients had a significantly
higher rate of tooth movement at the beginning
of orthodontic therapy than normal-weight
controls, which was associated with increased
levels of inflammatory markers (eg, leptin and
resistin) in GCF.231
Masticatory efficiency
The relationship between body weight
and masticatory efficiency may be an
important determinant of the obesity–oral
Obesity and the Oral Cavity
disease relationship. 232,233 If masticatory
function is compromised, individuals may
avoid hard-to-chew foods that contain fiber
and instead choose processed foods or foods
that are rich in carbohydrates, with only limited
amounts of fiber, protein, and other important
nutrients. The result may be a greater caloric
intake than what is expended, resulting in
weight gain.
Masticatory efficiency has been assessed
in patients with a range of dental conditions.
Participants chewed a test cylinder of silicone
rubber, and particle size was evaluated after 20
chewing cycles. Swallowing trigger was also
determined, participants were questioned about
their ability to chew, and an oral examination
was conducted to determine the number of
occluding teeth. Participants’ weights were
assessed as BMI.
Increased BMI was associated with fewer than
10 occluding pairs of teeth. Similarly, reduced
masticatory function and swallowing trigger
were associated with a higher BMI. However,
eating habits and masticatory function are com-
plex processes, and the authors emphasized
the importance of a multidisciplinary health
care approach to management of overweight
and obese patients. They suggest that dentists
can play different roles in this effort, including
counseling patients about the health hazards
associated with excessive weight and the impor-
tance of healthy eating, as well as the need
to restore masticatory function to enhance a
patient’s ability to eat a healthy diet. This should
be accompanied by dietary guidance.
Tooth loss can have several causes, including
dental caries, periodontal disease, and trauma.
A systematic review found a bidirectional
association between obesity and tooth loss.234
Because the studies included in the review were
cross-sectional in nature, causality could not be
determined. Further longitudinal studies are
necessary to assess the direction of the associ-
ation (ie, whether edentulism leads to obesity
or obesity leads to edentulism). In a 22-year
longitudinal study of the association of obesity
and edentulism in Swedish individuals aged 55
121
5 Obesity, Metabolic Syndrome, and Oral Health
to 84 years, the authors found a strong asso-
ciation that was more apparent in women.235
Obesity and Obstructive
Sleep Apnea
Obesity, as measured by BMI, neck circumfer-
ence, and waist-to-hip ratio, is the strongest
risk factor for the common sleep disorder
known as obstructive sleep apnea (OSA).236
More than 70% of individuals with OSA are
clinically obese based on their BMI, and prev-
alence has increased with the global rise in
obesity.237 Sleep apnea is characterized by com-
plete or partial obstruction of the upper airway
with associated respiratory effort and snoring.
These recurrent episodes of shallow or paused
breathing during sleep result in reduced blood
oxygen saturation and significant comorbidi-
ties (eg, daytime sleepiness, CVD, hypertension,
and neurocognitive deficits).238 The etiology of
OSA is complex, and in addition to obesity
there are many established risk factors, includ-
ing underlying craniofacial abnormalities (eg,
retrognathia, micrognathia), hyoid bone posi-
tion, nasal anatomy, and macroglossia.239
The prevalence of OSA in the US popula-
tion has increased almost 15-fold from 1993
to 2010.240 The Wisconsin Sleep Cohort, an
ongoing longitudinal study of sleep disorders,
estimated the prevalence of OSA to be 9% for
women and 17% for men between the ages of
50 to 70 years.241 Although measurement stan-
dards and levels of apnea differ among studies,
it is estimated that approximately one of every
five adults in the United States has mild OSA
and one of every 15 adults has moderate OSA.242
Predictors of an increase in OSA include male
sex, high BMI, increase in waist-to-hip propor-
tion, and increase in serum cholesterol.243
Obesity appears to affect control of the upper
airway by alterations in upper airway structure
and function, reductions in resting lung volume,
and negative effects on respiratory drive and
load compensation.244 Insulin resistance is also
122
associated with severity of OSA and may be
linked to sleep deprivation and activation of the
sympathetic nervous system.245 A reciprocal or
bidirectional relationship between OSA and obe-
sity has been described by Ong et al,244 in which
obesity may lead to OSA and OSA can have an
impact on body weight. OSA causes changes in
energy expenditure during sleep and wakeful-
ness, increases preference for energy-dense food,
alters hormonal regulation specific to appetite
and satiety, and affects sleep duration and qual-
ity, which may affect daytime physical activity
and increase lethargy and sleepiness.
In addition to adults, children and adoles-
cents are also affected by OSA. The primary
risk factor for OSA in children is adenotonsillar
hypertrophy, but underlying craniofacial anat-
omy and obesity are also significant risk factors.
The prevalence of OSA in children has been
estimated at anywhere between 2% and 20%,
with obese children having a prevalence as high
as 60%.242,246 Kohler et al247 found that among
adolescents, there was a 3.5-fold increase in
OSA risk with each standard-deviation increase
in BMI percentile. Studies have demonstrated a
relationship between OSA, inflammation, and
insulin resistance in obese and nonobese chil-
dren.248,249 Using imaging techniques, a strong
relationship was found between visceral adi-
posity and OSA, independent of BMI.250 The
authors concluded that the quantity and loca-
tion of adipose tissue was a factor that might
explain why some obese children do or do not
develop OSA.
Traditional nonsurgical therapies for OSA
include weight loss and continuous positive
airway pressure (CPAP) in the upper airway
during sleep. An increasingly popular and more
tolerable treatment option is oral appliance
therapy (OAT), which involves the fabrication
of removable mandibular repositioning appli-
ances.251 These appliances increase the upper
airway volume/opening by bringing the tongue
forward as the mandible is advanced anteriorly.
A recent study suggested that screening for OSA
in a dental office was well accepted by patients
and encouraged further medical evaluation.252

A recent systematic review of the effective-
ness of mandibular advancement appliances
demonstrated a reduction in the severity of
OSA and an increase in oxygen saturation.253
In a small crossover study, two different appli-
ances were shown to be effective in improving
symptoms in patients affected by mild to
moderate OSA.254,255 In addition, use of a man-
dibular advancement appliance was associated
with improvement in measures of quality of
life for both patients and their bed partners.256
A position paper from the Canadian Sleep
Society emphasized the importance of a team
approach for caring for patients with OSA.257
Clinical care requires that a physician should
make the diagnosis and that OAT provided by
dentists should be considered for appropriate
patients who request treatment for snoring
with or without OSA. Ideally, patients who are
considered candidates for OAT should have a
minimum of 10 healthy, well-supported, and
distributed teeth and no temporomandibular
pain or pathology. In addition, this appliance
is recommended for patients who fall in the
mild to moderate category of OSA only. It is
recommended that dentists who fabricate these
appliances have advanced training in dental
sleep medicine.
Dentists can play an active role in identi-
fying children and adults with possible OSA
and referring them for assessment.258 Early
detection, referral, and coordinated care with
a patient’s medical provider can prevent addi-
tional consequences of OSA and improve
quality of life.259 Long-term follow-up care
and assessment of treatment outcomes, includ-
ing polysomnography, can be provided by an
interdisciplinary team that includes dentists
and physicians.257,260
Conclusion
Obesity is now considered one of the most
important health problems in the United States
and across the globe. In 2012, the Institute of
Conclusion
Medicine of the National Academy of Sciences
issued a report titled, “Accelerating Progress
in Obesity Prevention: Solving the Weight of
the Nation,”261 which examined strategies and
made recommendations for the future. The
recommendations included an emphasis on
exercise and physical activity, the importance
of availability of healthy foods and beverages,
an emphasis on obesity management as an
important part of the work environment, and
the important role that schools should play by
focusing attention of younger individuals on
health and healthy living.
The relationships between obesity and
specific oral diseases and disorders (peri-
odontal disease, dental caries, and early tooth
eruption) are biologically plausible. The rela-
tionship between obesity and periodontitis
has attracted considerable attention. When
considering causation, it was concluded that
the cross-sectional nature of the majority of
studies did not allow for determination of
cause and effect.74 Suvan et al157 suggested
that proinflammatory mechanisms associated
with obesity (eg, increased local inflammatory
response, reduced insulin sensitivity, elevated
blood glucose levels leading to greater accu-
mulation of advanced glycation end products)
can exacerbate periodontitis. However, they
note that many confounders, including smok-
ing and diet, can influence both obesity and
periodontitis. A 5-year longitudinal study of
weight gain and progression of periodontitis
suggested that weight gain and periodontal dis-
ease progression occurred concurrently.161 The
relationship of obesity and periodontal disease
can be considered in the context of diabetes
mellitus and periodontitis. That relationship is
bidirectional, but the data supporting diabetes
mellitus affecting periodontitis is stronger than
the data supporting the converse.
Analysis of the causal relationship between
obesity and other diseases, including peri-
odontitis, has been the subject of conceptual
analysis. Two separate reports failed to find
such a causal relationship for obesity and
periodontitis.262,263 The review of the literature
123
5 Obesity, Metabolic Syndrome, and Oral Health
I. Complete medical
health history
Follow-up care
plan
Dental treatment NO
plan
Provider referrals:
physicians, nurse
practitioner,
psychologist, social
worker, diabetic
educators, tobacco
quit lines
Fig 5-6  |  Integrated oral health practice patient visit. (Reprinted from Myers-Wright and Lamster265 with per-
mission.)
included here emphasized the heterogeneous
nature of the studies, which were primarily
cross-sectional and differed in terms of mea-
sures of periodontitis and definitions of obesity.
These reports do not diminish the importance
of the call for greater involvement of oral
health care professionals in the management
of obesity.
Oral health care professionals can make
important contributions in different ways264
(Fig 5-6).265 Dental treatment in general and
treatment of periodontitis in particular may
help patients retain their dentition and thereby
maintain a healthy diet. Further, periodontal
therapy can help to reduce the systemic inflam-
matory burden. In addition to treating oral
disease and developing a preventive regimen
to avoid future disease, dental providers may
fabricate appliances to treat OSA. In the larger
sense, oral health care providers can advise
124
II. Complete oral III. Oral health
health history examination
Are
expanded
services indicated from
the health histories and oral
examination?
YES
Health promotion Health screening
activities: tobacco activities: HbA1c,
cessation, dietary HIV, hepatitis C,
counseling, disease- hypertension
related education
patients regarding their diet and caloric intake.
It has been proposed that oral health care pro-
viders take an active role in obesity prevention
and treatment266 (see Fig 5-6). The frequency
of dental visits for a significant segment of the
population as well as oral health care provid-
ers’ understanding of an appropriate diet that
emphasizes reduced caloric intake make this
a logical extension of dental practice. Treat-
ment of obesity requires an interprofessional
approach that includes physicians and other
health care providers, including dieticians.265
In the future, dentists and dental hygien-
ists should consider providing a broader
health message to their patients, including the
importance of a healthy lifestyle, exercise, diet
control, smoking cessation (if necessary), and
weight management. This new set of responsi-
bilities will require oral health care providers
to receive specific training and will value the

importance of interprofessional practice.267 The
result will be closer alignment of oral health
care providers with other health care providers
and ultimately improved oral health and health
outcomes.
This chapter has reviewed the impact of obe-
sity/overweight on diseases of the oral cavity.
These associations must be included in the
broader discussion of obesity and health. Much
remains unknown about obesity. We know that
there are overweight/obese individuals who are
healthy and underweight and normal-weight
individuals who are not healthy. Health care
providers must realize that for many people
Clinical Considerations: What You Can Take Back to Your Practice
Is there biologic plausibility for an association
between oral infections and obesity?  Obesity
is an inflammatory condition. Adipose tissue
contains both adipocytes and increased num-
bers of macrophages, which produce inflamma-
tory mediators that contribute to the systemic
inflammatory burden and can exacerbate the
local inflammatory response in the periodon-
tal tissues. Further, obesity is an important risk
factor for type 2 diabetes mellitus, which is a
recognized risk factor for periodontitis.
Are oral infections and disorders independent
risk factors for the development of obesity?  obese patients.
Though not fully addressed in the literature, it
is not biologically plausible that oral infections
directly increase the risk of obesity.
Can treatment of oral infections and disorders
reduce the risk for the development of obesity?  versely affect periodontal health, and a healthy
The provision of dental services, either preven-
tive or therapeutic (treatment of dental caries
or periodontal disease) does not directly con-
tribute to reducing obesity. However, treatment
of dental disease, elimination of pain, and es-
tablishment of a functional dentition can im-
prove mastication and allow patients to eat a
Clinical Considerations
with obesity, being overweight is not a failure
of willpower, and shaming and stigmatizing
them does not help them lose weight. Evidence
suggests that health care providers often have
implicit bias toward people who are obese.268,269
As oral health care providers, together with
our medical colleagues, we have the ability to
diagnose and treat many oral conditions that
are affected by obesity. After all diagnostic and
clinical data is collected and treatment is ren-
dered, all health care providers must deliver
compassionate and comprehensive care to all
patients, regardless of their weight, with respect
and understanding.
range of foods without the need to limit the
diet to softer, carbohydrate-rich foods. In the
larger context, oral health care providers can
deliver a healthy lifestyle message to dental pa-
tients, including the need to eat a healthy diet,
exercise, and control weight.
Is it safe to provide dental care to patients who
are obese?  Being overweight or obese is asso-
ciated with a number of important comorbid-
ities (eg, hypertension, cardiovascular disease).
In the absence of these comorbidities, it is safe
to provide dental services to overweight and
What should a dental practitioner tell a patient
about the association between oral infections
and obesity?  The relationship between oral
health and obesity is complex. Obesity may ad-
mouth will allow mastication of a full range of
foods and thereby a healthy diet. An important
message that can be delivered by oral health
care providers is that living a healthy lifestyle,
including not smoking, exercising, controlling
weight, and maintaining oral health, will de-
crease the risk of many chronic diseases.
125
5 Obesity, Metabolic Syndrome, and Oral Health
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Associations Between
Periodontal Disease and
Hyperglycemia/Diabetes
Wenche S. Borgnakke, dds, mph, phd
Robert J. Genco, dds, phd
Burden of Periodontal
Disease
Periodontitis is a dental plaque (biofilm)–initi-
ated, host-mediated disruption of the microbial
homeostasis (relatively stable equilibrium) that
in susceptible individuals manifests as destruc-
tion of soft and hard tissues surrounding the
teeth.1
There is a high burden of periodontal dis-
ease globally.2,3 While gingival bleeding was
found to be the most prevalent sign of disease
worldwide,2 severe periodontitis was the sixth
most prevalent condition in the world, not
only among the chronic conditions.3 Based on
World Health Organization (WHO) data, the
former report estimated 10% to 15% of adults
globally to have periodontal pockets at least
6 mm deep.2 This estimate is in accord with
findings from a systematic review of 72 studies,
which included 291,170 individuals aged 15
years in 37 countries, reporting the prevalence
of severe periodontitis to be 11.2%, which did
not change during the two decades from 1990
(95% confidence interval [CI]: 10.4%–11.9%)
to 2010 (95% CI: 10.4%–11.9%).3 Variations
in prevalence among countries were largely
attributed to socioenvironmental conditions
and behavioral risk markers as well as poor
oral hygiene and poor general health status
CHAPTER 6
of the populations studied, with greater lev-
els of periodontitis found among people with
diabetes.2,3
There is recent evidence for a much greater
burden of periodontitis—assessed more
accurately than in the past4—among dentate
adults in the United States than hitherto esti-
mated due to the first National Health and
Nutrition Examination Survey (NHANES)
protocol including periodontal probing at six
sites around all non–third molar teeth during
the NHANES cycles 2009 to 2014. The orig-
inal 2007 US Centers for Disease Control
and Prevention (CDC)/American Academy
of Periodontology (AAP) case definitions for
surveillance of periodontitis had only three cat-
egories, namely severe, moderate, and mild/no
periodontitis.5 In 2012, the mild/no group was
split in two; the definitions are displayed in
Table 6-1 and are referred to as the CDC/AAP
case definitions for surveillance of periodonti-
tis. They are increasingly considered the global
standard and were used in several studies.
Figure 6-1 shows the prevalence of peri-
odontitis in the 2009 to 2014 NHANES cycles,
covering all 6 years during which full-mouth
periodontal probing was conducted.7 Peri-
odontitis is categorized by the 2012 updated
CDC/AAP case definitions.6 Notably, the prev-
alence of mild and severe periodontitis does
not change drastically by age but remains less
135
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes

TABLE 6-1  |  Case definitions proposed for population-based surveillance of

periodontitis by the CDC/AAP*6
Case (category) Definition
Severe periodontitis > 2 interproximal sites with CAL > 6 mm (not on same tooth)
AND
> 1 interproximal site with PPD > 5 mm

Moderate periodontitis > 2 interproximal sites with CAL > 4 mm (not on same tooth)
OR
> 2 interproximal sites with PPD > 5 mm (not on same tooth)

Mild periodontitis > 2 interproximal sites with CAL > 3 mm

AND
> 2 interproximal sites with PPD > 4 mm (not on same tooth)
OR
1 site with PPD > 5 mm

No periodontitis No evidence of periodontitis

*Third molars excluded. CAL, clinical attachment loss; PPD, probing pocket depth.

80
Total PD Mild PD
70 Moderate PD Severe PD
60
Prevalence (%)

50
40
30
20
10
0
30 35 40 45 50 55 60 65 70 75 80
Age (y)

Fig 6-1  |  Prevalence of peri­odon­ti­tis (PD) by age among US dentate adults aged 30
6

years and older. Total PD includes mild, moderate, and severe cases.7

than or equal to 10% for mild and less than
or equal to 15% for severe, in contrast to the
moderate category, which drives the major-
ity of the prevalence increase by age of total
periodontitis (mild, moderate, or severe). The
10,683 NHANES participants who underwent
periodontal probing represent a weighted
population of approximately 143.8 million
noninstitutionalized US adults aged 30 years
and older.7 The overall prevalence of total peri-
odontitis of 42.2% included 7.8% with severe
periodontitis. The corresponding figures among
those with self-reported diabetes were 59.9%
and 10.8%, respectively.7 Almost 60% (59.9%)
of the dentate adults older than 65 years were
affected by total periodontitis, and 9.0% of
these cases were severe.7
Burden of Diabetes
Diabetes prevalence
Diabetes mellitus is a group of metabolic disor-
ders characterized by hyperglycemia that results
from defective insulin action or production

136

TABLE 6-2  |  Criteria for diagnosis of prediabetes and diabetes, respectively, by the American
Diabetes Association (2018)9
Prediabetes
Fasting plasma glucose (PG) 100–125 mg/dL (IFG)
or
2-h PG during 75-g oral 140–199 mg/dL (IGT)
glucose tolerance test or
A1C: 5.7–6.4%
A1C, glycated hemoglobin; fasting, no caloric intake for at least 8 hours; h, hours; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
or both. In the United States, 30.3 million or
9.4% of the entire population had diabetes in
2015, with 30.2 million being over 18 years
old, equivalent to 12.2% of US adults, includ-
ing one out of four adults aged 65 years and
older.8 Of these adults, 23.1 million were diag-
nosed, whereas almost one-quarter (23.8% or
7.2 million) were unaware of their condition.8
Overall, type 2 diabetes accounts for 90% to
95% of the cases. Type 1 or immune-mediated
diabetes, caused by autoimmune beta-cell
destruction and gestational diabetes (GDM)
diagnosed in the second or third trimester
of pregnancy constitute the majority of the
remaining cases.9 Other types of diabetes due
to other causes are rare, such as maturity-onset
diabetes of the young (MODY) and pancre-
atic disease– and drug- or chemical-induced
diabetes.9
Globally, the estimated number of adults
aged 20 to 79 years with diabetes has almost
tripled between the years 2000 and 2017,
from 151 million to 425 million. About 326.5
million of these are of working age (20 to 64
years old), and up to half (212.4 million) are
unaware of their condition.10 The continued
increase in the prevalence of diabetes is esti-
mated to reach 691 million by the year 2045.10
In 2017, the United States had the third-
highest number of adults aged 20 to 79 years
with diabetes globally—30.2 million—com-
pared with China’s 114.4 million and India’s
72.9 million. By 2045, these numbers are
expected to increase to 35.6 million, 134.3
Burden of Diabetes
Diabetes
5.6–6.9 mmol/L (IFG) > 126 mg/dL > 7.0 mmol/L
or or or
7.8–11.0 mmol/L (IGT) > 200 mg/dL > 11.1 mmol/L
or or or
39–47 mmol/mol > 6.5% > 48 mmol/mol
million, and 119.8 million, respectively.10
Population growth and aging, as well as urban-
ization resulting in changes in diet and exercise
habits, are likely to account for the majority of
this worldwide increase.
Additionally, one-third (33.9%) of US adults
(84.1 million) had prediabetes with elevated
blood glucose levels (hyperglycemia) that pre-
dispose to diabetes, with almost half of adults
aged 65 years and older being affected.8 Hyper-
glycemia affects about 16.2% or one in six
(21.3 million) of the 131.4 million pregnancies
worldwide, of which 86.4% of cases are due to
GDM.10 A large proportion of women experi-
encing GDM will eventually develop manifest
diabetes, as they are about 17 times more likely
to do so 3 to 6 years postpartum compared
with women without a history of GDM.11
In this chapter, we will use the term hyper-
glycemia to mean long-term elevated plasma
glucose levels, which represents all forms of
conditions and diseases such as prediabetes,
manifest types 1 and 2 diabetes, gestational
diabetes, and MODY.
Diabetes case definitions
The American Diabetes Association current-
ly classifies prediabetes and diabetes as shown
in Table 6-2, while stating that “Prediabe-
tes should not be viewed as a clinical entity
in its own right but rather as an increased
risk for diabetes and cardiovascular disease
(CVD)” and “Prediabetes is associated with
137
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
obesity (especially abdominal or visceral obe-
sity), dyslipidemia with high triglycerides and/
or low high-density lipoprotein (HDL) choles-
terol, and hypertension.”9
Diabetes complications
Diabetes complications are similar for any
type of diabetes because it is mainly hypergly-
cemia (especially of long duration) that leads
to the complications. Acute and chronic com-
plications include dehydration, poor wound
healing, stroke, myocardial infarction, criti-
cal limb ischemia, ketoacidosis, hyperosmolar
coma, kidney failure, retinopathy/blindness,
neuropathy, neurocognitive function/cognitive
decline, and serious infections possibly requir-
ing below-knee amputation.12
Diabetic retinopathy is the leading cause of
new cases of blindness among adults aged 20
to 74 years, and diabetic kidney disease is the
leading cause of kidney failure in the United
States.12 Of all cases of blindness, the propor-
tion that is due to diabetic retinopathy is rising,
with 1 of 39 cases globally being due to dia-
betic retinopathy.13 Overall, about one-third
of all people with diabetes have diabetic reti-
nopathy.10 Furthermore, about one-tenth (8%)
of individuals with newly diagnosed diabetes
have already developed diabetic neuropathy,
increasing to about 50% of those with diabe-
tes of long duration.14 Lastly, individuals with
diabetes are two to three times more likely to
have CVD and up to 10 times more likely to
have end-stage renal disease (ESRD).
People with diabetes with chronically poor
metabolic control experience morbidity, heart
disease, and stroke rates that are two to four
times higher than those in individuals without
diabetes15,16; subsequently, diabetes is found to
shorten life expectancy by 3.3 to 18.7 years
among US adults.17 Furthermore, pregnant
women with GDM are at high risk of trans-
generational effects in their offspring, such as
obesity,18 diabetes, hypertension, and kidney
disease.10
138
Diabetes costs
In parallel with the increasing prevalence of
diabetes, the economic burden of diabetes is
predicted to escalate, particularly among those
aged 70 years and older,10 with an estimated
global increase of USD 104 billion (B) between
2017 and 2045, with these costs estimated at
USD 727 B in 2017.10
In the United States, the overall cost of dia-
betes increased by about 25% from 2012 to
2017.19 An estimate for the total economic cost
of diabetes in the United States in 2017 was
USD 327 B, of which USD 237 B was attributed
to direct medical costs and the remaining USD
90 B to indirect costs, distributed among absen-
teeism (USD 3.3 B), presenteeism (reduced
productivity while at work, USD 26.9 B),
unemployment/long-term disability (USD
37.5 B), reduced productivity when not in the
workforce (USD 2.3 B), and premature mortal-
ity (USD 19.9 B).19 Diabetes greatly increases
annual health care costs.20 The average annual
medical expenditures among people with dia-
betes were 2.3 times higher than what would
be expected in the absence of diabetes in both
201221 and 2017,19 with the 2017 mean cost
increase of between $7,510 for those younger
than 18 years to greater than $13,000 for those
65 years of age and older.19 Similarly, lifetime
health care expenditures were estimated to be
between $8,946 and $159,380 greater in people
with diabetes, depending on demographic fac-
tors and degree of obesity.17 It is estimated that
the Veterans Administration could save up to $2
B a year via screening and early intervention.22
Links Between Periodontal
Disease and Hyperglycemia/
Diabetes
Unfortunately, there is general lack of aware-
ness of the links between diabetes and
periodontitis in spite of reports that a majority
 Links Between Periodontal Disease and Hyperglycemia/Diabetes
of adults with type 2 diabetes suffer from some
form of periodontitis.23 A considerable body of
evidence shows a close bidirectional associa-
tion between diabetes and periodontal disease.6
Evidence for these associations is reviewed in
this chapter along with its implications. While
most of the content regards chronic periodon-
titis, we use the term periodontal disease to
also include gingivitis when applicable. Howev-
er, periapical periodontitis is specified as such.
Other periodontitis types, such as early onset/
aggressive periodontitis, are not addressed in
this chapter due to their relatively low preva-
lence and scant evidence for their association
with diabetes.
Shared risk markers for
periodontitis and diabetes
With the current notion of inflammation being
considered the major mechanism underlying
the associations between periodontal disease
and hyperglycemia, these close links become
biologically plausible as both diseases lead to in-
flammation. As well, both the modifiable23 and
nonmodifiable24 risk markers for the two dis-
eases are largely identical, and they are shared
with other chronic diseases, such as athero-
sclerotic cardiovascular disease (ACVD). This
is why it is important to control for potential
confounders that can introduce bias in analyses
that seek to identify relationships—especially
potentially causal relationships—between cer-
tain markers that in reality are due to other
reasons than those analyzed.
In order to avoid any finite discussion or
determination of whether there is sufficient sci-
entific evidence for a given condition to indeed
be considered a true risk factor, defined as a
contributory cause of a condition in question,
the expression risk marker or simply marker
is used throughout this chapter to express the
notion of an indicator or predictor or determi-
nant or driver that could be a true risk factor
involved in the causal pathogenic pathway for
the disease in question.
Mechanisms linking diabetes and
periodontitis
Type 2 diabetes is characterized by a systemic
inflammatory process that leads to insulin re-
sistance and reduced pancreatic B-cell function
and apoptosis, both of which cause increas-
ing hyperglycemia. Periodontitis contributes
to systemic inflammation, which adversely
affects glycemic control in patients suffering
from diabetes. The elevated systemic inflam-
mation associated with periodontitis results
mainly from the entry of periodontal organisms
and their virulence factors into the system-
ic circulation. There is also strong evidence
that advanced glycation end products result-
ing from hyperglycemia lead to activation of
macrophages. Macrophages so activated then
produce inflammatory cytokines and reactive
oxygen species that increase the periodontal
soft and hard tissue destruction found in pa-
tients with diabetes24 (Fig 6-2).
The effects of hyperglycemia/diabetes on
periodontitis and of periodontitis on hyper-
glycemia/diabetes are likely based on them
both contributing to a hyperinflammatory
state, which may explain the bidirectional
relationship between periodontitis and dia-
betes.25 Hyperlipidemia is also suggested to
play an important role in this relationship,
as it is associated with an increase in both
diseases.26 Emerging evidence for the effect
of periodontitis on diabetes27,28 suggests that
periodontitis not only contributes to wors-
ened glycemic control but also is associated
with increased mortality and morbidity from
CVD and diabetic nephropathy.29–31 However,
a German study found no interaction between
periodontitis and diabetes and therefore sug-
gested that these two diseases are independent
risk factors for both all-cause and CVD-related
mortality.32 There is also emerging evidence
of a role for periodontitis in the develop-
ment of new cases of type 2 diabetes33,34 and
possibly GDM, although a 2016 systematic
review of the latter35 included only three small
case-control36–38 and five cross-sectional studies.
139
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes

Ligand RAGE
RAGE

Activation
Periodontal microbiota RAGE activation Nucleus

Exaggerated and
Impaired repair
sustained inflammation

Enhanced periodontal tissue breakdown

Fig 6-2  |  A “two-hit” model for the pathogenesis of accelerated periodontal destruction in patients with diabe-
tes mellitus. Bacterial challenge in an environment of enhanced RAGE expression, such as the periodontium of
an individual with diabetes mellitus, leads to exaggerated inflammation and impaired tissue repair, which in turn
cause accelerated and severe periodontal destruction.24 RAGE, receptor for advanced glycation end products.

Thus, prospective cohort studies are needed to Effects of hyperglycemia

ascertain any potential effect of periodontitis
on the development of GDM.
Evidence for the
Bidirectional Relationship
Between Periodontitis and
Diabetes
Diabetes and periodontal disease are complex
chronic diseases that affect each other and the
evidence for this bidirectional relationship has
been reviewed by several authors.24,39–43
Periodontitis
Poorly controlled diabetes is a risk marker for
periodontal disease. This has been known for
many years, but somehow the concept that sim-
ply “diabetes” without any quantifiers such as
“uncontrolled” or “poorly controlled” and “of
long duration” affects periodontal tissue has
been generally accepted. In 1993, Löe summa-
rized the scientific literature and concluded that
periodontitis should be regarded as the sixth
complication of diabetes.44
The effects of hyperglycemia on periodon-
tal tissues have been confirmed by several
studies of various designs, most importantly

140
 Evidence for the Bidirectional Relationship Between Periodontitis and Diabetes
prospective cohort studies that allow con-
clusions regarding the temporal sequence
and therefore of potential causation. That is,
hyperglycemia occurred before the periodontal
disease.
Longitudinal studies.  Elevated blood glucose
level and an increase in inflammatory mark-
ers were associated with periodontal disease
in a cohort of individuals with diabetes fol-
lowed for a period of 5 years.45 This 5-year
population study in Germany included 2,626
dentate men and women aged 20 to 81 years,
in which participants with uncontrolled type
1 or type 2 diabetes had both greater preva-
lence and greater progression of both probing
pocket depth (PPD) and clinical attachment
loss (CAL) compared to those with controlled
or no diabetes.45
Cross-sectional studies. Even though cross-
sectional studies cannot provide information
regarding the temporality of associated factors,
a few examples of large population studies
deserve mention.
The cross-sectional Study of Health in
Pomerania in northeastern Germany (SHIP)-
Trend that included 3,086 men and women
between the ages of 20 and 82 years reported
that whereas prediabetes (n = 576) and
well-controlled (glycated hemoglobin [A1c] <
7.0%) type 2 diabetes (n = 137) were not asso-
ciated with periodontitis, people with poorly
controlled (A1c > 7.0%) type 2 diabetes (n =
64) had greater mean CAL than normoglyce-
mic participants in the fully adjusted model.46
However, this association was weaker than
expected, and the association between poor
glycemic control and mean PPD was not sig-
nificant, possibly due in part to the low number
of participants having poorly controlled type
2 diabetes.
Analysis of the nationally representative
NHANES 2009 to 2012 data from 7,042
adults aged 30 years and older suggested a
dose-response relationship with a signifi-
cant increase of 18% in the odds of having
periodontitis5,6 for each 1-point increase in
mean A1c, hence regarding A1c as a linear pre-
dictor.47 Using the A1c cut-off values of 7.0%,
7.5%, 8.0%, 8.5%, and 9.0%, a distinctive,
statistically significant dose-response pattern in
the odds for having periodontitis in the groups
with A1c less than or greater than or equal to
the cut-off compared to the referent group
without diabetes was clearly demonstrated. For
instance, those with diabetes with A1c greater
than or equal to 7.0% had 33% greater odds
for periodontitis than the no-diabetes group;
those with A1c greater than or equal to 9.0%
had over two-fold (2.22) greater odds of having
periodontitis than people without diabetes.47
Using the same NHANES 2009 to 2012
data, similar patterns were reported for total,
severe, and nonsevere (moderate or mild) peri-
odontitis,5,6 respectively, even in people with
prediabetes who are at high risk of develop-
ing diabetes.48 Compared to those without
diabetes, the prevalence of total (mild, moder-
ate, or severe) periodontitis was 43% greater
in patients with prediabetes, 67% greater in
patients with controlled diabetes, and 72%
greater in patients with uncontrolled diabetes;
the corresponding figures for severe periodon-
titis were 66%, 112%, and 122%, respectively.
Such a dose-response relationship between
increasing fasting glucose levels in prediabetes
through diabetes and increasing prevalence of
periodontitis was also reported upon analyses
of data from 9,977 participants in the 2012–
2013 Korea National Health and Nutrition
Examination Survey (KNHANES).49
These and several other studies have docu-
mented the greater incidence (development of
new cases), prevalence, extent, and severity of
periodontal disease. The greater severity and
earlier onset of periodontitis in patients with
type 2 diabetes were clearly demonstrated in a
classic epidemiologic study of the Native Amer-
icans of the Gila River Indian Community in
Arizona.50 Even though results from studies
among this special population group may not
be directly generalizable to other populations,
they still serve to illustrate the concept.
141
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
Tooth eruption
In a cohort of 700 children aged between 6
and 14 years in Manhattan, half of whom had
diabetes (about 98% type 1 diabetes) with
18% very poorly controlled (A1c > 9.5%) and
38% of them being “overweight and at risk
for overweight,” children aged 10 to 14 years
with diabetes experienced early tooth eruption
compared to their peers without diabetes.51 Ex-
aminations of 4,876 children participating in
the NHANES 2009 to 2014 suggested that
overweight or obese children experienced 6
to 12 months accelerated eruption of the first
and second molars.52 Thus, even though the
study in Manhattan found only a weak associ-
ation between obesity and early tooth eruption,
obesity status may have contributed to the ob-
served finding.
Tooth loss
The ultimate outcome of untreated periodonti-
tis, namely loss of teeth, is greater in individuals
with hyperglycemia.53 An analysis of NHANES
2003 to 2004 data from 2,508 participants aged
50 years and older showed that people with di-
abetes had more missing teeth (9.8 versus 6.7
teeth) and were more than twice as likely to be
edentulous than those without diabetes upon
adjustment for other factors (adjusted odds
ratio [aOR]: 2.25; 95% CI: 1.19–4.21) with
28% versus 14% being edentulous.53 More
native Hawai’ians with diabetes had lost six
teeth or more compared to those without di-
abetes (OR: 1.64; 95% CI: 1.15–2.35)54; and
among 15,945 Hispanic Americans aged 18
to 74 years, those with uncontrolled diabe-
tes had a greater risk for missing nine teeth
than their normoglycemic counterparts, espe-
cially among the 18- to 44-year-olds, whereas
no such associations were detected in those
with well-controlled diabetes or prediabetes.55
Even though there is a global strong trend
toward loss of fewer teeth over time, as ex-
emplified in a study of NHANES data from
37,609 dentate adults aged 25 years and older
over the 40-year period from 1971 to 2012,
142
there still exists a two-fold difference in number
of missing teeth between those with and with-
out diabetes.56 During those four decades, the
number of missing teeth decreased from a mean
of 11.2 to 6.6 teeth missing in US adults with
diabetes versus 9.4 to 3.4 in the no-diabetes
group.
The finding of an association between tooth
loss and diabetes is not limited to the United
States. A German study showed greater tooth
loss over 5 years in both type 1 and type 2
diabetes when uncontrolled compared to the
groups with well-controlled or no diabetes.45 In
the SHIP-Trend study, participants with poorly
controlled type 2 diabetes had more missing
teeth than normoglycemic participants (OR:
2.19; 95% CI: 1.18–4.05).46 Among 24,313
middle-aged Germans, there was a clear inverse
relationship between decreasing number of
teeth present and increasing prevalence of
diabetes.57
Analyses using a French database with
533,378 people—including 27,305 individuals
with type 2 diabetes—concluded that compared
to people without diabetes, people with type
2 diabetes not only had greater loss of teeth
at all ages, but this loss also occurred at an
earlier age, peaking among 40- to 60-year-olds,
whereas the tooth loss steadily increased with
age in those without diabetes.58
Analyses of data from the KNHANES 2008
to 2012 study reported much greater tooth
loss among 2,078 adults with type 2 diabetes
compared to diabetes-free participants.59 More-
over, those with fewer teeth present were more
likely to also have diabetic retinopathy after
adjustment for potential confounders, includ-
ing age. For example, those with fewer than
20 natural teeth were 8.7 times more likely to
have diabetic retinopathy than those with at
least 28 teeth.
A small Japanese study reported that CVD
patients with co-occurring diabetes were miss-
ing significantly more teeth than CVD patients
without diabetes.60
This knowledge may assist dental care pro-
fessionals in suspecting possible undiagnosed
 Evidence for the Bidirectional Relationship Between Periodontitis and Diabetes
diabetes in their patients who are not aware of
their diabetes status. However, when assessing
studies of tooth loss, the impact of smoking
must always be considered. This is unfortu-
nately not always the case.
Effects of periodontitis on
glycemic control
Based on the available emerging evidence and
the underlying suggested mechanisms, it is
reasonable to suggest that periodontitis may
impact glycemic control and the incidence and
complications of diabetes. As an example of
microbiologic dysbiosis, Demmer et al found by
analyzing 1,188 subgingival plaque samples for
11 periodontal bacteria that greater abundance
of certain periodontal bacteria was associat-
ed with greater prevalence of prediabetes in
300 diabetes-free adults aged 20 to 55 years.61
It is especially important to know whether peri-
odontitis leads to elevation of blood glucose
levels in normoglycemic individuals and people
with prediabetes as they are principally those
who stand to benefit most from interventions
aimed at preventing the development of pre-
diabetes and its subsequent manifest diabetes.
There is evidence that periodontitis can
adversely affect glycemic control in persons
with diabetes, further supporting the bidirec-
tional relationship of the two diseases. This
evidence was summarized in a 2013 systematic
review of the evidence in which the direction
of the effect could be ascertained.27 An updated
systematic review in 2018 reached the same
conclusions.28 No prospective cohort studies
exploring the effect of periodontitis on predi-
abetes were identified by the two systematic
reviews,27,28 but more recent studies are reported
and mentioned in the following sections.
Longitudinal studies
A 2017 prospective cohort study among 1,331
initially diabetes-free men aged 58 to 72 years
in Northern Ireland who underwent baseline
clinical periodontal examinations followed the
participants for a mean of 7.8 years.62 Eighty
(6.0%) men developed type 2 diabetes, and
those with moderate/severe periodontitis5 at
baseline had almost 70% greater risk for de-
veloping diabetes compared to men with no/
mild periodontitis at baseline (hazard ratio
[HR]: 1.69; 95% CI: 1.06–2.69).62 Similar-
ly, a 2017 retrospective cohort study among
80 adults with type 2 diabetes reported that
a significant increase in A1c during the 3-year
study occurred both in those with severe peri-
odontitis at baseline as well as in participants
with CAL progression during the study.63 The
greatest increase in A1c level occurred in par-
ticipants with baseline severe periodontitis and
A1c less than 6.5% who actually had either pre-
diabetes or no diabetes, as per the current case
definitions.9
Nonetheless, a large, well-designed, and
well-executed population study concluded in
2017 that “Contrary to the currently available
literature, no convincing evidence was found of
any potential association between periodontitis
and diabetes incidence or HbA1c change.”64 This
was the result of an 11-year SHIP follow-up
study that included 2,034 German dentate
adults aged 20 to 81 years at baseline. A total
of 180 patients who were dentate and initially
diabetes-free developed diabetes during the
study. However, upon controlling for potential
confounders, importantly age and sex, neither
baseline CAL nor PPD were significantly associ-
ated with diabetes incidence or with long-term
changes in A1c levels. The authors list six poten-
tial limitations, none of which immediately
seem to indicate any strong bias that could lead
the reader to doubt these results. However, three
major circumstances need mention. First, as the
authors point out, periodontitis cases might
have been missed or misclassified by applying
the random half-mouth periodontal probing
at only four sites around each tooth. This is
because periodontitis manifests as a site-specific
breakdown of soft and hard periodontal tissues
that does not occur in any symmetric pattern
around any tooth, within an arch, or in the
143
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
entire dentition. Second, the general trend in the
region over the decade during which the study
was conducted was a decline in the number
of new cases of diabetes along with improved
glycemic control in people with existing diabe-
tes, possibly due to generally improved medical
care in this part of the former East Germany.
Third, the prevalence of severe periodontitis5,6
also seems to have decreased during these 11
years: “For example, among the 40-60 years old
participants, 25%, 31%, and 36% were catego-
rized as severe periodontitis in SHIP-0 at HbA1c
levels < 5.7%, 5.7% to 6.4%, and ≥ 6.5%,
respectively. The corresponding figures 10 years
later (SHIP-Trend) were 19%, 22%, and 25%,
respectively.”65 The latter two circumstances
are described in more detail elsewhere65 and
may be important in interpreting the findings.
However, it is not possible to know whether
following a full-mouth, six-sites-per-tooth peri-
odontal probing protocol and controlling for
both the improved diabetes prevalence and gly-
cemic control and for the decline in prevalence
of severe periodontitis5,6 might have produced
different results.
Effects of nonsurgical periodontal
treatment on glycemic control
It has long been generally accepted that acute
and chronic infections cause elevation of the
blood sugar levels as a normal part of the in-
flammatory response and thus adversely affect
glycemic control in patients with diabetes.66
Glycemic control typically improves once
such infections are resolved. A 2015 systematic
review concluded that nonsurgical periodontal
treatment can reduce the level of inflammatory
markers, such as C-reactive protein (CRP) and
tumor necrosis factor alpha (TNF-α).67 There-
fore, it is biologically reasonable to predict
that resolution of periodontal infections may
improve glycemic control in people with diabe-
tes. Several randomized controlled trials (RCTs)
have addressed the question of whether, and to
what extent, nonsurgical periodontal treatment
144
can improve glycemic control. Table 6-3 pro-
vides an overview of systematic reviews with
meta-analyses of such trials, mostly concluding
that nonsurgical treatment of periodontitis in
patients with diabetes can result in a modest
reduction of HbA1c of 0.2% to 0.4% at 3
months.
For type 2 diabetes at 3 to 4 months after
scaling and root planing (SRP), the decrease in
A1c level varies between 0.18%77 and 1.03%,74
while no review reports an A1c increase. Inter-
estingly, the smallest improvement was seen
with the use of adjunct antimicrobials.77 As also
concluded by a 2015 Cochrane review, SRP
without any adjunct antimicrobials seems to
lead to an A1c improvement of around 0.4%.77
This effect is of about the magnitude that could
be expected from adding a second anti-diabetic
oral medication to metformin.82
The largest RCT conducted so far involved
257 subjects with type 2 diabetes and 257 sub-
jects without diabetes at five centers.83 This study
failed to observe any improvement in A1c level
but attracted substantial critique, such as its fail-
ure to provide successful treatment that resulted
in acceptable periodontal health. At the end of
the 6-month study, a great proportion of the
participants had a periodontal health status suf-
ficiently poor to be eligible for inclusion into the
study. With 72.1% of the sites showing plaque
accumulation and 41.6% showing bleeding on
probing, and a mean of 15.7 sites with PPD
greater than or equal to 5 mm per participant,
affecting 10.2% of the probed sites, it is rea-
sonable to expect the residual inflammation to
continue to negatively impact the A1c. Hence, an
alternate conclusion would have been that due
to the failure to control the participants’ peri-
odontal inflammation, no conclusion could be
drawn regarding what the outcome would have
been with successful periodontal treatment to a
prespecified endpoint of periodontal health.84–87
Subsequently, several authors have reviewed
the systematic reviews to provide an overall
assessment of the integrated evidence.88–92 Such
overviews may be termed umbrella reviews.93
Most of these overviews of systematic reviews
 Evidence for the Bidirectional Relationship Between Periodontitis and Diabetes

TABLE 6-3  |  Effect of nonsurgical periodontal treatment on glycemic control in type 2 diabetes:
Meta-analyses in systematic reviews of RCTs published through April 6, 2018
No. of Pooled A1c
Author (year) RCTs N change %a 95% CI P value
Teeuw et al (2010)
68
3 (+ 2 CCTs) 180 –0.40 b
–0.77; –0.04 .03
Simpson et al69 (2010) 3 244 –0.40 –0.78; –0.01 .04
Sgolastra et al (2013)
70
5 315 –0.65 –0.88; –0.43 < .05
Engebretson and Kocher71 (2013) 9 775 –0.36 −0.54; −0.19 < .0001
Liew et al72 (2013) 6 422 –0.41 –0.73; –0.09 .013
Corbella et al73 (2013)
  6-month follow-up 3 235 –0.31 –0.74; 0.11 .15
Sun et al74 (2014) 10 587 –1.21 –1.68; –0.75 .000
  3-month follow-up 6 515 –1.03 –1.7; –0.31 .003
  6-month follow-up 3 150 –1.18 –1.64; –0.72 < .001
  9-month follow-up 1 72 –1.90 –2.2; –1.6 NA
Wang TF et al (2014)
75
3 143 –0.24 –0.62; 0.14 .217
Li et al76 (2015) 9 1,082 –0.27 –0.46; –0.07 .007
Simpson et al77 (2015)
  3–4-month follow-up SRP + AM 15 1,499 –0.29 –0.48; –0.10 .003
  3–4-month follow-up: SRP only 8 547 –0.41 –0.73; –0.08 .013
  3–4-month follow-up: SRP + AM 7 952 –0.18 –0.39; 0.03 .092

  6-month follow-up: SRP + AM 5 826 0.02 –0.20; 0.16 .84

  6-month follow-up: SRP only 3 263 –0.18 –0.58; 0.22 .38
  6-month follow-up: SRP + AM 2 563 0.02 –0.18; 0.22 .83
Teshome and Yitayeh78 (2016)
  3-month follow-up: SRP + AM 7 940 –0.48 –0.78; 0.18 .002
  At end of intervention 7 940 –0.53 –0.81; –0.24 < .001
  SRP plus AM/mouthwash 3 584 –0.51 –1.0; –0.03 .04
  SRP without AM/mouthwash 4 356 –0.53 –0.87; –0.19 .002
Studies with one study including type 1 DM each: (DM 1/DM 2)
Janket et al (2005)
79
1(+4 non-RCT) 268 (7/261) –0.66c –2.2; 0.9 NS
–0.71d –2.3; 0.9 NS
Darré et al80 (2008) 9 485 (53/432) –0.46b –0.82; –0.11 .01
Corbella et al (2013)
73

  3-month follow-up 15 678 (12/666) –0.38 –0.53; –0.23 .001

Wang et al (2014)
81

  3-month follow-up 10 1,135 (39/1,096) –0.36 –0.52; –0.19 < .001

  6-month follow-up 4 754 (39/715) –0.30 –0.69; 0.09 .13
a
percentage point = actual (absolute) difference (not relative difference); b standardized mean difference; c type 2 diabetes, except seven participants
with type 1 diabetes, without adjunct antibodies; d type 2 diabetes, except seven participants with type 1 diabetes, with adjunct antibiotics.
Bolded text: statistical significance (P < .05).
AM, antimicrobials; DM1, type 1 diabetes; DM2, type 2 diabetes; N, number of study participants; NA, not available; NS, not statistically significant;
SRP, scaling and root planing (“deep cleaning”).

145
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
and meta-analyses conclude that there is evi-
dence to suggest that nonsurgical periodontal
treatment can lead to a small decrease in A1c
but that the quality of the original RCTs vary
and their bias prevents any firm conclusion.
Further studies are clearly needed in various
patient groups, such as those who are resis-
tant to antidiabetic drug therapy and lifestyle
interventions and whose glycated hemoglobin
levels remain elevated. In addition, optimal
periodontal treatment aimed at reducing the
extent and severity of periodontitis is necessary
to establish whether and which treatments help
in affecting glycemic control. Most periodontal
intervention studies were undertaken for 3 to 6
months, but longer studies are needed.
Importantly, the group of adults aged 55
years and older has been largely ignored or
sparsely represented in intervention studies.94
The original target group for a 2017 review
was people 65 years old and older, but almost
no evidence was available, so the change to
a lower age limit was necessary.94 Yet it was
demonstrated that a combination of lifestyle
changes and dental care led to improved gly-
cemic control and periodontal health after 6
months in a small study of Thai adults aged
60 years and older with diabetes (n = 66 inter-
vention, n = 66 control).95 The few studies
available for review seem to suggest that older
individuals with diabetes might benefit from
nonsurgical periodontal therapy to decrease
blood levels of A1c.
If the potential effect on glycemic control is
reproducible and long term, nonsurgical peri-
odontal therapy could be considered a part of
the management of diabetes. This positive out-
come would be above and beyond the beneficial
effects of resolving periodontal infection to pre-
serve the dentition, which in turn would lead to
several desirable outcomes, among them better
nutrition, which would contribute indirectly
to diabetes control. Studies are also needed
to determine if the prevention or treatment
of periodontal disease and possibly other oral
infections can also reduce other complications
of diabetes, including CVD and nephropathy.
146
Screening for diabetes in the
dental office
Diabetes mellitus is a common metabolic disor-
der among patients who receive care in dental
practices. As previously discussed, periodontal
disease adversely affects metabolic control in
individuals with diabetes. Furthermore, tooth
loss from dental caries and periodontal disease
can lead to poor nutrition, compromising di-
etary efforts at glycemic control and weight loss
in individuals with diabetes. Hence, dental care
aimed at maintaining a healthy dentition free of
caries and with ideal periodontal health is nec-
essary for optimal care of patients with diabetes.
Knowledge of the glycemic status of dental
patients, especially those with periodontal dis-
ease and other oral manifestations of diabetes,
is important for their oral as well as overall
care. Uncontrolled diabetes is associated with
increased progression of periodontal disease.96
Early diagnosis of diabetes and stabilization
of glycemic control can reduce the risk of
complications. Furthermore, early detection
of prediabetes and intensive lifestyle changes
can reduce the incidence of type 2 diabetes.
Therefore, early diagnosis of diabetes and iden-
tification of patients at high risk for diabetes (ie,
those with prediabetes) are important for the
overall management of diabetes and especially
important for patients who are also seeking
dental care, including periodontal treatment
and dental implants. Patterns of health care
utilization suggest that many people obtain
routine, preventive dental care more often than
such medical care, so the dental office has been
proposed as a site for screening to identify risks
for undiagnosed systemic chronic diseases in
asymptomatic patients who are unaware of
their risks and have not paid a visit to their
medical care provider within a year.97
In a dental clinic population, prediabetes was
predicted in more than 90% of patients having
four or more missing teeth, periodontal probing
depths greater than or equal to 5 mm at about
25% of sites, and a capillary blood HbA1c level
greater than 5.7%.98 In a dental office field trial,
 Evidence for the Bidirectional Relationship Between Periodontitis and Diabetes
diabetes screening was carried out for 1,022
dental patients aged 45 years and older who
had no knowledge of their diabetes status.99
More than 40% of the 1,022 dental patients
had a capillary blood HbA1c level greater than
5.7%, defined as hyperglycemia (see Table 6-1),
and were therefore referred to a physician for
evaluation. Among the patients referred and
for whom a diagnosis was returned to the den-
tal office, 12% had diabetes and 23% were at
high risk for diabetes (had prediabetes). Hence,
there seems to be the potential for detection
of diabetes in one of eight—and for prediabe-
tes in about one of four—dental patients aged
45 years and older who are unaware of their
diabetes status.99 It should be mentioned that
about 80% of the dental patients were seen
in community health centers and about 20%
in private dental offices in Providence, Rhode
Island, or its vicinity.99 It should be noted that
HbA1c is a reliable measure for preclinical
screening for diabetes since it is also one of
the measures used in the diagnosis of diabetes
and is not changed by eating in the previous
12 hours as are random glucose measurements.
A similar study was conducted in 13 general
dental practices in southeast Michigan among
1,033 dental patients aged 30 years and older
who denied having diabetes. Almost one-third
(30%) of the 181 patients who were selected
based on their random capillary glucose lev-
els and periodontal health status actually had
hyperglycemia with 1.3% suffering from man-
ifest diabetes and 28.7% with prediabetes.100 It
turned out that patients at high risk for hyper-
glycemia could be identified based on only
the following self-reported information: age,
sex, hypertension, hypercholesterolemia, and
self-reported tooth loss, weight, and height, with
selection of those with body mass index (BMI)
greater than or equal to 35 kg/m2. The authors
concluded that random capillary glucose level
aided the identification but was not necessary.
Barriers to full implementation of HbA1c
screening for prediabetes and diabetes in dental
practices include cost, lack of insurance reim-
bursement, and, perhaps most importantly,
patient compliance with the referral to seek
a medical diagnosis. Many of these barriers
can likely be overcome in the future. Capillary
blood screening for A1c is a feasible, accurate
method of screening for diabetes and predia-
betes in a dental practice. The yield could be
improved by triaging patients based on prior
existing periodontal disease, missing teeth, and
their risk profile for diabetes.
Diabetes screening at clinical sites such as
dental offices and pharmacies could be of great
service because about one-quarter (23.8%) of
individuals with manifest diabetes are unaware
of their condition.8 Furthermore, about 90%
of those with prediabetes are unaware of their
condition, and a large percentage of individuals
with prediabetes are unaware of their high risk
for the development of diabetes. As previously
mentioned, early treatment of diabetes can lead
to better glycemic control with fewer medica-
tions and fewer complications. In addition,
lifestyle modifications including loss of 7% to
10% of weight and exercising 30 min/day for
5 days/week in patients with prediabetes can
prevent the onset of diabetes at least over a
3-year period.101 This is one of the few chronic
diseases for which a safe and effective regimen
has been developed to prevent its onset.
Of course, patients often may not comply
with lifestyle changes such as dietary changes
or exercise regimens on a long-term basis.
Dental professionals can help patients comply
with these regimens because dentists often see
these patients regularly; the dental team can
reinforce the need for lifestyle modification to
sustain diabetes prevention or management.
Due to the large proportion of individuals
with undiagnosed diabetes and because the vast
majority of type 2 diabetes cases—as well as
complications of all diabetes types—largely can
be prevented or ameliorated by early diagnosis,
intervention, and management, oral health care
professionals can contribute in meaningful ways
to this significant issue. Furthermore, potential
health benefits and improved quality of life, as
well as actual costs associated with dental office
screening for diabetes and interprofessional
147
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
management thereof, need to be rigorously
evaluated by well-designed randomized field
clinical trials under actual practice conditions.
Nutritional and dietary
consequences of tooth loss
Tooth loss, especially edentulism, can result in
difficulty in chewing, which leads to poorer nu-
trition, and in poor esthetics, a negative social
image, lower self-esteem, and an overall lower
quality of life.102 Periodontitis and severe den-
tal caries are the primary reasons for tooth loss
in adults.103 Factors such as low educational
level, low socioeconomic status, greater age,
poor access to care, lack of health insurance
coverage, and a history of smoking are risk
markers for tooth loss.
An association between tooth loss and
reduced consumption of important dietary con-
stituents, including fiber, fruits, and vegetables,
has been reported,104 and tooth loss was found
to independently predict a 30% lower intake of
both overall calories and protein, respectively,
in a study of 2,749 people with chronic kid-
ney disease participating in the 1988 to 1994
NHANES.105
In addition, tooth loss is associated with
a higher intake of refined sugars and satu-
rated fatty acids106 and with consumption
of decreased food variety,107 and it has been
shown to severely diminish the nutritional sta-
tus among elderly.108 A national study among
8,446 Finns followed for 13 years found the
missing of nine or more teeth to predict inci-
dent diabetes and even all-cause mortality.109
A review of the overall health and food
habits among older adults in Japan also sheds
light on the relationship between tooth loss
and diet.110 A program has been in existence
since 1991 to increase the number of individ-
uals who reach the age of 80 years with 20
teeth (the “80/20” program). The percentage of
80/20 achievers increased from 10.9% in 1993
to 24.1% in 2005. Those who had retained
20 teeth at 80 years old consumed fewer total
148
calories and lower levels of carbohydrates.110
The change in the diet likely resulted in part
from greater retention of teeth, and this is likely
to be associated with better overall health.
A study of largely older African American
and American Indian adult populations showed
that participants with fewer than 10 teeth con-
sumed less fruit, meat, beans, and oils. They
also derived more energy from solid fat, alco-
hol, and added sugar than did individuals with
11 or more teeth. Nutritional intervention for
older individuals should certainly consider the
effects of tooth loss on dietary patterns, espe-
cially in patients with diabetes.111
Overall, it is likely that the impact of peri-
odontitis on diabetes is in part related to the
altered diet associated with tooth loss. There-
fore, oral health care professionals should
highlight to patients the importance of main-
taining oral health with an emphasis on the
ability to eat any and all types of foods.
Other oral manifestations of
hyperglycemia
Complaints of xerostomia (subjective feeling
of dry mouth) may be associated with thirst,
which is a common complaint among patients
with diabetes. Xerostomia may also result
from sensory nerve dysfunction as a neurologic
complication of diabetes that can lead to hypo­
salivation (objective measure of decreased saliva
secretion).112 Dry mouth may also be caused by
medications. If medications are determined to
be the cause of the xerostomia, the oral health
care professional should consider consulting
with the patient’s physician who then could
change the medication or alter the dose, fre-
quency, or timing, which may provide relief for
the patient. If this is not feasible, patients may
benefit from the use of sugar-free gum or candy
as well as non–alcohol-containing mouthrinses
or saliva substitutes.
Diabetic neuropathy may moreover manifest
in the oral cavity as a burning sensation in the
mouth, which in turn may impede proper oral
 Evidence for the Bidirectional Relationship Between Periodontitis and Diabetes
Fig 6-3 |  Proportion of US adults
who had a dental visit in the past year
by diabetes status.114
Percentage
hygiene. The treatment protocols for xerosto-
mia are sometimes effective in reducing this
burning sensation. Diabetic neuropathy can
also result in taste impairment in patients
with diabetes.112 This dysfunction can seriously
affect the patient’s ability to maintain a proper
diet, which is central to glycemic control. The
management of diabetic neuropathy may
improve taste sensation. However, such treat-
ment is often ineffective. In any case, patients
with altered taste sensation should be made
aware that this is a side effect of diabetes and
that they should make efforts to consume a diet
recommended to maintain healthy blood sugar
levels, as well as control their weight while cop-
ing with the altered taste sensation.
Referral for dental examination by
medical care providers
The American Diabetes Association (ADA)
recognizes periodontal disease as a diabetes
comorbidity and recommends that patients
with diabetes be referred for dental exam-
ination, preventive care, and any treatment
as needed.113 Subscribing to the chronic care
model, it is stated in the ADA’s 2018 standards
of medical care in diabetes that dentists may
participate with physicians, nurse practitioners,
physician assistants, nurses, dietitians, exercise
specialists, pharmacists, podiatrists, and men-
tal health professionals in the patient-centered
interprofessional approach with active partici-
pation also by the patient with family or other
74–
72–
70–
68–
66–
64–
62– Diabetes
60– Prediabetes
58– No diabetes
56–
2004 2006 2008 2010 2012 2014
Year
support persons.113 Referral to a “dentist for
comprehensive dental and periodontal exam-
ination” is explicitly recommended as part of
the initial diabetes care management.113 As
well, the association recognizes that periodon-
titis is more severe in people with diabetes and
that periodontal infection is suggested to ad-
versely impact diabetes outcomes but that the
evidence for the effect of nonsurgical periodon-
tal treatment is inconclusive.113
Mutual referral by dental and medical profes-
sionals could contribute to overall health, which
includes both oral/dental and systemic health.
People with diabetes in the United States have
been known for many years to visit dentists
much less frequently than their diabetes-free
counterparts. A 2018 study illustrates this sit-
uation with analyses of data collected from
2004 to 2014 as part of the Behavioral Risk
Factor Surveillance System (BRFSS) conducted
via telephone surveys by the CDC in collabora-
tion with all states.114 The prevalence of diabetes
among the respondents increased significantly
from 6.7% in 2004 to 10.1% in 2014. The cor-
responding increase was from 0.8% to 1.5%
for prediabetes. Figure 6-3 illustrates the pro-
portion of US adults with a dental visit the year
preceding the interview by their self-reported
diabetes status.114 Not only is the proportion
of dental visits for people with known diabetes
much lower than among those without diabetes,
but this is also the case for people with predi-
abetes. Importantly, these data show declining
trends of having had a dental visit over the
decade, namely from 71.9% to 66.5% for
149
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
diabetes-free participants versus from 66.1%
to 61.4% for those with diabetes. It should be
kept in mind that an estimated quarter (23.8%)
of those with diabetes8 and almost 9 out of 10
(89%) of those with prediabetes115 are unaware
of their hyperglycemic state and hence are
unable to report belonging to those categories.
The association between dental visits, periodon-
titis, and diabetes may also be a reflection of an
individual’s overall health behavior.
A 2016 study that used nationally repre-
sentative data from the 2008–2012 Medical
Expenditure Panel Survey found that less than
half of subjects had a dental visit the preceding
year with great disparities by citizenship, as
only 43.6% of US-born citizens, 39.5% natu-
ralized citizens, and 23.1% of noncitizens had
at least one dental visit.116 Even though different
national US surveys report sizeable differences
in proportion of adults with dental visits in the
previous year, their trends over several years
tend to be comparable.117 The NHANES 2015
data indicate that 64.0% of adults aged 18 to 64
years and 62.7% of seniors aged 65 years and
older had dental visits.118 With an even smaller
percentage of people with diabetes having den-
tal visits and considering the potential of good
oral health to improve general health as well as
the diminished quality of life, including lower
self-esteem, caused by poor oral health, this is a
regrettable situation on which combined efforts
and initiatives by all health care professionals
potentially could have a positive impact.
A 2016 study used a sample of participants
of the Medicare Current Beneficiary Survey and
found an increase in the proportion of people
with diabetes who had preventive dental visits
in 2011 compared to 2002, namely from 28.8%
to 36.0%; this increase was comparable to that
among participants without diabetes, from
52.9% to 45.5%.119 However, the prevalence
of preventive visits in participants with diabetes
was still much lower than among their counter-
parts without the disease, leading the authors
to the following conclusion: “Additional efforts
are needed to encourage people with diabetes
to obtain preventive dental care.”119
150
Interprofessional
Collaboration
Clinical pathway programs have been devel-
oped to share medical and dental information
to provide optimal care for patients with dia-
betes who seek periodontal care.120 By linking
patients’ medical and dental records, it has
been shown that coordinated treatment plan-
ning can be carried out by physicians and
dentists and that outcomes are improved when
treatment is coordinated for those patients with
both diabetes and dental disease.
In another study, medical conditions asso-
ciated with dental conditions, including
periodontitis, were discovered using linked
electronic records from 2,475 patients under-
going dental treatment in a dental school
and medical treatment in the same university
hospital.121 Diabetes mellitus types 1 and 2,
hypertension, hypercholesterolemia, hyper-
lipidemia, and conditions related to adverse
pregnancy outcomes were associated with
periodontitis. For effective comanagement of
patients who attend both dental school clinics
and their related medical colleges for treatment,
it is important that specific patients who suffer
from these dental and medical conditions be
identified. This would allow treatment plans
and management to be coordinated to promote
better overall health in patients. Another study
conducted at a dental school among 2,370
patients found such dental electronic health
records helpful for education, treatment plan-
ning, and disease management.122
As previously mentioned, most risk markers
are common to periodontitis and diabetes, as
well as other chronic diseases, including CVD
and cancer. Therefore, modification of these
risk markers by both the dental and medi-
cal teams in collaboration with their mutual
patients, working in a coordinated fashion,
has great potential to provide major benefits to
society in reducing the morbidity and mortality
associated with these prevalent chronic diseases
as well as the risk for periodontal disease. In

the chronic care model, collaboration by
physicians, dentists, and other health care pro-
fessionals can be carried out to achieve better
clinical outcomes for patients. These practice
models have the potential to offer great benefits.
Effective patient communication and patient
cooperation are essential for success. Lalla et al
provided valuable, more detailed information
regarding dental and medical comanagement
of patients with diabetes elsewhere.123 These
researchers collaborated with local research-
ers to recalibrate their original findings made
in a study among a predominantly Hispanic
population living in Manhattan to a Caucasian
population in rural Wisconsin; they concluded
that the accuracy of predicting prediabetes and
diabetes increases when incorporating dental
findings with the medical information con-
tained in an electronic health record.124 Forty
statewide providers participated in a study to
further explore various collaborations and con-
cluded that “cross-disciplinary integrated care
delivery (ICD) models that bridge the tradition-
ally siloed health care domains of dentistry and
medicine,” aided by mutual access to health
records, supported improved screening and
referral implementation.125 Interprofessional
patient management may be optimally carried
out in a chronic care model or in a health home
model, but with some effort it is also likely
to be successful in more traditional practice
settings.125–131
Cost savings
Dental care providers not only contribute to
improvement of their patients’ general health
by screening for diabetes and other chronic
diseases and referring them for further exam-
ination and treatment as needed. Short-term
savings in cost of health care were estimated
at between $42.4 million and $102.6 million
for medical screenings for diabetes, hyperten-
sion, and hypercholesterolemia in the dental
office.132
There is evidence that periodontal treatment
may also lead to cost savings for health care in
Interprofessional Collaboration
people with type 2 diabetes. Analyses of inte-
grated claims data from 15,002 insureds aged
18 to 64 years with newly diagnosed type 2
diabetes from a commercial insurance com-
pany for dental, medical, and pharmacy care
showed that periodontal treatment during the
first two years after a diabetes diagnosis was
linked to savings in the two following years
(third to fourth year after diagnosis) of $1,799
for all health care, $1,577 for medical care, and
$408 for diabetes care, respectively.133
Compared to 10 other high-income coun-
tries, the United States spends the greatest
proportion of its gross domestic product,
namely almost one-fifth (17.8%) on health
care, compared to between 9.6% (Australia)
and 12.4% (Switzerland) in the other coun-
tries,134 and the United States has the greatest
proportion of overweight or obesity (70.1%)134
that is linked to type 2 diabetes. Therefore, it
should be possible to institute savings on medi-
cal care, and even small cost savings per patient
receiving medical care related to diabetes and
its complications will add up to large amounts
at the population basis. Oral health care pro-
fessionals might be able to contribute to such
financial savings.
Guidelines regarding periodontal
disease for medical and dental
care providers and patients with or
at risk for diabetes
Upon review of the scientific evidence, the con-
sensus of a group of dental experts in 2012
was that it is appropriate to provide guide-
lines for periodontal care in patients with
diabetes.41 These guidelines were reviewed
and updated in 2017 by another group of
dental experts from the European Federa-
tion of Periodontology and medical experts
from the International Diabetes Federation
who again found scientific evidence to sup-
port recommendations for medical and dental
professionals as well as their patients.135 These
updated guidelines are displayed in Boxes 6-1
151
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes

Box 6-1  |  Guidelines for physicians and other medical professionals for use in diabetes practice

Because of the increased risk for development of periodontitis in patients with diabetes, the following recommen-
dations are made:
• Oral health education should be provided to all patients with diabetes as part of their overall educational program.
• Patients with all forms of diabetes mellitus should be told that periodontal disease risk is increased and, if untreated,
the periodontitis has a negative impact on metabolic control and may also increase the risk of complications of
their diabetes such as cardiovascular and kidney disease.
• Patients should be advised that successful periodontal therapy may have a positive impact on their metabolic
control and diabetes complications.
• For people with diabetes, physicians should ask about a prior diagnosis of periodontal disease. If a positive diagnosis
has been made, the physician should seek to ascertain that periodontal care and maintenance are being provided.
• Investigating the presence of periodontal disease should be an integral part of a diabetes care visit. People
with diabetes should be asked about any signs and symptoms of periodontitis, including bleeding gums during
brushing or eating, loose teeth, spacing or spreading of the teeth, oral malodor and/or abscesses in the gums,
or gingival suppuration.
–– If a positive history is elicited, then a prompt periodontal evaluation should be recommended before the patient’s
scheduled annual checkup.
–– In the case of a negative history, people with diabetes should be advised to check for the above symptoms,
and if a positive sign appears, they should visit their dentist.
• For all people with newly diagnosed diabetes mellitus, referral for a periodontal examination should occur as
part of their ongoing management of diabetes. Even if no periodontitis is diagnosed initially, annual periodontal
review is recommended.
• For children and adolescents diagnosed with diabetes, annual oral screening is recommended through referral
to a dental professional.
• Patients with diabetes who have extensive tooth loss should be encouraged to pursue dental rehabilitation to
restore adequate mastication for proper nutrition.
• Patients with diabetes should be advised that other oral conditions such as dry mouth and burning mouth may
occur, and if so, they should seek advice from their dental practitioner. Also, patients with diabetes are at increased
risk of oral fungal infections and experience poorer wound healing than those who do not have diabetes.
• The physician should liaise with the dentist over diabetes management prior to the oral intervention and/or surgery
to avoid hypoglycemia and to consider its potential impact on the patient’s ability to eat.a,b

a The above guidelines also apply to people with prediabetes and metabolic syndrome.
b
These guidelines are modified from Chapple and Genco41 and also draw from http://www.aemmedi.it/files/Linee-guida_Raccomandazioni/2015/
Diabete%20e%20Parodontite_AMD_SID_SiDP.pdf
(Reproduced from Sanz et al.135)

to 6-4.135 Box 6-3 has been slightly modified
with further updated and expanded web ad-
dresses for the patient-friendly test described
in Box 6-3 and illustrated in Fig 6-4.135,136 The
2018 ADA professional criteria for testing
for diabetes and prediabetes in asymptomatic
adults9 is summarized as follows: Overweight
or obese patients (BMI > 25 kg/m2 or BMI >
23 kg/m2 for Asian Americans) should be con-
sidered for testing if they have at least one of
the following risk factors: a first-degree relative
who has diabetes, a high-risk race/ethnicity (eg,
African American, Hispanic, Native American,
Asian American, Pacific Islander), a history of
CVD, hypertension (blood pressure ≥ 140/90
mmHg) or therapy for hypertension, hypercho-
lesterolemia (HDL cholesterol level < 35 mg/
dL [0.90 mmol/L]), hypertriglyceridemia (tri-
glyceride level > 250 mg/dL [2.82 mmol/L]),
polycystic ovary syndrome, physical inactivity,

152
 Conclusion

Box 6-2  |  Guidelines for patients with diabetes at the physician’s practice/office

Why should I have my gums checked?

If your physician has told you that you have diabetes, you should make an appointment with a dentist to have your
mouth and gums checked. This is because people with diabetes have a higher chance of getting gum disease. Gum
disease can lead to tooth loss and may make your diabetes harder to control. The earlier you seek help, the better
the outcome will be.
What should I look for that may tell me I have problems with my gums?
You may have gum disease if you have ever noticed:
• Red or swollen gums
• Bleeding from your gums or blood in the sink after you brush your teeth
• Foul taste
• Longer-looking teeth
• Loose teeth
• Increasing spaces between your teeth
• Calculus (tartar) on your teeth
If you have noticed any of these problems, it is important to see a dentist as soon as possible.
Can I have gum disease without these signs being present?
Gum disease may also be present and get worse with no apparent signs to you, especially if you smoke, so even if
you do not think you have gum disease now, you should still have annual dental checkups as part of managing your
diabetes. Your dentist will be able to pick up early signs of gum disease.
What can I do to prevent gum disease?
You need to clean your teeth and gums twice daily at home for a minimum of 2 minutes. Also, cleaning between your
teeth daily is important, and your dentist will show you how to do this. You should visit a dentist as soon as possible
for a diagnosis and advice on what you need to do. It is important to keep your mouth as healthy as possible with
regular dental care, according to the recommendations of your dentist.
What other problems with my mouth should I be looking for?
If you have diabetes, you may also suffer from dry mouth, burning mouth, or poor healing of mouth wounds.

(Reproduced from Sanz et al.135)

or other clinical conditions associated with Conclusion

insulin resistance. Patients with prediabetes
(HbA1c ≥ 5.7% [39 mmol/mol], impaired glu-
cose tolerance, or impaired fasting glucose)
should be tested every year and women with
GDM should be tested every 3 years. All other
patients should be tested starting at age 45. Pa-
tients with normal test results should be tested
at least every 3 years, but more frequent testing
should be considered based on initial results
and risk status.
Diabetes and periodontitis are common, seri-
ous conditions that are linked in a two-way
mutually adverse association. The prevalence
and incidence of periodontal disease are greater
in patients with diabetes; periodontitis and its
local and systemic inflammatory responses can
adversely affect glycemic control in people with
diabetes or at risk for diabetes. Their adverse
reciprocal effects are likely based on them both
contributing to a hyperinflammatory state.

153
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes

Box 6-3  |  Guidelines for oral health professionals for use in the dental practice/office for people with
diabetes mellitus

• People with diabetes should be advised that they have an increased risk for gingivitis and periodontitis. They should
also be told that if they suffer from periodontitis, their glycemic control may be more difficult to achieve, and they
are at higher risk of other complications such as eye, kidney, and cardiovascular diseases.
• Collect a careful history to highlight the type of diabetes, the duration of the disease, the presence of any
complications, and any diabetes therapy and concomitant therapies, remembering that most people with diabetes
are also being treated with anticoagulant/antiplatelet drugs, antihypertensive drugs or lipid-lowering medications.
• Ask patients how well controlled their diabetes is and when they last had their blood glucose levels checked.
Request that patients bring a copy of their last HbA1c result or that they report their latest results.
• Oral health education should be provided to all patients with diabetes. This should include individualized advice
on relevant risk factors and a tailored oral hygiene regimen, including twice-daily brushing, interdental cleaning,
and, in some cases, the use of adjunctive chemical plaque control.
• People presenting with a diagnosis of any form of diabetes mellitus should receive a thorough oral examination,
which includes a comprehensive periodontal evaluation with full-mouth pocket chart and bleeding scores.
• If no periodontitis is diagnosed initially, patients with diabetes should be placed on a preventive care regimen and
monitored regularly for periodontal changes.
• People with diabetes presenting with any acute oral/periodontal infections require prompt oral/periodontal care.
If periodontitis is diagnosed, it should be managed without delay.
• Irrespective of the level of diabetes control, nonsurgical periodontal therapy should be provided, as this may help
to improve glycemic control.
• Surgical periodontal and implant therapy is not indicated in patients who do not have acceptable diabetes control.
In well-controlled patients, the results of surgical interventions are equivalent to patients without diabetes. However,
attention should be paid to the following:
–– People with poorly controlled diabetes, who have an increased risk of postoperative infections
–– Patients managed with insulin or sulfonylureas, when the physician should be consulted about the timing of the
planned procedure and a possible change in dosage of therapy to reduce the risk of intraoperative hypoglycemia
• People with diabetes who have extensive tooth loss should be encouraged to pursue dental rehabilitation to restore
adequate mastication for proper nutrition.
• People with diabetes should also be evaluated for other potential oral complications, including dry mouth, burning
mouth, Candida infections, and dental caries.
• For children and adolescents diagnosed with diabetes, an annual oral screening for early signs of periodontal
involvement and dental caries is recommended starting as early as possible.
• Patients who present in the dental surgery/office without a diagnosis of diabetes but with risk factors for type
2 diabetes should be informed about their risk for having diabetes and referred to a physician for appropriate
diagnostic testing and follow-up care:
–– Patients’ risk may be screened for using a validated questionnaire: eg, in a Caucasian population, FindRisk
Questionnaire; https://www.idf.org/type-2-diabetes-risk-assessment/; http://www.diabetes.org/are-you-at-
risk/diabetes-risk-test/ (USA, ADA online test); http://main.diabetes.org/dorg/PDFs/risk-test-paper-version.pdf
(USA, ADA print version); https://www.diabetes.fi/files/502/eRiskitestilomake.pdf (Original FINDRISC, Finnish
Diabetes Association) (see Fig 6-4).136
–– Oral health professionals with a special interest in diabetes may wish to consider screening based on the
recommendations of the American Diabetes Association.9
–– If symptomatic (polydipsia, polyuria, polyphagia, unexplained weight loss), refer directly to a physician.

(Reproduced from Sanz et al.135)

154
 Conclusion

Box 6-4  |  Guidelines for patients at the dental surgery/office who have diabetes or are found to be at risk of
diabetes

• People with diabetes have a higher chance of getting gum disease.

• You may think that you are doing well managing your gum health, but you may not be doing enough because you
have an increased risk of gum problems.
• Like diabetes, gum disease is a chronic condition and requires lifelong attention and professional care.
• You also need to clean your teeth and gums very carefully at home. Personalized advice will be provided by your
dentist. This may include the following:
–– Twice-daily brushing with either a manual or electric toothbrush
–– Cleaning between your teeth using interdental brushes where they fit; where they do not fit, flossing may be
useful
–– The use of specific dentifrices and/or mouthrinses with proven activity against dental plaque, if advised by
your dentist
• If left untreated, gum disease can lead to tooth loss and may also make your diabetes harder to control.
• Gum disease may be present and get worse with no apparent symptoms to you, so if your dentist told you that
you do not have gum disease now, you should still get regular dental checkups as part of managing your diabetes.
Your dentist will be able to pick up early signs of gum disease.
• You may have gum disease if you have ever noticed:
–– Red or swollen gums
–– Bleeding from your gums or blood in the sink after you brush your teeth
–– Foul taste
–– Longer-looking teeth
–– Loose teeth
–– Increasing spaces between your teeth
–– Calculus (tartar) on your teeth
• People with diabetes may also suffer from dry mouth, burning mouth, yeast infections of the mouth, or poor
healing of mouth wounds.
• Remember to inform your dentist about the outcome of your visits to your doctor and provide an update of the
results of your diabetes control and changes in medications.
• It is important to keep your mouth and your whole body as healthy as possible with regular dental and medical care.

(Reproduced from Sanz et al.135)

Dental management of patients with diabe-
tes requires knowledge of the patient’s diabetic
status, including metabolic control and medica-
tions, and comorbidities. It is advised that oral
health care professionals coordinate the care of
a patient with poorly controlled diabetes with
the patient’s physician. Such patients should be
routinely assessed for periodontal involvement
as well as other oral complications of diabe-
tes, including xerostomia, Candida infections,
and intraoral burning sensations. Oral health
care professionals should be aware of any
antidiabetic medications patients are taking
and ensure that their blood glucose levels are
adequate before undertaking dental procedures
to prevent hypoglycemic episodes in the dental
office.
Likewise, dental patients who have peri-
odontal disease and exhibit additional risk
markers for diabetes, such as obesity, should be
made aware of the relationship between these
two diseases and referred to their physician for
assessment of their diabetic status.
Early identification and early treatment of
prediabetes and diabetes have many benefits
for the patient in terms of improved health
and reduced risk of diabetes complications.
Involvement of oral health care professionals

155
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes

Fig 6-4 |  FINDRISC questionnaire for assessing risk for type 2 diabetes. (Based on Lindström and
Tuomilehto.136 Design by Jaakko Tuomilehto, Department of Public Health, University of Helsinki, and
Jaana Lindström, National Public Health Institute, Finland.)

156
 Conclusion

Fig 6-4  (cont) Reverse side of FINDRISC form.

157
6 Associations Between Periodontal Disease and Hyperglycemia/Diabetes
Clinical Considerations: What You Can Take Back to Your Practice
What is the effect of diabetes on oral health,
and what is the effect of oral health on glycemic
control?  Hyperglycemia (abnormally high lev-
els of blood glucose) is not merely a diagnosis
of diabetes but affects oral health by increasing
the risk for periodontal disease and ultimately
tooth loss. This in turn can result in poor nutri-
tion, as well as decreased psychosocial status.
Hyperglycemia can also lead to hyposalivation
and a burning sensation in the mouth. In the
other direction, periodontitis can adversely af-
fect glycemic control.
Is periodontal disease an independent risk
marker for the development or progression of
diabetes?  Emerging evidence suggests that es-
pecially severe periodontitis represents a risk
marker for the development of type 2 diabe-
tes and for the progression of existing type 2
diabetes.
What is the biologic plausibility of the associ-
ation between oral health and diabetes?  The
bidirectional relationship between diabetes and
periodontal disease is most likely related to the
increased level of systemic inflammation that
each disease causes. These elevated systemic
inflammatory responses result in insulin resis-
tance, poor glycemic control, and aggravated
destruction of periodontal soft and hard tis-
sues. Importantly, the hyperglycemia is the de-
ciding factor affecting periodontal tissues, not
simply a diagnosis of diabetes.
Does the delivery of periodontal care contri­­-
bute to improvement of glycemic control?  There
is evidence that provision of successful nonsur-
in screening for potential hyperglycemia
could have a beneficial effect. Furthermore,
the use of common electronic health records
and interprofessional, patient-centered coor-
dinated treatment planning and management
of the common risk markers among dentists,
158
gical periodontal treatment can reduce the level
of glycated hemoglobin, especially when signif-
icant periodontitis is present in patients with
poorly controlled type 2 diabetes. Moreover,
extraction of terminally periodontally diseased
teeth decreases the glycated hemoglobin level
and thereby improves glycemic control.
Is it safe to provide dental care to patients with
diabetes?  It is safe to provide dental care to
patients with diabetes. It is actually very im-
portant to deliver such care because there is
evidence that poor oral health and tooth loss
can affect diet and result in nutritional inad-
equacies that can contribute to poor glycemic
control.
What is the appropriate message to give to
the public about the association between oral
health and diabetes?  Diabetes, especially if
poorly controlled, is an important risk mark-
er for periodontal disease. Overall, the degree
of tooth loss in adult patients with diabetes is
twice that in normoglycemic individuals, and
this loss often leads to limitation of the range
of foods that can be properly chewed. In turn,
poor nutrition may result, which can make di-
etary control of diabetes more difficult. People
with diabetes—especially if poorly controlled
and of long duration—can also suffer from xe-
rostomia or hyposalivation and a burning sen-
sation in the mouth and are more susceptible
to fungal infections. In the opposite direction,
periodontal inflammation can negatively affect
glycemic control. However, nonsurgical peri-
odontal therapy can improve glycemic control.
physicians, pharmacists, nurses, and other
health care professionals is likely to improve
the overall health of patients with diabetes and
periodontitis and thus the overall quality of life
of these patients.

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163

The Cardiovascular System
and Oral Infections
Maurizio S. Tonetti, dmd, phd, mmsc
Filippo Graziani, dds, mclindent, phd
The hypothesis that oral infections may con-
tribute to atherosclerosis was formulated
in the mid-1980s by a group of Finnish
cardiologists.1 It is relevant to attempt an
understanding of the rationale for this line of
research. Groundbreaking epidemiologic stud-
ies had identified the classic risk factors for
atherosclerosis, but cardiologists were faced
with the clinical dilemma that only one in
two heart attacks could be explained by the
classic set of risk factors: hypertension, dyslip-
idemia, diabetes, and smoking. Research was
needed to identify mechanisms that explained
a significant portion of the burden of disease
and, more importantly, to find ways to pre-
vent it. An interesting hypothesis that chronic
infection (and later chronic inflammation)
may contribute to the atherosclerotic process
was formulated. In this broader context, and
given the obvious high prevalence of chronic
oral infections, early associations were sought
between the presence of oral infections and
cardiovascular events: Subjects with acute
cardiovascular events seemed to have poorer
oral health than control subjects. The field was
born.
At the turn of the 21st century, an impres-
sive collection of scientific evidence stood in
support of the hypothesis that chronic infec-
tions were among the major contributors to
atherosclerosis and its sequelae. The validity
164
CHAPTER 7
of this hypothesis was confirmed by studies
indicating that individuals exposed to chronic
infections have two to three times greater odds
of having carotid atherosclerosis.2 Chronic
obstructive pulmonary disease with infectious
exacerbations, chronic bronchitis, chronic
sinusitis, and chronic or recurrent urinary tract
infections—as well as an amorphous group
of other infections—were all associated with
higher odds of carotid atherosclerosis. Patho-
gens sustaining these chronic infections were
considered either to have a direct effect on the
vasculature or to act as a source of systemic
inflammation that in turn would trigger the
atherosclerotic process. Indeed, epidemiologic
studies linking systemic inflammation, athero-
sclerosis, and cardiovascular events have shown
consistent associations between levels of sys-
temic inflammatory markers and increases in
carotid intima-media thickness, myocardial
infarction, and nonhemorrhagic stroke.
The infection hypothesis was tested with
clinical randomized controlled trials (RCTs)
aimed at preventing cardiovascular events with
the use of long-acting broad-spectrum antibiot-
ics such as azithromycin. Early reports showed
encouraging results, but later full-scale stud-
ies and meta-analyses showed no preventive
effect from antibiotic treatment.3 The infection
hypothesis had failed to provide a tangible
benefit.

From the moment the systematic review
showed that there was no benefit in using
systemic antibiotics to eliminate obscure
infections to prevent cardiovascular events,
the hypothesis that oral infections could con-
tribute to the overall atherosclerotic burden
was seen with less favor. Supporters of the
link between oral infection and atheroscle-
rosis pointed out that azithromycin or other
systemic antibiotics would fail to act specifi-
cally against biofilm-centered infections, such
as periodontitis.4 Indeed, the periodontal lit-
erature has shown only marginal effects from
the use of systemic antibiotics in the absence
of mechanical root instrumentation (biofilm
dispersion).5
This is at least part of the reason why many
researchers active in this field stress that peri-
odontitis is a source of chronic, nonresolving
inflammation and frequently play down the fact
that periodontitis is a biofilm-centered infec-
tion: Cardiologists these days are much less
excited about infection than about inflamma-
tion as a mechanism leading to atherosclerosis.
From an oral health standpoint, the hypoth-
esis of a relationship between oral health and
systemic diseases fits very well with the key
developments of our understanding of periodon-
titis established in the late 1980s to mid-1990s:
the existence of a systemic predisposition to
periodontitis and in general the existence of a
relationship between local periodontal disease
and systemic inflammatory and immune chal-
lenges. Indeed, both epidemiologic research
pointing to the existence of high-risk groups and
pathophysiologic research pointing to the exis-
tence of biochemical changes that would prime
healthy sites in diseased subjects toward sus-
ceptibility to periodontitis seem to be consistent
with the notion that the periodontal disease pro-
cess does not remain localized to the oral cavity
and that the organism as a whole senses what
is going on in the periodontium. Accordingly,
a higher general inflammatory status is noted
in subjects with periodontitis, as witnessed by
the raise of specific cytokines such as C-reactive
protein (CRP), interleukin 6 (IL-6), and tumor
Mechanisms
necrosis factor alpha (TNF-α).6,7 In case-control
studies, individuals with periodontitis showed
1.65-mg/L higher concentrations of CRP than
unaffected subjects8–17 (Table 7-1). This is further
corroborated by recent evidence also showing
an increase of IL-6.18 These findings are signifi-
cant in several ways. First, they established that
periodontitis is sensed by the innate acute-phase
response system and leads to a chronic systemic
inflammatory status. Second, the size of the
elevation in cytokines is remarkable: IL-6 and
CRP are important predictors of cardiovascu-
lar outcomes, and cardiovascular risk has been
predicted based on their serum concentrations.
An increase of the magnitude observed for
periodontitis is sufficient to shift an otherwise
healthy subject to a high-risk category. These
data support the hypothesis that periodontitis—
as a chronic inflammatory condition driven by
a biofilm-centered infection—contributes to the
systemic inflammatory load of a subject.
Mechanisms
Over the last two decades, a wealth of mecha-
nistic data has been used to explore potential
mechanisms for the association between peri-
odontitis and atherosclerosis. Two types of
mechanisms are primarily involved: (1) Bac-
teria related to periodontal disease may enter
the circulation19 and contribute directly to the
development of atherogenesis (or thrombosis),
and (2) systemic inflammation resulting from
periodontitis can contribute to atherosclerotic
cardiovascular disease (ACVD). These data
have been reviewed in depth by the recent
European Federation of Periodontology/Amer-
ican Academy of Periodontology (EFP/AAP)
Workshop.20,21
There is some biologic evidence of a potential
role of periodontal pathogens in the formation
of atherosclerotic plaque. Oral and systemic
inoculation of Porphyromonas gingivalis in
apolipoprotein E–deficient (ie, more susceptible
to atherosclerosis) animal models has shown
165
7 The Cardiovascular System and Oral Infections

TABLE 7-1  |  Estimated difference in serum CRP concentration between individuals with
periodontitis and individuals without periodontitis from case-control studies
Periodontitis CRP
Study/subcategory n mean (SD) n Control CRP mean (SD)
Bizzarro et al /SeP8
38 3.10 (4.40) 39 1.90 (2.00)
Bizzarro et al8/MoP 53 3.10 (3.30) 39 1.90 (2.00)
Salzberg et al /GaP9
93 3.72 (2.88) 91 1.54 (2.95)
Salzberg et al9/LaP 97 2.57 (2.95) 91 1.54 (2.95)
Havemose-Poulsen et al10/GaP 27 5.00 (2.70) 25 3.00 (2.00)
Havemose-Poulsen et al10/LaP 18 5.00 (5.40) 25 3.00 (2.00)
Joshipura et al11 91 2.20 (2.25) 377 1.80 (3.00)
Buhlin et al 12
50 3.28 (4.64) 46 1.74 (1.68)
Amar et al13 17 2.30 (2.30) 21 1.00 (1.00)
Craig et al14
44 5.78 (1.07) 25 2.46 (1.44)
Noack et al15 50 4.06 (5.55) 65 1.70 (1.91)
Loos et al16 107 2.64 (3.48) 43 1.21 (1.34)
Fredriksson et al 17
17 2.62 (2.90) 17 0.87 (1.73)
Total (95% CI) 702 904
Test for heterogeneity: Chi2 = 51.41; df = 12 (P < .00001), I2 = 76.7%.
Test for overall effect: Z = 5.42 (P < .00001).
CRP, C-reactive protein; SD, standard deviation; SeP, severe periodontitis; MoP, moderate periodontitis; GaP, generalized aggressive periodontitis; LaP,
localized aggressive periodontitis; CI, confidence interval; WMD, weighted mean difference; df, degrees of freedom. (Reprinted from Paraskevas et al6
with permission.)

that together with infection of periodontal tis-
sues, measured as alveolar bone loss, a systemic
response toward P gingivalis was mounted.22,23
Higher aortic expression of vascular cell adhe-
sion molecule 1 and tissue factor was also noted
in the P gingivalis–inoculated animals.22 More-
over, atherosclerotic lesions of the proximal
aortas and aortic trees were more advanced
and occurred earlier in P gingivalis–challenged
animals.23 Conversely, atherosclerotic lesions
did not appear in the control animals despite
their higher susceptibility.
The following findings provide further evi-
dence of the association between periodontal
pathogens and atherosclerosis:
• The DNA of periopathogens has been
localized within atherosclerotic plaque.
Assessment of 50 human endoarterectomy
specimens showed that in at least 44% of the
specimens, the DNA of some target perio-
pathogens, including Tannerella forsythia, P
gingivalis, and Aggregatibacter actinomyce-
temcomitans, was present.24 Further studies
confirmed these findings.25–27
• Periopathogens are able to invade endothe-
lial cells and contribute to atherosclerosis.
P gingivalis has shown the capability to
invade several cell lines, and the majority
of P gingivalis strains may invade vascular
tissues.28 Moreover, P gingivalis has been
shown to modulate angiopoietin in human
aortic smooth muscle cells through gingipain
production.29
• Periopathogens may trigger platelet
aggregation on their membrane. Platelet
aggregation is characteristic of atheromas.
It has been shown that P gingivalis may
facilitate platelet aggregation through its
fimbriae and may determine a potent platelet

166
 Mechanisms

WMD (random) [95% CI] Weight (%) WMD (random) 95% CI

6.40 1.20 [–0.33, 2.73]
8.11 1.20 [0.11, 2.29]
9.10 2.18 [1.34, 3.02]
9.10 1.03 [0.19, 1.87]
7.33 2.00 [0.71, 3.29]
3.53 2.00 [–0.61, 4.61]
10.16 0.40 [–0.15, 0.95]
6.98 1.54 [0.17, 2.91]
7.77 1.30 [0.13, 2.47]
9.84 3.32 [2.67, 3.97]
6.14 2.36 [0.75, 3.97]
9.38 1.43 [0.66, 2.20]
6.15 1.75 [0.14, 3.36]
100.00 1.65 [1.05, 2.24]

–4 –2 0 2 4

aggregation–inducing activity through its This triggers a systemic acute-phase inflam-

vesicles (membrane evaginations projecting
to the outer environment).30
• P gingivalis accelerates the transition of
macrophages to foam cells. An important
feature in the development of early athero-
sclerotic lesions is cholesterol uptake into
macrophages to form foam cells. Murine
macrophages could be stimulated by P gingi-
valis to accumulate low-density lipoproteins
to form foam cells.31
• Periopathogens have been linked to an
increased host inflammatory reaction. Sys-
temic inflammation is closely linked to the
onset of atherosclerosis.32 Subjects affected
by periodontal disease develop an intense
local production of proinflammatory cyto-
kines that may enter the bloodstream, as
shown by the high levels of inflammatory
biomarkers in gingival tissues and serum.33,34
matory response, characterized by increased
levels of acute-phase proteins such as CRP
and by vascular dysfunction.11,35,36
The association between periodontal
pathogens and atherosclerosis is therefore bio-
logically plausible, and emphasis generally has
been given to the strength and the consistency
of the findings. A plausible biologic mecha-
nism would suggest that bacteria or their toxic
byproducts may easily gain access to the circu-
latory system. Indeed, episodes of bacteremia
have been detected after normal activity such as
chewing or tooth brushing. Similar to bacterial
dissemination, excessive local production of
proinflammatory cytokines may obtain access
to the bloodstream and trigger a systemic
acute-phase response. Thus, when compared
with matched periodontal healthy subjects,

167
7 The Cardiovascular System and Oral Infections

Chronic oral infection

B get to bloodstream Bacteremia Endotoxemia Proinflammatory

mediators (pocket)

Proinflammatory
Host response/ mediators (liver)
inflammation
Prothrombotic
B invade cells
mediators
B found in ath
B alive in ath Autoimmune
mediators
B induce ath

B mutants = less ath Atherothrombotic Dyslipidemia

B from ath cause disease lesion
Genetic background
Reyes et al20 Schenkein and Loos21

Fig 7-1  |  Biologically plausible mechanisms linking periodontitis and atherothrombogenesis. ath, atheroma; B,
bacteria. Dotted boxes indicate limited or no evidence. (Reprinted from Tonetti et al38 with permission.)

periodontal subjects show higher levels of components—and the effect of spillover of

CRP and IL-6, a lower number of erythrocytes,
lower hemoglobin concentrations, higher val-
ues of haptoglobin, moderate leukocytosis, and
increased cholesterol, low-density lipoprotein,
and glucose levels.37 These differences were also
significant when the analyses accounted for a
series of possible confounding factors (age, sex,
smoking, socioeconomic status, diabetes, body
mass index, and alcohol use).
The two hypotheses (bacteremia and chronic
inflammation) were reviewed at the 2012
Joint EFP/AAP Workshop on Periodontitis
and Systemic Diseases.38 Significant evidence
was identified for both hypotheses, and the
current understanding of the mechanisms is
described in Fig 7-1. The consensus delibera-
tions on the specific position papers highlighted
the fact that, at present, it is impossible to
recognize the relative contribution of a direct
bacterial effect—mediated by translocation
and a metastatic effect of bacteria or bacterial
inflammatory mediators produced locally in
the inflamed periodontal tissues on the vascu-
lar endothelium. While it is indeed recognized
that the two hypotheses would overlap and
that bacteremia will ultimately cause inflam-
mation, a better understanding of the relative
contribution of the two hypotheses may help
us to design better preventive or therapeutic
approaches.
A critical assessment of the mechanistic
evidence highlights that, while each piece of
evidence taken individually is moderately inter-
esting, the consistency of the data across in
vitro, ex vivo, and experimental research with a
variety of animal models provides high levels of
confidence regarding the existence of potential
mechanisms. Their relevance and actual clinical
importance must be assessed by different types
of studies, namely analytical epidemiology and
intervention trials.

168

Epidemiology
Early studies reported associations between
various definitions of periodontitis and athero-
sclerotic vascular diseases.39 The majority of the
early studies were cross-sectional, thus the valid-
ity of their results was hampered by the potential
of reverse causality bias (cardiovascular diseases
opening a window of susceptibility to periodon-
titis rather than the opposite) as well as by the
use of vastly different definitions of disease,
ranging from self-reporting to telephone inter-
view, to different protocols for partial-mouth
examinations. Furthermore, these studies did
not appropriately correct for confounding fac-
tors: Periodontitis and ACVD share a variety
of risk factors. Common risk factors (indica-
tors) include cigarette smoking, obesity, male
sex, stress, depression, physical inactivity, and
a low-quality diet. Critics have pointed out these
limitations and the need for better data analysis.
Nonetheless, the majority of early epidemio-
logic studies have indicated an increase in risk.
A previous meta-analysis acknowledging wide
variations in study design and disease defini-
tion estimated that the adjusted additional risk
was about 15% higher for cerebrovascular
outcomes and about 13% higher for cardiovas-
cular outcomes.40 The newest evidence suggests
that the presence of periodontitis indicates a
34% higher risk of cardiovascular disease,41
and recent data supports even higher risk for
incident stroke with relative risk ranging from
1.65 to 3.04, according to the study design.42,43
Emphasis must be placed on incident risk
estimated in longitudinal studies in which the
periodontal status had to be determined before
the observation period.44 This study design
addresses the reverse causality bias. The EFP/
AAP Workshop position paper included 12
studies (6 on coronary heart disease, 3 on cere-
brovascular disease, 2 on both coronary heart
and cerebrovascular disease mortality, and 1 on
peripheral arterial disease).38 All but one study
reported positive associations between various
periodontal disease measures and the incidence
of ACVD, at least in specific subgroups. The
Intervention Trials
association was stronger in younger adults,
and there was no evidence for an association
between periodontitis and incident coronary
heart disease in subjects older than 65 years; in
this respect, it must be emphasized that in most
epidemiologic studies of ACVD, single risk fac-
tors are significant in younger subjects. Only
one study evaluated the association between
periodontitis and a second cardiovascular
event. While heterogeneity in study outcomes
and design prevented a meta-analysis, the data
seemed remarkably consistent; indeed, partic-
ipants in the workshop believed that several
aspects of the epidemiologic evidence war-
ranted discussion and were sufficient to permit
conclusions to be made (Box 7-1).
Although it is well recognized that the epi-
demiologic evidence of an association between
periodontitis and ACVD has increased in
strength and overall quality, the majority of
the large longitudinal studies were designed for
different purposes and the periodontal com-
ponent was an additional element; hence, the
study design may be at risk of bias. Considerable
debate is taking place in the scientific commu-
nity about whether a better understanding of the
association between periodontitis and ACVD
requires a specifically designed epidemiologic
study or if it would be a better use of the scarce
available resources to simply focus on the needed
intervention studies to establish causality. This is
a reflection of a broader unresolved debate on
causality, risk, and prevention between epide-
miologists and clinical investigators.
Intervention Trials
Results from definitive clinical trials are
considered the ultimate element of proof in
establishing the nature of the relationship
between periodontitis and ACVD. The logical
framework is that if the elimination or atten-
uation of the cause is randomized through
treatment of periodontitis (or its prevention
at the population level), an attenuation of
169
7 The Cardiovascular System and Oral Infections

Box 7-1  |  Conclusions about epidemiologic evidence derived from the Joint EFP/AAP Workshop on
Periodontitis and Systemic Diseases38

• Risk: The outcome in all studies in the systematic review44 indicated that the occurrence of periodontitis was prior
to an incident cardiovascular event of ACVD. This higher level of evidence of association allows for statements
of risk to be made.
• Definitions of periodontitis: “Periodontitis measured using clinical attachment loss/periodontal probing depth
and/or radiographic assessment of bone loss has been associated with increased risk for various measures of
ACVD independent of established cardiovascular risk factors.” Periodontitis was not measured by self-reporting,
interview, or simplified partial-mouth recordings.
• Strength of association: “Statistically significant excess risk for ACVD in individuals with periodontitis was reported
to be independent of established cardiovascular risk factors.” The amount of excess risk adjusted for other
ACVD risk factors, however, varied by type of cardiovascular outcome and by age and sex. The risk was found
to be greater for cerebrovascular disease than for coronary heart disease and greater in males and in younger
individuals. No excess risk was reported between measures of periodontitis and incident coronary heart disease
in individuals aged older than 65 years, which supports previous findings that established individual ACVD risk
factors are weaker in older adults. This was an important point during the workshop discussions: The presence
of a degree of specificity in the association was thought to be an element that would strengthen the case for a
true relationship. In addition, the workshop consensus was that there is insufficient evidence to indicate whether
or not periodontitis is associated with the incidence of secondary cardiovascular events (a second ACVD event
after the original event). It was recognized that this finding has implications for future clinical trials and that, under
ideal circumstances, more epidemiologic evidence would be needed for the planning of such intervention trials.
Indeed, in the planning of intervention trials it is important to have a relationship between the outcome and the
exposure (primary or secondary cardiovascular event and periodontitis).
• Potential relevance: “Even low to moderate excess risk reported in studies is enough to be important from a
public health perspective because of the high prevalence of periodontitis.” Essentially, given the high burden of
periodontitis (and potentially gingivitis) in the population, even a moderate measure of risk may be relevant for a
population, because periodontitis is both preventable and treatable, and thus a large number of cases of ACVD
may be prevented by improving the oral health of the population.
• Confounding: Given the fact that chronic inflammatory diseases like cardiovascular disease and periodontitis
share several risk factors (such as smoking, diabetes, obesity, and nutrition), there is concern that the purported
association can be explained at least in part by such exposures. Indeed, the recent workshop concluded that “There
are many potentially important confounders of the association between periodontitis and ACVD risk, including
comorbidities such as diabetes and lifestyle factors such as smoking. However, established cardiovascular risk
factors do not completely explain the excess cardiovascular risk in subjects with periodontitis.” In all of the studies
reviewed, smoking status was controlled for, and in many studies excess risk was demonstrated in subjects who
had never smoked. Excess risk for periodontitis was also demonstrated in studies that controlled for diabetes.
However, excess risk could be associated with unknown confounders. The ENCODE project, a deep sequencing
project to identify all functional elements of the genome, recently found that common genetically determined
pathways underpin various complex inflammatory diseases. Therefore, such genetic determinants could be con-
founding factors. In support of this last statement, a recent report has identified a common susceptibility locus
for both cardiovascular disease and periodontitis on chromosome 9p21.3, in the long noncoding RNA ANRIL
locus.45,46 While all studies in the systematic review had to control for at least age and sex, and while smoking
was controlled for in the analyses, the potential for residual confounding in the explanation of the association
remains significant and is the result of the design of these epidemiologic studies.

170

the effect (the ACVD outcome under study)
should be observed. The design of such trials,
however, is an exceedingly complex exercise.
It requires a good understanding of the most
likely mechanism(s) to be targeted by the inter-
vention, the identification of a population that
is at risk and amenable to receive treatment,
and the availability of an ethically appropriate
control treatment.
Delivery of treatment
Surprisingly little attention has been paid in
recent years to identifying the best possible
periodontal intervention to achieve a general
health benefit. The assumption that the best
possible periodontal outcome (minimal gingi-
val inflammation and shallow pockets in the
whole of the dentition) represents the best
candidate for treatment is rational and rea-
sonable but far from having been proven. As
yet, only one series of studies aimed at assess-
ing the optimal benefit in terms of systemic
inflammatory markers has been performed, by
D’Aiuto et al, between 2002 and 2005.37,47,48
These studies explored different regimens of
root instrumentation and the adjunctive ben-
efit of local delivery of minocycline (with an
important anti-inflammatory effect). These
studies identified several important aspects in
terms of differential efficacy, adverse events,
and timing of the effect of treatment.
Efficacy
Better efficacy was observed for both peri-
odontal and systemic inflammatory outcomes
after an intensive treatment regimen consisting
of complete-mouth mechanical instrumen-
tation, extraction of teeth with hopeless
prognosis, local application of minocycline
microspheres in all sites with probing depths
greater than 4 mm, and oral hygiene instruc-
tions delivered over 24 to 36 hours.37 Efficacy
in terms of local periodontal parameters
paralleled changes in systemic inflammatory
parameters. Some studies have employed
Intervention Trials
periodontal treatment regimens that included
periodontal surgery to achieve optimal control
of periodontitis.49
Some large studies conducted in the United
States have shown limited changes in periodon-
tal outcomes and have been associated with
no change in the systemic parameter under
investigation. The limited results obtained
with periodontal therapy have been ques-
tioned and have highlighted that no systemic
benefit should be expected in the absence of
an effective delivery of the intervention. The
current recommendation among experts seems
to be to specify therapeutic targets that must be
achieved in terms of reducing gingival inflam-
mation and probing depths rather than to
specify a given regimen.
Adverse events
Shortly after the delivery of periodontal
treatment, subjects presented with a sys-
temic inflammatory response that included
an increase in acute-phase response (CRP,
serum amyloid A, fibrinogen, coagulation,
and neutropenia) and an increase in markers
of endothelial cell damage (E-selectin, von Wil-
lebrand factor, D-dimers, and flow-mediated
dilation of the brachial artery).48,50–52 These
adverse events are not unexpected, because
mechanical instrumentation induces significant
bacteremia and endotoxemia that are likely to
cause the observed changes. The intensity of
the observed changes, however, was surprising,
because for several parameters they represented
a 10-fold increase from baseline levels. These
changes persisted for a period of up to 1 week.
Follow-up studies to assess the relative inten-
sity of systemic inflammatory changes after
subgingival debridement or periodontal flap
surgery indicated that the greatest inflamma-
tory response was observed immediately after
complete-mouth subgingival debridement and
that, surprisingly, surgical trauma seemed to
have a smaller impact.53 A recent follow-up
trial indicated that the intensity of the sys-
temic inflammatory response to periodontal
171
7 The Cardiovascular System and Oral Infections
debridement is less pronounced when treatment
is delivered over multiple appointments (on a
quadrant basis), and this seems an important
consideration for periodontal treatment of sub-
jects at high risk for cardiovascular events.54
Minassian et al55 explored the relevance of this
systemic inflammatory response with its under-
lying bacteremia and trauma. They looked at a
large insurance claim database to examine the
incidence rate of cardiovascular events with
regard to their relationship to dental appoint-
ments in which invasive dental procedures were
performed. After invasive dental treatment,
there was a small but measurable increase in
the risk of having a cardiovascular event. The
increased risk persisted for up to 3 months
after the dental appointment.
Timing of treatment
Studies that have followed the time course
of systemic responses after local periodontal
therapy show a biphasic response characterized
by an early worsening of biochemical (CRP
and inflammation51) and functional parame-
ters (flow-mediated dilation56). This biphasic
response raises important issues related to the
timing of outcome assessment: For several
biochemical parameters, it seems important to
allow healing of the early acute-phase response
before assessing the potential benefit of treat-
ment. Repeated episodes of treatment (either
nonsurgical or surgical) complicate timing of
sampling and outcome assessment.
Recognition of the complexity of the systemic
treatment effects and the fact that periodontal
therapy initially may bring a small added risk,
rather than a benefit, in terms of cardiovascu-
lar events raises important ethical issues in the
design of the proper intervention trials, specif-
ically in terms of the target population.
Population at risk
Two types of population (and two types of
intervention trial) have been considered: (1)
individuals who are free from significant
172
identified systemic comorbidities (and at rel-
atively low risk of presenting cardiovascular
events) and (2) individuals who have already
suffered from a cardiovascular event (and are
at a much higher risk of having new events).
In the systemically healthy population, the
experimental rationale for treating periodon-
titis would be to interfere with the process
of atherogenesis and therefore to do a pri-
mary prevention trial. In such a population,
the adverse events of periodontal therapy
are probably less relevant in the sense that
a healthy individual could tolerate well the
increased burden associated with periodon-
tal therapy. This is the optimal population in
which to show prevention or delay of the ath-
erosclerotic process assessed by measuring a
variety of so-called surrogate cardiovascular
outcomes (eg, arterial elasticity, hypertension,
intima-media thickness). However, these sur-
rogate outcomes bear relatively little weight in
the decision-making process to identify aspects
to target with prevention; stronger evidence
based on true cardiovascular events is favored
in the cardiology community. The challenges
of running a trial aimed at preventing true
cardiovascular events in an otherwise healthy
population are formidable: The low rate of
expected events will require either a very large
sample size or a very long follow-up period.
Not unexpectedly, trials in systemically healthy
individuals with periodontitis have focused on
surrogate markers.
Running an intervention trial in a population
at increased risk (ie, with a previous experience
of a cardiovascular or cerebrovascular event)
poses great challenges as well. First, these
individuals are normally medicated to lower
the risk of a second event. Many of the drug
molecules may interfere with multiple aspects
of the mechanisms at the basis of a relation-
ship between periodontitis and atherosclerosis.
Second, the available periodontal intervention
may represent a small but concrete short-term
risk for a secondary event.55 The advantages of
performing a trial in this type of population are
associated with the higher incidence of events

in these populations; individuals have reached
an overall burden of atherosclerotic diseases
that put them at risk for a second event. There-
fore, it is possible to decrease the sample size
and/or the time of follow-up.
The periodontitis and vascular events (PAVE)
study represents a feasibility study for such a
secondary prevention trial.57 The trial was
remarkable because it was possible to recruit a
population among individuals who had recently
suffered from a primary cardiovascular event.
It also showed the challenge related to the
delivery of treatment: The experimental group
showed moderate periodontal improvements,
while the control group (left in the intention
of the study investigators to community care,
expected to be mainly supragingival cleaning
with a hygienist) received a considerable level
of periodontal treatment.57
Control intervention
Identification of an ethically acceptable con-
trol periodontal treatment seems to be a key
aspect in the design of a definitive trial. The
background of the ethical discussion is repre-
sented by the current standard of periodontal
care available to the population. Depending
on the different health care systems and the
existence of a waiting time to receive treatment
and/or the availability of specialist care, two
options have been considered. The first option
consists of delaying periodontal treatment until
the end of a relatively short follow-up period
of the trial and delivery of a standardized pla-
cebo treatment (eg, supragingival cleaning and
oral hygiene instructions) within the trial. The
second consists of leaving the control group to
community care.
Both options have limitations and advan-
tages and disadvantages. Delayed treatment
seems ethically possible only if the duration
of follow-up is adequately short (probably in
the range of 6 to 12 months); it also requires
adequate safety monitoring to ensure the
institution of standard-of-care treatment if
periodontitis progresses. The biggest advantage
Intervention Trials
of such an approach is that it will maximize
the difference in local periodontal parame-
ters—and, it is hoped, systemic inflammatory
burden—between the test and control groups.
Community care is probably one of the few
options for studies of longer duration. Its exper-
imental appeal is based on the assumption that
community periodontal therapy on one hand
represents the current standard of treatment
but on the other hand falls short of the optimal
level of care that can be delivered by highly
specialized teams in the context of the trial. The
experience with the PAVE study shows that,
at least in countries like the United States, the
periodontal-systemic link has received such a
level of professional and media attention that
subjects randomized to community care will
endeavor to receive the best level of care that
they can access.58 Indeed, the ethics associated
with the control group represent the biggest
challenge in running a trial in a society with
optimal access to periodontal care.
Results of intervention trials
Several RCTs have been performed to date to
assess the effect of periodontal intervention on
systemic parameters.
On one hand, no information is available
on true cardiovascular outcomes (incidence
of cardiovascular event [ie, angina pectoris,
myocardial infarction, stroke, death]).7 This
is probably due to intrinsic limitations of the
trials’ study design. Cardiovascular events are
rare, and extremely large sample sizes would
be needed to assess difference. Moreover, the
time needed to observe a clinical event would
impose a long follow-up. Lastly, there are
ethical concerns in designing a trial in which
the control group might receive suboptimal
treatment.59
On the other hand, important effects are
seen in terms of cardiovascular surrogate
outcomes.7,60,61 After periodontal treatment,
significant reduction of inflammatory bio-
markers is noted, reinforcing the hypothesis
that periodontitis might determine a systemic
173
7 The Cardiovascular System and Oral Infections
TABLE 7-2  |  Effect of periodontal therapy on serum CRP concentrations
Difference in experimental
Study n group, mean (SD)
D’Aiuto et al37 20 0.40 (1.01)
D’Aiuto et al37
21 0.00 (2.25)
Seinost et al67 31 0.60 (1.38)
Total (95% CI) 72 2.57 (2.95)
Test for heterogeneity: Chi2 = 0.57, df = 2 (P = .75), I2 = 0%.
Test for overall effect: Z = 2.32 (P = .02).
SD, standard deviation; WMD, weighted mean difference; CI, confidence interval; df, degrees of freedom. (Reprinted from Paraskevas et al6 with permission.)
inflammatory alteration. CRP, IL-6, TNF-α ,
fibrinogen, and E-selectin are diminished after
treatment. IL-6 diminishes by approximately
–0.5 ng/L, TNF-α by 0.75 pg/mL, and fibrin-
ogen by approximately –0.5 g/L.7 CRP values
are reduced by approximately 0.4 mg/L (Table
7-2), and even more in subjects with comor-
bidities.61 Subgroup analysis also indicated
that nonsmokers and nonobese individuals
would benefit from the higher reduction of
systemic inflammation.7 For comparison, such
an improvement would be sufficient to lower
the CRP-associated risk of future cardiovas-
cular events and falls within the range of CRP
improvement that can be obtained with phar-
macologic treatment with statins.
Traditional cardiovascular risk factors such
as lipids (ie, total cholesterol and high-density
lipoprotein [HDL]) also showed reduction after
periodontal treatment.7 The joint EFP-IDF
(International Diabetes Federation) Workshop
clearly identified that, in patients with diabetes,
periodontal treatment is capable of significant
reduction of HbA1c and free blood glucose.62
This is important considering that the latter
has been significantly associated with cardio-
vascular events.63
Furthermore, endothelial function as mea-
sured through flow-mediated dilation is
influenced by periodontal treatment, with a
suggested improvement in dilation in a range
of approximately 4% to 9% after treatment.60
The endothelium is a key regulator of blood
vessel biology because it affects coagulation,
174
Difference in control group,
n mean (SD)
24 –0.10 (1.65)
24 –0.10 (1.65)
31 0.00 (0.80)
79
inflammation, and growth and remodeling of
blood vessel walls. Impairment of endothe-
lial function and integrity, called endothelial
dysfunction, occurs in the early stages of ath-
erosclerosis and its progression.64,65 Endothelial
dysfunction is considered a long-term predictor
of ACVD events.66 It is frequently measured as
flow-mediated dilation of the brachial artery
using a noninvasive ultrasound technique.67
Of the RCTs aimed at assessing endothelial
dysfunction, the largest was performed by
Tonetti et al,56 who randomized 121 healthy
individuals suffering from severe generalized
periodontitis to either a cycle of supragingi-
val mechanical scaling and polishing (control)
or an intensive treatment regimen consisting
of complete-mouth scaling and root planing,
extraction of hopeless teeth, and local delivery
of minocycline microspheres in all pockets. At
6 months after therapy, the intensive treatment
regimen had led to an improvement in endothe-
lial function of 2.0% (95% confidence interval
of 1.2 to 2.8; P < .001) over the control treat-
ment (Fig 7-2). The observed improvement in
endothelial function was directly associated
with the obtained improvements in periodon-
tal parameters.
Higashi et al68,69 extended these results of
improved endothelial function to individuals
suffering from hypertension and ACVD. These
trials are significant because they seem to sug-
gest that periodontal treatment may reverse the
early stages of atherosclerosis, even in subjects
with established cardiovascular disease.
 Conclusion

WMD (random) [95% CI] Weight (%) WMD (random) 95% CI

28.84 0.50 [–0.29, 1.29]
13.38 0.10 [–1.07, 1.27]
57.78 0.60 [0.04, 1.16]
100.00 0.50 [0.08, 0.93]

–4 –2 0 2 4

IPT (n = 61)
10 CPT (n = 59)
Flow-mediated dilation of the brachial artery (%)

4
1

0
Baseline Day 1 Day 7 1 Mo 2 Mo 6 Mo

Fig 7-2  |  Effect of intensive periodontal therapy (IPT) compared with supragin-
gival debridement (community periodontal treatment [CPT]) on endothelial dys-
function. (Reprinted from Tonetti et al56 with permission.)

Conclusion and biologic mechanism, intervention trials

to date are not adequate to draw further con-
In light of the present incomplete evidence, the clusions. Nevertheless, the positive effects of
following conclusions should be drawn38: periodontal treatment on markers associated
with cardiovascular diseases are consistent.
• There is consistent and strong epidemio-
logic evidence that periodontitis imparts an The EFP/AAP Workshop consensus made
increased risk for future ACVD. the following recommendations to oral health
• The impact of periodontitis on ACVD is bio- practitioners38:
logically plausible. Translocated circulating
oral microbiota may directly or indirectly • Practitioners should be aware of the emerging
induce systemic inflammation that impacts and strengthening evidence that periodontitis
the pathogenesis of atherothrombogenesis. is a risk factor for the development of ACVD
• While in vitro, animal, and clinical studies and should advise patients of the risk.
do support the existence of the interaction

175
7 The Cardiovascular System and Oral Infections
• The rationale for prevention, diagnosis, and
treatment of periodontitis remains the pres-
ervation of the dentition and avoidance of
the crippling effects of periodontitis-induced
alveolar bone loss and tooth loss.
• Based on the weight of the evidence, peri-
odontitis patients with other risk factors for
ACVD, such as hypertension, obesity, and
smoking, who have not seen a physician
within the last year should be referred for
a physical.
• Modifiable lifestyle-associated risk factors
for periodontitis (and ACVD) should be
addressed in the dental office and in the con-
text of comprehensive periodontal therapy
(eg, smoking cessation programs and advice
on lifestyle modifications such as diet and
exercise). This goal may be better achieved in
collaboration with appropriate specialists and
may bring health gains beyond the oral cavity.
• Treatment of periodontitis in patients with a
history of cardiovascular events should fol-
low American Heart Association guidelines
for elective procedures.
Besides these consensus conclusions, it seems
important to recognize that the challenges of
having sufficient evidence to draw firmer con-
clusions are formidable and that dental and
medical practitioners and their patients will
Clinical Considerations: What You Can Take Back to Your Practice
What is the effect of oral health on cardiovascu-
lar disease?  Epidemiologic studies show strong
associations between poor oral health and car-
diovascular disease. This association may differ
among different populations and age groups.
Are oral infections independent risk factors for
the development of cardiovascular disease?  contribute to the eventual destabilization of
Epidemiologic studies demonstrate strong asso-
ciations between oral infections and cardiovas-
cular disease and events. The effect is of clinical
significance and is independent of other known
risk factors. However, we cannot yet claim that
176
have to deal with the present incomplete pic-
ture for years to come. At present, there seem to
be some firm points: The association between
periodontal disease and atherosclerosis seems
to be consistent. It is unclear, however, if the
link can be fully explained by modifiable risk
factors shared between periodontitis and car-
diovascular diseases.
Because risk factor modification is now a
well-recognized component of periodontal
therapy, a pragmatic approach will likely see
periodontists and other oral health care pro-
fessionals treat periodontitis and address the
risk factors as part of the periodontal therapy.
This may bring general health benefits because
of the control of the shared risk factors and
perhaps because of the control of the systemic
inflammatory burden contributed by peri-
odontitis. Conversely, and this is the important
implicit point made by the recent American
Heart Association statement that critically eval-
uated the evidence of a relationship between
periodontitis and cardiovascular disease,70 it
is wise for periodontists and oral health care
professionals to avoid making claims that
periodontal therapy improves cardiovascular
health. Such assertions are premature and may
confuse patients with cardiovascular disease,
who belong under the care of their physician
or cardiologist in a medical practice.
oral infections contribute to the development
or progression of cardiovascular events.
What is the biologic plausibility of the associ-
ation between oral health and cardiovascular
disease?  Oral microbes colonize atheroscle-
rotic lesions via bacteremia, and they may
the plaque. They may also lead to myocardi-
al infarction or ischemic stroke. Also, oral mi-
crobes contribute to the cumulative burden of
systemic inflammatory responses that may lead
to atherosclerosis.

Does the delivery of oral health care contribute
to improvement of cardiovascular disease out-
comes?  Well-designed intervention studies
demon­ strate improvement in several estab-
lished biomarkers for cardiovascular disease.
However, there are no studies showing im-
proved clinical signs or symptoms.
Is it safe to provide dental care to patients with
cardiovascular disease?
  From the perspective
of disseminating oral bacteria, the transient
bacteremia caused by infrequent dental pro-
cedures represents much less hazard than ev-
eryday activities such as tooth brushing and
flossing or mastication of hard food items. Pro-
vision of dental care to patients at risk for isch-
emic events should be done after consultation
with the attending physician/cardiologist.
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27. Pessi T, Karhunen V, Karjalainen PP, et al. Bacterial
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34. Offenbacher S, Farr DH, Goodson JM. Measurement
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45. Schaefer AS, Richter GM, Groessner-Schreiber B, et
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cancer, regulates ADIPOR1, VAMP3 and C11ORF10.
Hum Mol Genet 2013;22:4516–4527.
47. D’Aiuto F, Nibali L, Parkar M, Suvan J, Tonetti MS.
Short-term effects of intensive periodontal therapy on
serum inflammatory markers and cholesterol. J Dent
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48. D’Aiuto F, Parkar M, Andreou G, et al. Periodontitis and
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51. D’Aiuto F, Parkar M, Tonetti MS. Acute effects of peri-
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Clin Periodontol 2007;34:124–129.
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179

The Association Between Oral
Infections and Renal Disease
Karren Komitas, dmd, phd, mdsc
Effie Ioannidou, dds, mds
The growing population and continuously
increasing life expectancy worldwide have
resulted in a dramatic growth in the propor-
tion and absolute numbers of older adults.1,2
In the United States, the population aged 65
years and older reached 45 million in 2015
and is projected to reach almost 100 million
by 2060.3 These trends raise multiple health
care concerns regarding the greater preva-
lence of various local and systemic diseases
in older individuals and associated high eco-
nomic costs.4
Periodontitis is a polymicrobial multifacto-
rial inflammatory disease of tooth-supporting
tissues5 and is one of the most common human
infectious diseases. The overall prevalence of
periodontitis in the United States is currently
estimated at 42%,6 and its prevalence increases
with age, reaching 62% in individuals aged 65
years and older.7 It has been established that
the chronic nature of periodontitis leads to
continuous attachment loss over a long period
of time; impaired ability or inability to main-
tain proper oral hygiene, aging, smoking, poor
socioeconomic status, genetics, male sex, and
decreased health literacy are among the factors
that can contribute to the increased prevalence
of periodontitis in older adults.7
In addition, multiple lines of evidence
during the past two decades have demon-
strated that the development and progression
180
CHAPTER 8
of periodontitis, especially in older adults,
are associated with various inflammatory
systemic diseases, including type 2 diabetes
mellitus, obesity, rheumatoid arthritis, and
others.8,9 Underlying mechanisms of these
associations have been extensively studied in
various human and animal studies, which have
demonstrated that this association can be due
to similar mechanisms of development, shared
inflammatory pathways and mediators, and
host genetic predisposition.10–12 In addition,
older adults often present with age-associated
impaired adaptive immune system responses
and persistent low-grade inflammation, thus
making them more susceptible to microbiota of
periodontal tissues.13,14 Therefore, treatment of
a systemic comorbidity can potentially alleviate
the severity of periodontitis, and vice versa.10
The term periodontal medicine has been intro-
duced to define a branch of periodontology
that examines possible associations between
periodontitis and systemic diseases and devel-
ops novel diagnostic and treatment strategies
based on the evidence of these associations.15
The question whether periodontitis is an
independent risk factor for the development
of a systemic disease still remains a matter of
debate in the scientific community. The goal of
this chapter is to assess whether current evi-
dence exists for an independent association
between periodontitis and renal disease, and

if so, to gain insight into the biologic rationale
and mechanisms of this association. We have
reviewed the relevant pathophysiology and
predominant theories of the underlying mech-
anisms for the development and progression
of these diseases. We have also assessed the
clinical significance of these results to deter-
mine whether improved oral hygiene and
periodontal treatment can reduce a risk for
renal disease, and if so, what protocols these
strategies involve. Finally, we have aimed to
reveal gaps in our current knowledge to delin-
eate the directions of future research efforts.
Overview of Renal Diseases
Chronic kidney disease (CKD) is a worldwide
public health problem with global prevalence
ranging from 8% to 16%.16 CKD has recently
been ranked third in the list of diseases caus-
ing premature mortality following AIDS and
diabetes.17 Based on recent data, CKD is a
costly public health problem, with more than
4.6 million hospital outpatient visits and over
$50 billion USD in Medicare expenses (20% of
the total Medicare spending) in 2014.18
CKD is defined by impaired kidney function,
as measured by an estimated glomerular filtra-
tion rate (eGFR) less than 60 mL/min/1.73 m2
of body surface area, with or without kidney
damage, for at least 3 months.19 The eGFR
measures the clearance of a particular marker
by the kidney, and therefore it is the standard
measure of renal excretory function and kid-
ney health in general. Several exogenous and
endogenous clearance markers have been uti-
lized to assess kidney function and estimate
the eGFR, and among them serum creatinine
remains the most commonly employed marker.
There are five eGFR-based clinical stages of
CKD, which signify the degree of kidney dam-
age and reduced kidney function:
• Stage 1: Normal or increased eGFR (≥ 90
mL/min/1.73 m2 )
Overview of Renal Diseases
• Stage 2: Mild eGFR decrease (60–89 mL/
min/1.73 m2 )
• Stage 3: Moderate eGFR decrease (30–59
mL/min/1.73 m2 )
• Stage 4: Severe eGFR decrease (15–29 mL/
min/1.73 m2 )
• Stage 5: Kidney failure (eGFR < 15 mL/
min/1.73 m2 )
In a recent meta-analysis of the epidemio-
logic evidence on the global prevalence of CKD
by disease stage, stage 3 was found to have
the highest prevalence.20 CKD prevalence was
higher in developed countries with increased
numbers of elderly populations. After geo-
graphic stratification, Europe demonstrated
the highest mean CKD prevalence in stages
1 to 5 of 18.38% (95% confidence interval
[CI]: 11.57–25.20). When CKD prevalence was
restricted to stages 3 to 5 and compared among
regions, the United States showed the highest
mean CKD prevalence of 14.44% (95% CI:
8.52–20.36).20 This finding may result from
methodologic heterogeneity in creatinine mea-
surements inherent in most studies. Among
the rest of the world, Iran presented with sim-
ilarly high CKD prevalence due to high rates
of comorbidities such as high body mass index
(BMI) and high systolic blood pressure.20
As diagnostic methods have evolved, each
CKD stage has been divided into substages to
incorporate albuminuria (presence of albumin
in the urine), given that the levels of albumin
in the urine affect disease progression and
outcomes.21 More specifically, each substage is
defined based on specific albuminuria cutoffs:
• A1: Normal to mildly increased (< 30 mg/g
or < 3 mg/mmol)
• A2: Moderately increased (30–300 mg/g or
2–20 mg/mmol)
• A3: Severely increased (> 300 mg/g or > 30
mg/mmol)
When an eGFR is less than 15 mL/min/1.73
m2 and weekly renal urea clearance is below
2.0 (a sign of severe uremia), patients are
181
8 The Association Between Oral Infections and Renal Disease
diagnosed with end-stage renal disease (ESRD)
and treated with renal replacement therapy.22
The most recent data (2015) on the distribu-
tion of renal replacement treatment modalities
reveal that the majority of patients are main-
tained with hemodialysis (87.3%), followed by
peritoneal dialysis (9.6%), and only 2.5% with
kidney transplantation.23 In the United States
in 2015, approximately 26 million individu-
als were diagnosed with CKD, and there were
703,243 patients with ESRD on dialysis.23
CKD risk factors include diabetes, hyper-
tension, autoimmune diseases (eg, systemic
lupus erythematosus), urinary tract infections,
urinary stones, neoplasia, family history of
kidney disease, low birth weight, and demo-
graphic characteristics such as race and age.21
In addition, chronic use of nonsteroidal
anti-inflammatory medications has been a
documented risk factor for CKD.22,24 Between
25% and 40% of patients with type 1 or type 2
diabetes mellitus develop diabetic nephropathy
with progressive loss of kidney function.25 As
diabetes prevalence has dramatically increased
in the last few decades, CKD prevalence has also
increased. The CKD progression is predicted
by several factors, including the underlying
diagnosis, kidney function and albuminuria,
age, sex, race, hypertension, hyperlipidemia,
hyperglycemia, smoking, history of cardiovas-
cular disease (CVD), and obesity.21 Although
CKD prevalence has increased over the last
few decades, systematic efforts in glycemic
control and antihypertensive measures includ-
ing renin-angiotensin blockers have resulted
in a stabilization of its incidence in the United
States.26 More specifically, in the advanced
CKD stages, the adjusted prevalence of stages
3 and 4 increased during the early 2000s and
then stabilized.26 Once the disease progressed
to the ESRD stage, epidemiologic data have
shown that the age-, sex-, and race-adjusted
incidence rates for ESRD increased from 1980
to 2001, were stable through 2006, and then
slightly declined. However, the overall ESRD
prevalence has increased by 3.4% since 2014
due to longer survival among patients with
182
ESRD.23 This finding highlights the success of
the systematic efforts for the treatment of kid-
ney failure in the United States.
Epidemiology of Periodontitis
in Patients with CKD/ESRD
Epidemiologic evidence based on large pop-
ulation studies in CKD has shown that the
prevalence of moderate and severe peri-
odontitis ranges from 11.5% to 14.7%.27–29
Heterogeneity in disease cutoffs, examination
methodologies (full- versus partial-mouth pro-
tocols), as well as population demographic
differences do not allow the direct comparison
of periodontitis estimates in CKD with those in
the general population total periodontitis (mild
to severe) estimate.30 Using the National Health
and Nutrition Examination Survey (NHANES)
III database, our group has demonstrated a
statistically significant higher prevalence of
moderate periodontitis in patients with CKD
compared to non-CKD populations also
characterized by racial disparities as shown
in Table 8-1.29 Overcoming the NHANES III
limitations for periodontitis prevalence assess-
ments,31 our group has adapted appropriate
prevalence adjustments, as described before,
and estimated approximately 6 million patients
with CKD with moderate and severe periodon-
titis,29 emphasizing an important public health
problem in this special-needs population.
Other research groups have reported the
prevalence of periodontitis among individ-
uals with ESRD ranging between 29% and
64%.32–36 Despite recognition of periodontitis
as a critical public health problem,37 disease
awareness, especially in medically complex
populations, is low.38 Poor oral health has
been shown to compromise chewing capac-
ity, which affects protein intake, energy levels,
and serum albumin levels in CKD/ESRD pop-
ulations, thus resulting in malnutrition and
disease progression.39 Given the detrimental
effects of periodontitis on oral health, effective
 Biologic Plausibility for the Increased Prevalence of Periodontitis in Patients with CKD/ESRD
TABLE 8-1  |  Periodontitis prevalence as stratified by race in CKD and non-CKD populations (n = 11,604)
Non-Hispanic whites
Non-CKD
CKD N=
N = 437 4,216
Periodontitis 12.9 (1.8) 7.5 (0.4)
Data represents prevalence (%) and standard deviation (SD). Notice the statistically significant difference in prevalence between CKD and non-CKD
populations in every racial group. For the entire sample, inflation-adjusted prevalence was 35.28% in CKD (data not shown). (Data from Ioannidou and
Swede.29)
treatment and control of periodontitis focused
on improving and maintaining oral health may
need to become a priority in medically complex
renal populations.
Biologic Plausibility for the
Increased Prevalence of
Periodontitis in Patients with
CKD/ESRD
Periodontitis is a complex disease that involves
the interaction of subgingival biofilms with the
susceptible host resulting in connective tissue
and bone changes.14,40 In renal disease, several
mechanisms have been proposed to contribute
to the pathogenesis of periodontitis, includ-
ing uremic effects on the oral environment,
uremic immunosuppression, and vitamin D
deficiency.34,41,42 With the progressive decline
in glomerular filtration, uremic solutes/tox-
ins, typically eliminated in the urine, are
retained in the body,43 contributing to anemia,
immunosuppression, inflammation, infec-
tion, cardiovascular morbidity, and mortality.
The deleterious effects of uremia are most
pronounced in ESRD.44 As uremia becomes
pronounced, it has been shown that salivary
urea levels dramatically increase from 7.5
μmol/L to 17 to 26 μmol/L.45
Non-Hispanic blacks Mexican Americans
Non-CKD
CKD N= CKD Non-CKD
P value N = 88 3,182 P value N = 81 N = 3,600 P value
.001 38.9 (5.8) 14.6 (0.5) .001 37.3 (6.8) 9.0 (0.5) .001
In our conceptual model, high urea levels in
the serum and gingival crevicular fluid (GCF)
could alter the oral ecosystem, promoting the
growth of periodontal pathogens, similar to
the demonstrated uremia-related changes in the
gut environment46 (Fig 8-1). More specifically,
evidence has shown that high urea levels in the
gut environment resulted in a distinct microbi-
ome in a renal failure rat model46 (see Fig 8-1).
Because GCF derives primarily from serum,
increased serum urea levels are also reflected
in GCF.47,48 A variety of bacteria such as Strep-
tococcus salivarius and Actinomyces naeslundii
produce urease, which catalyzes the hydrolysis
of urea, resulting in ammonia, which may then
be protonated to produce ammonium ion and
directly alkalize the bacterial cytoplasm49 or the
extracellular environment.50 Selected periodon-
tal pathogens such as Prevotella intermedia,
Fusobacterium nucleatum, Porphyromonas
gingivalis, and even Helicobacter pylori show
optimal growth in alkaline pH.51 Although
there have been limited cross-sectional obser-
vations indicating a higher frequency of red
complex periodontal bacteria in ESRD sub-
jects with periodontitis than in systemically
healthy controls,52,53 the role of uremia-related
factors (urea, subgingival pH) as ecologic
determinants has never been examined. In a
comprehensive investigation of the microbial
communities in the uremia-modified subgingi-
val environment, Araújo et al characterized the
183
8 The Association Between Oral Infections and Renal Disease
Subgingival Host
microbiome response
•  Uremic saliva •  Uremic innate
•  Urease activity and adaptive
•  Alkaline pH dysfunction
•  Oral ecosystem •  Oxidative stress
alterations •  Vitamin D
deficiency
Fig 8-1  |  The conceptual model of modified periodontitis pathogenesis in CKD.
subgingival microbiome of patients with ESRD
and compared it to systemically healthy control
individuals using 16S rRNA gene sequencing.54
Although the study did not reveal differences
in proportions of periodontitis-associated
taxa, there is a negative correlation between
microbiome diversity and dialysis vintage
(years on dialysis). More specifically, the study
showed that the years on dialysis negatively
correlate with the diversity of the microbial
communities.54
Additional effects of the uremic milieu on
both innate and adaptive immunity55 alter
host response by several mechanisms such as
functional abnormalities of neutrophils, mono-
cytes/macrophages, and dendritic cells43,56–58;
abnormal neutrophil activity 59; impaired
maturation of T helper cells60; and increased
oxidative stress.61,62 As uremia increases with
CKD progression, uremic effects become
critical in ESRD.63 The innate and adaptive
immunity effects of uremia may lead to a dis-
abled immune response and, in combination
with dialysis-related factors (such as membrane
biocompatibility and type of vascular access),
increase infection susceptibility as confirmed
by high prevalence of chronic infection by
Chlamydia pneumoniae and Mycobacterium
184
Connective Clinical
tissue and bone presentation of
breakdown periodontitis
•  Vitamin D
deficiency
•  Renal
osteodystrophy
•  Oxidative stress
tuberculosis,64 reflected in a relative risk (RR)
for active tuberculosis of 7 to 2565,66 in patients
with ESRD. Thus, the uremic effects on innate
and adaptive host response may also repre-
sent a modifying factor in the pathogenesis of
periodontitis as CKD progresses to advanced
stages.
As the renal function is compromised, the
metabolic pathway of vitamin D—conversion
to 1,25(OH)2D in the kidneys—is disturbed
due to the inhibition of 1-α-hydroxylase activ-
ity (produced by the kidney).67 Vitamin D
deficiency has been found to play a dual role in
abnormal bone breakdown and turnover (renal
osteodystrophy)68 and alteration of the innate
(monocyte activation and phagocytosis) and
adaptive (modulation of cytokine production)
immunity.69
Figure 8-1 summarizes our conceptual
model, in which the pathogenesis of peri-
odontitis (shown in blue boxes) is modified
by CKD/ESRD comorbid factors (shown in
white boxes). The interaction of the CKD/
ESRD comorbid factors and periodontitis eti-
ologic events not only explains the increased
prevalence of periodontitis in this population
but can also affect the response to periodontal
treatment in these populations.

Periodontitis and the
Inflammatory Burden in
Patients with CKD/ESRD
Within the last few decades, the high inflamma-
tory burden in CKD/ESRD has been attributed
to the “uremic puzzle,” with pieces developing
and connecting in an intricate manner70 con-
tributing to CVD mortality. We now know that
the complexity of the “uremic puzzle” extends
past the Framingham CVD risk factors involv-
ing systemic inflammation and oxidative stress
as variables strongly associated with poor CVD
outcomes in CKD.70 Overwhelming evidence
has indicated that the enzymatic activity of
myeloperoxidase links oxidative stress and
inflammation in uremia, thus emphasizing
the importance of both in the atheroscle-
rotic process.71 Consequently, research has
focused on identifying factors contributing
to systemic inflammation and oxidative stress
at different levels. At an ethnic level, sev-
eral culture-related dietary habits have been
identified as anti-inflammatory, correlating with
a low CVD risk.72 Dialysis-related factors such
as membrane bioincompatibility, type of access,
and impure dialysate have also been linked to
systemic inflammation.73 At the patient level,
additional comorbid factors including bacterial
infections, volume overload, failed transplant,
and depression have been implicated in the
elevated serum C-reactive protein (CRP)74 and
are targeted in anti-inflammatory therapeutic
efforts.63,74
In the same context, the American Heart
Association has recognized the independent
association between periodontitis and systemic
inflammation75 as expressed by high levels of
inflammatory biomarkers such as interleukin
6 (IL-6) and CRP.76–78 Our group and others
produced evidence supporting the contribu-
tion of periodontitis to inflammation in CKD
as measured by CRP levels.28,42,79 Moreover,
the impact of periodontitis on serum CRP lev-
els has been shown to be significant in ESRD,
Response of Patients with CKD to Periodontal Therapy
with a dose-response association between
CRP and periodontitis stages possibly lead-
ing to increased all-cause mortality rates.80 As
confirmed by analogy,81 other infections have
shown to result in increased levels of inflamma-
tory mediators in ESRD and to consequently
contribute to the atherosclerotic process and
increased mortality.64,82,83 Therefore, the rela-
tionship between periodontitis and CKD/ESRD
is potentially bidirectional, with CKD/ESRD
not only potentiating the incidence of peri-
odontitis but periodontitis likely contributing
to sustained inflammation and poor outcomes
in CKD/ESRD.
Response of Patients with
CKD to Periodontal Therapy
The elimination of the etiologic factors of
periodontitis is the main therapeutic goal of
nonsurgical periodontal therapy. Such therapy
results in biofilm disruption, reduction of clini-
cal signs of inflammation, and improvement of
surrogate clinical periodontal parameters such
as probing pocket depth (PPD) and clinical
attachment loss (CAL).84 Importantly, periodon-
tal status seems to have a significant impact on
oral health–related quality of life as measured
by patient-centered outcomes.85 In terms of
microbiologic outcomes, the immediate effect of
nonsurgical periodontal therapy is the disrup-
tion and modification of the composition of the
bacterial biofilm, as shown by a reduction in the
total mass of subgingival plaque and decreased
levels and prevalence of periodontitis-associated
species.86 Although the most drastic changes in
biofilm composition occur immediately after
therapy, the prevalence of red complex spe-
cies has been shown to remain low during
a 12-month follow-up.84 However, in the
absence of supportive periodontal therapy, 50%
of the originally infected sites are recolonized
within 12 months.87 Hence, sustained improve-
ments after therapy are dependent on effective
initial intervention and adequate maintenance.
185
8 The Association Between Oral Infections and Renal Disease
Effectiveness of Periodontal
Therapy
Periodontal outcomes
Nonsurgical periodontal therapy consists
of scaling and root planing (SRP) under
local anesthesia with the primary goal to
eliminate the microbial disease etiology (bac-
terial plaque), reduce PPD, improve CAL,
and ultimately prevent tooth loss.88 Peri-
odontal treatment response is based on the
improvement of periodontal parameters and
is maintained through maintenance visits
to prevent disease relapse based on patient
periodontal risk assessment.89 Studies have
assessed the clinical effectiveness of the non-
surgical periodontal intervention in CKD and
systemically healthy populations focusing on
periodontal outcomes. Despite the hetero-
geneous study designs and methods, studies
agree that periodontal intervention is less
effective in CKD/ESRD populations com-
pared to systemically healthy populations.
These data emphasized the need for a modi-
fied periodontal therapy approach in patients
with ESRD in order to achieve results similar
to those in systemically healthy individuals.90,91
Currently, only 11% of patients with CKD/
ESRD have one dental visit a year,44 possibly
due to low socioeconomic status and low oral
health awareness. Therefore, access to care
and oral health awareness would need to be
addressed in this population with the develop-
ment of a multidisciplinary care model. Oral
health models especially for ESRD patients on
dialysis might need to be tailored to accommo-
date patient fatigue and physical limitations.
Systemic outcomes
The systemic anti-inflammatory effect of
periodontal therapy is expected once a posi-
tive treatment response occurs at a local/oral
level with improved periodontal measures.92
In systemically healthy populations, peri-
odontal intervention results in approximately
186
80% reduction in periodontal lesions, which
significantly correlates with changes in inflam-
matory markers.93 Many studies94,95 have been
criticized for not achieving clinically accept-
able endpoints prior to evaluating systemic
endpoints. When the treatment-associated oral
response is not pronounced, systemic effects are
not evident.91,96
A single 6-month randomized controlled trial
(RCT) that examined the effect of periodontal
treatment on ESRD presented inconclusive
results due to design limitations, including
(1) the episodic periodontal therapy approach
without maintenance, as confirmed by the poor
oral hygiene scores and declining periodontal
parameters within the observational period,
and (2) the overrepresentation of diabetic
patients in the treatment arm (62%) versus
control arm (38%).91 Evidently, the episodic
treatment approach is not effective enough
to promote optimal oral hygiene, prevent
recurrent periodontitis, and control systemic
inflammation.97–99
For anti-inflammatory strategies to be
effective, they need to consider all comorbidi-
ties.100,101 Oral health care needs to be a part of
the interprofessional collaboration taking place
in the outpatient dialysis units, which include
nephrologists, nurses, dietitians, social work-
ers, and renal access surgeons. To facilitate this,
general practitioners and specialists need to be
familiar with the therapeutic needs of patients
with CKD/ESRD.
Dental Management of
Patients with CKD/ESRD
For successful management of patients with
CKD/ESRD, a dental practitioner needs to
develop a close collaboration with a nephrology
team. Appropriate clinical and pharmaceuti-
cal decisions and management depend on the
severity and staging of CKD. In CKD stages 1
to 4, the oral health practitioner has to follow
kidney function as measured by an eGFR as

well as other medical comorbidities in order to
understand the severity of kidney disease and to
increase patient awareness about periodontal
risk and prescribe medications accordingly. For
patients with CKD stage 5 or ESRD, the oral
health provider will have to know the dialysis
maintenance schedule as well as patient com-
pliance as it may affect access to dental care.
The majority of patients with renal diseases
have an underlying diagnosis of either diabe-
tes or hypertension. Therefore, they require
close monitoring of their vital signs (ie, blood
pressure and pulse) as well as their glycated
hemoglobin (HbA1c) levels. Ensuring stable
vital signs and controlled HbA1c levels will
improve periodontal therapeutic outcomes.
As kidney function becomes more compro-
mised, dental management needs to be adjusted
with more attention to drugs commonly used in
dentistry and metabolized and/or eliminated in
the kidney. More specifically, anti-inflammatory
drugs such as ibuprofen and aspirin should be
avoided in patients with an eGFR less than 30
mL/min/1.73 m2 as they may result in further
deterioration of kidney function, cause water
retention, and increase the risk of gastric hem-
orrhage. In addition, prolonged therapy with
anti-inflammatory medication is not recom-
mended for patients with an eGFR less than 30
mL/min/1.73 m2 . Alternatively, acetaminophen
could be used as an analgesic of choice in this
category of patients.
Antibiotic therapy is another important
consideration for patients with CKD/ESRD.
For patients with an eGFR less than 15 mL/
min/1.73 m2 , there is a high risk for crystalluria
when penicillin is administered. When amino-
glycosides, macrolides, and fluoroquinolones
are used in patients with an eGFR less than 30
mL/min/1.73 m2 , their dose should be reduced.
Antifungals is another class that should be
avoided in patients with an eGFR less than 30
mL/min/1.73 m2 .21
Once patients with CKD enter the ESRD stage
with an eGFR less than 15 mL/min/1.73 m2,
they require renal replacement therapy, which
includes hemodialysis, peritoneal dialysis, or
Dental Management of Patients with CKD/ESRD
kidney transplantation. Patients on hemodial-
ysis have vascular access to be able to connect
to the dialysis device in a frequency of three
treatments per week. Patients with ESRD on
hemodialysis usually receive anticoagulation
with unfractionated heparin (UFH) depending
on their bleeding risk.102 In cases where the
patient is determined to be at a high bleeding
risk (eg, patients with clotting factor disor-
ders), heparin-free hemodialysis is performed.
In the United States, UFH is administered in a
bolus dose of 50 IU/kg at the beginning of the
hemodialysis session followed by a constant
fixed infusion of heparin of 800 to 1,500 IU
per hour.102 Low–molecular weight heparin
(LMWH) is used to bridge other anticoagulants
prior to an invasive procedure. UFH has a short
half-life of 1 hour after the last infusion, while
LMWH’s half-life is two to four times higher.103
The notion that dental visits for patients on
hemodialysis take place on the day of dialysis
has not been supported by evidence.104 The
main factors to be considered when scheduling
dental appointments for patients on hemodi-
alysis include the type of dental procedure,
the presence of any bleeding disorder, UFH or
LMWH dosing, serum-activated partial throm-
boplastin time (aPTT), or activated clotting
time (ACT).103 Further, uremia has been shown
to affect platelet function, resulting in increased
bleeding tendency in ESRD.105 Depending on
the type of dental procedure (surgical versus
nonsurgical), the above factors become critical.
The aPTT measures the time needed for plasma
to clot, assessing the intrinsic and common
pathways of coagulation and recommended
for heparin therapy monitoring.102 The aPTT
shows a 2.5- to 3.5-fold increase compared to
its upper limit in patients on UFH and inde-
pendently predicts postoperative bleeding
complications following tooth extractions.106
However, this test is performed in a hospital
setting, limiting its utilization in outpatient
units. Although there is no evidence-based
recommendation on the dental management
of patients on hemodialysis, empirical evidence
has supported dental surgical visits the day of
187
8 The Association Between Oral Infections and Renal Disease
dialysis. The rationale for this practical sugges-
tion is based on the logistics of hemodialysis,
its treatment duration, the anticoagulation
half-life, and clearance depending on the anti-
coagulant medication and dose. However,
nonsurgical dental procedures could be sched-
uled on the same day without any reported
contraindications. In any case, the commu-
nication between dental and renal providers
becomes important in the decision-making
process. Because patients on peritoneal dialysis
receive their treatment through the abdomen
via a catheter at home,102 there are no special
hemorrhagic considerations for patients on
peritoneal dialysis.
Currently, there is no evidence-based recom-
mendation to use prophylactic antibiotics in the
dental management of patients with ESRD. In
addition, there is a lack of data on the dura-
tion and effects of transient bacteremia in ESRD
populations following dental intervention.
Transient bacteremia has been shown to resolve
in less than 20 minutes in systemically healthy
individuals.107 Given the risks related to antibi-
otic overutilization associated with the selection
of resistant microorganisms and reduced antibi-
otic efficacy, no prophylactic antibiotic has been
recommended for these populations.
Conclusion
CKD/ESRD is a global public health problem
involving high health care costs and is highly
188
associated with periodontitis. Although the
exact mechanism of this association has not
been elucidated, there are several potential
biologic hypotheses examining plausibility.
Evidence has demonstrated that periodontitis
contributes to the inflammatory burden in the
medically complex CKD/ESRD populations.
Therefore, periodontitis could be considered as
the hidden comorbidity of CKD/ESRD.
Focusing on anti-inflammatory strategies
in CKD/ESRD populations, therapies aim to
control several comorbidities related to med-
ical and demographic characteristics as well
as dialysis-related factors. In this context and
to control local and systemic inflammation,
periodontal therapeutic modalities have been
tested with a goal to improve periodontal and
systemic outcomes. Therefore, the prevention
and treatment of periodontitis could modify
oral and systemic inflammatory biomarkers
and improve the quality of life of patients with
CKD/ESRD. With this in mind, general practi-
tioners need to understand the needs of patients
with renal diseases, emphasize the importance
of oral care, and feel confident with the dental
management of patients with renal diseases.
Close collaboration with the renal team could
be instrumental in the selection of the appro-
priate pharmaceutical protocols according to
disease staging and residual renal function.
Additional considerations related to renal
replacement therapy need to be discussed with
the renal team to serve a multidisciplinary care
model for improved patient outcomes.

Clinical Considerations: What You Can Take Back to Your Practice
Is there a biologic plausibility for the associa-
tion between periodontal infections and renal
disease?  Although evidence is limited, there
are speculations that uremia, the main conse-
quence of renal disease, could modify the oral
environment, possibly promoting the growth of
periodontal pathogens, and also alter host in-
nate and adaptive immunity affecting infection
susceptibility. In addition, renal osteodystrophy
manifested by abnormal bone breakdown and
turnover in patients with renal diseases may
promote alveolar bone breakdown.
Are periodontal infections independent risk fac-
tors for the development of adverse systemic
outcomes in renal disease?  Limited evidence
has also shown that the presence of periodonti-
tis in patients with renal diseases may increase
all-cause and cardiovascular mortality rates.
Can periodontal therapy reduce the risk for the
development of adverse systemic outcomes in
renal disease?  There is not enough high-quality
evidence to support the hypothesis that peri-
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85. Needleman I, McGrath C, Floyd P, Biddle A. Impact of
oral health on the life quality of periodontal patients. J
Clin Periodontol 2004;31:454–457.
86. Teles RP, Haffajee AD, Socransky SS. Microbiological
goals of periodontal therapy. Periodontol 2000 2006;
42:180–218.
87. Magnusson I, Lindhe J, Yoneyama T, Liljenberg B.
Recoloni­zation of a subgingival microbiota following
scaling in deep pockets. J Clin Periodontol 1984; 11:
193–207.
88. Research, Science and Therapy Committee of the Amer-
ican Academy of Periodontology. Treatment of
plaque-induced gingivitis, chronic periodontitis, and
other clinical conditions. J Periodontol 2001; 72:
1790–1800.
89. Matuliene G, Studer R, Lang NP, et al. Significance of
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odontitis and tooth loss. J Clin Periodontol 2010; 37:
191–199.
90. Artese HP, Sousa CO, Luiz RR, Sansone C, Torres MC.
Effect of non-surgical periodontal treatment on chronic
kidney disease patients. Braz Oral Res 2010; 24:
449–454.
91. Wehmeyer MM, Kshirsagar AV, Barros SP, et al. A
randomized controlled trial of intensive periodontal ther-
apy on metabolic and inflammatory markers in patients
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92. Armitage GC. Effect of periodontal therapy on general
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93. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of peri-
odontitis and endothelial function. N Engl J Med 2007;
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94. Engebretson SP, Hyman LG, Michalowicz BS. Hemo-
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95. Offenbacher S, Beck JD, Moss K, et al. Results from
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96. Borgnakke WS, Chapple IL, Genco RJ, et al. The
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Based Dent Pract 2014;14:127–132.
97. Axelsson P, Lindhe J. Effect of controlled oral hygiene
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Results after 6 years. J Clin Periodontol 1981; 8:
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98. Lindhe J, Westfelt E, Nyman S, Socransky SS, Haffajee
AD. Long-term effect of surgical/non-surgical treatment
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99. Wilson TG Jr, Glover ME, Malik AK, Schoen JA, Dorsett
D. Tooth loss in maintenance patients in a private peri-
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100. Seliger SL. Comorbidity and confounding in end-stage
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disorders in uremia. Semin Nephrol 2006;26:46–51.
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117:3118–3125.

The Association Between
Oral Infections and
Pulmonary Disease
Karren Komitas, dmd, phd, mdsc
Effie Ioannidou, dds, mds
Periodontitis is one of the most common
human inflammatory diseases, with an over-
all prevalence estimated at 42% in the United
States.1 Annual direct and indirect expenses
associated with periodontitis and periodontal
treatment worldwide are estimated at several
hundred billion USD.2 Therefore, periodontitis
represents a substantial health care and eco-
nomic burden, and considerable efforts have
been made during the past several decades to
gain insight into the factors associated with its
etiology and progression.
Current scientific evidence suggests that
periodontal pathogens contained in the dental
plaque of a susceptible individual lead to the
development of periodontitis.3 The National
Health and Nutrition Examination Survey
(NHANES) studies have also shown that envi-
ronmental factors, such as smoking, should be
considered as risk factors for the development
and progression of periodontitis.4,5 In addi-
tion, various contributory factors, including
but not limited to age, neglected oral hygiene,
and poorly controlled systemic diseases (such
as diabetes mellitus), represent significant pre-
dictive covariates associated with periodontal
breakdown.3,6,7 These local, environmental, and
systemic factors are especially relevant in older
adults, as they have increased prevalence of
periodontitis1 and systemic diseases8 and have
CHAPTER 9
been exposed to hazardous environmental
factors for longer than the general popula-
tion. Therefore, a better understanding of the
mechanisms linking periodontitis and systemic
diseases is essential for the development of
innovative treatment approaches to minimize
the prevalence of these diseases and provide
better treatment outcomes.
This understanding is essential for dental
practitioners, physicians, and other health
care personnel who depend on effective
evidence-based treatment protocols. As mul-
tiple studies have explored whether or not
periodontitis is an independent risk factor for
systemic diseases (and vice versa), the goal
of this chapter is to provide an overview of
pulmonary diseases (including pneumonia
and chronic obstructive pulmonary disease
[COPD]) and demonstrate the current evidence
of the association between pulmonary disease
and oral infections in patients with periodonti-
tis. This chapter focuses on pulmonary diseases,
as they represent one of the most clinically
significant respiratory health care entities. In
addition, some similarities in the mechanisms
of development and/or progression of the pul-
monary diseases and periodontitis suggest that
elimination of the etiologic factors can provide
a substantial improvement in treatment out-
comes for both of these disease entities.
193
9 The Association Between Oral Infections and Pulmonary Disease
Definition, Classification, and
Manifestation of Pulmonary
Diseases
Pneumonia
Pneumonia is an acute infection of the lung
parenchyma and is the most common lower
respiratory tract infection.9 Clinically, it is char-
acterized by acute symptoms and signs of lower
respiratory tract infection without other appar-
ent causes, dyspnea, cough, fever, and in some
cases a headache, confusion, upper respiratory
involvement, and skin changes.10 Macro-
scopically, inflammation is characterized by
nonspecific inflammatory events, including red-
ness, swelling, heat, pain, and loss of function.
Microscopically, typical signs of inflammation,
such as vasodilation, increased vascular perme­
ability, and resulting infiltration of inflammatory
cells can be observed.11,12 Chronic inflammation
as a result of an incomplete resolution of acute
inflammation is characterized predominantly by
recruitment of macrophages and lymphocytes
engaged in the elimination of necrotic debris
and apoptotic cells to prevent further spread of
persistent infection.12
Based on a patient’s age, pneumonia can be
classified into childhood and adult categories.
The most recent classification of childhood
pneumonia from 2014 includes “pneumonia”
and “severe pneumonia.”13 This chapter focuses
on periodontitis, which in an overwhelming
majority of cases occurs in adults, so our
review is aimed at discussion of adult pneumo-
nia. Although various types of classifications
for adult pneumonia have been proposed,9 the
American Thoracic Society and the Infectious
Diseases Society of America propose the fol-
lowing classification according to the site of
acquisition.
Hospital-acquired pneumonia
Health care–associated pneumonia. The first
category of hospital-acquired pneumonia
194
(HAP, or nosocomial pneumonia) is health
care–associated pneumonia (HCAP). HCAP
is defined as pneumonia that occurs in any
patient who has been (1) hospitalized in an
acute care hospital for two or more days within
90 days of infection; (2) resided in a nursing
home or long-term care facility; (3) received
recent intravenous antibiotic therapy, chemo-
therapy, or wound care within the past 30
days of the current infection; or (4) attended a
hospital or hemodialysis clinic.14 HAP is cate-
gorized into ventilator-associated pneumonia
and aspiration pneumonia.
Ventilator-associated pneumonia. Ventilator-
associated pneumonia (VAP) is defined as
pneumonia that occurs at least 48 hours after
endotracheal intubation and initiation of
mechanical ventilation.15 According to a sys-
tematic review that included nine publications,
VAP is the most common subcategory of HAP,
occurs in 10% to 20% of patients who undergo
mechanical ventilation, and is associated with
a longer hospital stay and increased financial
costs.15 The same study also showed that VAP
is associated with one of the highest mortality
rates, ranging between 20% and 55%.16
Aspiration pneumonia. Aspiration pneumonia
(AP), a commonly occurring type of HAP, is
an acute lung infection due to inhalation of
large-volume bacteria-colonized oropharyn-
geal material that leads to the development of
a radiographic infiltrate,17,18 although various
alternative definitions have been proposed.19
AP constitutes approximately 5% to 15% of
all pneumonia cases and affects 300,000 to
500,000 individuals in the United States annu-
ally.17,18 Up to 50% of healthy individuals can
aspirate small volumes of oropharyngeal secre-
tions during sleep, but due to the low virulence
of these secretions and adequate cellular and
humoral host immune mechanisms, these aspi-
rations do not lead to an acute inflammatory
response (“silent aspirations”).18,20 A study that
included 259 Japanese older adults receiving
nursing care (aged 65 to 74 years, 75 to 89
 Definition, Classification, and Manifestation of Pulmonary Diseases
years, and 90 years and older) showed that
the prevalence of AP is similar among younger
and older individuals.21 Commonly reported
risk factors for AP include male sex, intubation,
dehydration, sputum suctioning, gastroesopha-
geal reflux, and dysphagia as a consequence of
various cerebrovascular and neurodegenerative
conditions (such as Alzheimer’s disease, Par-
kinson’s disease, dementia, multiple sclerosis,
and stroke).21–24
Community-acquired pneumonia
Community-acquired pneumonia (CAP) is the
second most common type of pneumonia in
the United States and worldwide, which can
occur in any individual living in a commu-
nity.25 Epidemiologic studies have shown that
CAP remains the most common cause of death
from infectious diseases among the elderly
population.26 The annual incidence of CAP is
estimated to be 25 to 44 cases per 1,000 indi-
viduals,27 and it can occur at any age. A study
that included 46,000 older adults showed that
individuals aged 85 years and older have almost
a three-fold greater incidence of CAP compared
to those aged 65 to 69 years (59.3 versus 18.2
cases per 1,000 person-years, respectively).28 A
recent prospective, population-based study of
hospitalized adults with CAP showed that the
annual incidence of CAP is 24.8 per 10,000
adults and that adults aged 50 to 64 years,
65 to 79 years, and 80 years and older have
4.0, 9.0, and 25.0 times greater incidence of
CAP as compared to 18- to 49-year-old adults,
respectively.29 In addition to age, other indepen-
dent CAP risk factors include male sex, COPD,
bronchial asthma, history of pneumonia, con-
gestive heart failure, and smoking.28,30
The microbiota of older adults with CAP
and HCAP predominantly consists of Strep-
tococcus pneumoniae (approximately 30% to
58%), Haemophilus influenzae (approximately
14%), Staphylococcus aureus (approximately
4% to 7%), and Pseudomonas aeruginosa
(approximately 1% to 5%).27 A variety of
oral and periodontal pathogens, including
Fusobacterium nucleatum, Prevotella mela-
ninogenica, Streptococcus intermedius, and
Clostridium species, have been identified in
bronchoalveolar lavage samples of patients
with CAP.31 In addition to bacterial pathogens,
viruses, including rhinovirus, influenza A or B,
and parainfluenza viruses, can also be isolated
from nasopharyngeal, oropharyngeal, or spu-
tum samples of these patients.27,29
Chronic obstructive pulmonary
disease
COPD is a chronic pulmonary disease charac-
terized by persistent respiratory symptoms and
airflow limitation due to airway and/or alveolar
abnormalities.32 In 2010, the global prevalence
of COPD was estimated at 11.7%,33 making it
the fourth leading cause of death worldwide34;
COPD is expected to become the third leading
cause of death worldwide by 2030, account-
ing for 8% of deaths.35 In the United States,
700,000 hospital admissions and 124,000
deaths occur due to COPD annually.36 Clin-
ically, COPD is manifested as dyspnea, chest
inflation, chronic cough, sputum production,
wheezing, and chest tightness. Macroscopically,
COPD is characterized by the destruction of
lung parenchymal tissues, the breakdown of
lung framework, increased size and numbers
of pores of Kohn (small fenestrae in alveolar
walls), and thickening of the airway epithe-
lial layer due to chronic inflammation.37–39
Microscopically, it is presented as epithelial
cell metaplasia, immune cell infiltration, and
peribronchial fibrosis.37,39 Smoking is consid-
ered the most important risk factor, whereas
chronic exposure to environmental factors
(such as air pollution, biomass fuel exposure,
occupational dust, and home cooking smoke)
and genetic factors (such as congenital abnor-
mal lung development, accelerated aging, and
family history of COPD) are considered con-
tributory factors.32
Prior to 2017, COPD was diagnosed only
spirometrically when a postbronchodilator
195
9 The Association Between Oral Infections and Pulmonary Disease
Tiffeneau-Pinelli index (FEV1/FVC, or a pro-
portion of a person’s vital capacity that he or
she is able to expire in the first second of forced
expiration to the full vital capacity) was less
than 0.70.32 In 2017, the Global Initiative for
Chronic Obstructive Lung Disease (GOLD)
updated its diagnostic criteria and classification
for COPD, which also took into consideration
a patient’s respiratory symptom and exacer-
bation history (which are the main targets for
treatment). Once the initial diagnosis of COPD
is established spirometrically (FEV 1/FVC
< 0.70), four distinct groups of COPD can
be identified based on the severity of clinical
symptoms using exacerbation history, mMRC
(modified British Medical Research Council
questionnaire), and CAT (COPD Assessment
Test) criteria40:
• Group A: Exacerbation history 0–1; mMRC
0–1; CAT < 10
• Group B: Exacerbation history 0–1; mMRC
≥ 2; CAT ≥ 10
• Group C: Exacerbation history > 1; mMRC
0–1; CAT < 10
• Group D: Exacerbation history > 1; mMRC
≥ 2; CAT ≥ 10
Based on these criteria, patients from groups
A and B do not require hospital admission;
patients from groups C and D do. Treatment of
COPD includes but is not limited to smoking
cessation (for current smokers), bronchodila-
tors (such as β2 agonists, antimuscarinic drugs,
and methylxanthines), and anti-inflammatory
drugs (such as inhaled corticosteroids, gluco-
corticoids, and antibiotics).40
In addition to the GOLD classification,
COPD can also be classified as chronic bron-
chitis, emphysema, and small-airway disease.41
Clinically, chronic bronchitis is characterized
by cough and sputum production; emphy-
sema is characterized by enlarged distal air
spaces distal to terminal bronchioles due to
the destruction of the airway walls, whereas
small-airway disease is caused by obstruction
of smaller conducting airways.41,42
196
Epidemiologic Association
Between Periodontitis and
Pulmonary Diseases
Similar to periodontitis, pulmonary diseases are
inflammatory diseases of polymicrobial nature,
sharing similar cellular and molecular mech-
anisms of development and progression.43 In
addition, these diseases share similar contrib-
utory and risk factors, including smoking and
diseases with impaired neutrophil function,44
thus raising a biologic plausibility for the asso-
ciation between these conditions.
During the past two decades, accumulat-
ing evidence in the literature has suggested
increased prevalence of pulmonary diseases
(pneumonia and COPD) in patients with peri-
odontitis. Early studies have demonstrated
that patients with AP have a higher plaque
index and periodontal score.45 Further, a
case-control study that included 22 patients
with HAP and 81 non-HAP controls (all 103
individuals had periodontitis) showed that
the prevalence of periodontitis (defined as
≤ four teeth with ≤ one site showing probing
pocket depth [PPD] ≥ 4 mm, clinical attach-
ment loss [CAL] ≥ 3 mm, and bleeding on
probing) was significantly greater in patients
with HAP (adjusted odds ratio [OR]: 3.67;
95% confidence interval [CI]: 1.01–13.53;
P < .05).46 A recent 7-year prospective cohort
study that included 211 Japanese patients
undergoing hemodialysis (mean patient age
64.4 years) demonstrated that HCAP mortal-
ity (although the authors did not specify the
exact type of HCAP) is significantly associated
with the presence of periodontitis (defined as
CAL ≥ 4 mm in ≥ 30% of the probed sites)
(confounder-adjusted hazard ratio [HR]: 3.03;
95% CI: 1.14–10.64; P < .05).47 A 4-year
study of 672 older Japanese adults (mean age
80 years) has shown that the presence of 10 or
more teeth with PPD greater than 4 mm is asso-
ciated with significantly greater mortality from
AP compared to patients with AP and health-
ier periodontium (confounder-adjusted HR:
 Mechanisms for Increased Association of Periodontitis and Pulmonary Diseases
3.9; 95% CI: 1.1–13.9; P < .05).24 However,
these conclusions should be taken with caution
considering an extremely wide CI with a low
limit of only 1.1. Similar to studies on pneu-
monia, a systematic review with meta-analysis
of 14 publications that included 3,988 patients
with COPD and 22,871 non-COPD controls
showed that patients with periodontitis have
significantly greater prevalence of COPD (OR:
2.08; 95% CI: 1.48–2.9; P < .001).48
Similarly, a number of studies, including
large-scale studies, have assessed the prevalence
of periodontitis in patients with pulmonary dis-
eases (primarily COPD). Based on NHANES
III data that included 7,625 participants, no
significant association has been found between
COPD and periodontitis (defined at CAL ≥ 4
mm), unless current smoking is included as
a cofactor (OR: 3.71; 95% CI: 1.74–7.89;
P < .01).49 A Korean NHANES study from
2010 to 2012 of 697 patients with COPD and
5,181 non-COPD controls demonstrated that
patients with COPD have significantly greater
prevalence of periodontitis (defined as PPD
≥ 3.5 mm) (58.1% versus 34.0%, respectively;
P < .001) and significantly fewer teeth (21
versus 24.5, respectively; P < .001) compared
to patients without COPD after adjust-
ment for other confounders.50 A nationwide
population-based cohort study that included
22,232 Taiwanese patients with COPD and
43,762 non-COPD controls reported that
patients with COPD have a minor but statis-
tically significant increase in the prevalence of
periodontitis (OR: 1.20; 95% CI: 1.15–1.25;
P < .001) that is not associated with sex, age,
or comorbidities.51 Similar findings have been
reported by various smaller-scale studies.52–54
Taken together, these studies show that
patients with periodontitis have statistically
significant greater prevalence of pulmonary dis-
eases, and the outcomes of pulmonary diseases
in patients with periodontitis are more adverse
compared to those with healthier periodontium.
In addition, patients with pulmonary diseases
(primarily COPD) also have statistically signif-
icant greater prevalence of periodontitis.
Mechanisms for Increased
Association of Periodontitis
and Pulmonary Diseases
Although the exact pathophysiologic
mechanisms that predispose patients with peri-
odontitis to pulmonary diseases (pneumonia
and COPD) have yet to be identified, several
possible mechanisms have been proposed in
the literature.55–58
Periodontitis and pneumonia
Extravascular mode
Direct aspiration of periodontal and/or respi-
ratory pathogens into the lower respiratory
tract, or transmission of oral pathogens during
mechanical ventilation and intubation. The
human oral cavity is colonized with over 700
bacterial species localized in the mucosal sur-
faces, saliva, and teeth. Saliva contains 108 to
109 bacteria per mL, which have a high ten-
dency to attach to the teeth and form dental
plaque, a highly complex and organized bio-
film containing over 100 different bacterial
species and therefore serving as a reservoir for
opportunistic pathogens.59 The total counts of
pathogens in the dental plaque can reach 1011
to 1012 per gram.60
Because saliva is a major component of
AP microaspirations, salivary bacteria have
been suggested to predispose older patients or
those with immunocompromised conditions to
develop pneumonia. Colonization of the respi-
ratory tract with oropharyngeal bacteria is an
undesired but often inevitable event during AP
or VAP61 and therefore can serve as a possible
way of dissemination of periodontal pathogens
into the lungs. Aspirated pathogens in contact
with the respiratory epithelium can produce a
variety of inflammatory mediators, including
reactive oxygen species and cytokines that will
recruit immune cells to the site of contact and
stimulate mucus secretion by lung goblet cells,
resulting in tissue inflammation.12 Early studies
197
9 The Association Between Oral Infections and Pulmonary Disease
examining sputum and transtracheal samples
from older adult veterans have demonstrated
that in addition to respiratory pathogens (such
as S pneumoniae and S aureus), these samples
contain periodontitis-associated pathogens,
including Prevotella intermedia and F nuclea-
tum.45 This suggests that periodontal pathogens
can colonize the lungs when aspirated, thus
possibly resulting in inflammation and AP.17
Using 16S and quantitative polymerase
chain reaction (qPCR) approaches, a recent
study that included 18 patients with periodon-
titis demonstrated that similar to subgingival
plaque, the saliva of these patients contained
readily detectable counts of periodontal patho-
gens, including Porphyromonas gingivalis,
Treponema denticola, Tannerella forsythia,
P intermedia, and Parvimonas micra.62 The
same study also reported that saliva lacks
periodontal pathogens if they are not detected
in the subgingival samples, suggesting that
pathogens contained in subgingival plaque of
patients with periodontitis can shed into the
saliva. Similarly, another study using the qPCR
approach that included 462 patients with mod-
erate and severe periodontitis demonstrated a
significantly greater prevalence of salivary peri-
odontal pathogens (P gingivalis, T forsythia,
and P intermedia) compared to the saliva of
individuals with healthy periodontium.63
A recent prospective human study using the
qPCR approach with 42 patients with pneumo-
nia (predominantly HAP) demonstrated that
periodontal pathogens, such as P gingivalis, P
intermedia, and F nucleatum can be detected
in respiratory tract specimens in 31% to 57%
of patients, suggesting a possibility that peri-
odontal pathogens can proliferate in the lower
respiratory tract.64 The attempt to further
explore this possibility has been performed in a
systematic review of one case-control and four
prospective cohort studies.57 However, the lack
of properly designed randomized controlled
trials (RCTs) included in this systematic review
makes its conclusions debatable.
Another series of studies aimed to exam-
ine the possibility that inflammatory changes
198
during pneumonia (mostly VAP and AP) can
be triggered not only by periodontal pathogens
but also by respiratory pathogens contained
in dental plaque aspirated with saliva. Early
prospective nonrandomized study of 34 older
adults admitted to the intensive care unit (ICU)
demonstrated that more of these patients har-
bored S aureus and P aeruginosa in the dental
plaque compared to a group of 25 systemi-
cally healthy dental patients.65 A 3-month
study that included 57 ICU-admitted patients
showed that they tend to accumulate more
dental plaque upon admission, and it is sig-
nificantly associated with the occurrence of
HCAP and bacteremia.66 Using a pulsed-field
gel electrophoresis approach, it has further
been demonstrated that respiratory pathogens
(S aureus, P aeruginosa, and Acinetobacter
species) isolated from the supragingival
plaque samples are genetically indistinguish-
able from the respiratory pathogens isolated
from lungs of ICU-admitted patients with
VAP.67 Using a checkerboard DNA–DNA
hybridization approach, it has been demon-
strated that dental plaque of patients with
periodontitis contains readily detectable counts
of pneumonia-associated pathogens, such as S
aureus.68 This may further suggest a common
environmental source of infection and that the
dental plaque can serve as a reservoir for respi-
ratory pathogens.69
Advances in microbiologic techniques during
the last few decades have allowed detection and
quantification of microbiota with much higher
precision. Using 16S rRNA gene sequencing in
a group of 12 patients with VAP, it has been
shown that the 20 most abundantly detected
dental plaque pathogens are also potential
respiratory pathogens, including S pneumo-
niae (the most abundant species), Enterococcus
hirae, F nucleatum, S aureus, P aeruginosa, and
H influenzae.70 Similarly, a study that included
107 patients with VAP showed that S aureus
and P aeruginosa have been readily detected
in supragingival plaque samples.71 Interest-
ingly, S aureus and P aeruginosa have been
primarily detected during hospitalization, as
 Mechanisms for Increased Association of Periodontitis and Pulmonary Diseases
a large percentage of patients do not harbor S
aureus and P aeruginosa prior to intubation,
and many of them do not harbor S aureus and
P aeruginosa after extubation.71 This suggests
that the presence of these pathogens can be
due to their dissemination during intubation
because they are typically not associated with
healthy oral microflora and represent patho-
gens commonly found in patients with chronic
periodontal and pulmonary diseases. A recent
human RCT study of 16 ICU-admitted patients
with VAP used DNA sequencing to evaluate
the changes in the composition of oral and
dental plaque microbiota upon admission
and demonstrated a rapid colonization of oral
mucosa with methicillin-resistant S aureus and
Klebsiella pneumoniae.72
Because a large proportion of patients with
pneumonia are older adults, many of them
wear partial dentures, thus raising concern
about denture plaque accumulation. Using
a culture technique, a cross-sectional study
that included 138 older Japanese adults with
poor oral hygiene showed that dentures are
populated with respiratory pathogens, predom-
inantly Streptococcus (approximately 85% of
samples) and Neisseria (approximately 50%)
species.73 A recent study using qPCR analysis
that included 130 older nonpneumonia Scot-
tish adults (mean age 70.4 years and average
denture age of 4.5 years) demonstrated that
in 65% of patients, partial dentures harbored
potential respiratory pathogens, including P
aeruginosa (most abundant), S aureus, S pneu-
moniae, H influenzae, and other species.74
Interestingly, a 3-year study that included
524 older Japanese adults (mean age 87.8
years) showed that patients who wore partial
dentures during night sleep have a 1.5-fold
increase in the incidence of AP compared to
those who did not have this habit (HR: 2.38;
95% CI: 1.25–4.56; P < .05).75 In addition,
the patients who wore partial dentures during
night sleep had poorer oral hygiene compared
to those who did not wear dentures during
night sleep. This was evidenced by a signifi-
cantly greater percentage of patients with
denture-adhered plaque, significantly lower
use of denture cleaners, and significantly fewer
dental visits compared to patients who did not
wear dentures during sleep (P < .05 for all
comparisons).75 These results further suggest
that poor oral hygiene associated with wear-
ing dentures while sleeping can lead to the
increased prevalence of AP.
In addition to human clinical studies, several
animal studies have shown that intratracheal
inoculation of periodontal pathogens (such
as P gingivalis and T denticola) results in the
development of high-mortality pneumonia,
increased levels of proinflammatory mediators,
and activation of toll-like receptor 2 (TLR-2)
signaling.76–79 These results further support the
biologic plausibility of AP and VAP induced by
periodontal pathogens.
Taken together, these data indicate that
periodontal pathogens contained in dental
plaque and saliva can disseminate into the
lungs with microaspirations. In addition, older
adult patients (especially those with dentures)
tend to accumulate greater amounts of dental
plaque that contains not only periodontal but
also respiratory pathogens. Thus, these mech-
anisms contribute to the development of AP in
susceptible individuals.
Damage or modification of the epithelial lin-
ing of the lungs. It has been proposed that
periodontal pathogens could facilitate colo-
nization of respiratory pathogens and induce
respiratory inflammation via several possible
mechanisms.58 For example, periodontal patho-
gens could modify the lining of the respiratory
epithelium by altering the transmembrane
receptors on the surface of target mucosal cells
to promote adhesion of pulmonary pathogens
promoting inflammation. Using a human-
ized bronchial xenograft model in nude mice
and human airway epithelial cell cultures, a
study showed that an S aureus strain deficient
of fibronectin-binding protein is decreased
five-fold compared to a nonmutant S aureus
strain.80 Because saliva contains enzymes capa-
ble of fibronectin degradation81 and fibronectin
199
9 The Association Between Oral Infections and Pulmonary Disease
is a component of the extracellular matrix,82
it is suggested that during aspiration of saliva,
these enzymes are capable of damaging
fibronectin and alleviating penetration of respi-
ratory pathogens into the underlying tissues.
Current evidence for this mechanism linking
periodontitis and pneumonia is uncertain.
Intravascular mode
Hematogenous bacterial dissemination of
periodontal pathogens during periodontal
treatment. As discussed previously, periodontal
pathogens can trigger respiratory inflamma-
tion.76,77,79 Because gingival bleeding is one of
the earliest signs of gingivitis and periodonti-
tis, and because bacteremia can be observed in
patients with gingivitis and periodontitis imme-
diately following tooth brushing,83 periodontal
probing,84 ultrasonic scaling,85 and scaling and
root planing (SRP),86 the increased prevalence
of pneumonia in patients with periodontitis
can be due to hematogenous dissemination
of periodontal pathogens to the lungs. This
assumption has been supported by a system-
atic review of nine cross-sectional studies that
included 219 patients with periodontitis that
showed that periodontal pathogens can be
cultured from blood samples of these patients
following periodontal procedures.87 In addi-
tion, a study that included 25 patients with
periodontitis demonstrated the presence of
intact P gingivalis within the blood dendritic
cells of these patients for 24 hours.88
However, the clinical significance of bacter­
emia in the possible development of distant
inflammation foci is unclear. Bacteremia is a
transient event, even after periodontal proce-
dures, and the host immune system eliminates
bacteria from the blood within 20 to 30 min-
utes after the procedure.86,89 A systematic
review with meta-analysis of seven studies
demonstrated a lack of statistically significant
association between the patient’s periodon-
tal status and bacteremia following tooth
brushing.83 Although it is possible that in sus-
ceptible older or immunocompromised patients
200
bacteremia may be persistent and therefore
can lead to inflammatory events in the lungs,
current evidence supporting this assumption
is unclear.
Release of periodontal pathogen toxins and
proinflammatory cytokines in the systemic
blood circulation. Although dental plaque is
considered an etiologic factor for periodonti-
tis, pathogenesis and concomitant destruction
of periodontal tissues are driven by the com-
plex interaction between various types of
immune cells and mediators that regulate this
delicate process.90 Among these regulators are
cytokines, which are secreted polypeptides
produced by various types of cells and exert
pleiotropic effects on immunity and inflam-
mation.90 A recent systematic review with
meta-analysis that included up to 15 studies
demonstrated that the levels of proinflamma-
tory cytokines (interleukin 1 [IL-1], tumor
necrosis factor alpha [TNF-α]) in gingival
crevicular fluid are significantly increased, but
the magnitude of these increases is modest,
and a high degree of bias has been observed in
some publications.91 A recent cross-sectional
study that included 239 patients with
periodontitis demonstrated a statistically sig-
nificant association between serum levels of
proinflammatory cytokines (TNF-α , interferon
gamma [INF-γ]) and the number of teeth with
CAL ≥ 6 mm.92
However, the clinical significance of ele-
vated serum cytokine levels in patients with
periodontitis and their negative impact toward
the development of pneumonia has yet to be
understood. Similar to periodontitis, increased
levels of proinflammatory cytokines have been
detected in the serum of patients with CAP,
and they positively correlated with the sever-
ity of the respective diseases.93 However, there
is currently no evidence in the literature that
demonstrates a direct causative effect of the
increased serum cytokine levels in patients
with periodontitis on the development of
pneumonia.
 The Effects of Antimicrobial Oral Hygiene Treatment on Outcomes of Pulmonary Disease
Periodontitis and COPD
Although the detailed underlying mechanisms
of the increased association between periodon-
titis and COPD have not been described in the
literature, it appears that environmental factors
play a crucial role in this relationship. As dis-
cussed previously, smoking is considered the
most significant risk factor for both periodon-
titis and COPD, and it can induce inflammation
via a variety of mechanisms.94,95 Multiple studies
have demonstrated that smoking is significantly
associated with the prevalence of periodontitis95
and poorer outcomes of periodontal treat-
ment.96 In addition, a recent systematic review
with meta-analysis of six studies reported
that not only smoking but also environmental
tobacco smoke lead to the increased prevalence
of periodontitis (OR: 1.34; 95% CI: 0.93–1.94;
P > .05) and tooth loss (OR: 1.33; 95% CI:
0.52–3.40; P > .05).97 Another recent system-
atic review with meta-analysis of 42 studies
that included 547,391 participants showed
that the prevalence of COPD is highest in
smokers and former smokers and decreased
in never-smokers.98 Interestingly, an NHANES
III–based study that included 7,625 participants
(993 patients with COPD and 6,632 non-COPD
controls) demonstrated that the increased prev-
alence of periodontitis (defined as CAL > 4
mm) in patients with COPD occurs only in cur-
rent smokers (OR: 3.71; 95% CI: 1.78–21.66;
P ≤ .01), especially in cases of moderate and
severe COPD (OR: 6.21; 95% CI: 1.74–7.89;
P ≤ .01), whereas no significant differences
are observed for former and never-smokers.49
Nevertheless, these conclusions should be taken
with caution considering the extremely wide CI
with a low limit of only approximately 1.8. Sim-
ilarly, another systematic review that included
five studies (1,401 patients with COPD and
1,158 non-COPD controls) demonstrated that
the significant association between periodonti-
tis (evidenced by increased plaque index) and
COPD occurs in current smokers (OR: 3.99;
95% CI: 2.58–6.16; P < .001) but not in for-
mer smokers and never-smokers.99
A few alternative mechanisms for the asso-
ciation between periodontitis and COPD
have been reported. An older study suggested
that emphysema (one of the clinical entities
of COPD) and periodontitis are initiated by
deposition of foreign material, leading to acti-
vation of neutrophils, release of neutrophil
proteinases, and connective tissue destruc-
tion.100 In 2013, the Joint European Federation
of Periodontology/American Academy of Peri-
odontology Workshop on Periodontitis and
Systemic Diseases proposed that hematogenous
dissemination of dental plaque organisms and
inflammatory mediators from periodontal
pockets to the lungs might occur and mod-
ify the inflammatory status of patients with
COPD.101 However, current evidence in the lit-
erature that supports these mechanisms linking
periodontitis and COPD is unclear.
Taken together, currently available evi-
dence in the literature suggests that the direct
aspiration of saliva containing periodontal
pathogens appears to be the most plausible
mechanism explaining the increased prevalence
of pneumonia in patients with periodontitis.
In addition, scientific evidence suggests that
smoking may be a key factor linking peri-
odontitis and COPD. Although an underlying
biologic and physiologic rationale exists for
other mechanisms reviewed earlier, the lack of
scientific evidence to support these assump-
tions, especially demonstrated in the literature
during the past two decades, makes their role
in linking periodontitis and pulmonary dis-
eases unlikely.
The Effects of Antimicrobial
Oral Hygiene Treatment on
Outcomes of Pulmonary
Disease
The oral health of older adults in nursing
homes is considered less adequate than that
of the general population.102 Therefore, dental
201
9 The Association Between Oral Infections and Pulmonary Disease
plaque can be an important confounding fac-
tor for the increased prevalence of pulmonary
diseases in this group of patients. Considering a
positive association between periodontitis and
pulmonary diseases, various studies have aimed
to examine the role of oral hygiene interven-
tions in the prevalence of pulmonary diseases
and associated financial cost and morbidity.
Pneumonia
There is high-quality evidence in the litera-
ture that the use of chlorhexidine mouthwash
adjunct to mechanical oral hygiene procedures
exerts a substantial effect on the reduction in
the amount of dental plaque in patients with
gingivitis and periodontitis.103,104 Consider-
ing these positive effects of chlorhexidine in
patients with periodontitis, the US Centers for
Disease Control and Prevention developed an
intensified oral hygiene protocol to minimize
the risk of complications of HAP in patients
with periodontitis.14 This protocol includes
oropharyngeal cleaning and decontamina-
tion with an antiseptic agent (most commonly
chlorhexidine) as well as development and
implementation of a comprehensive oral
hygiene program for patients at high risk for
developing pneumonia.
Several systematic reviews with meta-analysis
have examined the effect of the intensified oral
hygiene protocol on the incidence of pneumo-
nia and pneumonia-associated morbidity and
mortality and reported contradictory results.
The first set of studies showed that intensified
oral hygiene did not have significant clinical
effects on patients with pneumonia compared
to control subjects who followed the routine
oral hygiene protocol. A study that included
four RCTs (a total of 1,202 patients) reported
that the use of 0.12% to 0.2% chlorhexi-
dine mouthwash or gel does not significantly
impact the incidence of HAP (OR: 0.42; 95%
CI: 0.16–1.06; P > .05) or HAP-associated
mortality (OR: 0.77; 95% CI: 0.28–2.11;
P > .05).105 Another study that included four
RCTs (a total of 828 patients) showed that
202
patients with VAP who used 0.12% chlor-
hexidine with or without tooth brushing had
similar incidence of VAP (relative risk [RR]:
0.77; 95% CI: 0.50–1.21; P > .05) and ICU
mortality (RR: 0.88; 95% CI: 0.70–1.10;
P > .05) compared to those who followed a
routine oral hygiene protocol.106 A study that
included seven RCTs (a total 2,144 patients)
demonstrated that the intensified oral hygiene
protocol using antiseptics does not affect the
incidence of VAP-associated mortality (RR:
0.96; 95% CI: 0.69–1.33; P > .05).107 A
study that included 5 to 18 RCTs (a total of
up to 2,451 patients) showed that the intensi-
fied oral hygiene protocol with chlorhexidine
mouthrinse or gel has no significant effect on
VAP-associated mortality (RR: 1.09; 95% CI:
0.95–1.23; P > .05), duration of mechanical
intervention (mean difference [MD]: –.09
days; 95% CI: –1.73–1.55 days; P > .05), and
duration of ICU stay (MD: 0.21 days; 95%
CI: −1.48–1.89 days; P > .05).108 Finally, a
study that included five RCTs (a total of 3,490
patients) showed that the intensified oral
hygiene protocol (performed by nursing home
personnel or dentists/dental hygienists) in older
adults in hospitals and nursing homes leads
to only weak reduction in the HAP-associated
mortality rate compared to routine oral care
(RR: 0.80; 95% CI: 0.49–1.31; P > .05).109
Interestingly, this study also showed that the
outcome of the intensified oral hygiene proto-
col on incidence of HAP is almost three-fold
as efficient when performed by dentists/den-
tal hygienists (RR: 0.43; 95% CI: 0.25–0.75;
P < .05) compared to nursing home person-
nel (RR: 1.20; 95% CI: 0.97–1.48; P > .05).
Although these studies failed to demonstrate
positive effects of the intensified oral hygiene
protocol, almost all outcomes of these studies
did not reach statistical significance.
On the other hand, another set of systematic
reviews with meta-analysis showed the positive
outcomes of the intensified oral hygiene pro-
tocol in patients with pneumonia compared
to control subjects who followed the routine
oral hygiene protocol. A study that included

five RCTs demonstrated that the intensified oral
hygiene protocol significantly decreased the
incidence of HAP (OR: 3.0; 95% CI: 2.1–4.4;
P < .05).110 Another study that included seven
RCTs (a total of 2,144 patients) showed that the
intensified oral hygiene protocol using chlor-
hexidine resulted in significant reduction in the
incidence of VAP (RR: 0.56; 95% CI: 0.39–
0.81; P < .05)107; however, this study failed
to demonstrate any benefit of intensified oral
hygiene with antiseptics on VAP-associated mor-
tality. A study that included 18 RCTs (a total of
2,451 patients) showed that the intensified oral
hygiene protocol with chlorhexidine mouthrinse
or gel significantly reduced the incidence of VAP
(RR 0.75; 95% CI 0.62–0.91; P < .01),108 but
this study also failed to demonstrate any effect
of this protocol on VAP-associated mortality.
Another study that included 12 RCTs (a total
of 2,341 patients) also showed that the inten-
sified oral hygiene protocol with chlorhexidine
significantly reduced the incidence of VAP (RR:
0.72; 95% CI: 0.55–0.94; P < .05), but the
use of povidone iodine antiseptic mouthwash
had no effect (RR: 0.39; 95% CI: 0.11–1.36;
P > .05).111 A study that included 13 RCTs (a
total of 1,640 patients) showed that the inten-
sified oral hygiene protocol with chlorhexidine
significantly reduced the incidence of VAP only
at 2% concentration (RR: 0.53; 95% CI: 0.31–
0.91; P < .05), but not at 0.12% (RR: 1.0; 95%
CI: 0.51–1.99; P > .05) or 0.20% (RR: 0.63;
95% CI: 0.32–1.22; P > .05) concentration.112
A study that included four RCTs (a total of
1,009 patients) on patients with AP reported
that the intensified oral hygiene protocol pro-
vided by nursing home personnel and dentists/
dental hygienists is associated with a reduced
risk for the development of HAP (RR: 0.61;
95% CI: 0.40–0.91; P < .05) and decreased
mortality (RR: 0.41; 95% CI: 0.23–0.71; P
< .01) compared to the control group that
included patients performing oral hygiene care
themselves.113 This set of studies showed pos-
itive outcomes of the intensified oral hygiene
protocol, and a majority of the outcomes of
these studies reached statistical significance.
Conclusion
Taken together, despite the discrepancy in
the scientific evidence, a majority of systematic
reviews show that the intensified oral hygiene
protocol using chlorhexidine (but not povi-
done iodine) results in a statistically significant
reduction in the incidence of pneumonia (HAP
and VAP). However, the effectiveness of this
protocol in reducing HAP- or VAP-associated
mortality is still unclear.
COPD
A series of studies have also examined the
effect of improved oral hygiene on clinical
manifestations of COPD. A 2-year RCT study
that included 59 Chinese patients with COPD
and periodontitis reported that both supragin-
gival scaling and SRP significantly decreased
the incidence of frequent COPD exacerbations
compared to control patients who received no
periodontal treatment (15% versus 3.0% versus
66.7%, respectively; P < .05).114 However, the
baseline mean PPD of the patients in each group
was approximately 3.0 mm, thus questioning
the poor periodontal status of these patients.
Another study that included 40 patients with
COPD and moderate and severe periodonti-
tis demonstrated that SRP does not result in
substantial improvement in periodontal health
(thus questioning the clinical effectiveness of
this treatment) but significantly reduced exac-
erbation frequency rate compared to untreated
controls.115 Taken together, these results sug-
gest that improved periodontal health leads to
improved clinical outcomes of COPD.
Conclusion
In summary, accumulating evidence in the liter-
ature suggests an existing association between
periodontitis and pulmonary diseases (pneumo-
nia and COPD). Among the different categories
of pneumonia, AP appears to have the great-
est evidence for this association. However, as
critical readers, we need to interpret these data
203
9 The Association Between Oral Infections and Pulmonary Disease
with caution, as this association may or may
not apply to a wide population of patients. It
appears that in a majority of cases this associ-
ation exists in older or immunocompromised
adults (eg, hospitalized patients, smokers) and
that systemically healthy patients with periodon-
titis are not more prone to pulmonary diseases
than systemically healthy individuals with no
periodontitis. Thus, periodontitis can predispose
a susceptible individual to the development of
pulmonary diseases or their more severe clinical
manifestation, but no current data that support
a causative association between these two con-
ditions exist. Most likely, this causality will
never be established, as in this case periodon-
titis should always precede the occurrence of
pulmonary diseases, which is not supported by
any current epidemiologic study. Nevertheless, a
temporal relationship between periodontitis and
pulmonary diseases (pneumonia and COPD)
can be established, as many examples provided
in this chapter (eg, use of ventilators, stay in
ICU) are not chronic in nature.
We have reviewed several mechanisms pre-
viously proposed in the literature that could
explain the increased association between peri-
odontitis and pulmonary diseases. Based on
the current scientific evidence, we have con-
cluded that a direct aspiration of saliva and
oropharyngeal secretions containing periodon-
tal pathogens or mechanical dissemination of
these pathogens during intubation provide the
most plausible explanation for the increased
association of periodontitis with AP and VAP,
respectively. The increased association between
periodontitis and COPD appears to be due to
detrimental effects of smoking, which is the
main risk factor for both diseases.
We have also shown that periodontitis is
associated with greater complications/mortal-
ity among patients with pulmonary diseases. A
majority of systematic reviews also suggest that
the intensified oral hygiene protocol in the risk
populations provides a statistically significant
reduction in the incidence of pulmonary dis-
eases. This signifies a high importance of oral
hygiene for patients with pulmonary diseases
204
to reduce financial costs and inpatient hospital
days and improve the quality of life of these
patients. However, the intensified oral hygiene
protocol may not be effective in reducing the
mortality rates in patients with HAP and VAP,
suggesting that when patients have advanced
cases of pneumonia with severe inflammation,
the contribution of periodontal pathogens to
the total inflammatory burden of these patients
is not clinically relevant.
The periodontal health of patients with pul-
monary diseases (pneumonia and COPD) can
be improved by cooperation between patients
and dental professionals. The improved oral
health of these patients leads to a decreased
incidence of pneumonia (specifically, differ-
ent categories of HAP) and COPD, especially
when performed professionally by dentists
and dental hygienists compared to hospital/
nursing home personnel. Oral self-care and
periodontal procedures appear to be safe for
patients with pulmonary diseases unless these
patients have medical conditions that would
contraindicate this treatment. Therefore, based
on the current evidence in the literature, med-
ical and dental personnel should discuss the
importance of oral hygiene maintenance for
improved outcomes of pulmonary diseases with
patients and rigorously implement it as a part
of their routine treatment protocol. In addition,
patients should not wear removable dentures
during sleep because this is when plaque
accumulates, resulting in greater numbers of
periodontal pathogens and increased incidence
of AP. Equally important, medical and dental
personnel should be educated about the bene-
fits of improved oral hygiene for better clinical
outcomes and quality of life for these patients.
However, we should remember that despite
the observed clinical benefits, no current evi-
dence that periodontal treatment can prevent
the development of pulmonary diseases exists.
This review also highlights some gaps in
our current understanding of the association
between periodontal and pulmonary diseases.
A majority of studies that examined the asso-
ciation between periodontitis and pneumonia

included patients with HAP (AP and VAP)
but not CAP. Although several systematic
reviews with meta-analysis were included in
this chapter, some of these studies reported
and acknowledged the poor quality and biased
data representation of the original publications.
Some studies included a limited number of
patients, and therefore their outcomes should
be interpreted with caution. In addition, studies
Clinical Considerations: What You Can Take Back to Your Practice
Is there a biologic plausibility for an association
between oral infections and disorders and pul-
monary diseases?  Among the proposed mech-
anisms for the association between periodon-
titis and pulmonary diseases, aspiration of
periodontal and/or respiratory pathogens of
oropharyngeal secretions and their mechan-
ical dissemination during intubation are con-
sidered the most plausible mechanisms for the
increased prevalence of aspiration pneumo-
nia and ventilator-associated pneumonia, re-
spectively. Among the proposed mechanisms of
the increased association between periodonti-
tis and chronic obstructive pulmonary disease,
smoking and smoking-associated detrimental
effects are considered the most plausible mech-
anism linking these diseases.
Are oral infections and disorders independent
risk factors for the development of adverse sys-
temic outcomes of pulmonary diseases?  Peri-
odontitis is associated with the increased prev-
alence of pulmonary diseases, even after adjust-
ment for other potential confounding factors.
In addition, adjunctive periodontal treatment
significantly improves the outcomes of pulmo-
nary disease treatment. Although a temporal re-
lationship between periodontitis and pulmo-
nary diseases can be established, there is no evi-
dence in the literature that supports a causative
association between these two conditions. Thus,
periodontitis cannot currently be considered an
independent risk factor for pulmonary diseases.
Can treatment of oral infections and disorders
reduce the risk for the development of adverse
systemic outcomes of pulmonary diseases?  disease treatment.
Clinical Considerations
examining associations between periodontitis
and pulmonary diseases used various defini-
tions of periodontitis, making interpretation
of the results more challenging. Therefore,
an accurate and consistent definition of
periodontitis, properly designed controlled
interventional studies, and a new series of sys-
tematic reviews are needed to make current
conclusions more scientifically solid.
Several studies have demonstrated that adjunc-
tive periodontal treatment significantly im-
proves outcomes of pulmonary disease treat-
ment and decreases the incidence of treatment
complications. However, there is insufficient ev-
idence to conclude that periodontal treatment
leads to the reduction in pneumonia-associated
mortality. In addition, although few studies
have reported positive outcomes of periodontal
treatment on the incidence of chronic obstruc-
tive pulmonary disease, higher-quality studies
are needed to validate this conclusion.
Is it safe to provide dental care for patients with
pulmonary diseases?  Evidence in the literature
reports improved outcomes of the intensified
oral hygiene protocol in patients with pulmo-
nary diseases. Therefore, intensified oral self-
care and professional periodontal care appear
to be safe and highly recommended for pa-
tients with pulmonary diseases, unless other lo-
cal and/or systemic conditions contraindicate
these procedures (this should be established in
consultation with a physician).
What should a dental practitioner inform a pa-
tient about the association between oral infec-
tions and disorders and the development of sys-
temic outcomes of pulmonary diseases?  Cur-
rent evidence in the literature has demonstrated
that patients with pulmonary diseases have bet-
ter outcomes of the pulmonary disease treat-
ment if they have no concurrent periodontitis.
Therefore, these patients should be informed
that the maintenance of adequate oral hygiene
might improve the outcomes of the pulmonary
205
9 The Association Between Oral Infections and Pulmonary Disease
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209

Periodontal Infections and
Adverse Pregnancy Outcomes
Yiorgos A. Bobetsis, dds, phd
Wenche S. Borgnakke, dds, mph, phd
Panos N. Papapanou, dds, phd
For the past two decades, the association
between periodontal diseases and adverse
pregnancy outcomes has been the focus of
investigation in a variety of studies, ranging
from experimental animal models to epidemio-
logic association studies and intervention trials
in humans. Yet several uncertainties remain,
and oral health care professionals and the
public alike are exposed to frequently con-
tradictory information that must be clarified.
This chapter addresses the following specific
questions:
• What is the effect of pregnancy on the peri-
odontal tissues?
• What is the biologic plausibility of the asso-
ciation between periodontal diseases and
adverse pregnancy outcomes?
• Are periodontal diseases independent risk
factors for the development of adverse preg-
nancy outcomes?
• Does the delivery of periodontal therapy in
pregnant women contribute to an improve-
ment in pregnancy outcomes?
• Is periodontal therapy during pregnancy safe
for mother and child?
• What is the appropriate message to give the
public about this association?
The impact of adverse pregnancy outcomes
on society cannot be overestimated. The Global
210
CHAPTER 10
Burden of Disease Study identified neonatal
disorders and specifically preterm birth (PTB),
defined as the live birth of an infant before
completion of the 37th gestational week, as
significant contributors to global mortality.1
Every year, more than 15 million babies (1 in
every 10 live births) are born too soon around
the world,2 and about 1 million children die
each year as a result of complications of PTB.1,3
Surviving PTB infants often face multiple life-
long challenges, including respiratory distress,
impaired motor skills, cognitive and intellec-
tual impairment, psychiatric diseases, and
social, visual, and learning difficulties; some
of these complications even prevent living
independently.4,5
PTB largely occurs for three reasons: (1)
medically indicated PTB, (2) spontaneous PTB,
and (3) preterm premature rupture of mem-
branes. The rate of PTB varies greatly, from
5% to 18% among babies born across 184
countries.6 Among 39 countries with a Very
High Human Development Index ranking, the
PTB rate ranged from a low of 5.3% (Lat-
via) to a high of 14.7% (Cyprus).5 The United
States ranked 37th on this list (Fig 10-1) but
54th highest among 184 countries.7 Based on
the most recent global data, the United States
had the 6th highest number of PTBs among the
world’s 184 countries, surpassed only by India,
China, Nigeria, Pakistan, and Indonesia.7
 Periodontal Infections and Adverse Pregnancy Outcomes

14.7
14.0
15
12.0
11.5
10.9
10.5
9.2
9.2
10

8.6
8.0
8.0
8.0
7.9

7.8
7.8

7.7
7.6
7.6
7.6
7.4
7.5
7.4
7.3
7.1

6.7
6.7
6.7

6.6
6.5
6.4
6.3
6.0
5.9
5.9
5.7
5.7
5.5
5.5
5.3
5

0
Cyprus
Bahrain
United States
Singapore
Austria
Qatar
Germany
South Korea
Hungary
Israel
Netherlands
Argentina
Belgium
United Kingdom
Canada
Portugal
Australia
United Arab Emirates
New Zealand
Slovenia
Spain
Switzerland
Czech Republic
Chile
Poland
France
Denmark
Greece
Italy
Ireland
Slovakia
Norway
Sweden
Japan
Estonia
Lithuania
Finland
Croatia
Latvia
Preterm birth rate (per 100 live births)

Fig 10-1  |  Preterm birth rates in 2010 for 39 countries with a Very High Human Development Index ranking.
(Reprinted from Chang et al5 with permission.)

Grade Range
A 8.1 or less
B 8.2 – 9.2
C 9.3 – 10.3
D 10.4 – 11.4
F 11.5 or greater

Fig 10-2  |  US preterm birth rates and grades by state.2

The prevalence of PTB in the United States
has declined since its peak of 12.9% in 2006
to a rate of 9.85% in 2016,8 earning the United
States a grade of C on a scale from A to F from
the March of Dimes.2 Infants in the United
States are born preterm at almost double the
rate of infants in the western industrialized
countries in Northern Europe (around 5%).
The US PTB rate of live births is highest for
non-Hispanic black infants (13.4%), followed
by Hispanic (9.1%) and non-Hispanic white
(8.9%) infants.8 Large geographic disparities
in these rates exist within the United States, as
illustrated in Fig 10-2.

211
10 Periodontal Infections and Adverse Pregnancy Outcomes
Box 10-1  |  Risk factors/markers of preterm birth and low birth weight9
The diverse nature of the exposures and phenotypic characteristics associated with PTB have led to the proposal
to classify PTB as a syndrome, the development of which depends on the interaction of environmental exposures
and genotypic characteristics:9,10
• Young maternal age
• African American or Afro-Caribbean maternal
genotype
• Intrauterine infections
• Interpregnancy interval of < 6 months
• Drugs and heavy alcohol use
• Tobacco use
• Multiple gestation
• In vitro fertilization
• Psychologic and social stress
PTB babies are further subdivided into the
categories extremely preterm (born before 28
weeks), severely premature (between 28 and 31
weeks), moderately premature (between 32 and
33 weeks), and near term (between 34 and 36
weeks). Additional neonatal disorders or preg-
nancy complications include low birth weight,
defined as having a weight at birth of less than
2,500 g (5 lb 8 oz), approximately one-third
less than the average weight of a term infant
(3.5 kg/7 lb); intrauterine growth restriction
or small for gestational age, defined as weight
of less than the 10th percentile at any given
gestational age; preeclampsia (ie, high maternal
blood pressure [> 140/90 mmHg] and signifi-
cant proteinuria [300 mg/24 h]) after the 20th
gestational week; eclampsia (ie, occurrence of
life-threatening maternal seizures); and gesta-
tional diabetes (ie, glucose intolerance with
onset or first recognition during pregnancy,
most commonly during the second trimester).
Several risk factors have been associated
with adverse pregnancy outcomes, some of
which involve infectious or inflammatory path-
ways (Box 10-1).
212
• Depression
• Obesity-related preeclampsia
• Diabetes
• Hypertension
• Low prepregnancy body mass index
• Low socioeconomic status
• Low educational status
• Fetal genotype
• History of previous preterm birth
Effects of Pregnancy on the
Periodontal Tissues
While dental plaque is the primary etiology
for the development of periodontitis, the
presence of bacterial biofilms adjacent to the
gingival margin is necessary but not always
sufficient for the initiation and progression of
the disease. A number of systemic factors may
increase the susceptibility of the host to the
microbial challenge, contribute to enhanced
gingival inflammation and bacterial dysbio-
sis, and hence affect the extent and severity of
periodontitis. Several hormones, including the
sex steroids, have an influence on the cellular
components of the periodontal tissues and may
interfere with the mechanisms involved in the
pathobiology of periodontitis. Fluctuations in
the levels of these hormones in physiologic or
nonphysiologic conditions may result in signifi-
cant alterations in the periodontium, especially
in the presence of preexisting plaque-induced
gingival inflammation.

Natural sex steroids, also known as gonadal
steroids, are steroid hormones produced by the
gonads (ovaries or testes), by adrenal glands, or
by conversion from other sex steroids in other
tissues, such as the liver or adipose depots. The
main classes of sex steroids are androgens,
estrogens, and progestogens, of which the most
important human derivatives include testoster-
one, estradiol, and progesterone, respectively.
In general, androgens are considered male sex
hormones because they have masculinizing
effects, while estrogens and progestogens are
considered female sex hormones; however, all
three types are present in both sexes at differ-
ent levels.
Because periodontal tissues possess receptors
for sex steroids, researchers have extensively
studied the effects of these hormones on the
periodontium, which include the following:
• An impact on the degree of keratinization
of the gingival epithelium, and thus its bar-
rier function as a first line of defense against
bacterial pathogens.11
• Involvement in vascular functions such as
angiogenesis and vascular permeability.
Specifically, higher estrogen levels stimu-
late angiogenesis, while elevated circulating
progesterone enhances capillary permeability
and dilation, resulting in increased gingival
exudate that may facilitate the recruitment
of inflammatory cells in the gingival area
and the crevicular fluid. The enhanced vas-
cular permeability may also be partly due to
stimulating effects of progesterone on pros-
taglandin synthesis.12
• Involvement in periodontal connective tissue
turnover,13 because estrogen has been shown
to enhance the proliferation of fibroblasts
and the production and maturation of col-
lagen, while progesterone has the opposite
effects.14
• An effect of estrogen on salivary peroxi-
dases, which are active against a variety of
microorganisms. Estrogen changes the redox
potential of the salivary peroxidases.15
Effects of Pregnancy on the Periodontal Tissues
• Estrogen-mediated suppression of leuko-
cyte production in the bone marrow and
inhibition of polymorphonuclear leukocyte
chemotaxis and phagocytosis.16
• Progesterone-induced reduction of the
anti-inflammatory effects of glucocorti-
coids, either directly via receptor binding
on osteoblasts or indirectly by antagonizing
glucocorticoid receptors.17
Therefore, periods of hormonal flux during
puberty, menstruation, pregnancy, menopause,
hormone replacement therapy, or use of contra-
ceptives have been associated with periodontal
manifestations.
There is a significant rise in the amount of
sex steroids produced during the course of
pregnancy; secreted near-term levels of estra-
diol, estriol, and progesterone reach 20.0, 80.0,
and 300.0 mg/d, respectively, compared with
normal secretion levels of 0.6, 3.0, and 19.0
mg/d, respectively, in nonpregnant women.18
This temporary hormonal elevation correlates
with an increase in the prevalence, extent, and
severity of gingival inflammation, commonly
referred to as pregnancy gingivitis, which occurs
in approximately 50% of pregnant women19,20
and usually affects interdental papillae of ante-
rior areas. The severity of gingival inflammation
is accentuated from the second gestational
month and as pregnancy progresses under
consistent plaque colonization.21 After the 8th
gestational month, and especially after delivery,
gingival inflammation subsides and reverts to
the levels of the first trimester. This spontaneous
improvement in the absence of periodontal
therapy correlates closely with the concomi-
tant dramatic reduction in the secretion of sex
steroids.22 However, despite this exacerbated
inflammatory response and accompanying
increases in sulcular depth, gingival crevicular
fluid (GCF) flow, and bleeding on probing,13
loss of clinical attachment is infrequent.21
In a small percentage of pregnant women (at
frequencies reported in the literature ranging
between 0.5% and 10.0%), the combined stim-
ulatory effects of sex steroids on angiogenesis
213
10 Periodontal Infections and Adverse Pregnancy Outcomes
Fig 10-3  |  Clinical presentation of pregnancy gran-
uloma or epulis.
and extracellular matrix can lead to an exag-
gerated inflammatory response to dental
plaque and the formation of a localized mass of
highly vascularized granulation tissue, referred
to as pregnancy granuloma or epulis (Fig 10-3).
This lesion commonly arises from the proximal
gingival tissues of the maxillary anterior, can
reach dimensions that usually do not exceed
2 cm in diameter, has a pedunculated base,
and clinically and histologically resembles a
pyogenic granuloma, or rather a telangiectatic
granuloma or a capillary hemangioma, because
it is usually not purulent. It is characterized by
rapid growth and a bright red, hyperemic, and
edematous appearance because of increased
vascularization and may show ulceration of
its thin epithelial lining. The lesion is typically
not painful but may bleed spontaneously or
when mechanically stimulated.
Occasionally, surgical removal of the gran-
uloma may be necessary, especially when it
interferes with mastication or normal speech,
but full excision should be accompanied by
thorough debridement and meticulous oral
hygiene to minimize the risk of recurrence.
However, in most cases, its removal is best
deferred until after parturition, when there is
often considerable regression in its size.23
In parallel to the clinical manifestations,
pregnancy results in altered periodontal micro-
bial colonization profiles, including an increase
in the proportion of anaerobic over aerobic
214
bacteria during the second trimester.24,25 In
comparison with nonpregnant patients, preg-
nant patients harbor higher levels of Prevotella
intermedia, Prevotella nigrescens, and Por-
phyromonas gingivalis,26 and colonization by
the aforementioned species was shown to be
enhanced throughout gestation.27–29 Although
the exact mechanisms underlying these shifts
are unclear, hormone-enhanced inflammation
and gingival bleeding appear to increase the
bioavailability of nutrients, augment bacte-
rial growth, and facilitate the proliferation of
hemolytic bacteria, such as P gingivalis.30
Local immunologic modifications may also
underlie the occurrence of pregnancy gingivi-
tis. Sex steroids were shown to decrease the
production of interleukin 6 (IL-6) by fibro-
blasts and to reduce the levels of plasminogen
activator inhibitor 2 in the GCF.12,31,32 High
levels of estrogen and progesterone inhibit
polymorphonuclear leukocyte chemotaxis and
phagocytosis and suppress antibody and T-cell
responses because of the reduction of B lym-
phocytes and CD3 and CD4 cells,33 suggesting
that pregnant women may experience a state of
compromised immunity that may also facilitate
bacterial growth.
Biologic Plausibility
The hypothesis that a number of local or
systemic pathologic conditions, such as tonsil-
litis, pneumonia, endocarditis, and septicemia,
originated from oral foci of infection was first
formulated by Miller in 1891,34 but lack of sci-
entific evidence condemned the theory of focal
infection to dormancy. Almost 100 years later,
the landmark experimental studies in the preg-
nant hamster by Collins et al35 paved the way
for an intense research effort focusing on the
role of periodontal infection and inflammation
in adverse pregnancy outcomes.
To better appreciate the pathogenic mecha-
nisms that may underlie the association between
periodontal infection and inflammation and

adverse pregnancy outcomes, some basic
knowledge of the physiology of normal and
complicated pregnancies is essential. After con-
ception, the fetus is nourished by the mother
through the vessel-rich placenta and the umbili-
cal cord. Provided with the necessary nutrients,
the fetus grows in the amniotic fluid contained
by the amniotic sac. The walls of this cavity
consist of the amnion and the chorion, both of
which are attached to the uterus through the
decidua (the uterine lining or endometrium)
and the myometrium (the middle layer of the
uterine wall). As the fetus grows, satisfaction
of its increasing needs for nutrients and coping
successfully with the decreasing space are crit-
ical for the survival of both mother and fetus.
As pregnancy progresses, amniotic fluid
levels of prostaglandin E2 (PGE2) and inflam-
matory cytokines such as tumor necrosis factor
alpha (TNF-α) and interleukin 1β (IL-1β)
rise steadily until a critical threshold level is
reached, at which point they induce rupture
of the amniotic sac membranes, uterine con-
traction, cervical dilation, and delivery.36 Thus,
normal parturition is controlled by inflam-
matory signaling. This process represents a
triggering mechanism that can be modified by
external stimuli, including infection and inflam-
matory stressors.
In the medical literature, high levels of inflam-
matory mediators (such as IL-1β, IL-6, TNF-α ,
and PGE2)37–40 in the amniotic fluid and the
serum have been associated with various preg-
nancy complications. C-reactive protein (CRP),
an acute-phase reactant synthesized by the liver
in response to proinflammatory cytokines and
hence a marker of systemic inflammation, has
also been associated with an increased risk for
PTB, low birth weight, and preeclampsia.41,42
In addition, genitourinary tract infections
have been implicated in intrauterine infections.
Microorganisms gain access to various sites
of the fetoplacental compartment primarily
by ascending from the vagina and cervix or
by hematogenous dissemination through the
placenta. This microbial invasion is frequently
associated with intra-amniotic inflammation and
Biologic Plausibility
fetal inflammatory responses, which are both
linked to adverse pregnancy outcomes.43 Several
non–genital tract infections, such as pyelo­­
nephritis, asymptomatic bacteriuria, pneumonia,
and appendicitis, have also been associated with,
and probably predispose to, PTB.44
Periodontal diseases are also infectious, and
although they occur at a distance from the
fetoplacental unit, inflammatory mediators
produced at the gingiva, periodontal patho-
gens, and bacterial byproducts may enter the
blood circulation and disseminate throughout
the body. This low-grade bacteremia may trig-
ger the induction of systemic inflammatory
responses and/or the establishment of ectopic
infections.45,46
A mechanistic model potentially explaining
the biologic association between periodontal
infection and inflammation and adverse preg-
nancy outcomes46 is illustrated in Fig 10-4. The
model consists of two alternative pathways, one
direct and one indirect. In a direct pathway,
periodontal bacteria and/or their byproducts
disseminate to the fetoplacental unit, where
they establish an ectopic infection and/or trig-
ger a local inflammatory response that results
in the elevation of inflammatory cytokines
and mediators that contribute to pregnancy
complications. In an indirect pathway, inflam-
matory cytokines and mediators produced in
the periodontal tissues in response to peri-
odontal pathogens enter the blood circulation
and reach (1) the fetoplacental unit, where
they contribute to an enhanced concentration
of these mediators in this compartment, and
(2) the liver, where they stimulate a systemic
inflammatory response through the production
of acute-phase reactants. In turn, these media-
tors enter the blood circulation and reach the
fetoplacental unit, where they exacerbate intra-
uterine inflammation.
Current evidence indicates that the majority
of intrauterine infections originate in the lower
genital tract, with the infectious agents ascend-
ing into the otherwise sterile womb.47 Hence,
it is possible that periodontal pathogens may
reach the amniotic space as a result of ascending
215
10 Periodontal Infections and Adverse Pregnancy Outcomes
Fig 10-4 |  Biologic pathways associating periodontal infection and inflammation with ad-
verse pregnancy outcomes. TLR-4, toll-like receptor 4; LBW, low birth weight. (Reprinted
from Madianos et al46 with permission.)
infection following oral-genital transfer. How-
ever, this third pathway is probably the least
likely, because from an ecologic point of view it
is difficult for oral bacteria to establish colonies
in the vagina as a result of oral-genital contact
due to colonization resistance.
The direct and indirect pathways have been
extensively studied in human and animal mod-
els. The two more common animal models
used include the bacteremia infection model,
in which periodontal pathogens are injected
in the circulation to mimic bacteremia from
periodontal pathogens in humans, and the
chamber model, in which periodontal patho-
gens are injected in a subcutaneously implanted
chamber to mimic a distant site of infection
and inflammation such as periodontal infec-
tion. Although these experimental models are
meant to simulate a periodontal infection in
a simplified and reproducible manner, they
have several key limitations. The amount of
bacteria injected in the circulation may not
correspond to a transient bacteremia induced
by periodontal infection, and the injection of
a single bacterial species in the circulation or
216
the chamber resembles a monoinfection rather
than a mixed, biofilm-mediated infection such
as periodontitis. The discussion that follows
summarizes key research findings that support
the biologic plausibility of each of the two
pathways.
Direct pathway
Probably the strongest evidence in favor of
a hematogenous dissemination of periodon-
tal pathogens to the amniotic cavity derives
from two case reports of women with adverse
pregnancy outcomes. In the first case, the same
clonal type of uncultivable oral Bergeyella was
identified in the subgingival plaque as well as
the amniotic fluid of a woman with PTB, while
no Bergeyella was detected in the mother’s vag-
inal tract.48 In the second case, an oral strain
of Fusobacterium nucleatum was identified as
the cause of a term stillbirth and was isolated
from the lung and stomach of the infant. The
same clonal type of F nucleatum was present
in the subgingival plaque of the mother but not
in her vaginal or rectal microflora.49

Immunologic studies in humans also support
the direct pathway. In these studies, serum from
the umbilical cord was collected, and levels of
immunoglobulin (Ig) M and IgG were evaluated
against specific periodontal pathogens. The idea
behind these experiments is that fetal exposure
to periodontal pathogens and/or their byprod-
ucts would result in specific antibody responses
against these bacteria. Presence of IgM antibod-
ies in the umbilical cord blood would suggest
direct exposure of the fetus in utero, because the
fetus is not immunocompetent and the size of
the IgM molecule prevents its passage through
the placental barrier, precluding the possibility
that the antibodies are of maternal origin. In
contrast, IgG antibodies against the periodontal
pathogens would be of maternal origin, indicat-
ing a chronic exposure of the mother to these
bacteria or their byproducts.
Studies evaluating IgM antibodies against
specific periodontal bacteria have revealed a
higher prevalence of umbilical cord IgM sero-
positivity for one or more organisms of the red
complex (P gingivalis, Tannerella forsythia, and
Treponema denticola) or the orange complex
(Campylobacter rectus, F nucleatum, Pepto-
streptococcus micros, P intermedia, and P
nigrescens) in women who experienced preterm
or vaginal bleeding.50,51 The concomitant pres-
ence of these bacteria in the dental plaque of
pregnant women with pregnancy complica-
tions implies a hematogenous dissemination
of these pathogens to the amniotic cavity and
fetal exposure.
However, findings from maternal serum IgG
antibody levels are not always consistent. For
example, data from a large obstetrics and peri-
odontal therapy trial indicated that mothers
who delivered preterm had significantly lower
serum IgG levels against P gingivalis or other
red complex bacteria than did mothers who
delivered at term.52 In another study, the high-
est rate of PTB occurred in mothers with low
or no IgG responses to red complex species
and high IgG responses to orange complex
species.50 Other studies have found elevated
serum IgG antibodies against F nucleatum in
Biologic Plausibility
women who suffered a fetal loss, while higher
IgG levels against P gingivalis were associ-
ated with more low–birth weight infants.53
These seemingly contradictory findings from
seroepidemiologic studies may indicate that
low levels of maternal serum IgG antibodies
to periodontal bacteria signify inadequate
protection against the disseminating oral
pathogens, allowing them to translocate to the
fetoplacental unit and contribute to pregnancy
complications. Alternatively, elevated mater-
nal serum IgG could indicate either an increase
in systemic exposure by oral pathogens or a
hyperinflammatory phenotype, which may
predispose these women to an increased fetal
inflammatory response and injury.
Additional evidence indicating that peri-
odontal pathogens may translocate to the
fetoplacental unit derives from studies that
detected bacterial DNA in this compartment.
Indeed, DNA from several periodontal patho-
gens, such as P gingivalis, Aggregatibacter
actinomycetemcomitans, F nucleatum, and
Bergeyella species has been identified in amni-
otic fluid, placenta, and even neonatal gastric
aspirates obtained from complicated pregnan-
cies.48,54 A study that investigated placental
microbiome profiles using a comparative 16S
ribosomal RNA–based and whole-genome shot-
gun metagenomic approach showed that they
were most similar to the human oral microbiome
rather than to the microbiome of the vagina, the
gut, or the skin.55 Corroborating findings have
been obtained from experiments with animal
models. Specifically, using the chamber model
in mice, researchers found DNA from P gin-
givalis and C rectus in the maternal liver and
uterus of infected pregnant animals and in the
placenta of fetuses showing intrauterine growth
restriction.56,57 However, intravenous infection
of mice with F nucleatum was restricted inside
the uterus without spreading systemically.58
Nevertheless, to fully appreciate the signifi-
cance of these findings, it must be remembered
that periodontal pathogens have been detected
in human amniotic fluid and fetoplacental tis-
sues in normal pregnancies as well.59 Hence, it
217
10 Periodontal Infections and Adverse Pregnancy Outcomes
is still unclear which factors determine whether
fetal exposure to periodontal bacteria will con-
tribute to pregnancy complications. It is likely
that varying levels of host susceptibility to peri-
odontal pathogens may render some pregnant
women more vulnerable to adverse pregnancy
outcomes than others.
Another possibility is that variation in vir-
ulence properties within a single species may
enable some, but not all, strains to colonize the
amniotic cavity and induce pregnancy compli-
cations. This notion is further supported by
mechanistic studies. Indeed, in mice, F nuclea-
tum was shown to reach the placental blood
vessels after hematogenous dissemination
and to invade the endothelial cells lining the
vessels, cross the endothelium, proliferate in
the surrounding tissues, and finally spread
to the amniotic fluid.58 Intravenous injection
of P gingivalis into pregnant rats resulted in
strain-dependent colonization in the placenta.60
In vitro studies showed that specific C rectus
strains were able to invade human trophoblast
cells.61 Thus, it appears that the ability of bac-
teria to invade the fetoplacental unit may be an
important property in the context of induction
of adverse pregnancy outcomes.
Infection of the placenta with periodontal
pathogens may result in the induction of local
inflammatory responses, including elevation of
IL-2 and interferon γ and reduction in IL-10.56
These responses are probably mediated by the
release of major components of the bacterial
cell wall, such as lipopolysaccharide or outer
membrane vesicles, and are dependent on the
potency of these virulence factors and the
inflammatory profile of the host. In pregnancy,
the innate proinflammatory immune response
is strictly regulated within the uterus to pre-
vent immunologic rejection of the fetal allograft.
However, the local increase in proinflammatory
mediators may disrupt this delicate balance and
elicit an inflammatory burden that may contrib-
ute to preterm rupture of the membranes and
uterine contraction, which in turn may lead to
miscarriage or PTB.62 Histologically, this inflam-
matory response is accompanied by an increase
218
in the inflammatory infiltrate, predominantly by
neutrophils, and in decidual necrosis.63
C rectus infection in mice induces major
alterations in the structure of the placenta,
as indicated by the decrease in the size of the
labyrinth.63 This may be partly due to the
attenuation in the expression of genes related
to placental and fetal growth, such as placental
growth factor (PGF) and insulin-like growth
factor 2 (IGF2).64 Because the labyrinth is the
area of the placenta where the exchange of
nutrients and waste between the mother and
the fetus takes place, its diminished volume
may result in insufficient nutrition for the fetus,
resulting in restricted fetal growth and low
birth weight. Furthermore, structural damage
in the placenta may disrupt the normal blood
flow between the fetus and the mother, affect-
ing maternal blood pressure, and may thus lead
to preeclampsia.
Finally, C rectus infection in mice results in
an increased rate of neonatal mortality. In the
surviving pups, C rectus can be detected in the
brain and may induce a local inflammatory
response, which is accompanied by increased
apoptosis and defects in nerve myelination.63
Comparable effects have also been reported
in humans; neonates exposed to both C rectus
and P gingivalis infection are twice as likely
to be admitted to the neonatal intensive care
unit.65 It has also been established that preterm
infants demonstrate an increased risk for
developing neurodevelopmental, behavioral,
and learning problems. Thus, fetal exposure
to periodontal pathogens may induce tissue
damage to fetal organs, and depending on the
extent of this damage, the fetus may die or the
neonate may demonstrate an increased risk of
perinatal mortality or morbidity. Detrimental
exposures during fetal development may man-
ifest themselves later in life.
Indirect pathway
Patients with periodontal infection and/or
inflammation show an increased production
of proinflammatory cytokines and mediators
 Epidemiologic Studies of Maternal Periodontitis and Adverse Pregnancy Outcomes
from periodontal tissues. Once released, these
cytokines may diffuse in the GCF or enter
the blood circulation and reach the fetopla-
cental unit. Inflammatory cytokines (such
as IL-1β, IL-6, and TNF-α) could then stim-
ulate the production of prostaglandins in the
chorion and exacerbate cervical ripening and
uterine contraction, leading to an increased risk
for PTB. However, limited evidence is available
to date to suggest an association between these
cytokines in the GCF, serum, or amniotic fluid
and pregnancy complications in women with
periodontitis.66
Another possibility is that proinflammatory
cytokines released in the maternal circulation,
along with disseminated bacteria or bacterial
byproducts from the periodontal tissues, may
induce a low-grade systemic inflammation by
stimulating hepatic production of acute-phase
reactants, such as CRP and fibrinogen. Elevated
plasma CRP could then augment the inflam-
matory responses at the fetoplacental interface
through complement activation, tissue damage,
and induction of proinflammatory cytokines.
Although elevated levels of CRP have been
associated with PTB, intrauterine growth
restriction, preeclampsia, and gestational dia-
betes mellitus (GDM), there are only a few
studies evaluating the association between
pregnancy complications and CRP levels in
pregnant women with periodontitis, and the
findings are inconsistent.67 Thus, significantly
less evidence is available to support the indirect
than the direct pathway.
Epidemiologic Studies
of Maternal Periodontitis
and Adverse Pregnancy
Outcomes
Observational studies
Since the first case-control study of pregnant or
postpartum women published in the mid-1990s
that showed that women giving birth to preterm,
low–birth weight babies had significantly greater
mean levels of clinical attachment loss than did
mothers with full-term, normal–birth weight
babies,68 a large number of publications have
reported on the association between maternal
periodontal status and pregnancy outcomes. As
expected, a number of studies corroborated and
extended these early observations, while others
failed to detect an association. Several systematic
reviews have been carried out so far on this topic,
including one by Ide and Papapanou,69 which
was recently updated by Petrini et al70 to include
additional publications appearing between June
2012 and April 2017. Predefined criteria were
used to evaluate the existing evidence associat-
ing maternal periodontitis, defined broadly and
encompassing a variety of conditions ranging
from gingivitis to aggressive periodontitis, and
three primary pregnancy complications: PTB,
low birth weight, and preeclampsia. The review69
discussed in detail a number of features related
to the methodology used and the overall quality
of the studies, all of which could conceivably
have an impact on the strength of the association
between the putative exposure under investiga-
tion (ie, poor maternal periodontal status) and
the outcome (ie, adverse pregnancy outcomes).
These study features included the type of peri-
odontal examination performed (whether it was
based on a complete-mouth or partial-mouth
examination); the consistency in the timing of
the examination with respect to gestational
age (antepartum or postpartum); whether the
study examiners were blinded with respect to the
occurrence of the particular adverse pregnancy
outcome, excluding the possibility of examina-
tion bias; and whether additional exposures
with known or suspected roles in pregnancy
outcome were also considered in the data anal-
yses along with maternal periodontitis. In this
context, accounting for the role of confounding
factors (ie, additional exposures associated with
both periodontitis and adverse pregnancy out-
comes) was deemed to be critically important.
Another issue highlighted in the review
was the use of continuous versus categorical
219
10 Periodontal Infections and Adverse Pregnancy Outcomes
definitions of periodontitis: While some stud-
ies defined maternal periodontal status using
continuous variables (eg, mean probing depth
and clinical attachment loss, percentage of sites
with bleeding on probing), other studies used
categorical (dichotomous) definitions to clas-
sify the women as having periodontitis or being
periodontally healthy. Given the absence of
universally accepted definitions of periodontitis
in general and in women of childbearing age
in particular, the threshold values used across
studies to define a case of periodontitis varied
substantially.
Finally, because of the generally low prev-
alence of adverse pregnancy outcomes in the
population, the majority of the studies used a
case-control design rather than the preferred
longitudinal prospective cohort design. The
latter is much better suited for the assessment
of interactions among different exposures but
requires recruitment of considerably larger
numbers of participants and is therefore more
demanding logistically.
The review reiterated that there is a high
degree of variability among the study popula-
tions involved in the available studies as well as
in the methodologies used for recruitment and
periodontitis assessment. More than 50 contin-
uous parameters and 14 different definitions of
cases (not specific to pregnancy) were applied
in studies exploring relationships between peri-
odontal disease and preterm delivery and/or
low–birth weight infants.71 Therefore, it is dif-
ficult to compare the findings of these reports
with regard to the prevalence of periodontal
disease among pregnant women. To illustrate
the importance of choice of case definitions,
Manau et al71 calculated the prevalence of peri-
odontal disease to be between 2.2% and 70.8%
when 14 different case definitions were applied
to the same data from 1,296 pregnant women.
Ide and Papapanou69 found that poten-
tially detrimental exposures that may be
shared between periodontitis and adverse
pregnancy outcomes did not appear to have
been adequately accounted for in all stud-
ies. Another observation that emerged was
220
that studies that used categorical definitions
of periodontitis were more likely to detect
statistically significant associations between
maternal periodontitis and adverse pregnancy
outcomes than studies that used continuous
measures of periodontitis. Likewise, studies
using a case-control design were more likely
to detect associations than the more robust
prospective cohort studies. Nevertheless, and
despite the aforementioned shortcomings in
the existing evidence, the systematic review
concluded that there is a positive association
between poor maternal periodontal status and
all three adverse pregnancy outcomes exam-
ined (PTB, low birth weight, and preeclampsia).
With respect to the magnitude of the adverse
effect, the review identified it as modest but
as independent of other exposures. In other
words, the identified association between peri-
odontitis and adverse pregnancy outcomes
cannot solely be ascribed to common risk fac-
tors that are also more prevalent in women
with periodontitis, such as poor socioeconomic
status, young maternal age, certain race or eth-
nicity characteristics, and tobacco smoking.
Thus, the epidemiologic evidence from the
association studies available so far is largely
consistent with the biologically plausible role
of periodontitis as a systemic stressor that was
described in the first part of this chapter. This
conclusion is also corroborated by a recently
published overview of systematic reviews72 that
reported positive associations between peri-
odontal disease and PTB (relative risk [RR]:
1.6; 95% confidence interval [CI]: 1.3–2.0; 17
studies, 6,741 participants), low birth weight
(RR: 1.7; 95% CI: 1.3–2.1; 10 studies, 5,693
participants) and preeclampsia (odds ratio
[OR]: 2.2; 95% CI: 1.4–3.4; 15 studies, 5,111
participants). Based on the above figures, the
estimated population-attributable fractions for
periodontal disease were between 5% and 38%
for PTB, 6% and 41% for low birth weight,
and 10% and 55% for preeclampsia.
A limited number of studies73–76 suggest a
potential association between maternal peri-
odontitis and GDM, a condition characterized
 Epidemiologic Studies of Maternal Periodontitis and Adverse Pregnancy Outcomes
by first-onset glucose intolerance and incident
hyperglycemia during pregnancy.77 GDM may
reverse postpartum or develop to prevalent type
2 diabetes mellitus and is associated with sig-
nificant maternal and fetal morbidity.78 Given
that infectious and/or inflammatory stimuli
have been associated with the pathogenesis
of GDM,78,79 a link between maternal peri-
odontitis and GDM appears to be biologically
plausible. Two recent systematic reviews80,81
reported statistically significant positive asso-
ciations between the two conditions based on
a limited number of studies but cautioned that
the degree of heterogeneity with respect to clin-
ical definitions and analytical methodology in
the underlying studies was high and therefore
does not allow firm conclusions.
Intervention studies
Given the positive association between peri-
odontitis and adverse pregnancy outcomes,
an obvious question arises that is of major
interest for both patients and clinicians: Can
treatment of maternal periodontitis result in
improved gestational outcomes? The public
health implications of such a possibility are
obviously profound, because approximately
half the variance in the prevalence of PTB and
low birth weight is unexplained by the cur-
rently established risk factors. Therefore, even
if a relatively small proportion of the cases
could be ascribed to maternal periodontitis,
and this risk turned out to be modifiable by
means of periodontal therapy, the benefits
would be substantial.
This question is arguably one of the most
thoroughly investigated in the field of dental
medicine: At least 15 randomized controlled
trials (RCTs) reported thus far have collectively
enrolled in excess of 7,000 pregnant women
with periodontitis or gingivitis. Approximately
half these women were randomized to receive
scaling and root planing (SRP), occasionally
accompanied by adjunctive antimicrobial
pharmacotherapies, prior to completion of the
second trimester, while the other half received
similar periodontal treatment after delivery.
Table 10-1 summarizes the key features and
study outcomes of RCTs with a sample size of
at least 100 women.
The data from these studies have been
included in meta-analyses in several systematic
reviews94–96 that concluded that nonsurgical
treatment of periodontitis during the second
trimester does not result in a decreased rate
of preterm delivery or have a positive impact
on birth weight. Although individual trials
that reported improved gestational outcomes
in pregnant women allocated to the active
intervention arm do exist, the findings of the
higher-quality studies and the outcomes of the
aggregate analyses are unequivocal and do not
support this notion. A thoughtful discussion of
the potential reasons underlying these diverse
findings was published by Michalowicz et al.93
Given that the larger, high-quality RCTs were
consistent in documenting that nonsurgical
periodontal therapy provided during the second
trimester has no positive effect on gestational
outcomes, these authors questioned whether
there is a need for additional studies of similar
design. Nevertheless, a recent systematic review
of the effectiveness of periodontal therapy to
improve adverse pregnancy outcomes97 pointed
out that although periodontal treatment was
found to have no significant effects on PTB or
low birth weight overall, data analyses from
studies in populations with high occurrence
(≥ 20%) of PTB and low birth weight indi-
cated that periodontal treatment seemed to
reduce the risk of PTB (OR: 0.42; 95% CI:
0.24–0.73) and low birth weight (OR: 0.32;
95% CI: 0.15–0.67) in these cohorts, although
trial sequential analyses showed that firm evi-
dence was not reached.
A frequent criticism of the available RCTs is
that the periodontal treatment rendered failed
to result in adequate improvement of mater-
nal periodontal status to the extent needed
to impact pregnancy outcomes. Although
this is indeed a possibility, given that peri-
odontal inflammation was not eliminated in
most studies, the subgroups of individuals in
221
10 Periodontal Infections and Adverse Pregnancy Outcomes

TABLE 10-1  |  RCTs with a total sample size of > 100 that examined the effect of nonsurgical
periodontal treatment during gestation on preterm birth
Statistically
improved
Randomized Study pregnancy
Study; country N Intervention quality* outcome
López et al82 (2002); Chile 400 SRP + 0.12% chlorhexidine mouthrinse† Low Yes

Jeffcoat et al83 (2003); USA 366 SRP and adjunctive systemic metronidazole High No
in approximately half of the women in the
treatment arm

López et al84 (2005); Chile 870‡ SRP + 0.12% chlorhexidine mouthrinse Low Yes

Michalowicz et al85 (2006); USA 823 SRP High No

Offenbacher et al86 (2006); USA 109 SRP Low Yes

Tarannum and Faizuddin87 (2007); India 200 SRP + 0.2% chlorhexidine mouthrinse Low Yes

Newnham et al88 (2009); Australia 1,082 SRP + 0.12% chlorhexidine mouthrinse High No

Offenbacher et al89 (2009); USA 1,806 SRP High No

Macones et al90 (2010); USA 759 SRP High No

Oliveira et al91 (2011); Brazil 246 SRP Low No

Weidlich et al92 (2013); Brazil 303 SRP High No

*As assessed by Michalowicz et al.93

†
18% of the women in the test group also received adjunctive systemic antibiotics (amoxicillin and metronidazole).
‡
Includes exclusively women with gingivitis.
SRP, scaling and root planing.

whom a pronounced resolution of periodontal periodontal therapy indicated that interven-

inflammation was achieved did not appear to
experience the best pregnancy outcomes. On the
other hand, the induction of bacteremia98 and
the increase in systemic inflammation99 shown
to occur in conjunction with instrumentation
of the periodontal tissues may have posed a sig-
nificant challenge to the fetoplacental unit and
negated the positive effects of the subsequent
improvement in gingival inflammation.
It has therefore been argued that the ideal
timing of delivery of the periodontal inter-
vention is prior to conception. Obviously, the
logistics involved in the conduct of such a trial
are complicated, and the concept cannot be
tested easily. However, it is noteworthy that
a nonrandomized trial100 that tested the effect
of an antiseptic oral mouthrinse as the sole
tions that are not likely to induce bacteremia
and a rise in systemic inflammation may
improve pregnancy outcomes.
Dental and Periodontal
Therapy During Pregnancy
Dentists have a general reluctance to treat
pregnant women, for reasons ranging from the
relative paucity of objective data to support
safety claims regarding specific dental proce-
dures or use of adjunctive therapeutic agents
to a genuine concern that they may cause harm
to the pregnant woman or the fetus. In some
countries, these attitudes are likely further

222

promoted by a fear of litigation. Conversely, it
is known through surveys in a variety of pop-
ulations that a relative minority of pregnant
women (between 25% and 50%) receive any
dental care, including prophylaxis, even when
insured. All types of dental services decrease
during pregnancy and increase after pregnancy,
compared with prepregnancy usage.101 Utiliza-
tion of dental services is still lower for pregnant
women of low socioeconomic status102 or
women of certain cultural backgrounds in
whom the fear of harm to the fetus as a result
of dental care is deeply rooted.103
The first study that addressed issues of safety
of dental treatment in pregnant women as part
of an RCT was the Obstetrics and Periodontal
Therapy study,104 which randomly assigned 823
women with periodontitis to receive SRP, either
at 13 to 21 weeks’ gestation or up to 3 months
after delivery. All women were evaluated for
essential dental treatment needs, defined as
the presence of moderate to severe caries and
fractured or abscessed teeth, and 351 women
received essential dental care prior to the
completion of the second trimester. The study
demonstrated that the rates of serious adverse
events, defined as spontaneous abortions or
stillbirths, fetal or congenital anomalies, and
PTBs, were not statistically different between
groups of women that received essential dental
care alone, essential dental care combined with
nonsurgical periodontal therapy, or no dental
treatment during pregnancy. Thus, this study
provided high-quality evidence demonstrating
that dental and periodontal treatment that also
involved use of local anesthetics is safe during
the second trimester. These findings have been
further corroborated by the additional large
RCTs mentioned earlier (see Table 10-1),
none of which reported a statistically signif-
icant higher incidence of adverse pregnancy
outcomes among women who received peri-
odontal therapy during gestation than among
those who received periodontal treatment
after delivery. A more recent study105 evalu-
ated the safety of exposure to local anesthetics
as part of dental care (including endodontic
Dental and Periodontal Therapy During Pregnancy
treatment, tooth extraction, and tooth resto-
ration, with or without exposure to diagnostic
radiation) during pregnancy in a prospective
observational study. The authors followed 210
pregnant women exposed to dental local anes-
thetics (approximately half of whom were in
the first trimester) and compared them with
794 pregnant women who were not exposed
to any teratogens. The rate of major anom-
alies was not significantly different between
the groups (4.8% versus 3.3%, P = .3), and
no differences in the rate of miscarriage, ges-
tational age at delivery, or birth weight were
observed.
Based on a thorough review of the existing
scientific evidence, a national consensus state-
ment developed by the national Oral Health
Care During Pregnancy Expert Workgroup106
concluded that “Oral health care, including
use of radiographs, pain medication, and local
anesthesia, is safe throughout pregnancy.” The
statement calls for interprofessional collabora-
tion between health care providers throughout
the pregnancy and on delivery to ensure the
best possible health of the mother and child.
All health care providers, including physicians
and their assistants, nurses, midwives, nurse
practitioners, dentists, and dental hygienists,
are encouraged to educate themselves regard-
ing oral health and dental care in pregnancy,
to provide pertinent oral health education, and
to collaborate to ensure that pregnant women
and new mothers attain and maintain the best
possible oral health.
The national consensus statement also con-
tains step-by-step guidance targeting prenatal
health care professionals, oral health care pro-
fessionals, pregnant women, and new mothers.
Moreover, it provides a user-friendly table-form
overview of pharmaceutical agents with their
indications, contraindications, and special con-
siderations. Last, the statement provides the
address for the National Maternal and Child
Oral Health Resource Center’s website with
links to informative brochures in English and
in nine additional languages with tips for good
oral health during pregnancy.
223
10 Periodontal Infections and Adverse Pregnancy Outcomes
The statement also introduces the dental
home concept, developed by the American
Association of Public Health Dentistry107 and
supported by the American Association of Pedi-
atric Dentists (AAPD). The dental home model
delineates an ongoing relationship between the
dentist and the patient, inclusive of all aspects
of oral health care, delivered in a comprehen-
sive, continuously accessible, coordinated, and
family-centered way. Pregnant women should
be encouraged to obtain periodontal and
restorative treatment to attain and maintain
good oral health throughout their pregnancy
and beyond.108
Because teenage mothers are among those at
the highest risk for preterm delivery, the AAPD
has developed guidelines on oral health care for
pregnant adolescents.109 The advice is aimed at
not only the future mother but also the den-
tal professionals who must be familiar with
state statutes that govern consent for care for
a pregnant woman who is not categorized as
an adult of legal age. If a pregnant adolescent’s
parents are unaware of the pregnancy and
state laws require parental consent for dental
treatment, the practitioner should encourage
the adolescent to inform her parents so that
the appropriate informed consent for dental
treatment can occur. The AAPD recommends
incorporating positive youth development that
goes beyond traditional care and suggests that a
strong interpersonal relationship be cultivated
between the adolescent and her dental care pro-
viders. Through positive youth development,
the dentist can promote healthy lifestyles, teach
positive patterns of social interaction, and pro-
vide a safety net in times of need.
Conclusion
The association between poor maternal
periodontal status and adverse pregnancy
outcomes is biologically plausible, and mul-
tiple lines of evidence support a number of
mechanistic links through which maternal
224
periodontal infection and inflammation may
contribute to an increased incidence of PTB,
low birth weight, preeclampsia, and possibly
GDM. Meta-analyses of the available epide-
miologic association studies also support the
notion that maternal periodontal infections
have a negative impact on pregnancy outcomes,
independent of known confounders. However,
the strength of this association is rather modest
and may vary in different populations.
The effect of maternal periodontal treatment
during pregnancy on the incidence of adverse
pregnancy outcomes has been investigated in
several high-quality RCTs, all of which have
administered nonsurgical periodontal therapy
prior to the completion of the second trimes-
ter. The preponderance of evidence from these
trials indicates that periodontal therapy does
not improve pregnancy outcomes. Thus, at first
glance, the findings from the mechanistic and
epidemiologic association studies on the one
hand and those from the intervention studies
on the other appear to be conflicting. However,
a strict and appropriate interpretation of the
RCTs is that the particular intervention tested
(ie, nonsurgical periodontal therapy adminis-
tered after the first trimester and prior to the
completion of the second trimester) does not
result in improved pregnancy outcomes.
This conclusion is clearly not synonymous
with the notion that maternal periodontal
infections are unrelated to adverse pregnancy
outcomes. What the RCTs suggest is that any
increased risk for adverse pregnancy outcomes
documented in the mechanistic and epidemio-
logic association studies cannot be reversed by
the particular interventions performed.
The possible effects of different interventions
with respect to timing or intensity have not been
examined. Therefore, it is unknown whether
alternative therapeutic approaches may yield
improved outcomes. However, the primary
reason RCTs are conducted is to identify the
best therapies, to update standards of care, and
to inform stakeholders responsible for public
health policy. RCTs are not designed to accept
or refute a hypothesized causal relationship

between an exposure and an outcome. Instead,
they adopt a strategy that minimizes the effects
of confounders and focus on whether any risk
conferred by the exposure can be modified by
means of the tested intervention. In the case of
maternal periodontal infections and adverse
pregnancy outcomes, it may be argued that
the central question from a public health
point of view—that is, whether treatment of
pregnant women with periodontitis will result
in improved pregnancy outcomes—has been
addressed by several high-quality trials, and
the answer is no.
It is probably not meaningful to focus on the
fact that periodontal treatment in the existing
RCTs improved but clearly did not eliminate
periodontal inflammation in the treated women
and thus to advocate that more intensive or
effective interventions would have resulted
in improved outcomes. Indeed, the pragmatic
therapeutic approach adopted by the available
RCTs (ie, full-mouth SRP followed by regu-
lar periodontal maintenance until delivery)
is probably what the majority of pregnant
women can tolerate and accommodate within
the busy prenatal period. The improvement in
periodontal status that is typically achieved by
this type of intervention in pregnant women
falls short of eliminating (or even substantially
suppressing) gingival inflammation. While one
can speculate about what other types of inter-
ventions would have achieved or focus on
pregnancy outcomes occurring in the subset of
women who were the most compliant with the
research protocol or those whose periodontal
health improved the most, it is the response
that occurs in the majority of women that is
interesting from a public health point of view,
not what occurs in small subgroups that may
be atypical and may not represent the source
population. Although from a biologic point of
view, valuable conclusions can still be drawn
based on the pregnancy outcomes achieved in
Conclusion
the most compliant women or in those whose
periodontal inflammation was most effectively
suppressed, recommendations regarding prena-
tal care policy cannot be based on subgroup
findings but must adhere to the intent-to-treat
principle that is the cornerstone of RCTs.
The possibility that the optimal time point
to provide periodontal interventions in women
with periodontitis is prior to conception is cer-
tainly compatible with current understanding
of the effects of maternal periodontal infection
and inflammation on the fetoplacental unit.
Indeed, it is known that periodontal therapy
results in a substantial, short-term increase in
systemic inflammation.110 Furthermore, find-
ings from an RCT of the effects of periodontal
treatment on vascular endothelial function
demonstrated that periodontal therapy results
in immediate, significant impairment of endo-
thelial function that is restored to pretreatment
levels within approximately 2 months after
intervention, while the beneficial effects of
therapy manifest at 6 months after interven-
tion.111 This timeline may be too extended to
translate into any tangible improvements in the
context of pregnancy outcomes. Therefore, res-
toration of maternal periodontal health prior
to conception makes biologic sense. However,
a formal assessment of the potential effects of
periodontal treatment administered prior to
conception in an RCT is logistically difficult,
and such a study may not be available in the
near future.
In the meantime, while it is not justified to
recommend that pregnant women be treated
periodontally for the sole purpose of improv-
ing pregnancy outcomes, maternal periodontal
therapy is safe for the mother and the unborn
child. It improves oral health and is an indis-
pensable part of a holistic approach geared
toward the advancement of general health,
risk factor control, and enhancement of
health-promoting behaviors.
225
10 Periodontal Infections and Adverse Pregnancy Outcomes
Clinical Considerations: What You Can Take Back to Your Practice
What is the effect of pregnancy on periodontal
health?  The significant increase in sex ste-
roids during pregnancy affects the periodon-
tal tissues via multiple mechanisms, and their
net effect is manifested as an increase in the
prevalence, extent, and severity of gingival
inflammation (pregnancy gingivitis). These
changes are infrequently associated with loss of
connective tissue attachment and usually revert
after parturition.
Are oral infections independent risk factors
for the development of adverse pregnancy
outcomes?  Epidemiologic studies demonstrate
an association between poor maternal peri-
odontal health and adverse pregnancy out-
comes (preterm birth, low birth weight, and
preeclampsia). The magnitude of this effect is
moderate but independent of other confound-
ers. Emerging evidence suggests that maternal
periodontitis may be associated with increased
risk for gestational diabetes, but the findings
need to be substantiated in larger studies in di-
verse populations.
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80. Esteves Lima RP, Cyrino RM, de Carvalho Dutra B, et
al. Association between periodontitis and gestational
diabetes mellitus: Systematic review and meta-analysis.
J Periodontol 2016;87:48–57.
81. Abariga SA, Whitcomb BW. Periodontitis and gestational
diabetes mellitus: A systematic review and meta-analysis
of observational studies. BMC Pregnancy Childbirth
2016;16:344.
82. López NJ, Smith PC, Gutierrez J. Periodontal therapy
may reduce the risk of preterm low birth weight in
women with periodontal disease: A randomized
controlled trial. J Periodontol 2002;73:911–924.
83. Jeffcoat MK, Hauth JC, Geurs NC, et al. Periodontal
disease and preterm birth: Results of a pilot intervention
study. J Periodontol 2003;74:1214–1218.
84. López NJ, Da Silva I, Ipinza J, Gutiérrez J. Periodontal
therapy reduces the rate of preterm low birth weight in
women with pregnancy-associated gingivitis. J Peri-
odontol 2005;76:2144–2153.
85. Michalowicz BS, Hodges JS, DiAngelis AJ, et al. Treat-
ment of periodontal disease and the risk of preterm
birth. N Engl J Med 2006;355:1885–1894.
86. Offenbacher S, Lin D, Strauss R, et al. Effects of peri-
odontal therapy during pregnancy on periodontal status,
biologic parameters, and pregnancy outcomes: A pilot
study. J Periodontol 2006;77:2011–2024.
87. Tarannum F, Faizuddin M. Effect of periodontal therapy
on pregnancy outcome in women affected by periodon-
titis. J Periodontol 2007;78:2095–2103.
88. Newnham JP, Newnham IA, Ball CM, et al. Treatment of
periodontal disease during pregnancy: A randomized
controlled trial. Obstet Gynecol 2009;114:1239–1248.
89. Offenbacher S, Beck JD, Jared HL, et al. Effects of
periodontal therapy on rate of preterm delivery: A
randomized controlled trial. Obstet Gynecol 2009;114:
551–559.
References
90. Macones GA, Parry S, Nelson DB, et al. Treatment of
localized periodontal disease in pregnancy does not
reduce the occurrence of preterm birth: Results from
the Periodontal Infections and Prematurity Study (PIPS).
Am J Obstet Gynecol 2010;202:147.e141–148.
91. Oliveira AM, de Oliveira PA, Cota LO, et al. Periodontal
therapy and risk for adverse pregnancy outcomes. Clin
Oral Investig 2011;15:609–615.
92. Weidlich P, Moreira CH, Fiorini T, et al. Effect of nonsur-
gical periodontal therapy and strict plaque control on
preterm/low birth weight: A randomized controlled clin-
ical trial. Clin Oral Investig 2013;17:37–44.
93. Michalowicz BS, Gustafsson A, Thumbigere-Math V,
Buhlin K. The effects of periodontal treatment on preg-
nancy outcomes. J Clin Periodontol 2013;40(suppl 14):
S195–S208.
94. Polyzos NP, Polyzos IP, Mauri D, et al. Effect of peri-
odontal disease treatment during pregnancy on preterm
birth incidence: A meta-analysis of randomized trials.
Am J Obstet Gynecol 2009;200:225–232.
95. Boutin A, Demers S, Roberge S, Roy-Morency A, Chan-
dad F, Bujold E. Treatment of periodontal disease and
prevention of preterm birth: Systematic review and
meta-analysis. Am J Perinatol 2013;30:537–544.
96. Iheozor-Ejiofor Z, Middleton P, Esposito M, Glenny AM.
Treating periodontal disease for preventing adverse birth
outcomes in pregnant women. Cochrane Database Syst
Rev 2017;6:CD005297.
97. Schwendicke F, Karimbux N, Allareddy V, Gluud C.
Periodontal treatment for preventing adverse pregnancy
outcomes: A meta- and trial sequential analysis. PLoS
One 2015;10:e0129060.
98. Zhang W, Daly CG, Mitchell D, Curtis B. Incidence and
magnitude of bacteraemia caused by flossing and by
scaling and root planing. J Clin Periodontol 2013; 40:
41–52.
99. D’Aiuto F, Parkar M, Tonetti MS. Acute effects of peri-
odontal therapy on bio-markers of vascular health. J
Clin Periodontol 2007;34:124–129.
100. Jeffcoat M, Parry S, Gerlach RW, Doyle MJ. Use of
alcohol-free antimicrobial mouth rinse is associated
with decreased incidence of preterm birth in a high-
risk population. Am J Obstet Gynecol 2011; 205:
382.e381–386.
101. Jiang P, Bargman EP, Garrett NA, Devries A, Springman
S, Riggs S. A comparison of dental service use among
commercially insured women in Minnesota before,
during and after pregnancy. J Am Dent Assoc 2008;
139:1173–1180.
102. Milgrom P, Lee RS, Huebner CE, Conrad DA. Medicaid
reforms in Oregon and suboptimal utilization of dental
care by women of childbearing age. J Am Dent Assoc
2010;141:688–695.
103. Ressler-Maerlender J, Krishna R, Robison V. Oral health
during pregnancy: Current research. J Womens Health
(Larchmt) 2005;14:880–882.
104. Michalowicz BS, DiAngelis AJ, Novak MJ, et al. Exam-
ining the safety of dental treatment in pregnant women.
J Am Dent Assoc 2008;139:685–695.
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105. Hagai A, Diav-Citrin O, Shechtman S, Ornoy A. Preg-
nancy outcome after in utero exposure to local
anesthetics as part of dental treatment: A prospective
comparative cohort study. J Am Dent Assoc 2015;146:
572–580.
106. Oral Health Care During Pregnancy Expert Workgroup.
Oral Health Care During Pregnancy: A National Consen-
sus Statement. http: / / www.mchoralhealth.org/PDFs/
OralHealthPregnancyConsensus.pdf. Accessed 31
August 2018.
107. Oral Health Policy and Advocacy Committee, Health
Home Subcommittee. Toward a Comprehensive Health
Home: Integrating the Mouth to the Body. http://www.
aaphd.org/ assets/ resolution-statements/ aaphd%20
final%20health%20home%20resolution%20-%20
last%20revision%20oct%202011.pdf. Accessed 30
August 2018.
230
108. American Academy of Pediatric Dentistry. Council on
Clinical Affairs. Guideline on perinatal oral health care.
Reference Manual 37; 6: 140–145. http: / / www.aapd.
org/media/Policies_Guidelines/G_PerinatalOralHealth-
Care.pdf. Accessed 30 August 2018.
109. American Academy of Pediatric Dentistry. Council on
Clinical Affairs, Committee on the Adolescent. Guideline
on oral health care for the pregnant adolescent. Refer-
ence Manual 37; 6: 159–165. http: / / www.aapd.org/
media/Policies_Guidelines/G_Pregnancy.pdf. Accessed
30 August 2018.
110. Graziani F, Cei S, Orlandi M, et al. Acute-phase response
following full-mouth versus quadrant non-surgical peri-
odontal treatment: A randomized clinical trial. J Clin
Periodontol 2015;42:843–852.
111. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of peri-
odontitis and endothelial function. N Engl J Med 2007;
356:911–920.

Oral Infections and Cancer
Dominique S. Michaud, scd
Over the past 50 years, the number of heart
disease deaths in the United States has rapidly
declined while the number of cancer deaths has
gradually increased.1 In 2016, 595,930 people
died of cancer and 633,842 died of heart dis-
ease, and in coming years the number of cancer
deaths is predicted to surpass those from heart
disease.1 Cancers of the lung, breast, prostate,
and colon (including rectum) are the most
common cancers and combined account for
45% of all cancer deaths in the United States.2
Although the total number of cancer deaths
(absolute) is increasing, cancer death rates have
been slowly decreasing since the 1990s,1 with
the most notable decreases occurring for lung,
colorectal, and prostate cancers.2 No changes
in cancer death rates, even increases, have been
observed for other cancers.2
There are large racial and ethnic dispari-
ties in cancer incidence and death rates in the
United States.2 Disproportionate poverty can
explain a portion of these disparities,2 but dif-
ferences in behaviors (and risk factor profiles)
also account for some of these differences.
Understanding which risk factors are caus-
ally related to cancer risk is critical to address
cancer prevention. Established risk factors for
the most common cancers are discussed in
the following sections. Considering these fac-
tors when studying the relationship between
CHAPTER 11
periodontal disease (and oral microbiota) and
cancer risk is vital to adequately address bias.
Shared Risk Factors for
Periodontal Disease and
Cancer
Implications for causality
Establishing causality between any risk fac-
tor and cancer risk is extremely challenging
because of the long latency period often
observed between exposure and cancer man-
ifestation. For most known carcinogens, the
evidence needed to confirm causality took
decades to accumulate and required hundreds
of studies to address bias (including confound-
ing), temporality, and biologic mechanisms.
Even for cigarette smoking, one of the stron-
gest known cancer risk factors, three decades
elapsed between the first reports of an associa-
tion3 and acceptance of causality.4 The biggest
challenge in evaluating potential causality
between periodontal disease and cancer risk
is being able to rule out bias that arises from
unbalanced prevalence of risk factors in indi-
viduals with periodontal disease and those
without periodontal disease. Consequently,
231
11 Oral Infections and Cancer
it is important to understand that numerous
behavioral factors and health conditions are
associated with both periodontal disease and
cancer.
Smoking, obesity, and type 2
diabetes
Cigarette smoking is estimated to account
for 30% of all cancer deaths and more than
80% of lung cancer cases.5 Cigarette smok-
ing has been causally associated with 13 types
of cancer.6 The strongest associations are
observed for lung cancer, with relative risks
(RRs) ranging between 15 and 30, depend-
ing on smoking intensity.7 Similarly, smoking
has been estimated to account for a substan-
tial proportion of periodontal disease cases
(approximately 40%), and RRs for smoking
and periodontal disease range between 3 and
7.8 Former smokers experience higher risks
than never-smokers for both lung cancer and
periodontal disease.7,8 Tobacco smoke is known
to contain numerous carcinogens, but smoking
also influences other important biologic mech-
anisms, including the immune response, which
impacts both the development of cancer and
periodontal disease.8 Consequently, to avoid
bias, all observational studies evaluating the
association between periodontal disease and
cancer must comprehensively account for cur-
rent smoking status, as well as for smoking
duration and intensity; unfortunately, not all
published studies on this topic have done so,
limiting the interpretation of results.
Although associations for obesity and cancer
are not as strong in magnitude as those for ciga-
rette smoking, with most RRs ranging between
1.5 and 3, obesity is estimated to account for
approximately 8% of incident cancer cases and
has been causally related to cancer at 13 ana-
tomical sites by the International Agency for
Research on Cancer (IARC).9 The association
between obesity and periodontal disease is not
causally established, but the evidence for a pos-
itive association between obesity, weight gain,
232
and periodontal disease development and pro-
gression is strong (for more detail, see chapter
5). Given that obesity appears to be a risk fac-
tor for periodontal disease as well as for many
cancer types, observational studies examining
associations between periodontal disease and
cancer need to account for differences in sub-
ject adiposity, in addition to smoking history,
to provide unbiased results.
Type 2 diabetes has been associated with
several cancers, including pancreatic and co­
lorectal cancers, as well as with periodontal
disease (see chapter 6). Type 2 diabetes is a
complex disease that shares many risk factors
with cancer, including obesity, smoking, phys-
ical inactivity, and diet.10 Although causality
has not been established for type 2 diabetes
and cancer,10 it should be considered as a po-
tential confounder in analyses on periodontal
disease and cancer, as it is unclear whether lack
of adjustment in observational studies will re-
sult in bias.
Genetic susceptibility
There is some evidence that dental conditions,
including periodontal diseases, have a genetic
component. The best studies to address this
directly are those that compare periodon-
tal disease prevalence in monozygotic (MZ)
and dizygotic (DZ) twins. Three large twin
studies have reported higher concordance for
adult periodontitis in MZ compared to DZ
twins11–13; after adjusting for environmental
factors, the heritability component has been
estimated to be between 30% and 50%.12,13
In addition, aggressive periodontitis has been
reported to aggregate in families and is also
likely to have a strong genetic component.14
A number of genome-wide association stud-
ies (GWASs) have been conducted to identify
genetic variants associated with periodontal
disease.15–17 However, results from these studies
have not been reproducible (each identifying
unique genetic loci). As periodontal disease
definitions are complex (and not consistent
across studies), it is possible that the lack of
 Biologic Plausibility for an Association Between Periodontal Disease and Cancer
consistency across findings underlie the com-
plexity of the disease rather than evidence
for a lack of genetic contribution. In a recent
GWAS, unique genetic variants were identified
for six periodontal complex traits character-
ized by dysbiotic microbial communities and
inflammatory markers15; this suggests that dif-
ferent periodontal disease traits have different
underlying molecular mechanisms, thus argu-
ably making it more difficult to identify genetic
variants when using one clinical definition.
The possibility that associations reported
between periodontal diseases and cancer risk
are explained by shared genetic factors has
been examined in one twin study.18 The authors
reported an attenuated association between
periodontal disease and cancer among MZ
twins, suggesting genetic factors may partially
explain the observed association for cancer risk
in DZ twins. However, it should be noted that
the definition of periodontal disease in the twin
study was based on tooth mobility and not
clinical measurements.18 Given that a number
of genetic variants linked to periodontal dis-
eases have been identified in genes associated
with the immune response,15 it is important
to acknowledge the possibility that shared
genetic susceptibility may account for some of
the associations observed between periodontal
disease and cancer risk in other studies; unfor-
tunately, adjusting for genetic susceptibility in
statistical analyses is not easily achieved, as the
genetic factors remain mostly unknown.
Biologic Plausibility for
an Association Between
Periodontal Disease and
Cancer
Up through the 1980s, known associations
between infection and carcinogenesis were
largely limited to viruses and parasites; decades
of research on viruses and cancer development
have established numerous causal associations
and clearly demonstrated how DNA mutations
arise from the integration of viruses into human
DNA. In 1994, the IARC reported that there
was sufficient evidence on Helicobacter pylori
and stomach cancer to classify this bacterium
as a Class I carcinogen. The extensive research
that has been conducted on H pylori, partly to
establish causal associations with cancer, has
revealed how bacteria can cause inflammation,
induce oxidative stress and DNA damage,
and increase cell proliferation.19 Over the past
decade, the number of studies on bacteria and
cancer has exploded, with some of the earliest
research arising from interest in microbiota and
oral cancer.20,21 Biologic plausibility, impor­
tant in establishing causality, has solidified
with mechanistic studies demonstrating how
bacteria can impact the immune response and
interact with human cells to activate signaling
pathways that can lead to carcinogenesis.22
Fusobacterium nucleatum and Porphyromonas
gingivalis are two oral bacterial species that
have been recently associated with cancer risk.
The plausible mechanisms for these two species
are discussed in more detail in the following
sections.
Fusobacterium species and cancer
Over the past 5 years, there has been tremen-
dous growth in the interest in Fusobacterium
species and how they may play a role in can-
cer, especially colorectal cancer. Fusobacterium,
particularly F nucleatum, has been detected
in a high proportion of colon cancer tissue
(higher than in normal colon tissue).23–25 Mice
infected with F nucleatum have an increase in
tumor growth and tumor burden compared to
those mice not infected.23,24,26,27 Infection with
F nucleatum using mouse models has also been
shown to promote tumor progression in the
oral cavity.28 In a recent study, antimicrobial
treatment in mice with xenografts of human
primary colorectal adenocarcinoma positive
for Fusobacterium reduced Fusobacterium load
and led to a reduction in cancer cell prolifera-
tion and overall tumor growth.25
233
11 Oral Infections and Cancer
In experimental studies, immune response
and signaling pathways have been shown to be
affected by proteins produced by F nucleatum.
For example, F nucleatum has been shown
to inhibit antitumor immunity by natural
killer cells through the production of protein
Fap2.29 Bacteria with a mutated Fap2 gene,
and thereby inability to produce this protein,
can no longer inhibit natural killer cells from
recognizing and removing tumor cells.29 F
nucleatum has also been shown to promote
cell proliferation by activating the β -catenin
signaling pathway,30,31 an important pathway
in colorectal cancer. These data provide sup-
port for a causal link between F nucleatum
and cancer, although these results need to be
evaluated in conjunction with human studies
to determine causality.
Porphyromonas gingivalis and
pancreatic cancer
One of the keystone bacteria for periodontal
disease, P gingivalis,32 has been implicated in
pancreatic carcinogenesis (discussed later) and
has been extensively studied due to its unique
ability to evade the immune response.33 P gin-
givalis has been shown to evade the immune
response by modification of its lipid A, the
biologic core of bacterial lipopolysaccha-
ride, universally recognized by the toll-like
receptor 4–myeloid differentiation factor 2
(TLR-4–MD-2) complex.34–36 In addition, P
gingivalis has been shown to alter dendritic
cell maturation37,38 and promote expansion
of myeloid-derived suppressor cells (MDSCs),39
providing further support for its active role in
immune evasion and suppression.
Research on how bacteria may impact can-
cer is in its infancy, and much more work is
needed to elucidate their role in carcinogenesis.
Examining how the microbiome impacts the
innate immune response and causes inflamma-
tion is becoming an important field in cancer
research.
234
Observational Studies Linking
Periodontal Disease to Cancer
All cancers
Despite the heterogeneity in measures used
to ascertain periodontal disease status, asso-
ciations reported in observational studies
evaluating risk for all cancers combined have
been surprisingly consistent. To date, findings
from eight unique cohort studies have been
published with RRs ranging between 1.14
and 1.5518,40–46 (only one study was not statis-
tically significant, and the number of cancers
was small in that cohort41). Unfortunately,
three of these studies did not adjust for smok-
ing status42–44; after removing these studies, the
highest RR is 1.24.46
Associations for periodontal disease and can-
cer risk among never-smokers have not been as
strong; either weak45,47 or null41 associations
were reported in three of the four cohort stud-
ies with separate results on never-smokers.41,47,48
It is unclear if these findings indicate that the
overall associations are confounded by smok-
ing status or if there is an interaction between
smoking and periodontal disease status such
that only smokers are at higher risk of can-
cer with periodontal disease. The differences
observed between smokers and never-smokers
(for periodontal disease) may also be due to
heterogeneity of types of cancers represented
in the smoking groups, given that associations
between periodontal disease and cancer vary
by cancer type.
Head and neck cancers
It is not surprising that interest in the role of
oral health (including periodontal disease)
and cancer risk was first raised with oral can-
cers. A large number of studies have reported
positive associations between tooth loss,
oral health, and oral cancers, most of which
are case-control studies.49 The quality of these
studies, however, has varied, and it is difficult to
 Observational Studies Linking Periodontal Disease to Cancer
identify causal associations with retrospective
study designs. Case-control studies have also
addressed the potential link between periodon-
tal disease and head and neck cancers, including
oral cancers. Periodontal disease has been mea-
sured with different levels of accuracy; however,
more recent studies have included measures of
bone loss due to periodontitis50,51 and peri-
odontal pocket depth.52 Overall, findings are
inconsistent, with earlier studies showing
weak inverse associations53 and more recent
studies reporting strong associations, with
four- to five-fold higher risks for severe peri-
odontitis.50,51 Associations from cohort studies
have been weaker, with RRs ranging between
1.10 and 1.20; however, numbers of cases were
small overall, and thus analyses could not be
done on oral cancers separately.44,45,48
Given that head and neck cancers have
different causes, with human papillomavirus
(HPV)–positive cancers forming a distinct
group, there is growing interest in the rela-
tionship between periodontal disease and
persistence of HPV infections in the oral cav-
ity. HPV has been identified in 26% of gingival
biopsies of subjects with periodontal pockets,
suggesting that periodontal disease may play
a role in persistence of HPV infection.54 One
study reported higher HPV-positive oral tumors
among individuals with periodontal disease.55
Moreover, a recent study reported that His-
panic individuals (with no history of cancer)
with severe periodontal disease had a close to
three-fold higher risk of having HPV-positive
oral saliva than those without periodontal
disease.56 While the direction of association
cannot be determined for HPV and periodon-
tal disease, these findings highlight the need to
stratify results for periodontal disease and head
and neck cancer by cancer site.
Lung cancer
Some of the strongest associations between
periodontal disease and cancer have been
observed for lung cancer. A meta-analysis con-
ducted on smoking-adjusted RRs estimated a
33% increased risk of lung cancer for indi-
viduals with a history of periodontal disease
compared to those with no periodontal disease
(95% confidence interval [CI]: 1.19–1.49).49
In a cohort study using dental examinations
for the classification of periodontal disease sta-
tus that was published after the meta-analysis
was conducted, a two-fold increase in risk of
lung cancer was observed in participants with
baseline severe periodontitis compared to those
with no or mild periodontitis.47 In that study,
a higher risk was also noted among those par-
ticipants who were edentulous (hazard ratio
[HR]: 2.60; 95% CI: 1.65–4.08) compared to
those with no or mild periodontitis. While the
association persisted among never-smokers, the
number of cases was small, and no associations
were observed among black participants.47
Figure 11-1 provides the meta-analysis for all
cohort studies (including the newest study).
Results for associations between periodon-
tal disease and lung cancer have varied among
never-smokers (with null results in two cohort
studies48,57), but particularly interesting is the
possibility that smokers may be at greater
risk of developing lung cancer if they have
periodontal disease. An interaction between
smoking and periodontal disease was observed
for women with higher smoking intensity and
periodontal disease compared to those with
higher smoking dose and no periodontitis in
the Women’s Health Initiative (WHI) Obser-
vational Study cohort (HR: 1.29; 95% CI:
1.95–3.87).57 The number of missing teeth has
also been associated with a higher risk of lung
cancer in two out of four cohort studies.40,43,58,59
Colorectal cancer
Studies reporting associations between peri-
odontal disease and colorectal cancer risk
have been less consistent and weaker than
those for lung cancer but deserve attention
because of the known link between inflam-
mation and colorectal cancer, as well as the
findings on F nucleatum (discussed previously).
Although F nucleatum is not considered a
235
11 Oral Infections and Cancer
Study Participants
Hujoel, 2003 Both sexes
Michaud, 2008 Male
Arora, 2010 Both sexes
Mai, 2014 Female
Mai, 2016 Female
Michaud, 2018 Both sexes
Overall (I-squared = 0.0%; P = .426)
0.3 0.5
Fig 11-1  |  Meta-analysis of cohort studies on periodontal disease and lung cancer.
keystone pathogen for periodontal disease, it
is commonly found in the oral cavity and may
disseminate more easily to the gut in individu-
als with periodontal disease.
In a recent meta-analysis, having a history of
periodontal disease was estimated to increase
the risk of colorectal cancer by 47% compared
to those with no periodontal disease (although
this association was not statistically significant;
95% CI: 0.95–2.29).49 Results from the ARIC
cohort (published after the meta-analysis)
were of similar magnitude for colorectal can-
cer (HR: 1.51; 95% CI: 0.95–2.42 for severe
periodontitis compared to no or mild periodon-
titis).47 Moreover, results were stronger among
never-smokers (HR: 2.12; 95% CI: 1.00–4.47
for severe periodontitis versus no or mild peri-
odontitis), and edentulous individuals had a
three-fold higher risk of colorectal cancer in the
same cohort.47 Three additional studies have
been published since the meta-analysis was
conducted; a positive association was reported
in a retrospective cohort study conducted in
Taiwan using insurance records of periodontal
treatment (RR: 1.64; 95% CI: 1.50–1.80),60
but no association was observed in the WHI
cohort study (RR: 0.98; 95% CI: 0.82–1.17),45
and only a modest association for moderate/
severe periodontal disease was noted in the
Nurses’ Health Study cohort (RR: 1.22; 95%
CI: 0.91–1.63).61
236
Adjusted RR (95% CI)
1.73 (1.01, 2.97)
1.36 (1.15, 1.60)
1.41 (0.81, 2.46)
1.25 (1.06, 1.48)
4.61 (0.55, 38.70)
1.79 (1.21, 2.65)
1.36 (1.22, 1.51)
1 2 5 10 20 40
Pancreatic cancer
To date, positive associations between peri-
odontal disease and pancreatic cancer risk or
mortality have been reported in six prospec-
tive cohort studies18,42,43,47,62,63 (although one
study defined periodontal disease using a tooth
mobility measure18). In the first exploratory
study to examine periodontitis and pancreatic
cancer, individuals with periodontitis at base-
line had a higher risk of fatal pancreatic cancer
compared to those with healthy periodontium
(RR: 1.77; 95% CI: 0.85–1.85); unfortunately,
results were not presented with adjustment
for cigarette smoking.43 A statistically sig-
nificant 64% increase in risk of pancreatic
cancer was observed in a second study on
periodontal disease, after adjusting for age,
smoking, diabetes, and body mass index.47 In
a follow-up analysis of this cohort (with 10
additional years of follow-up), never-smokers
with periodontal disease at baseline had a 57%
higher risk of pancreatic cancer compared to
those with no periodontal disease.48 Similar
positive associations were reported in four
additional cohort studies with data on peri-
odontitis,18,42,62,63 although smoking was not
adjusted in two of these studies.42,62 Although
data were not available on periodontal disease
status, a study conducted in Sweden linking
oral health examinations to cancer registries
 Future Directions and Potential Opportunities for Cancer Prevention or Early Detection
with an average of 28.7 years of follow-up
observed a two-fold increase in pancreatic can-
cer risk among individuals who were reported
as having “unacceptable dental plaque” on the
baseline dental examination.64 Only one cohort
study to date has reported no association
between periodontal disease (self-reported)
and pancreatic cancer.45 In contrast to reports
on the assaociation of periodontal disease and
pancreatic cancer, findings on tooth loss (a pos-
sible marker of past severe periodontitis) and
pancreatic cancer have been inconsistent but
largely null.49
Several studies have examined the rela-
tionship between oral bacteria previously
associated with periodontal disease and risk of
pancreatic cancer to explore the potential role
of bacteria. The association between antibodies
to periodontal pathogens and risk of pancreatic
cancer was first examined in a large prospec-
tive cohort study using blood samples stored
on over 385,000 men and women at baseline
(ie, prior to cancer diagnosis).65 A greater than
two-fold increase in risk of pancreatic cancer
was reported among those subjects with high
levels of antibodies to a pathogenic strain of
P gingivalis (OR: 2.38; 95% CI: 1.16–4.90;
comparing greater than 200 ng/mL versus less
than 200 ng/mL) after adjusting for known risk
factors, including smoking.65 In contrast, no
associations were detected for other oral bac-
teria tested in that study. In a separate cohort
study, individuals with antibodies to P gingiva-
lis (greater than 69.1 EU compared to less than
69.1) were associated with a three-fold higher
risk of orodigestive cancer mortality (RR: 3.03;
95% CI: 0.99–9.31); unfortunately, small case
numbers did not allow for a separate analysis
on pancreatic cancer.63 In a separate cohort
analysis (combining data from two large pro-
spective cohort studies), a 1.6-fold increased
risk was reported for the presence of P gin-
givalis taxa measured directly in saliva using
16S RNA genes, and a two-fold increased risk
was observed for higher mean of Aggregati-
bacter actinomycetemcomitans taxa, another
periodontal pathogen.66 Unlike other studies
measuring bacterial DNA in saliva in cancer
patients,67–69 the cohort analysis was unique in
that saliva samples had been obtained up to 10
years prior to cancer diagnosis.66
Future Directions and
Potential Opportunities for
Cancer Prevention or Early
Detection
New studies conducting research on oral health
and cancer have increased rapidly in the past
decade and have made substantial contribu-
tions to this field. However, many questions
remain, including whether periodontal disease
prevention and/or treatment can reduce cancer
incidence and mortality, whether periodontal
disease associations with cancer vary by race/
ethnicity, and whether therapeutic opportu-
nities for cancer treatment may arise from
microbial research. No intervention study has
been conducted to examine if treatment of peri-
odontal disease reduces the risk of cancer; such
a study would require an extremely large sam-
ple size and a very long follow-up period (if the
study were even ethically feasible). An observa-
tional study using the Taiwan National Health
Insurance system database compared incidence
cancer rates among subjects who received peri-
odontal disease treatment to those who did
not receive treatment in the population.70 The
main assumption in this analysis was that the
comparison group, randomly selected from the
Taiwanese population (age- and sex-matched),
had a high prevalence of untreated periodontal
disease; however, the prevalence of periodontal
disease in Taiwan is estimated to be approx-
imately 20%.71 Consequently, the inverse
associations reported in that study, including
for gastrointestinal and lung cancers, should
be interpreted with caution because they do
not directly demonstrate that treatment of peri-
odontal disease reduces cancer risk and also did
not adjust for smoking. Observational studies
237
11 Oral Infections and Cancer
with strong study designs are urgently needed
to address the critical question of whether pre-
vention or treatment for periodontal disease
will impact cancer development, recurrence,
or mortality.
Although a number of small intervention
studies on periodontal disease suggested that
nonsurgical treatment could improve glyce-
mic control in diabetic patients, findings from
a large randomized controlled trial did not
confirm the earlier findings.72 The controversy
over the effectiveness of periodontal therapy
on glycemic control in diabetic patients, an
example where the data were originally very
promising, should serve as a cautionary note
when evaluating the potential impact of peri-
odontal therapy on cancer (given the current
paucity of data in this field). Cancer develop-
ment, from tumor initiation to diagnosis, takes
place over several decades, and exposures that
are known to cause cancer often occur decades
prior to diagnosis. Because at this time we do
not know if oral infections and associated
immune responses impact cancer initiation or
progression, it is difficult to predict whether
Clinical Considerations: What You Can Take Back to Your Practice
Is there a biologic plausibility for an associa-
tion between oral infections and cancer?  Ex-
perimental studies have provided important
clues on how oral bacteria cause inflammation,
modulate the immune response, and impact
key cancer pathways. Whether associations be-
tween oral infections and cancer are causal re-
mains to be determined, but biologic plausibil-
ity is strong.
Are oral infections and disorders independent risk
factors for the development of cancer?  Yes, oral
infections and periodontal disease appear to be
independent risk factors for the development of
cancer as associations have remained strong in
studies that have adjusted for known cancer risk
factors. In addition, associations for certain can-
cers remain positive among never-smokers, ar-
guing against confounding by smoking.
238
treatment of periodontitis would translate to
a reduction in cancer burden. In animal mod-
els, oral bacterial infections promote tumor
growth,23–25 suggesting that these exposures
may have a late effect in carcinogenesis, but
it is less clear in humans when these bacteria
disseminate to the different body sites.
If the associations with oral infections are
indeed causal, prevention of periodontal dis-
ease will likely have a more pronounced impact
on cancer than treatment, given the long
latency periods seen with cancer. With RRs
between 1.2 and 1.5 for periodontal disease
and cancer, the number of preventable can-
cers from removing periodontal disease as an
“exposure” (through prevention of periodontal
disease) could be high given that periodontal
disease is a highly prevalent condition. Improv-
ing our understanding of the relationship
between periodontal disease and other risk
factors as they relate to cancer risk, as well as
the identification of potential bacteria that may
be involved in carcinogenesis, may also provide
new opportunities for early cancer detection
(through biomarker discovery).
Can treatment of oral infections and disorders
reduce the risk for the development of cancer? 
Causality has not been clearly established for
periodontal disease and cancer; therefore, we
cannot be certain at this time that treatment
will reduce the risk of cancer. More research is
needed to provide an answer to this question.
What should a dental practitioner inform a pa-
tient about the association between oral infec-
tions and cancer?  Dental practitioners should
be able to inform patients that there is a pos-
sibility that periodontal disease increases the
risk of cancer, particularly oral, lung, colorec-
tal, and pancreatic cancers, but it is too early to
know if periodontal treatment can reduce the
risk of these cancers.

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241
 CHAPTER 12

Oral Manifestations of
Systemic Diseases
Alessandro Villa, dds, phd, mph
Sook-Bin Woo, dmd, mmsc

The general dentist in daily practice encounters
a variety of oral mucosal disorders, most of
which are straightforward and easy to diag-
nose. However, even a banal-appearing lesion
may be a manifestation of systemic disease or
side effect of treatment for systemic disease.
Moreover, the oral signs may be the first pre-
sentation of a systemic disorder, and the dentist
is in a unique position to facilitate an early
diagnosis. Early diagnosis and management
can often diminish the morbidity associated
with a systemic disease, improve well-being,
and reduce health care costs.
This chapter presents eight common oral
conditions (Box 12-1) that are encountered
in routine general dental practice. For each

Box 12-1  |  Common oral conditions that are encountered in routine general dental practice

Oral ulcers Gingivitis –– Heavy metal pigmentation

• Traumatic ulcer
• Recurrent aphthous ulcer/
stomatitis
• Aphthous-like ulcers from
systemic disease
• Drug-induced oral ulcers
• Viral infections
• Erythema multiforme
• Deep fungal infections
• Vesiculobullous disease
White/red lesions
• Frictional/factitial keratosis
• Leukoplakia
• Oral lichen planus/lichenoid
lesions
• Candidiasis
• Coated/hairy tongue
• Migratory glossitis
• Conventional gingivitis
• Desquamative gingivitis and
hypersensitivity reactions
• HIV/AIDS-associated linear
gingivitis and necrotizing
ulcerative gingivitis
Diffuse gingival hyperplasia
• Drug-induced gingival hyperplasia
• Acute leukemia
• Gingival fibromatosis
• Destructive membranous
periodontal disease
Pigmented lesions
• Extrinsic pigmentation
–– Medication-induced
pigmentation
–– Foods and dentifrices
–– Amalgam tattoo
–– Others
• Intrinsic pigmentation
–– Melanin
–– Blood pigment
Poorly or nonhealing extraction
sockets and osteonecrosis
• Dry socket
• Infection
• Osteoradionecrosis
• Drug-induced osteonecrosis
• Metastatic tumor to the jaw
Xerostomia and hyposalivation
• Hyposalivation associated with
normal glands
• Hyposalivation associated with
damaged glands
Burning mouth syndrome (oral
dysesthesia syndrome)

242

condition, the discussion first presents one or
two “most likely” diagnoses based on the fre-
quency of occurrence and then offers a detailed
description of other conditions that may look
similar but represent the oral presentation of
a systemic condition or drug effect. The differ-
ences in history, clinical findings, and diagnostic
tests that may help distinguish between each of
them are also presented.
Oral Ulcers
An ulcer is a loss of epithelium over an area of
the mucosa covered by a yellow or whitish-gray
fibrin pseudomembrane. Traumatic ulcers are
the most common type, followed by aphthous
ulcers. However, oral ulcers associated with
systemic diseases, use of some medications,
infections in immunocompromised patients,
vesiculobullous diseases, and immune-mediated
diseases such as erythema multiforme may
resemble idiopathic aphthous ulcers.
Traumatic ulcer
Traumatic ulcerations are caused by sharp or
broken teeth, rough fillings, acute biting of the
mucosa, and friction from ill-fitting dentures.
As such, the side of the tongue, buccal mucosa,
and lower lip are the most frequently affected
sites, and removal of traumatic factors leads
to resolution.
Recurrent aphthous ulcers/
stomatitis
Idiopathic recurrent aphthous stomatitis (RAS),
popularly known as canker sores, affects 10%
to 20% of the population and usually first man-
ifests in childhood or adolescence; the frequency
of episodes usually diminishes with age.1 The
etiology is multifactorial, and some factors
include trauma, smoking cessation, hormonal
changes, stress, genetics, some hypersensitivity
Oral Ulcers
Fig 12-1 |  Aphthous ulcer with grayish-white fibrin
pseudomembrane and erythematous halo.
reactions, and immunologic factors; many cases
are idiopathic.2 However, many systemic con-
ditions may present with aphthous-like ulcers,
and patients must be carefully questioned and
evaluated for such systemic conditions.
RAS generally presents as shallow oval or
round ulcers covered by a grayish-white fibrin
pseudomembrane with an erythematous halo
(Fig 12-1). They occur on the nonkeratinized
mucosa and resolve completely between epi-
sodes. Except for major RAS, they rarely occur
on the hard palatal mucosa, dorsum of the
tongue, or attached gingiva. The frequency of
episodes varies from monthly to only a few
times a year. A minority of women develop
minor RAS just before their menses.
There are four main forms: minor, major,
herpetiform, and severe (Table 12-1). Biopsy,
usually performed to rule out other conditions
(such as bullosing disorders), shows an ulcer
with nonspecific acute and chronic inflamma-
tion. RAS is not caused by a virus or other
infectious agent.
Treatment, whether idiopathic or related to
systemic disease, depends on the severity and
frequency of the lesions and centers around
pain control, definitive treatment of the ulcers,
and reducing the frequency of outbreaks.
Patients who experience one or two episodes
243
12 Oral Manifestations of Systemic Diseases

TABLE 12-1  |  Presentation of recurrent aphthous stomatitis

Minor* Major Herpetiform

Size and number of ulcers < 1 cm; usually 1 to 5 ulcers ≥ 1 cm; usually 1 ulcer < 0.5 cm; usually 10 ulcers or more

Duration 7 to 10 d Months 7 to 10 d

Scarring No Yes/No No

*There is a severe variant of minor RAS in which an affected individual is almost never without ulcers.

TABLE 12-2  |  Topical immunosuppressive agents and pain medications

Immunosuppressive agents Instructions

Triamcinolone, 0.1% in methylcellulose paste Apply to affected site three to four times a day; methylcellulose is an effective
(for solitary lesions only) covering agent, although triamcinolone is only of moderate potency.

Clobetasol, 0.05% gel or cream
Bethametasone, 0.05% gel or cream
Fluocinonide, 0.05% gel or cream
Fluocinolone, 0.05% gel or cream
Tacrolimus, 0.1% ointment
Dry area and apply to affected site three to four times a day (on gauze if
appropriate). Do not consume food or drink for 20 min after application.
OR
Place gel in stent and wear for 15 to 30 min two to three times a day (for
extensive gingival lesions).

Dexamethasone elixir, 0.5 mg/5 mL Dispense 300 mL; swish 5 mL for 3 to 5 min (timed) and spit out three to four
Compounded clobetasol, 0.05% solution times a day. Do not consume food or drink for 20 min after use.
Tacrolimus solution, 5 mg/mL

Intralesional steroid injection with Administer 10 to 15 mg triamcinolone per cm2 of ulceration.

triamcinolone

Pain medications

Benzydamine hydrochloride, 0.15% Swish and spit out 5 to 15 mL three to four times a day when in pain.
Dyclonine hydrochloride, 1% Viscous lidocaine may be mixed in equal volume with diphenhydramine,
Viscous lidocaine, 2% aluminum/magnesium, and bismuth subsalicylate.

Benzocaine, 10% to 20% Apply to the affected area three to four times a day when in pain.

a year probably just require reassurance and incorporated in a mucoadhesive, is sometimes

the use of over-the-counter local anesthetics
(such as 10% benzocaine) or mucoadhesive
agents such as methylcellulose paste (Orabase
Paste, Colgate-Palmolive) and polyvinylpyrro-
lidone sodium hyaluronate (Gelclair, Helsinn
Healthcare). Amlexanox (OraDisc A, ULURU),
a prescription anti-inflammatory agent
effective. More frequent or severe outbreaks
may be treated with topical corticosteroids and
other immunosuppressive agents, and larger,
recalcitrant ulcers or those of major RAS may
require intralesional therapy such as triamcin-
olone injections at a dosage of 10 to 15 mg/
cm2 of ulcer size (Table 12-2). The same topical

244

management strategies are used for ulcers asso-
ciated with other disorders. Systemic therapy
for severe outbreaks is with prednisone (usually
at 0.75 to 1 mg/kg) and maintenance therapy
with pentoxifylline, colchicine, azathioprine,
mycophenolate, or thalidomide.
Aphthous-like ulcers from
systemic disease
Several systemic conditions have been associ-
ated with aphthous-like ulcers, and these ulcers
resolve when systemic disease is controlled,
unlike idiopathic RAS for which there is no
specific etiologic agent. Aphthous-like lesions
may occur in patients deficient in folic acid,
iron, or vitamins B1, B2, B6, or B12; these are
readily diagnosed with a blood test, and ulcers
typically resolve or improve with repletion,
although not always.
Inflammatory bowel diseases such as Crohn
disease and ulcerative colitis often lead to oral
ulcers. Patients experience abdominal pain,
diarrhea, fever, fatigue, weight loss, and anemia,
and these can be elicited by a careful history,
although oral findings may precede systemic
symptoms. Crohn disease is a granulomatous
inflammatory disorder of unknown etiology,
although genetic, immunologic, environmental,
microbial, dietary, and vascular factors have
been implicated. It affects the ileum and large
bowel in more than 90% of patients, although
any part of the gastrointestinal tract may be
affected.3
Crohn disease is strongly associated with
aphthous ulcers that generally have a linear
appearance if located in the oral vestibule.
Other findings include angular cheilitis; swell-
ing of the lips (Fig 12-2), face, and gingiva; and
edema of the oral mucosa resulting in fissuring,
or a “cobblestone” appearance. In addition to
aphtheiform ulcers, patients with ulcerative
colitis may present with pustular and ulcerative
eruptions in the oral cavity referred to as pyosto-
matitis vegetans. The pustules often coalesce and
break down, leaving superficial erosions.
Oral Ulcers
Fig 12-2  |  Swelling of the lips in a patient with oro-
facial granulomatosis.
Management of intestinal disease involves
the use of systemic medications (eg, corticoste-
roids, salicylates, immunosuppressive agents,
and biologic agents such tumor necrosis factor
alpha [TNF-α] inhibitors) or surgical resection.
Gluten-sensitive enteropathy (also known
as celiac disease or celiac sprue) is an autoim-
mune disease of the small intestines caused by
a hypersensitivity reaction to gliadin, a gluten
protein. Almost all patients have the HLA-DQ2
allele and some the HLA-DQ8 allele. A spe-
cific association was found with chromosome
15q26, chromosome 5q, and possibly 11q.
Aphthous-like ulcers are seen in 3% to 61%
of patients, and dental enamel defects have
been reported.4 If this condition is suspected,
blood tests for antigliadin, antiendomysial,
and anti–tissue transglutaminase antibodies
should be performed. Signs and symptoms are
relieved on a gluten-free diet. Because of mal-
absorption after iliectomy, patients may develop
aphthous-like ulcers from vitamin B12 deficiency.
Hypersensitivities to other foods such as eggs
or chocolate may cause aphthous ulcers and a
periodic fever syndrome (periodic fever, aph-
thae, pharyngitis, adenopathy [PFAPA]), which
is usually seen in the first and second decade.5
245
12 Oral Manifestations of Systemic Diseases
Behçet disease is a systemic vasculitis associ-
ated with the HLA-B51 gene. It is characterized
by aphthous-like ulcers, genital ulcers, ocular
lesions (especially anterior uveitis), and skin
lesions (such as erythema nodosum). Cardio-
vascular, musculoskeletal, gastrointestinal, and
neurologic symptoms are variably present.
Onset is usually during the third and fourth
decade of life, and it is more prevalent in indi-
viduals from Turkey, Japan, the Middle East,
and other Asian countries.6,7 MAGIC (mouth
and genital ulcers with inflamed cartilage)
syndrome combines features of both relaps-
ing polychondritis and Behçet disease with
major aphthous ulcers and, rarely, multifocal
neurologic abnormalities. Oral ulcers in these
patients are treated using the same approach
used for RAS. Treatment for the disease
includes the use of anti–TNF-α biologic agents,
such as etanercept and infliximab.
Cyclic neutropenia is a rare inherited condi-
tion due to mutations in the gene for neutrophil
elastase. These patients usually have a circu-
lating neutrophil count that fluctuates and
severe neutropenia occurring every 3 weeks
and lasting for 3 to 5 days. During these
periods, patients are susceptible to bacterial
infections and may report a history of recur-
rent fever, lymph node enlargement, malaise,
aphthous-like ulcers, and pharyngitis. Other
oral findings include gingivitis, gingival ulcers,
and periodontitis. Blood tests during these epi-
sodes reveal low neutrophil counts. Treatment
is mostly with topical steroids (see Table 12-1)
because of its relapsing-remitting nature.
The prevalence of oral complications in
patients with HIV/AIDS has decreased since
the advent of antiretroviral therapy. Patients
affected by HIV/AIDS often present with major
aphthous-like oral ulcers that may affect both
nonkeratinized and keratinized epithelium. All
such ulcers in patients with HIV/AIDS must be
biopsied to rule out infectious etiologies before
a diagnosis of aphthous-like ulcer can be con-
firmed. Topical and systemic therapy is often
required for resolution. These ulcers resolve if
the patient is adequately treated for HIV/AIDS.
246
Drug-induced oral ulcers
Drug-induced oral ulcers must be consid-
ered in older adults with a sudden onset
of aphthous-like ulcers because idiopathic
RAS usually has an onset in the first and
second decade of life. Several medications,
especially those used in oncology settings,
have been associated with ulcers in the oral
cavity. Targeted therapies and biologic agents
are used increasingly in the treatment of can-
cers, autoimmune diseases, and even chronic
mucosal disease. Dentists should be familiar
with the names of these medications as they
may encounter patients taking these medica-
tions. These ulcers do not represent aphthous
ulcers but are rather considered aphthous-like
ulcers because they resolve when the drug is
withdrawn and recur only when the patient
is rechallenged with the drug. Therefore, a
detailed drug history is extremely important
when evaluating abrupt-onset oral ulcers.
Oral mucositis, ulcerative or otherwise,
still represents a major acute complication
of cancer chemotherapy. The most stomato-
toxic agents include antimetabolites, such as
capecitabine, fluorouracil, and methotrexate;
alkylating agents, such as cyclophosphamide
and melphalan; antimitotics, such as paclitaxel,
vinblastine, and vincristine; and anthracycline
antibiotics, such as daunorubicin, doxorubicin,
carboplatin, cisplatin, and hydroxyurea. Muco-
sal soreness and sensitivity generally begin about
3 to 5 days after the first infusion, oral erythema
or ulcers develop a few days later, and resolu-
tion occurs in approximately 15 days.8 Lesions
involve mostly nonkeratinized sites and tend to
be more diffuse than discrete (Fig 12-3). Ulcers
that affect the keratinized mucosa of the hard
palate, gingiva, or dorsal tongue during chemo-
therapy are likely caused by herpes infections
(discussed later). Topical anesthetics (such as
viscous lidocaine or morphine rinses for severe
cases) or systemic or narcotic pain medications
help relieve symptoms until the ulcers heal.
Methotrexate is an immune-modulating
and antimetabolite drug. Methotrexate at low

Fig 12-3  |  Oral mucositis after radiation therapy in-
volving large ulcers of the tongue.
doses is used to control chronic inflammatory
disorders such as psoriasis and rheumatoid
arthritis. At higher doses, methotrexate acts
as a chemotherapeutic agent in the treatment
of non-Hodgkin lymphoma, leukemia, and
some solid tumors. Oral lesions associated
with methotrexate toxicity are typically char-
acterized by dose-dependent erythema and
ulceration (broadly termed mucositis). Folate
supplementation is an effective way to reduce
such mucosal damage. Treatment of these
lesions is with topical corticosteroids and, if
necessary, dose reduction.
Mammalian target of rapamycin (mTOR)
inhibitors are a group of agents prescribed
for the management of soft tissue sarcomas
(temsirolimus and ridaforolimus), advanced
metastatic renal cell carcinoma (everolimus),
and immunosuppression following organ
transplantation (sirolimus and everolimus).
The side effect of mTOR inhibitors of most
significance to dentists is that of discrete
aphthous-like oral ulcers (Fig 12-4), clini-
cally distinct from the more diffuse ulcers and
erythema of chemotherapy-induced muco-
sitis. This condition has been termed mTOR
inhibitor-associated stomatitis and occurs
within 10 days of start of the drug. Management
is with topical or intralesional corticosteroids.
Sodium lauryl sulfate (SLS) is the most com-
monly used detergent in dentifrices. Patients
Oral Ulcers
Fig 12-4 |  mTOR inhibitor oral ulcer of the left
tongue. (Courtesy of Dr Ryan Trowbridge, Division of
Dermatology, Brigham and Women’s Hospital, Bos-
ton, Massachusetts.)
often experience a burning sensation while
brushing their teeth with a toothpaste contain-
ing SLS. The denaturing effect of SLS on the
mucin layer overlying the epithelium may result
in inflammation of the oral mucosa, sloughing,
and ulcers. SLS has also been shown to be a
predisposing factor for RAS, although this is
equivocal since this may represent a contact
irritation rather than true RAS.9
Finally, nonsteroidal anti-inflammatory
drugs (NSAIDs) such as piroxicam, indometh-
acin, and ibuprofen may cause oral ulcers. For
SLS- or medication-induced lesions, discontin-
uation leads to resolution.
Viral infections
Herpes simplex virus 1 (HSV-1), also known
as human herpesvirus 1 (HHV-1), is one of
the most common viral infections that pro-
duces oral ulcers as part of primary herpetic
gingivostomatitis, recrudescent oral disease,
mucocutaneous orofacial disease, and ocular
disease. Occasionally oral lesions are caused
by HSV-2, a virus historically considered spe-
cific for the anogenital area but no longer so
because of changing sexual practices. Primary
herpetic gingivostomatitis typically occurs
in children and young adults, although most
primary HSV infections are asymptomatic or
exhibit only very mild symptoms.
247
12 Oral Manifestations of Systemic Diseases

TABLE 12-3  |  Herpes virus infections

Type Clinical presentation Location of ulcers in the oral cavity

HHV-1 (HSV-1) Primary herpetic Painful clusters of 1- to 5-mm oral Keratinized and nonkeratinized mucosa
gingivostomatitis ulcers, flulike symptoms

Recrudescent herpetic Lip prodrome of tingling, followed by Junction of lip vermilion and skin (most
infection in healthy a papule, blister, clustered vesicles, common), intraoral keratinized mucosa
individuals and ulcer, scabbing, and resolution (less common)
on lip vermilion; oral ulcers

Recrudescent herpetic infec- Clustered vesicles, coalescent Keratinized and nonkeratinized mucosa
tion in immunocompromised ulcers, or single aphthous-like oral
patients ulcers

HHV-2 (HSV-2) Same as HSV-1 Usually found on skin and mucosa below
the waist; may also be found in the mouth

HHV-3 (VZV) Primary varicella zoster virus Flulike symptoms and pruritic Skin, intraoral (uncommon)
(chicken pox) papular skin rash followed by vesicle
formation; oral form (uncommon):
0.1- to 0.5-cm painful oral ulcers

Shingles (herpes zoster Skin shingles; oral lesions resemble Facial or oral shingles along distribution
infection) recrudescent HSV; usually unilateral of trigeminal nerve

HHV-4 (EBV) Primary EBV infection Infectious mononucleosis

Recrudescent EBV infection Asymptomatic white papules and Lateral or dorsal tongue (most common
plaques with vertical lines (hairy sites)
leukoplakia) often secondarily
infected with Candida

HHV-5 (CMV) Primary CMV infection Asymptomatic or infectious

mononucleosis–like symptoms or
mild flulike symptoms

Recrudescent CMV infection Mostly in immunocompromised Oral mucosa

patients; large (usually > 1 cm),
painful, penetrating ulcers

HSV, herpes simplex virus; VZV, varicella zoster virus; EBV, Epstein-Barr virus; CMV, cytomegalovirus.

Seroepidemiologic evidence reveals that 50%
to 60% of adults in the United States have
circulating antibodies to the virus, although
few would remember experiencing a primary
infection.10 Following an incubation period
of 2 to 20 days, some patients will develop
flulike symptoms (such as fever, lethargy, and
headache) 2 or 3 days before the onset of a
sore throat and painful oral ulcers. These
resolve within 1 to 2 weeks. The virus then
establishes latency within the sensory ganglion.
Subsequently, trigger factors such as sunlight,
illness, trauma, emotional stress, or menses
may reactivate the latent virus in the ganglia,
resulting in viral replication and transport via
nerves to the skin or mucosal surfaces.
HSV reactivation results in either asympto­
matic shedding in bodily fluids or secretions or
the development of recurrent clinical lesions
(recrudescent HSV). Asymptomatic shedding
remains one of the most important causes of
transmission. Differences in presentation are
presented in Table 12-3, and a typical ulcer
is shown in Fig 12-5. Hydration, nutritional

248
 Oral Ulcers

a b

c d

Fig 12-5 |  Recurrent HSV infection in a cancer patient. (a) Large ulcer of the tongue dorsum and coated
tongue; (b) primary HSV infection of the palatal gingiva presenting as clustered ulcers; (c) herpes labialis; and (d)
recrudescent HSV infection presenting as clustered ulcers of the hard palate.

support, topical and systemic pain control, and
use of antipyretics are important management
strategies. Antiviral therapy reduces conta-
giousness, and this is presented in Table 12-4.11
Primary varicella zoster virus (VZV) infec-
tion usually occurs in childhood and begins
with flulike symptoms and a pruritic papu-
lar rash followed by vesicle formation. These
lesions eventually become crusted and scabs
fall off in 1 to 3 weeks. In the oral cavity, pri-
mary VZV infection presents as small (0.1- to
0.5-cm), painful ulcers that heal in approxi-
mately 2 weeks. Reactivation of VZV infection
leads to oral shingles. These may resemble
recrudescent HSV except they are almost
always unilateral. A culture differentiates
between the two. Treatment of primary VZV
is reported in Table 12-4.
Infection with cytomegalovirus (CMV), or
human herpesvirus 5 (HHV-5), remains one
of the major complications after solid organ
transplantation and may result in severe pul-
monary, gastrointestinal, or neurologic disease.
Seroepidemiologic studies show that 60% to
65% of the adult population in the United
States has antibodies to CMV.12 Primary CMV
infection may be asymptomatic or present with
infectious mononucleosis–like or mild flulike
symptoms. Recrudescent CMV in the oral
cavity occurs mostly in immunocompromised
patients as large (usually larger than 1-cm),
painful ulcers on the oral mucosa.

249
12 Oral Manifestations of Systemic Diseases

TABLE 12-4  |  Antiviral agents for the treatment of oral viral infections

Topical agents Dosage and instructions

Acyclovir, 5% ointment or cream Apply to lesions every 2 h for 7 d

Penciclovir, 1% cream
Docosanol, 10% cream

Systemic agents

Acyclovir, 400- or 800-mg tablet Primary HSV infection:

400 mg three times a day for 7 to 10 d
800 mg two to five times a day for 7 to 10 d
Recurrent HSV infection:
400 mg three times a day for 5 d
800 mg two times a day for 5 d

Valacyclovir, 500- or 1,000-mg Primary HSV infection:

caplet 1 g two times a day for 7 to 10 d
Recurrent HSV infection:
500 mg two times a day for 3 d
Labial HSV infection:
2 g at first sign of recurrence, then 2 g 12 hours later
Prophylaxis (when precipitating event is known):
2 g two times on the day of the dental procedure or event, then 1 g two times the next day
(up to 1 to 3 d after the event or procedure)
Immunosuppressed individuals:
1 g daily
VZV infection:
1 g three times a day for 7 to 14 d

Famciclovir, 125- or 250-mg tablet Primary HSV infection:

250 mg three times a day for 7 to 10 d
Recurrent HSV infection:
125 mg two times a day for 5 d
VZV infection:
500 mg three times a day for 7 to 14 d

VZV, varicella zoster virus.

Because CMV, unlike HSV, infects cells deep
in the connective tissue, a swab culture may not
be diagnostic. A biopsy is the most useful tool
for the diagnosis of CMV, and the presence of
virus can be detected by immuohistochemistry
and in situ hybridization techniques. CMV can
also be detected in blood by testing for CMV
antigen on white blood cells or polymerase
chain reaction studies to detect CMV DNA.
Management is directed toward pain control,
and definitive therapy is with ganciclovir, val-
ganciclovir, or cidofovir.
Epstein-Barr virus (EBV)–associated muco-
cutaneous ulcers are large ulcers of the oral
mucosa, gastrointestinal tract, and/or skin
that occur either in immunocompromised or
immunosenescent individuals.13 They resolve
on reducing immunosuppression or sponta-
neously over time.

250

Coxsackievirus (a group of enteroviruses)
infection is associated with two diseases most
commonly seen in children: hand, foot, and
mouth disease and herpangina. The incuba-
tion period is 3 to 7 days, followed by flulike
symptoms in some cases. Herpangina is char-
acterized by multiple small, coalescent ulcers
on the tonsillar pillars and the soft palate.
Hand, foot, and mouth disease has a similar
oral manifestation with cutaneous vesicles of
the hands and feet. Both diseases occur as sea-
sonal outbreaks among young schoolchildren.
The infection is typically self-limiting, resolv-
ing within 7 to 10 days. Coxsackievirus is also
implicated in lymphonodular pharyngitis that
causes a sore throat. Treatment includes pain
management, hydration, and soft diet until
signs and symptoms resolve.
Erythema multiforme
Erythema multiforme (EM) is a self-limiting
mucocutaneous hypersensitivity reaction,
usually to an infectious agent, with an acute
onset; however, some cases may be recurrent.
From a dermatologic point of view, EM can
be divided into minor and major forms. EM
minor is mainly cutaneous (less than 10%
skin involvement), with minimal or no muco-
sal involvement. EM major involves either the
skin with at least one mucosal site or a sin-
gle mucosal site with extensive involvement.
However, some cases may involve only the oral
cavity. Up to 70% of the cases of EM repre-
sent a hypersensitivity reaction to a recent HSV
infection, to asymptomatic HSV reactivation,
to Mycoplasma pneumoniae infection, and less
commonly, to the use of certain medications.14,15
The most common disease-precipitating med-
ications include NSAIDs, sulfonamides, and
anticonvulsants.
Patients with EM may report fever, head-
ache, malaise, and sore throat a few days or 1
to 2 weeks prior to the onset of lesions. Oral
lesions present as painful ulcers with crusting
of the lips. Skin lesions are symmetric, erythem-
atous, and edematous papules with a target
Oral Ulcers
or bullseye appearance and typically affect the
extremities (especially the palms). The ocular
and genital areas can also be affected.
EM is self-limiting, lasting from 2 to 4 weeks,
and lesions heal without scarring. The history
and clinical presentation are usually sufficient
for diagnosis, and a biopsy is confirmatory. Cul-
tures for HSV and a biopsy should be obtained
when the clinical presentation is atypical. If M
pneumoniae infection is a suspected trigger, the
evaluation includes a chest radiograph, poly-
merase chain reaction testing of throat swabs,
and serologic tests. Therapy includes topical
and systemic analgesics, skin wound care, and
hospital-based supportive care.16
Stevens-Johnson syndrome is a separate
entity from EM and considered an epidermal
necrolytic disease. The more severe form is
toxic epidermal necrolysis, usually associated
with the use of medications such as allopurinol,
imidazole antifungals, anticonvulsants, sulfon-
amides, or NSAIDs. EM major, Stevens-Johnson
syndrome, and toxic epidermal necrolysis man-
ifest with similar extensive mucosal ulcers,
erosions, and hemorrhagic crusts on the lips.
Skin blistering is always present. Treatment
includes thalidomide, intravenous immuno-
globulin, and supportive care. The mortality
rate is 6% to 20%.17
Deep fungal infections
Deep fungal infections are invasive and often
lead to necrotic ulcers of the oral cavity;
systemic dissemination is common.18 These
include aspergillosis and mucormycosis in
patients with cancer and diabetes mellitus; coc-
cidioidomycosis and histoplasmosis, which are
endemic in the southwestern United States and
the Ohio-Mississippi valleys, respectively; and
blastomycosis, which is endemic in many areas
of Central and South America.
Mucormycosis appears as black, necrotic,
and/or fungating lesions that resem-
ble malignancy; patients with diabetes
mellitus (especially if ketoacidotic), neutrope-
nia, or malignancy and individuals who have
251
12 Oral Manifestations of Systemic Diseases
Fig 12-6 |  Mucous membrane pemphigoid: des-
quamative gingivitis with erythematous attached gin-
giva.
undergone organ transplantation may develop
rhinocerebral mucormycosis, and the mortality
rate is 60% to 90%.19,20
Aspergillosis (caused by Aspergillus fumiga-
tum or Aspergillus flavus) is a fungal infection
characterized by noninvasive and invasive
forms. Noninvasive aspergillosis affects an
immunocompetent host and may present as a
“fungus ball” (mycetoma) within the maxillary
sinus or a hypersensitivity to the fungus, leading
to allergic fungal sinusitis. Invasive infections
tend to affect immunocompromised patients
such as those with leukemia, and the clinical
presentation is similar to that of mucormycosis.
Vascular involvement leads to necrosis.
The primary infection of histoplasmosis is
usually mild and presents as a self-limiting
pulmonary disease. Immunosuppressed indi-
viduals may develop a disseminated form with
multiorgan involvement (lung, liver, spleen,
meninges, and adrenal glands). Oral lesions are
usually present in patients with disseminated
histoplasmosis and begin with an erythematous
area that eventually forms a papule and then
an ulcer.
Blastomycosis is characterized by a pul-
monary infection with mild symptoms. If
untreated, the symptoms worsen, and the
microorganism spreads to the mucosa, skin,
and bone, forming indurated ulcers. Oral
lesions include verrucous ulcers and radiolu-
cent bone lesions.
252
Diagnosis is made after biopsy and histo-
pathologic examination, as well as culture
and serologic and polymerase chain reaction
studies. Imaging studies are recommended
to assess the extent of systemic involvement.
Treatment requires surgical debridement and
aggressive systemic antifungal therapy for all
such infections.18
Vesiculobullous disease
Similar to the vesicles of HSV, the blisters
of autoimmune vesiculobullous disease rup-
ture, creating shallow erosions that over time
become covered by fibrin, forming an ulcer.
Necrotic, whitish, ragged epithelial tags from
the ruptured blister roof may be seen piled up
at the edges of such erosions and ulcers.
Mucous membrane pemphigoid (MMP)
is an autoimmune vesiculobullous disease
associated with increased frequency of the
HLA-DQB1*0301 allele. It is characterized
by autoreactive antibodies, usually immu-
noglobulin G (IgG) and sometimes IgA, that
target antigens in the epithelium-attachment
complex, resulting in subepithelial blistering
and mucosal fragility.21 MMP may involve the
larynx, nose, eyes, and genital mucosa. One
of the major complications is conjunctival
scarring that can lead to blindness (hence the
older term, cicatricial pemphigoid). Scarring
may also involve the larynx and esophagus but
fortunately is uncommon in the oral mucosa.
The oral mucosal lesions almost always
affect the gingiva, leading to bright red or des-
quamative gingivitis (Fig 12-6). This develops
when epithelium peels off the gingiva, leaving
only exposed connective tissue, which is the
basis for a positive Nikolsky sign (slight rub-
bing leads to dislodgement of the epithelium).
Ulcers may develop on the gingiva and else-
where in the mouth, such as the palatal, buccal,
and tongue mucosa. These ulcers differ from
RAS because they are more diffuse and tend
not to heal completely. Biopsy of a perilesional
area for histopathologic examination and direct
immunofluorescence studies are essential for a

Fig 12-7  |  Custom tray to hold topical immunosup-
pressive agent covering the involved gingiva in a pa-
tient with MMP presenting as desquamative gingivitis.
definitive diagnosis; direct immunofluorescence
shows deposition of IgG, C3, and sometimes
IgA at the basement membrane zone.
Management of desquamative gingivitis
includes topical treatment with corticosteroids
or tacrolimus delivered in a custom tray that
covers the involved gingiva (Fig 12-7). This
technique may also be used for management
of other gingival inflammatory conditions.
Systemic agents such as prednisone, dap-
sone, azathioprine, tetracycline, nicotinamide,
mycophenolate, and cyclophosphamide may
be required for management of refractory oral
MMP. When the skin is involved, the diagnosis
is usually bullous pemphigoid.
Pemphigus vulgaris (PV) is an uncommon
autoimmune vesiculobullous disorder that
affects mainly older adults and was fatal in the
presteroid era. PV has a predilection for peo-
ple of Ashkenazi Jewish descent, who exhibit
a high frequency of the HLA-DRB*0402
allele whereas non-Jewish persons exhibit
HLA-DQB*0503 more frequently. Autoanti-
bodies, mostly IgG, are directed toward the
interepithelial cementing substance, leading to
intraepithelial blistering.22 Oral ulcers, pres-
ent in 95% of patients, are often the first sign
of PV, with skin lesions developing later. Oral
lesions are characterized by painful, irregular,
erythematous depressed erosions with whitish
tissue tags at the edges; yellow ulcerations may
White/Red Lesions
Fig 12-8 |  Pemphigus vulgaris: ulcers of the left
buccal mucosa.
also be present (Fig 12-8). The most commonly
affected oral sites are the hard and soft palatal
mucosa (likely because of physiologic trauma
from swallowing), gingiva (also presenting
as desquamative gingivitis), buccal mucosa,
and tongue. Diagnosis is established through
perilesional tissue biopsy for histopathologic
evaluation and direct immunofluorescence,
which shows intercellular deposition of IgG.
Oral PV should be treated with a combina-
tion of prednisone, mycophenolate, and topical
steroid therapy. For severe cases and if the skin
is involved, specialist referral is indicated; in
such cases, treatment generally involves pred-
nisone, rituximab (a monoclonal antibody),
intravenous immunoglobulin, or extracorpo-
real photopheresis.
White/Red Lesions
White papules (less than 5 mm) and plaques
(greater than 5 mm) are extremely common
in the mouth, and often they have a red or
erythematous component. The most common
is frictional keratosis from chronic chewing or
nibbling, which occurs on the buccal mucosa,
lateral tongue, and lower lip mucosa, often
bilaterally on the retromolar pad and on eden-
tulous mucosa.
253
12 Oral Manifestations of Systemic Diseases
Fig 12-9  |  Leukoplakia of the left buccal mucosa in
a patient with active oral chronic GVHD.
Leukoplakia
Leukoplakia (and its variants verrucous,
nodular, and erythroleukoplakia) is the most
common premalignant lesion and is defined
by the World Health Organization as “a white
plaque of questionable risk having excluded
(other) known diseases or disorders that carry
no increased risk for cancer.”23 While this is
generally associated with cigarette smoking,
it is seen with some frequency in patients who
have a history of another cancer, are immu-
nocompromised from systemic disease or use
of immunosuppressive medications, or who
have chronic graft-versus-host disease (GVHD)
after treatment with allogeneic hematopoietic
stem cell transplantation for leukemia or other
bone marrow failure syndromes24 (Fig 12-9).
Patients with dyskeratosis congenita are also
prone to develop leukoplakia and squamous
cell carcinoma.
Oral lichen planus/lichenoid
lesions
Oral lichen planus (OLP) is a fairly common,
chronic, immune-mediated inflammatory
mucocutaneous condition that occurs in 1% to
2% of adults.25 Middle-aged women are twice
as likely to be affected as men. OLP can affect
any mucosal surface. Approximately 70% of
individuals with cutaneous disease develop
254
concomitant OLP, while only 10% to 15% of
patients with OLP have concomitant cutaneous
lesions.26
OLP may be idiopathic or associated with
a variety of local and systemic conditions.
Amalgam and composite restorations may
cause localized contact lichenoid hyper-
sensitivity reactions, possibly to mercury.
Some cases are caused by a hypersensitivity
to medications such as thiazide diuretics,
angiotensin-converting enzyme inhibitors,
beta blockers, gold salts, sulfasalazine, sul-
fonylureas, and penicillamine. New biologic
agents, such as TNF-α inhibitors, may also
cause lichen planus–like eruptions.
Patients with hypothyroidism, including
Hashimoto thyroiditis, also develop OLP, but it
is unclear whether it is thyroid disease that pre-
disposes to OLP or the medications used to treat
it, such as levothyroxine. Hepatitis C virus infec-
tion is associated with the development of OLP
in individuals living in areas of southern Europe,
particularly Italy, Portugal, and Spain, and there
may be a genetic or ethnic predilection.25
OLP most commonly affects the buccal
mucosa and tongue bilaterally and can present
with three distinct forms: reticular/keratotic
(classic), erosive/erythematous, and ulcerative.
The reticular/keratotic form, characterized
by Wickham striae (Fig 12-10), is the most
common form and is often asymptomatic.
Occasionally patients report discomfort and
describe the buccal mucosa as “rough,” “thick,”
or “tight.” The erosive/erythematous form
typically presents as desquamative gingivitis.
Patients may complain of sensitivity and dis-
comfort while eating acidic, spicy, or crunchy
foods. The ulcerative form is the most severe
and presents as shallow ulcerations that have a
yellow fibrin membrane on the surface. Often,
patients exhibit a combination of the three
forms at different sites or at different times.
Most patients exhibit characteristic bilateral
and usually symmetric distribution of lesions,
typically involving the buccal mucosa, dorsum
and ventral surfaces of the tongue, and/or gin-
giva. A biopsy specimen should be obtained

for histopathologic examination when the
presentation is not typical (such as unilateral
presentation or lack of reticulations).
Treatment is aimed at relieving pain and
resolving or reducing erythema and ulcer-
ations. The primary therapies include topical
corticosteroids and topical tacrolimus (see
Table 12-2). Occasionally systemic cortico-
steroids and immunomodulating agents (such
as the antimalarial drug hydroxychloroquine)
may be necessary. Malignant transformation to
squamous cell carcinoma may occur in approx-
imately 0.1% to 0.2% of cases of OLP, and
patients should be followed on a regular basis.27
Two other conditions may present with oral
lesions similar to OLP: lupus erythematosus
and chronic GVHD. Lupus erythematosus is
an autoimmune connective tissue disorder with
many subtypes characterized by distinct clini-
cal features, serologic findings, and patterns of
humoral and cellular autoimmunity. Women
are nine times more commonly affected than
men, and the onset is in young adulthood. Two
common presentations often associated with
oral findings are systemic lupus erythematosus
(SLE) and discoid lupus erythematosus (DLE).
Common signs and symptoms of SLE include
weight loss, arthritis, fever, fatigue, and gen-
eral malaise. Clinically, 30% to 60% of these
patients may present with an erythematous
“butterfly” rash over the malar area. The kid-
neys, heart, skin, nervous system, and joints are
commonly involved. Often, patients affected
by SLE develop secondary Sjögren syndrome,
resulting in dry mouth. Oral lesions develop in
up to 44% of patients, and these may be red
with white reticulations (lichenoid) or ulcer-
ative. A biopsy obtained from normal-appearing
mucosa for direct immunofluorescence shows a
positive result for a lupus band (linear deposi-
tion of IgG at the basement membrane zone).
Serology is positive for antinuclear antibodies
(ANA, positive in more than 95% of patients),
anti–double-strand DNA antibodies, anti-Smith
antibodies, and antiribonucleoprotein.28
DLE is characterized by scaly, atrophic, and
red plaques on the skin. Oral lesions develop
White/Red Lesions
Fig 12-10 |  Oral lichen planus: Typical white lacey
reticulations with an ulcer surrounded by an erythem-
atous halo.
in up to 20% of patients and are similar to
those seen in SLE.29 A biopsy obtained from
lesional tissue exhibits a positive lupus band
test in 90% of active lesions. Because there is
no systemic involvement, serologic studies are
not helpful.
For both SLE and DLE, topical and systemic
therapy for oral involvement depends on the
severity of the lesions (see Table 12-2). Sys-
temic treatment includes immunosuppressive
or immunomodulatory therapy.
Chronic GVHD remains a significant com-
plication of allogeneic hematopoietic cell (bone
marrow) transplantation and continues to be
the leading cause of nonrelapse mortality. The
oral cavity is affected in around 80% of cases,
and mucosal lesions resemble those of OLP and
are characterized by erythema, reticulation,
and ulceration.30 Topical therapy is similar to
that for OLP (see Table 12-2).
Candidiasis
Oral candidiasis is the most common fungal
infection encountered in dental patients. Can-
dida albicans is a commensal organism of the
oral cavity in approximately 20% to 30% of
individuals.31 It is an opportunistic organism,
and candidiasis develops when the normal flora
is altered, in hyposalivation, or when there is an
immune dysfunction; it also commonly overlies
dysplastic lesions.32 Local factors include use
255
12 Oral Manifestations of Systemic Diseases
Fig 12-11  |  Pseudomembranous candidiasis: white,
curdy papules and plaques with mild erythema.
of topical immunosuppressive agents, hypos-
alivation, wearing of dentures, and smoking.
Contributing systemic factors include diabetes
mellitus, anemia, immunosuppression (eg, HIV
or AIDS), antibiotic use, infancy, advanced age,
and endocrine dysfunction.
Candidal infections present in three main
forms: pseudomembranous, erythematous,
and hyperplastic. Pseudomembranous candi-
diasis (thrush) is characterized by thick, white,
cheesy papules and plaques that can be rubbed
off, leaving, in some cases, a bleeding area
(Fig 12-11). The erythematous form of can-
didiasis is mainly encountered on the palatal
mucosa under dentures, presenting as diffuse
erythema demarcated by the shape of the den-
ture base. Tongue lesions show atrophy of the
filiform papillae with erythema and a smooth
tongue surface. Hyperplastic candidiasis is an
uncommon chronic variant that presents as
white plaques that do not rub off, suggestive
of leukoplakia.
Oral candidiasis is treated with topical and
systemic antifungal agents. The most com-
monly used topical agents include clotrimazole
troches (10 mg), which are dissolved in the
mouth, four times a day for 7 to 10 days; and
nystatin suspension (100,000 U/mL), which
is swished around the mouth in a dose of 5
mL four times a day. Systemic therapy using
256
Fig 12-12 |  Coated hairy tongue: hyperplastic fili-
form papillae forming a matted area.
fluconazole, 100 to 200 mg daily for 7 to 10
days, is extremely effective because patients
usually exhibit good compliance. Dentures
should be soaked overnight in an antibacterial
solution such as 0.12% to 2% chlorhexidine
digluconate or 3% sodium hypochlorite diluted
in water (1:10 solution), and they should not
be worn overnight.
Finally, candidal infections also cause angu-
lar cheilitis, which manifests as bilateral, bright
red erythematous fissures at the corners of the
mouth. Angular cheilitis is managed with top-
ical nystatin/triamcinolone or clotrimazole/
betamethasone cream or ointment. Aggravat-
ing factors include poor support of the perioral
musculature from reduced vertical dimension
and hematinic deficiencies.
Coated/hairy tongue
Coated/hairy tongue is a benign, painless con-
dition characterized by hyperplastic filiform
papillae and the accumulation of keratin on the
dorsum (Fig 12-12). It is often mistaken for can-
didiasis, but treatment with antifungal agents
is invariably unsuccessful. A positive culture
for Candida (normally present in 20% to 30%
of the population as a commensal)31 is indica-
tive of carriage rather than candidal infection.
The two common etiologic mechanisms are
 Gingivitis

increased retention and reduced exfoliation of

keratin of the filiform papillae, which become
elongated and “hairy.” Increased retention is
related to dehydration and hypo­salivation so
that there is less watery saliva and proportion-
ally more mucinous, sticky saliva. Precipitating
factors include a recent history of illness and
antibiotic therapy, radiation therapy, smoking,
use of alcoholic mouthrinses, and polyphar-
macy (especially diruretics, antihistamines, and
anticholinergic medications such as for bladder
Fig 12-13  |  Migratory glossitis: white, arcuate lines
control). Poor diets in which meals are com- enclosing erythematous mucosa.
posed primarily of soft rather than coarse foods
(such as fresh fruits and vegetables) also lead
to reduced keratin exfoliation, and therefore
coated tongue is frequently seen in patients
convalescing from illness.
The tongue has a white, coated, matted, or mouthrinse preparation. Topical corticoste-
hairy appearance and may become pigmented roid treatment is usually necessary because of
from food metabolic products of resident bac- the chronic, relapsing-resolving nature of the
teria. Patients may complain of a pasty, stale disorder.
taste in the mouth and even gagging because
the coating tends to localize to the posterior
tongue near the circumvallate papillae. Man-
agement is directed toward hydration, stopping
Gingivitis
use of alcoholic or dehydrating mouthrinses, Conventional gingivitis
smoking cessation, improved diet, and/or gen-
tle brushing or scraping of the tongue two or The most common gingival pathology
three times a day. in dentistry is plaque-induced gingivitis.
Plaque-induced gingivitis is a common inflam-
matory disease of the gingiva resulting from
Migratory glossitis production of inflammatory cytokines in
Migratory glossitis (also known as geographic response to plaque bacterial lipopolysaccha-
tongue, migratory stomatitis, and erythema rides located at the gingival margin. Gingivitis
areata migrans) is a chronic resolving-relapsing is common in adolescents and pregnant women
condition that occurs in 1% to 2% of the because of hormonal changes. Progesterone
population,33 mainly in adults. It presents associated with pregnancy seems to increase the
as well-demarcated, patchy erythematous permeability of gingival blood vessels and ren-
depapillation of the dorsum of the tongue with der the area more sensitive to physical, bacterial,
a raised, linear or ringlike, white peripheral rim and chemical irritants. Conventional gingivitis
(Fig 12-13). Migratory glossitis is associated is characterized by erythema, edema, bleeding
with fissured tongue in 25% of cases as well upon provocation, tenderness, and sensitivity of
as with atopy (history of asthma, eczema, hay the gingiva. Patients who are mouthbreathers
fever, or food intolerance) and psoriasis.34 have a unique pattern of gingivitis, with a red
Some cases are associated with the HLA-Cw6 and swollen anterior facial gingiva.
allele. Management includes pain control with Good oral hygiene and mechanical plaque
viscous lidocaine and diphenhydramine as a removal reduce or eliminate the inflammation,

257
12 Oral Manifestations of Systemic Diseases
thereby allowing gingival tissue to heal.35 Some
patients may require antibiotic therapy with
low-dose doxycycline or metronidazole, espe-
cially if there is underlying periodontitis.
Desquamative gingivitis and
hypersensitivity reactions
Desquamative gingivitis is a common chronic
condition of adults with a female predilection,
most often representing OLP, MMP (discussed
earlier), plasma cell gingivitis, and other hyper-
sensitivity reactions.36 Other immunobullous
disorders such as PV (discussed earlier), linear
IgA disease, and epidermolysis bullosa aquisita
are less common conditions that may also pres-
ent in this fashion, although the last two do not
present in the oral cavity without concomitant
skin findings.
Desquamative gingivitis is characterized by
fiery red, denuded attached gingiva, sometimes
ulcerated (with a yellow fibrin pseudomem-
brane), primarily on the buccal or facial aspect
(see Fig 12-6). The gingiva is painful, and oral
hygiene procedures may be challenging. Plaque
accumulation secondary to poor oral hygiene
further aggravates the pain, erythema, and pro-
pensity for gingival bleeding. The patient’s diet
may also be limited because of pain. Patients
with desquamative gingivitis respond well to
topical corticosteroid treatment applied within
custom trays.
Plasma cell gingivitis is a contact hypersensi-
tivity reaction to contactants such as flavoring
agents (eg, cinnamic aldehyde) in toothpaste,
chewing gum, or candies and presents as des-
quamative gingivitis. Plasma cell gingivitis may
be accompanied by glossitis and cheilitis; some-
times the term plasma cell orificial mucositis
is used because lesions may involve the upper
airway. Examination of a biopsy specimen
reveals sheets of plasma cells that raise the sus-
picion for a plasma cell malignancy, but in situ
hybridization studies for light chain restriction
show the cells to be polyclonal, typical for an
inflammatory process.
258
Plasma cell gingivitis is reversible and resolves
completely with avoidance of the allergen.
However, treatment with topical immunosup-
pressive agents speeds the healing process. A
patch test may help to identify the causative
agent. However, some hypersensitivity reactions
may be of a nonspecific nature, and a biopsy
may not exhibit sheets of plasma cells.
HIV/AIDS-associated linear
gingivitis and necrotizing
ulcerative gingivitis
HIV/AIDS-associated linear gingivitis is charac-
terized by a 2- to 3-mm linear band of marked
erythema along the gingival margin that does
not respond to conventional oral hygiene pro-
cedures and represents a form of erythematous
candidiasis. Treatment is with antifungal medi-
cations together with mechanical debridement.
Immunocompromised individuals are also at
higher risk of developing necrotizing ulcerative
gingivitis.37 This condition presents as ulcer-
ated and necrotic, edematous and hemorrhagic
interdental papillae and marginal gingiva and
is a result of a polymicrobial infection by spi-
rochetes, Fusobacterium species, Treponema
species, and Prevotella intermedia. These
patients may also report pain and halitosis.
Treatment includes use of antibiotics, daily
rinses with chlorhexidine gluconate, and
debridement under local anesthesia.
Diffuse Gingival Hyperplasia
Diffuse gingival hyperplasia has been asso-
ciated with multiple factors, including poor
oral hygiene, as a long-term sequela to con-
ventional gingivitis, hormonal changes (such as
pregnancy and puberty), adverse drug effects,
and hereditary conditions. Gingival hyperpla-
sia is caused by a proliferation of fibroblasts
and an accumulation of connective tissue fibers
and extracellular matrix. Bacterial plaque and

Fig 12-14 |  Drug-induced gingival hyperplasia: dif-
fuse dense, fibrotic gingival hyperplasia secondary to
nifedipine and cyclosporine use. (Courtesy of Dr Hani
Mawardi, Harvard School of Dental Medicine, Boston,
Massachusetts.)
hormones, such as progesterone, may exac-
erbate this process. Clinically the gingiva is
overgrown either diffusely or multifocally
throughout the mouth. When the cause is
hereditary or syndromic, the tissue tends to
be densely fibrotic, while hyperplastic gingiva
caused by other conditions tends to be edem-
atous and tender and bleeds easily. Good oral
hygiene practices may resolve this condition if
it is mild, but once there is significant fibrosis,
surgery is usually required to remove the excess
tissue.
Drug-induced gingival hyperplasia
Gingival hyperplasia is commonly induced
by three main classes of drugs: anticonvul-
sants (phenytoin and less commonly sodium
valproate, primidone, vigabatrin, and phe-
nobarbital), calcium channel blockers (such
as amlodipine, bepridil, diltiazem, felodip-
ine, nicardipine, nifedipine, nimodipine,
nitrendipine, and verapamil), and immuno-
suppressants (such as cyclosporine and rarely
tacrolimus).38 Drug-induced gingival enlarge-
ment associated with long-term phenytoin use
occurs in approximately 15% to 50% of cases.
For calcium channel blockers the prevalence
ranges from 10% to 20%, and for cyclosporine
the prevalence is approximately 27%. There
are rare cases associated with trimethoprim
Diffuse Gingival Hyperplasia
Fig 12-15 |  Mandibular and maxillary gingival en-
largement in a patient with acute myeloid leukemia.
sulphamethoxazole and erythromycin. This is
mediated by decreased cationic influx of folate
resulting in a reduction in metalloproteinases
and collagenases (leading to accumulation of
matrix) and/or an increase in fibroblast activity.
Not all patients taking these medications
develop gingival hyperplasia, and it is more
common in patients with poor oral hygiene.39
There may be a genetic predisposition, perhaps
related to drug metabolism.
Unlike plaque-induced gingival hyperplasia,
the drug-induced form tends to be less erythem-
atous, more fibrotic, and less inflamed (Fig
12-14), although inflammation often results
if pseudopockets form. The gingival enlarge-
ment may resolve on discontinuation of the
medication if the condition is mild. For more
severe cases, excision of the hyperplastic tissue
is required together with maintenance of good
oral hygiene and daily use of chlorhexidine
rinses. A low dose of doxycycline may reduce
the risk of recurrence.
Acute leukemia
Acute myeloid leukemia is the most serious
systemic condition associated with diffuse gin-
gival enlargement. The leukemic cells infiltrate
the tissues, resulting in gingival enlargement
(Fig 12-15). Bone marrow involvement by leu-
kemia reduces the body’s ability to form the
259
12 Oral Manifestations of Systemic Diseases
normal components of blood, such as platelets,
resulting in petechiae and ecchymosis of the
mucosa and gingiva and spontaneous bleeding.
Lack of red blood cells leads to anemia, fatigue,
and pallor of the mucosa, and poorly func-
tioning cancerous white cells lead to recurrent
infections in the mouth that may exacerbate
periodontal disease. Teeth may become mobile,
and suppuration may be noted around the gin-
giva. In addition, systemic symptoms such as
night sweats, recurrent infections, or lethargy
may be present.
Dentists play an important role in the diag-
nosis of leukemia by taking a careful history,
performing a biopsy of the gingiva or refer-
ring the patient for a biopsy, and obtaining a
complete blood count to establish a prelimi-
nary diagnosis. Gingival hyperplasia typically
resolves with effective chemotherapy.
Hereditary and syndromic gingival
hyperplasia
Gingival fibromatosis is a diffuse gingival
fibrous overgrowth that occurs either in com-
bination with rare syndromes or as an isolated
disease from spontaneous mutation. Some
associated syndromes are Cowden syndrome
(associated with trichilemmomas, oral muco-
sal papillomatosis, acral and palmoplantar
keratoses, and increased risk for breast and
thyroid carcinoma), Zimmerman-Laband
syndrome (ear, nose, bone, and nail
defects), Murray-Puretic-Drescher syndrome
(juvenile hyaline fibromatosis with nodular/
papular skin lesions), Rutherford syndrome
(corneal dystrophy), and Cross syndrome
(microphthalmia, hypopigmentation, mental
retardation, and athetosis).
Hereditary gingival fibromatosis is a rare
gingival hereditary condition that usually
develops during childhood and is transmit-
ted through both autosomal-dominant and
autosomal-recessive modes. This disease is char-
acterized by firm, pink gingival enlargement
that is nonhemorrhagic and asymptomatic.
260
The growth is multifocal, diffuse, and nodular
or smooth surfaced. The enlargement is slow
growing and becomes more prominent during
the eruption of both primary and permanent
teeth. The gingival enlargement often leads to
impaction and displacement of teeth, diaste-
mas, and malocclusion. Patients may also have
difficulty speaking and painful mastication.
Treatment for both hereditary and syndromic
gingival hyperplasia includes surgical removal
of excess gingival tissue with recontouring.
Destructive membranous
periodontal disease (ligneous
gingivitis and periodontitis)
Ligneous gingivitis, or destructive membra-
nous periodontal disease, is a rare condition
characterized by generalized nodular gingival
enlargement with or without ulceration. It is
associated with plasminogen deficiency that
leads to the formation of fibrin deposits that
accumulate in the connective tissue. Ligne-
ous gingivitis is seen in approximately one of
three patients with severe homozygous plas-
minogen deficiency and is often accompanied
by ligneous conjunctivitis. Additional clinical
manifestations include involvement of the
mucosa of the female genital tract, nasophar-
ynx, and tracheobronchial tree. Some patients
may benefit from topical and systemic cortico-
steroids or systemic warfarin.
Pigmented Lesions
Pigmentations of the teeth and oral mucosa
occur from pigments of either extrinsic or
intrinsic origin.
Extrinsic pigmentation
Extrinsic pigmentation is almost always caused
by local factors such as tobacco products, tea,
coffee, and chlorhexidine mouthrinse, and

traumatically implanted amalgam or graphite
particles cause readily recognizable tattoos.
Medication-induced pigmentation
Several medications, including antibiotics of the
tetracycline family, antimalarials, oral contra-
ceptive agents, antipsychotics (phenothiazines
such as chlorpromazine), and chemothera-
peutic agents may cause oral pigmentation.40
While many chemotherapeutic agents have
been reported to cause pigmentation, some of
these may represent postinflammatory hyper-
melanosis at sites where mucositis and ulcers
had developed (such as the buccal mucosa,
tongue, and lips) and should not be consid-
ered true medication-induced pigmentation.
Three mechanisms have been proposed to
explain drug-induced pigmentation. First, drug
metabolites that are pigmented are deposited
in the connective tissue causing pigmenta-
tion. Second, the pigmentation is caused by
breakdown products of the drug that chelate
with melanin or iron. Third, the drug (or drug
metabolite) stimulates an increase in melanin
production. Diagnosis of drug-induced pig-
mentation is typically made from a history
of exposure to medications, as noted above.
Oral lesions present as diffuse, painless, sym-
metric, bluish-gray macular pigmentations of
the hard palatal mucosa that may occur con-
comitantly with skin and nail pigmentation.
Tetracycline is a broad-spectrum antibiotic
used to treat bacterial infections. It chelates
to bone and teeth and results in brown or
gray discoloration, with fluorescence under
ultraviolet or other light sources. Minocycline
is a long-acting compound with powerful
anti-inflammatory properties that is widely
used to treat dermatologic conditions such as
acne, as well as systemic infections and peri-
odontal disease. Tetracycline and minocycline
pigmentation typically occurs after long-term
use and involves the skin, thyroid, nails, con-
junctiva, sclera, and oral mucosa; bone and
teeth developing during the time of adminis-
tration are discolored in a similar fashion. In
Pigmented Lesions
the oral cavity, darkening of the mucosa may
occur because the grayish-black color of the
underlying bone shows through the mucosa.
However, breakdown products of minocycline
may be noted within the connective tissue.
Antimalarials, such as chloroquine, hydroxy-
chloroquine, quinacrine, and amodiaquine,
have anti-inflammatory and immunosuppres-
sive functions. Chloroquine is also widely used
as an adjunct in the treatment of autoimmune
diseases. Long-term use may cause diffuse
grayish-black pigmentation of the palatal
mucosa, as does imatinib, a tyrosine kinase
inhibitor that is used as a first-line treatment
for chronic myelogenous leukemia. Skin and
nails may also be affected.
Estrogens, either alone or in combination
with progesterone, have also been reported to
cause oral pigmentation caused by an increase
in the activity of melanogenic enzymes. Oral
involvement most often involves the palatal
mucosa and facial gingiva. Upon cessation of
the medication, the oral and cutaneous lesions
(melasma or chlorasma) slowly resolve.
Heavy metal pigmentation
Poisoning with heavy metals such as lead,
mercury, silver, platinum, arsenic, or bismuth
presents as a dark-colored or black band along
the gingival margin, likely caused by deposition
of sulfides of heavy metals within the gingiva.
These are mostly of historical interest, and it
is extremely rare to see oral manifestations of
such heavy metal toxicity now.
Intrinsic pigmentation
The two most common pigmented lesions
in the oral cavity caused by intrinsic agents
arise from melanin deposition and blood or its
breakdown products.
Melanin
The most common melanotic lesion is the
solitary melanotic macule, which presents
261
12 Oral Manifestations of Systemic Diseases
as a brown to black macule on the lip, pal-
atal mucosa, or gingiva. Multiple melanotic
macules may occur in an idiopathic fash-
ion or be related to syndromes such as
Addison disease and lentigines syndromes
including neurofibromatosis, Peutz-Jeghers
syndrome, McCune-Albright syndrome, and
Carney complex.
Melanotic macules are seen in Addison dis-
ease (primary adrenocortical insufficiency), a
condition where the adrenal cortex does not
produce enough glucocorticoids and sometimes
mineralocorticoids as well, leading to compen-
satory overproduction of adrenocorticotropic
hormone (ACTH). Most cases are autoimmune,
but it can also be caused by infection or other
etiologies. It is typically seen in middle-aged
or young adults, and patients report fatigue,
dizziness, hypotension, and abdominal pain.
β -melanocyte-stimulating hormone is integral
to the ACTH molecule, so whenever levels of
ACTH are high, regardless of the etiology, mel-
anosis results. Patients present with generalized
bronze coloration of the genitalia and skin
(especially flexural areas) and sites of trauma.
The oral mucosa may exhibit a sudden onset
of melanotic macules. Diagnosis is made by
observation of clinical signs and symptoms,
confirmation of elevated levels of ACTH, and
the inability to produce cortisol on stimulation
using synthetic ACTH.
Neurofibromatosis is a group of genetic dis-
orders with autosomal-dominant inheritance;
the most common form is neurofibromatosis
type 1 (NF-1, von Recklinghausen disease of
the skin). NF-1 is characterized by pigmented
lesions that are usually present at birth. These
lesions appear as freckles and tan to brown
café-au-lait macules with smooth edges (resem-
bling the coast of California). Other clinical
manifestations include oral and skin neurofi-
bromas and Lisch nodules in the eyes.
Peutz-Jeghers syndrome is a rare autosomal-
dominant disorder characterized by intesti-
nal polyposis and multiple mucocutaneous
melanocytic macules. Brown macules are gen-
erally several millimeters wide and typically
262
“peppered” on the skin around periorificial
sites such as the mouth, nose, and eyes; on the
extremities; and in the oral cavity. Peutz-Jeghers
syndrome is also associated with short bowel
syndrome, small intestine intussusception, and
anemia. Management consists of surveillance
of intestinal polyps.
McCune-Albright syndrome is characterized
by fibrous dysplasia of bone, irregularly shaped
café-au-lait skin macules (resembling the coast
of Maine) and precocious puberty. Oral mela-
notic macules may occur in some individuals
although these are rare.
Carney complex is an autosomal-dominant
family of disorders characterized by multi-
ple lentigines of the skin and oral mucosa,
cardiac and skin myxomas, and endocrine
hyperactivity.
Laugier-Hunziker syndrome is a rare
acquired disorder characterized by multiple
melanotic macules of the oral mucosa and
occasionally of the genital mucosa, conjunc-
tiva, esophagus, and acral surfaces as well as
brown melanotic bands on the nails (melanon-
ychia). Lesions may be treated with a laser as
necessary.
Blood pigment
Pigmentations may occur from vascular lesions
or from extravasated blood and their break-
down products.
Petechiae and ecchymoses. The most common
oral lesions related to blood pigment are those
from trauma, namely petechiae (less than 5
mm, clustered and pinpoint), ecchymoses, and
hematomas, which tend to be deeper. The onset
of frequent and extensive petechiae and ecchy-
moses in the mucosa and of the skin raises the
specter of a blood dyscrasia such as leukemia
where the platelets are reduced in number and/
or function or thrombocytopenia where plate-
lets are reduced in number such as from aplastic
anemia or adverse effects of medications (such
as antiplatelet aggregation medications). A sim-
ple complete blood count usually establishes
 Poorly Healing or Nonhealing Extraction Sockets and Osteonecrosis
the diagnosis of low platelet count. Coagulop-
athies caused by dysfunction of the intrinsic or
extrinsic pathway generally lead to deep tissue
rather than mucosal bleeding.
Vascular lesions. Vascular lesions may lead
to pigmented lesions that appear as small
red, blue, or purple blebs or nodules on the
mucosa that often blanch on pressure. Pregnant
women may develop these lesions (granuloma
gravidarum), often on the gingiva. If small, they
usually regress postpartum, but they may also
fibrose and require excision. Vascular lesions
may bleed excessively when traumatized and
are readily excised or ablated with a laser.
Sturge-Weber syndrome. Sturge-Weber syn-
drome (encephalofacial angiomatosis) is a
rare congenital neurocutaneous condition
characterized by a port-wine stain of the skin,
typically in the ophthalmic and maxillary dis-
tributions of the trigeminal nerve. Patients
present with bluish-purple plaques on the
buccal mucosa and gingiva on the same side
as the skin lesions. These represent hamarto-
matous vascular hyperplasia. Abnormal vessels
in the leptomeninges of the brain and choroid
are the cause of seizures. Diagnosis is made
through clinical examination, angiography, and
imaging. The treatment is symptomatic and
includes laser therapy to remove or lighten the
skin and mucosal lesions, anticonvulsants for
seizure control, symptomatic and prophylactic
therapy for headache, and treatments to reduce
intraocular pressure.
Hereditary hemochromatosis. Hereditary
hemochromatosis results from an inherited
autosomal-recessive disorder, while hemosid-
erosis may occur from multiple transfusions.
Hereditary hemochromatosis is caused by
increased absorption of dietary iron in the gut
leading to iron accumulation in parenchymal
organs and end-organ damage. Iron deposi-
tion in the form of hemosiderin and ferritin
leads to skin bronzing, cirrhosis, hypopituita-
rism, diabetes mellitus, nephrogenic diabetes
insipidus, and cardiomyopathy. Brown to gray
diffuse macules of the palatal mucosa and gin-
giva occur in approximately 15% to 20% of
patients.41 Phlebotomy and chelation therapy
are the preferred treatment for these patients.
Poorly Healing or Nonhealing
Extraction Sockets and
Osteonecrosis
After dental extractions, a blood clot is formed
within 24 to 48 hours. The clot is replaced
with granulation tissue, and bone formation
is well established by 6 to 8 weeks and com-
pleted by 6 months. Intact mucosa is noted
within 2 to 3 weeks. Local factors such as
infection or cemento-osseous dysplasia that
leads to bone sclerosis and poor vascularity
may lead to a poorly healing or nonhealing
socket, but several systemic conditions must
also be considered.
Diabetes mellitus
Patients with poorly controlled type 1 diabetes
mellitus are at risk for poorly healing sockets
because these patients are prone to infections
and more severe periodontal disease, which in
itself may impair glycemic control. Conversely,
treatment for severe periodontitis has shown
to improve glycemic control. Studies in dia-
betic animals have shown that the formation
of the collagenous framework in the tooth
extraction socket is inhibited and that aberrant
endothelial activation and impaired angiogenic
response result in delayed socket healing and
the development of dry socket.42
Primary bone diseases
Paget disease of bone (osteitis deformans) is
a disease of unknown etiology characterized
by hyperactivity of osteoclasts and increased
263
12 Oral Manifestations of Systemic Diseases
bone remodeling that lead to the formation of
disorganized bone. Paget disease usually occurs
after the age of 55 years and typically affects
the axial skeleton, especially the pelvis. The
skull is involved in about 40% of patients, and
involved bones enlarge over time.43
The most common symptom of Paget dis-
ease is bone pain and neurologic signs related
to pressure on the cranial nerves when their
ostia become progressively narrowed from
bone deposition. Enlargement of the maxilla
and mandible may result in the development
of diastemas of teeth and malocclusion. Early
lesions are radiolucent with coarsening of the
trabecular pattern. Later, cortical thickening
develops and radiopacities form, resulting in
a cotton wool–like appearance. Patients with
Paget disease are at higher risk of developing
osteosarcoma (less than 1% of cases).44
The diagnosis is made on the basis of serol-
ogy (greatly increased bone-specific alkaline
phosphatase and other bone-turnover markers),
histopathology, and radiographic appearance.
Dentists should recognize the symptoms and
signs of Paget disease and be aware that a
dental extraction may be associated with
postextraction bleeding and secondary osteo-
myelitis. Mild cases of Paget disease do not
require treatment whereas patients with pain
and severe involvement are treated with antire-
sorptive therapy.
Osteopetrosis is a genetic heterogeneous
group of heritable diseases of the bone char-
acterized by osteoclastic dysfunction and
osteosclerosis. Infection, osteonecrosis, and
osteomyelitis may ensue after extractions due
to the reduced blood supply.
Medication-related osteonecrosis
of the jaw
Medication-related osteonecrosis of the jaw
(MRONJ) is a sequela of the use of antiresorptive
agents such as bisphosphonates and denosu­
mab as well as antiangiogenic agents such as
bevacizumab and other targeted therapies such
264
as sorafenib and sunitinib. Bisphosphonates are
potent inhibitors of osteoclast-mediated bone
resorption and have been used in the manage-
ment of multiple myeloma, bone metastases,
and osteoporosis.
The use of bisphosphonates is associated with
MRONJ in both osteoporosis (frequency of
0.1% to 0.2%)45 and cancer therapy (frequency
of 3% to 8%).46 The single most important risk
factor for MRONJ is cumulative dose, which is
related to duration of therapy47; this is related
in part to the long half-life of 10 years of this
medication. Patients with osteoporosis who are
prescribed intravenous bisphosphonates gen-
erally receive a single annual 5-mg infusion of
zoledronic acid, compared with patients with
myeloma or metastatic cancer to the bones who
receive a 4-mg infusion monthly, usually for
24 months. Other risk factors include dental
extractions, other dentoalveolar surgery, phys-
iologic trauma, and odontogenic infections,
although some cases are idiopathic.
The American Academy of Oral and Maxil-
lofacial Surgeons defines MRONJ on the basis
of three criteria: (1) current or prior treatment
with antiresorptive or antiangiogenic agents,
(2) exposed bone or bone that can be probed
through an intraoral or extraoral fistula in the
maxillofacial region that has persisted for more
than 8 weeks, and (3) no history of radiation
therapy to the jaws or obvious metastatic
disease to the jaws.48 Staging and clinical find-
ings are presented in Table 12-5. Radiographic
findings are variable and may include altered
bony trabeculae with mottled osteosclerotic
changes, bone sequestra and osteolytic changes,
thickening of the lamina dura and narrowed
periodontal ligament space, and persistent
rarefaction at the site of dental extractions (at
least 6 months after extraction).
Patients present with either painful or painless
areas of exposed bone often on the mylohyoid
ridge, tori, or nonhealing extraction sockets with
exposed bone. Some patients may develop ulcers
on the tongue from trauma from sharp bone
edges. Sinus tracts are often seen around the
exposed bone and are a particularly important
 Poorly Healing or Nonhealing Extraction Sockets and Osteonecrosis

TABLE 12-5  |  MRONJ staging

Stage Clinical presentation

At risk No clinical or radiographic changes consistent with MRONJ in patients who have been treated with either oral or
intravenous bisphosphonates

Stage 0 No clinical evidence of necrotic bone, but radiographic changes and clinical findings consistent with MRONJ

Stage 1 Asymptomatic exposed bone or fistula that probes to bone, with no evidence of infection

Stage 2 Exposed and necrotic bone, or a fistula that probes to bone, with pain, erythema, and infection with or without
purulent drainage

Stage 3 Exposed and necrotic bone or a fistula that probes to bone with pain, erythema, and infection with or without purulent
drainage, and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone
(ie, inferior border and ramus in the mandible, maxillary sinus and zygoma in the maxilla) resulting in pathologic
fracture, extraoral fistula, oroantral/oronasal communication, or osteolysis extending to the inferior border of the
mandible or the sinus floor

(Modified from Ruggiero et al.48)

a b

Fig 12-16 |  MRONJ. (a) Nonviable sequestrum on the mylohyoid ridge. (b) Bed of hemorrhagic granulation
tissue after dislodgement (nonsurgical sequestrectomy).

finding in stage 1 disease. Treatment is aimed
at pain and infection control, and at every visit
an attempt should be made to gently dislodge
the bone fragment (nonsurgical sequestrectomy)
(Fig 12-16). Stages 2 and 3 are treated with anti-
biotics (amoxicillin with or without clavulanic
acid, clindamycin, or metronidazole) for a 2-
to 4-week or 1- to 2-month course of therapy.
Chlorhexidine or other antimicrobial oral rinses
should be prescribed for all patients at any stage.
If the patient has had substantial exposure
to bisphosphonate therapy, endodontic therapy
is preferable to extraction for nonmobile teeth
that have good bone support; nonrestorable
teeth can be decoronated. However, there is
no absolute contraindication to extraction.
Extraction may be the most appropriate treat-
ment for teeth that are extremely mobile and
at risk for aspiration that are within obvious
areas of MRONJ as determined radiographi-
cally, if the patient has continued to have pain
and infection in spite of multiple courses of
antibiotic therapy. Contrary to earlier findings,
current data show that surgical resection may
lead to durable remission of disease.49 Preven-
tion of MRONJ, especially in cancer patients,
involves a protocol similar to that for patients
who are scheduled for head and neck radiation.

265
12 Oral Manifestations of Systemic Diseases
Denosumab (Prolia, Amgen; Xgeva, Amgen)
is a monoclonal antibody with bone antiresorp-
tive properties that has been cleared by the
US Food and Drug Administration for use in
patients with osteoporosis and metastatic can-
cer to the bone as an alternative medication to
bisphosphonates. Denosumab binds to a mole-
cule on the osteoclast, inhibiting its activity and
thereby causing inhibition of bone resorption.
As such, its use has also been associated with
the development of MRONJ in patients with
cancer at a frequency of 2% to 3%, similar to
that associated with bisphosphonates.50
Prolia is used for treatment of osteoporosis
and is administered at a dose of 60 mg subcu-
taneously once every 6 months, while Xgeva is
indicated for management of bone metastases
from solid tumors in adult patients and is admin-
istered at a dose of 120 mg subcutaneously every
4 weeks. Prevention and treatment strategies for
denosumab-associated ONJ are the same as for
bisphosphonate-associated ONJ.51
Antiangiogenic agents (such as bevacizumab
and sunitinib) are prescribed for the man-
agement of metastatic cancers and are also
associated with an increased risk of MRONJ,
especially when used together with bisphos-
phonates that themselves have antiangiogenic
properties. Both agents act against blood vessel
growth factors essential for normal jawbone
remodeling and wound repair and can lead to
ONJ. Management principles are the same as
for bisphosphonate-associated ONJ.
Metastatic tumor to the jaw
Metastases to the oral cavity are rare and
represent approximately 1% of all oral malig-
nancies. Two-thirds of metastatic tumors to the
oral cavity occur to the jawbones, and nearly
80% involve the mandible; one-third occur in
the soft tissues, usually involving the gingiva
and sometimes the tongue.52 Cancers of the
breast, lung, prostate, kidney, and colon/rectum
are the most common primary sites.
Patients with metastasis to the jaw may com-
plain of pain, paresthesia, or anesthesia of the
266
skin or mucosa, tooth mobility, and gingival
or jaw swelling. Radiographically, the lesions
present as poorly defined radiolucencies. A
common scenario when such involved mobile
teeth are extracted is that the socket fails to
heal but is instead filled with fleshy soft tissue.52
Xerostomia and
Hyposalivation
Saliva plays a critical role in lubrication, buff-
ering, mastication, swallowing, speech, taste,
tooth remineralization, and prevention of oral
infection. Therefore, patients with hyposali-
vation are at risk of developing erythematous
areas from friction; experience difficulty with
eating, swallowing, taste, and speech; and are
at a greater risk of caries and candidiasis.53
Xerostomia is a common subjective com-
plaint of dryness in the mouth. It is only a
symptom and may or may not be associated
with reduced saliva in the mouth. Salivary
gland hypofunction and hyposalivation are the
terms used for objective and measurable reduc-
tions in the amount of saliva in the mouth. The
measurable reduction occurs because saliva
production and flow are reduced either in nor-
mally functioning glands or in damaged glands.
A simple subjective test for objective dryness
from hyposalivation that correlates well with
saliva collection studies involves asking the
following four questions54:
1. Do you feel you have less saliva than
normal?
2. Does your mouth feel dry when eating a
meal?
3. Do you have difficulty swallowing?
4. Do you need to drink water to swallow dry
foods?
A positive answer to all four is strongly asso-
ciated with hyposalivation. A modified Schirmer
test (normally used in the eyes) also subjectively
identifies patients with marked hyposalivation.55

Besides feeling that the mouth is dry, patients
may report that they experience sensitivity on
eating foods that are spicy, acidic, or crunchy or
have symptoms of burning. Food may not taste
the way it used to, and patients may report a
metallic or salty taste. In less severe cases, the
saliva is frothy, ropey, or thick. In more severe
cases, the mucosa looks dry and erythematous
(especially the tongue) and there is little to no
pooling of saliva in the floor of mouth.
Hyposalivation associated with
normal glands
Hyposalivation associated with normal glands
is by far the most common type of hyposali-
vation. Causative factors include dehydration
(eg, from poor oral intake of fluids, overcon-
sumption of caffeinated beverages, and/or
smoking), the use of drugs with anticholin-
ergic activity, the use of multiple medications
(polypharmacy), and chronic anxiety. Strongly
xerogenic medications include antidepressants,
antipsychotics, diuretics, anticholinergics, anti-
hypertensives, anxiolytics, sedatives, NSAIDs,
antihistamines, and opioid analgesic agents.
Hyposalivation associated with
damaged glands
Radiation therapy of the head and neck
region, especially for head and neck cancer,
and Sjögren syndrome occur less commonly
but result in severe hyposalivation because of
destruction of salivary glands. Salivary glands
(especially parotid glands) exposed to radiation
doses of greater than 60 Gy sustain permanent
damage with no recovery in salivary hypofunc-
tion over time.
Sjörgen syndrome is a systemic autoim-
mune disorder that mainly affects middle-aged
women. Affected individuals produce autoan-
tibodies that attack and destroy the salivary
and other exocrine glands.56 The primary form
involves mostly the exocrine glands (especially
Xerostomia and Hyposalivation
the salivary and lacrimal glands), while the
secondary form is associated with other auto-
immune diseases such as lupus erythematosus
and rheumatoid arthritis. Patients typically
report a dry mouth, dry eyes (keratoconjunc-
tivitis sicca), and dry nasal passages.
To establish a diagnosis of Sjörgen syndrome,
individuals with symptoms and signs suggestive
of Sjörgen syndrome need to have at least two
of the following three objective features: (1)
positive serum anti–SSA/Ro and/or anti–SSB/La
or positive rheumatoid factor and antinuclear
antibody titer ≥ 1:320; (2) labial salivary gland
biopsy exhibiting focal lymphocytic sialadenitis
with a focus score ≥ 1 focus/4 mm2; (3) kera-
toconjunctivitis sicca with an ocular staining
score of 3 (assuming that the patient is not
currently using daily eye drops for glaucoma
and has not had corneal surgery or cosmetic
eyelid surgery in the last 5 years).
Other possible conditions that may contrib-
ute to hyposalivation are IgG4-related disease,
which results in salivary gland enlargement and
hyposalivation similar to Sjörgen syndrome,
chronic GVHD, poorly controlled diabetes, and
malnutrition.
Treatment of xerostomia aims to relieve
symptoms and, in cases of true salivary gland
hypofunction, increase salivary flow. Thera-
peutic strategies include improved hydration
and avoidance of harsh and dehydrating den-
tifrices; avoidance of crunchy hard foods; use
of saliva substitutes, mucosal lubricants, and
saliva stimulants such as sugar-free candy or
gum; and daily fluoride treatment for caries
prevention. Nonalcoholic oral care products
such as Biotene products (GlaxoSmithKline)
and children’s toothpaste are good options.
Medications include pilocarpine (5 to 10 mg
three times a day for at least 3 months) and
cevimeline (30 mg three times a day for at least
3 months). Saline nasal sprays help in lubrica-
tion and sometimes improve flavor discernment
in food.
Damage to the salivary glands with radia-
tion can be somewhat mitigated with the use of
intensity-modified radiation therapy, where the
267
12 Oral Manifestations of Systemic Diseases
radiation is better targeted; with the use of ami-
fostine (a free radical scavenger that protects
the glands); and with the use of pilocarpine
during radiation.
Burning Mouth Syndrome
(Oral Dysesthesia Syndrome)
Primary burning mouth syndrome (BMS) is a
chronic pain condition and neuropathy char-
acterized by a burning dysesthesia mainly
localized to the tip of the tongue and anterior
dorsum, the lip mucosa, and the anterior hard
palatal mucosa and is often associated with
xerostomia, hyposalivation, and taste and smell
changes.57
The pathophysiology of BMS is not well
understood and may be secondary to both
biologic and psychologic factors.58 Hematinic
deficiencies (such as iron and vitamin B12 defi-
ciencies) should be ruled out first, although in
such cases patients usually present with signs
of atrophic glossitis. BMS is often triggered
by stressful events in a patient’s life and is
strongly associated with sleep disorders, anx-
iety, depression, psychiatric illness, and signs
and symptoms of somatization. More serious
conditions associated with BMS include multi-
ple sclerosis, trigeminal neuralgia, and central
nervous system lesions. BMS is classified into
three types: type I, with burning sensation
developing in the late morning, gradually
increasing in severity during the day, and reach-
ing its peak intensity by evening; type II, with
continuous symptoms throughout the day and
difficulty falling asleep at night; and type III,
with pain-free periods during the day.59
Several drug classes have been associ-
ated with dysgeusia and dysosmia through
a multifactorial mechanism; these drugs
include fluoroquinolones, macrolides (clar-
ithromycin), antimycotics (terbinafine),
angiotensin-converting enzyme inhibitors, pro-
tein kinase inhibitors, proton pump inhibitors,
and statins.60
268
Some patients present not with burning
but with other symptoms, including tingling,
a rough (sandpaper) sensation, a crawling
sensation, or taste changes, in which case the
general term of oral dysesthesia may be more
appropriate.
Treatment of BMS is aimed at managing
symptoms, reducing anxiety, and managing
underlying psychiatric illnesses. Topical ther-
apies include capsaicin extract used in a rinse,
clonazepam rinse, and topical anesthetic solu-
tions. Systemic therapy includes alpha lipoic
acid (300 mg twice a day), clonazepam (0.5
to 2.0 mg per day, usually taken at night), low
doses of the tricyclic antidepressants amitripty-
line and nortriptyline, and gabapentin.61
Because this is a chronic condition that often
lasts for years, nonpharmacologic approaches
to management are particularly important to
reduce dependence on medications and include
stress management/reduction, yoga, exercise,
and cognitive behavioral therapy. Cases that
are refractory to therapy should be referred to
a neurologist or pain specialist.
Multitargeted tyrosine kinase inhibitors
(such as sunitinib, sorafenib, pazopinib, and
cabozantinib) are antineoplastic drugs that
have been associated with oral dysesthesias
and palmar-plantar erythrodysesthesia.62,63
In severe cases, a dose reduction or discon-
tinuation of the medication is recommended.
Symptoms may resolve upon discontinuation
of tyrosine kinase inhibitor therapy.
Conclusion
We have presented eight common oral condi-
tions that may also indicate systemic disease.
Many patients see their dentist on a regular
basis for scaling and prophylaxis, and the dental
hygienist and dentist are therefore in a unique
position to notice subtle changes in the mucosa
or bone that may be the first indication of a sys-
temic disease, be it as common as iron-deficiency
anemia or as life-threatening as leukemia.

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Oral Complications in the
Immunocompromised Patient:
The Oncology Prototype
Douglas E. Peterson, dmd, phd, fds rcsed
Oral complications in cancer patients can have
considerable adverse impact on both the clini-
cal condition of the cancer patient and the cost
of cancer care.1,2 This dynamic occurs for a
number of reasons, including the intensity of
cancer treatment regimens as well as the extent
of preexisting oral disease, which can evolve
into acute and/or chronic toxicity.
However, substantive advances in the field
of oral oncology over the past two decades
have resulted in reduced incidence and sever-
ity of selected oral toxicities. Key drivers for
this progress include the increasingly effective
modeling of molecular science into clinical
practice as well as the leading role that scien-
tists and clinicians from dental medicine have
taken in interprofessional research, production
of clinical guidelines, and education of health
professionals. These advances have occurred
even as combination cancer therapies for
advanced stages of oral cancer have become
increasingly prominent:
• Neoadjuvant (debulk): Sole use prior to sur-
gery (eg, 5-fluorouracil, which can cause oral
mucositis)
• Adjuvant (curative): Use after surgery and
before radiation therapy (eg. 5-fluorouracil,
which can cause oral mucositis)
CHAPTER 13
• Concurrent/concomitant (synergistic): Com-
bination with radiation therapy (eg, head and
neck radiation therapy plus weekly cisplatin)
Although considerable evidence exists about
treatment-based oral toxicity in relation to
tumor type, new frontiers in research are
beginning to delineate patient-based factors
with more precision. This evolving evidence
base continues to more precisely define the
interrelationships between the more classic
modeling of disease (and its treatment) and
new knowledge directed to patient-based risk
determinants3,4 (Fig 13-1). This line of research
represents a promising foundation for future
implementation of personalized medicine in
which customized oral prevention and man-
agement interventions are developed for each
individual patient.
The management of acute myeloid leuke-
mia is utilized in this chapter as a principal
prototype by which the science and its clinical
translation can be applied to clinical decision
making and patient care (Figs 13-2 and 13-3).
The high-dose induction chemotherapy regi-
men that is used to treat patients with acute
myelogenous leukemia is profoundly myelosup-
pressive and typically causes severe ulcerative
oral mucositis of at least 2 weeks’ duration.
The interface of profound myelosuppression
with disruption in integrity of the oral mucosal
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13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

Patient

Toxicity

Treatment Tumor

Fig 13-1  |  Toxicity of cancer treatment, including oral Fig 13-2 |  Peripheral blood smear from a patient
complications, occurs as a result of patient-based, with newly diagnosed acute myelogenous leukemia
tumor-based, and treatment-based components. in blast crisis.

a b

Fig 13-3 |  Acute leukemia can be considered “naturally metastatic” in that the neoplasm arises within the
white blood cell progenitors produced in the bone marrow. Because of the inherent circulation of these cells,
the disease is widespread by the time of diagnosis. (a) Histopathology based on hepatic biopsy, demonstrating
widespread infiltrate of the blast leukemic cells. (b) Gingival leukemic infiltrate in a patient newly diagnosed with
acute myelogenous leukemia. Extensive gingival engorgement has been caused by the infiltrating leukemic cells.
The resulting ischemia can contribute to the development of tissue necrosis as well as opportunistic infection
such as pseudomembranous candidiasis.

barrier can result in a risk of life-threatening
bacteremia and/or sepsis.
Because of their high clinical importance and
frequency, this chapter highlights the following:
• Acute toxicities of mucosal injury and their
associated pain, as well as oral infection, in
the setting of multiple acute sequelae that
can occur (Table 13-1). By comparison,
however, chronic toxicities caused by che-
motherapy are not common; this aspect of
oncology patient care will thus not be spe-
cifically addressed in detail.
• Management of oral mucosal injury associ-
ated with targeted cancer therapies. This will
illustrate the unique characteristics of these
lesions in relation to oral mucositis caused
by conventional cancer treatments.
• Contemporary clinical issues associated with
medication-related osteonecrosis of the jaw.
Discussion of these lesions is presented in
the context of risk for emergence of this tox-
icity in selected oncology patients who are
receiving bone-stabilizing agents in order to
prevent skeletal bone fractures.

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 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

TABLE 13-1  |  Oral toxicities in cancer patients

Complication Weighted prevalence

Bisphosphonate-associated All studies: 6.1% (mean)

osteonecrosis  Studies with documented follow-up: 13.3%  
Studies with undocumented follow-up: 0.7%  
Epidemiologic studies: 1.2%  

Dysgeusia  CT only: 56.3% (mean)  

RT only: 66.5% (mean) 
Combined CT and RT: 76% (mean) 

Oral fungal infection  Clinical oral fungal infection (all oral candidiasis):
Pretreatment: 7.5% 
During treatment: 39.1% 
Posttreatment: 32.6% 
Clinical oral candidiasis infection by cancer treatment:
During HNC RT: 37.4% 
During CT: 38% 

Oral viral infection  Patients treated with CT for hematologic malignancies:

Patients with oral ulcerations/sampling oral ulcerations: 49.8% 
Patients sampling oral ulcerations: 33.8% 
Patients sampling independently of the presence of oral ulcerations: 0% 
Patients treated with RT:
Patients with RT only/sampling oral ulcerations: 0% 
Patients with RT and adjunctive CT/sampling oral ulcerations: 43.2% 

Dental disease  Dental caries in patients treated with cancer therapy:

All studies: 28.1% 
CT only: 37.3% 
Post-RT: 24% 
Post-CT and post-RT: 21.4% 
Severe gingivitis in patients undergoing CT: 20.3% 
Dental infection/abscess in patients undergoing CT: 5.8% 

Osteoradionecrosis  Conventional RT: 7.4% 

IMRT: 5.2% 
RT and CT: 6.8% 
Brachytherapy: 5.3% 

Trismus  Conventional RT: 25.4% 

IMRT: 5% 
Combined RT and CT: 30.7% 

Oral pain*  VAS pain level (0–100) in HNC patients: 

Pretreatment: 12/100 
Immediately posttreatment: 33/100 
1 mo posttreatment: 20/100 
EORTC QLQ-C30 pain level (0–100) in HNC patients: 
Pretreatment: 27/100 
3 mo posttreatment: 30/100 
6 mo posttreatment: 23/100 
12 mo posttreatment: 24/100 

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13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

TABLE 13-1 (cont)  |  Oral toxicities in cancer patients

Complication Weighted prevalence

Salivary gland hypofunction and All studies: 
xerostomia (in HNC patients by type Pre-RT: 6% 
of RT) During RT: 93% 
1–3 mo post-RT: 74% 
3–6 mo post-RT: 79% 
6–12 mo post-RT: 83% 
1–2 y post-RT: 78% 
> 2 y post-RT: 85% 
Conventional RT: 
Pre-RT: 10% 
During RT: 81% 
1–3 mo post-RT: 71% 
3–6 mo post-RT: 83% 
6–12 mo post-RT: 72% 
1–2 y post-RT: 84% 
> 2 y post-RT: 91% 
IMRT:
Pre-RT: 12% 
During RT: 100% 
1–3 mo post-RT: 89% 
3–6 mo post-RT: 73% 
6–12 mo post-RT: 90% 
1–2 y post-RT: 66% 
> 2 y post-RT: 68% 

*Pain is common in patients with HNCs and is reported by approximately half of patients before cancer therapy, by 81% during
therapy, by 70% at the end of therapy, and by 36% at 6 months posttreatment.
CT, chemotherapy; RT, radiation therapy; HNC, head and neck cancer; IMRT, intensity-modulated radiation therapy; VAS, visual
analog scale; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30.
(Adapted from the National Cancer Institute website.1)

Given the scientific and medical complexity
of cancer and its treatment, the multidisci-
plinary oncology team has essential value in
achieving optimal outcomes while minimizing
side effects of that treatment. As a part of this
team, the dental professional has vital respon-
sibilities, including the following:
patients whose immune function is attenuated
as a result of systemic disease. Examples of
these diseases include genetically based or
acquired immunodeficiencies, as well as adverse
outcomes of non-neoplastic disease treatment.

• Education of the patient and family members

Acute Oral Toxicities in
• Education of the medical and nursing staff the Myelosuppressed
• Diagnosis and treatment of oral com­pli­
cations
Oncology Patient
• Prevention of oral complications
• Oral health follow-up and maintenance Oral Mucositis
Clinical impact
The interprofessional model as described
for the oncology patient can also provide con- Oral mucositis can have a significant delete-
text for research and clinical management of rious impact on the cancer patient receiving

274
 Oral Mucositis

Fig 13-4 |  Oral mucositis in a breast cancer patient

receiving high-dose chemotherapy. Extensive pseu-
domembranous lesions can significantly impair normal
oral function and represent a portal of entry for severe
systemic infection.

Box 13-1  |  Key developments in the field of oral mucositis over the past 20 years2

• Initiation of research studies into pathobiology and clinical trials

• The creation of international organizations of health professionals directed to the mission of supportive care in
cancer
• The first two American Society of Clinical Oncology educational sessions addressing mucositis, held in 2003 and
2004
• Publication of the first evidence-based mucositis guidelines by the Multinational Association of Supportive Care
in Cancer and International Society of Oral Oncology (MASCC/ISOO), which have since been updated twice
• Incorporation of mucositis as a MeSH term by the National Library of Medicine
• The publication of clinical practice guidelines for mucositis by other organizations
• Comprehensive updating of the National Cancer Institute’s Physician Data Query website1 to include a section on
oral complications of chemotherapy and head and neck radiation

high-dose chemotherapy2,4–6 (Fig 13-4). The le-
sion can be so painful that oral functions such
as eating, speaking, and swallowing are severe-
ly compromised. In cancer patients receiving
multicycle chemotherapy regimens, the oral
pain can necessitate subsequent dose delays or
reductions to lessen the extent of oral injury
and discomfort. In neutropenic cancer patients,
ulcerative oral mucositis can be a portal of
entry for systemic infection, resulting in bac-
teremia and/or sepsis. The collective sequelae
of the lesion can require extensive use of health
care resources,7 including by some estimates
approximately US $41,000 in the hematopoi-
etic stem cell transplant (HSCT) population.8
Oral mucositis can thus be clinically and eco-
nomically consequential.
Despite the importance of the condition,
however, until the early 1990s oral mucositis
had been viewed by many clinicians and thus
patients as an inevitable consequence of
high-dose cancer therapy. Fortunately, sub-
stantial progress over the past 20 years at the
research and clinical levels has set the stage
for new opportunities for prevention and treat-
ment (Box 13-1).
Pathobiology and future research
directions
One of the key advances in the last two
decades has been the delineation of a contem-
porary pathobiologic model that illustrates the
complex interactions within and across oral ep-
ithelial and connective tissues5,6,9 (Fig 13-5). An
additional major advance in recent years has
been the scientific and clinical linkage of oral

275
 13

276
Oral Complications in the Immunocompromised Patient: The Oncology Prototype

Fig 13-5  |  The conceptual framework for oral mucositis pathobiology consists of five stages, ranging from initial injury within hours of exposure to high-dose cancer
therapy to eventual healing approximately 2 to 4 weeks after cessation of that treatment. Although the illustration depicts an orderly and sequential mechanistic pro-
cess, the course of molecular and cellular events is more likely dysregulated and biologically chaotic. (Reprinted from Sonis5 with permission.)
 Oral Mucositis

a b

Fig 13-6  |  Systemic chemotherapy causes architectural and functional disturbances throughout the alimentary
tract, including the intestine. (a) Normal jejunal mucosa in a healthy patient, as imaged by video-capsule endos-
copy. Black arrows, normal villi. (b) Extensive ulceration (white arrow) and hemorrhage (black arrows) of the in-
testine in an HSCT patient approximately 7 days after the last dose of high-dose chemotherapy as a component
of the conditioning regimen. This lesion of the gastrointestinal tract is not typically painful but can be associated
with severe diarrhea, cramping, and compromised absorption of nutrients. (Reprinted from Triantafyllou et al10
with permission.)

mucositis with gastrointestinal mucositis3,4,10,11 typically incorporate multiple considerations,

(Fig 13-6). This paradigm of alimentary tract
mucositis has provided an essential founda-
tion for new research frontiers that collectively
could permit personalized medicine for each
oncology patient based on a priori prediction
of both risk for mucositis and likely response
to therapeutics (Box 13-2).
Achievement of this goal is important
because the incidence and severity of oral
mucositis vary across cancer patient cohorts,
from approximately 40% of patients receiving
standard-dose chemotherapy to approximately
80% of patients receiving myeloablative con-
ditioning regimens for HSCT.2 There is thus a
need to implement customized prevention and
management for selected, but not all, cancer
patients who are about to begin mucotoxic
cancer treatment.
Patients with advanced stages of head and
neck cancer (Fig 13-7) typically receive multi-
modality treatment that includes approximately
two cycles of induction chemotherapy followed
by high-dose head and neck radiation with or
without weekly concomitant chemotherapy.
Decisions on types of oral cancer treatment
including the location and staging of the can-
cer, the age of the patient, and anticipated cure
rates. Although the chemotherapy utilized in
these treatment protocols is not highly myelo-
suppressive, it can cause oral mucositis that is
clinically significant in some patients.
At present, the US Food and Drug Admin-
istration has cleared only one nondevice
intervention for oral mucositis.12 This agent,
palifermin, is a member of the keratinocyte
growth factor family and is cleared for pre-
vention of oral mucositis in HSCT patients
receiving chemotherapy with or without total
body radiation in the autologous transplant
setting. Despite phase IV studies, the agent has
not demonstrated consistent efficacy in the
nonautologous transplant setting.13
Additional preclinical and clinical develop-
ment of drugs and biologics continues, directed
to key molecular targets and network hubs (see
Box 13-2). Notable among many current stud-
ies is work being conducted by investigators
at the National Institutes of Health, who are
pursuing the use of tempol for prevention of
oral mucositis14 and gene therapy for treatment

277
13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

Box 13-2  |  Future research questions: Oral mucositis caused by cancer therapies

Pathobiology
• What is the role of the oral microbiome relative to causation, progression, and/or healing of oral mucositis?
• What are the molecular bases for incidence and severity of pain in relation to degree of oral mucosal injury?
• Why do patients with comparable characteristics, including age, sex, cancer diagnosis, and treatment regimen,
collectively exhibit variability of toxicity expression, including oral mucositis?
• How can delineation of molecular pathogenesis lead to novel models for prediction of incidence, severity, and
response to thera­peutics in individual patients, in contrast to a cohort-wide basis?
• What biologic characteristics contribute to native protection against development of mucositis at selected non–
alimentary tract mucosal sites such as vaginal and conjunctival mucosa?
• What crosstalk occurs between at-risk mucosal and dermal sites for which common etiologies can be
delineated?
• How can systems biology technology be optimally applied to study the regulatory function of gene clusters in
comparison with single gene expression? In addition, how do these interrelated gene cluster functions translate
to studies of symptom burden that are observed in many oncology patients undergoing high-dose cancer
therapies?

Development of pharmacologics, biologics, and devices to manage oral mucositis

• What are the key molecular targets that, if successfully perturbed, are likely to permit achievement of a high
degree of clinical efficacy with the least extent of side effects?
• What is the most efficient preclinical and clinical development strategy to bring new therapeutics to clinical
practice in a cost-effective fashion?

Impact of evidence-based clinical practice guidelines

• What are the most effective ways to ascertain the impact of utilization of evidence-based oral mucositis clinical
practice guide­lines relative to enhanced clinical outcomes and reduced cost of cancer care?

(Reprinted from Peterson et al2 with permission.)

Fig 13-7 |  Advanced stage of squamous cell carci-

noma on the right lateral side of the tongue. Advanced
stages of oral squamous cell carcinoma typically war-
rant multimodality cancer treatment, including surgery
and/or chemotherapy followed by high-dose head and
neck radiation. The chemotherapeutic regimens utilized
are not usually profoundly myelosuppressive, although
they can cause clinically significant oral mucositis.

of chemoradiation-induced oral mucositis.15 of the mucositis trajectory in patients via

This and related lines of biologic research are genetic6,17–21 and imaging-based22 approaches.
being enhanced by the development of novel High-throughput deep sequencing of the oral
technologies such as in vitro tissue engineering microbiome23 is permitting delineation of puta-
models of oral mucosa16 as well as prediction tive pathogens that are not typically cultivable

278

by conventional methods. Systems biology
technology is increasingly being utilized to inte-
grate the complex and extensive data sets into
cohesive models of pathobiology that translate
to the clinical trajectory.2,24–26
Thus, basic, translational, and clinical
research has successfully shifted the historic
paradigm of “inevitable consequence” to a
contemporary model for which prediction of
incidence and severity of oral mucositis as well
as response to therapeutics is likely to emerge
over the next few years. These advances will
likely provide an evidence base on which
comprehensive clinical guidelines for mucosi-
tis management can position the clinician to
develop a personalized, customized approach
to prevention and treatment of oral mucositis
for each individual oncology patient.
Pain management for patients with
oral mucositis
The complex proinflammatory and neu-
rotransmitter cascade associated with oral
mucositis can result in moderate to severe oral
pain that can compromise delivery of cancer
treatment regimens.27 The pain can escalate
mood changes such as anxiety and depres-
sion, which in turn can further contribute to
the patient’s pain experience. There are likely
multiple molecular mechanisms that contrib-
ute to the degree to which patients report pain
severity.28 It is important to note that objective
measures of oral mucosal inflammation (eg,
erythema, ulceration) are not wholly homol-
ogous with patient-based subjective reports
of pain.
Thus, both objective and subjective eval-
uation of the pain component is warranted
clinically in order to optimize pain manage-
ment. It is essential that an aggressive and
systematic pain assessment and interven-
tion strategy be incorporated. The paradigm
begins with education of the patient and
caregiver regarding oral mucositis and its
consequences prior to initiation of cancer
Oral Mucositis
therapy.29 Systematic oral tissue and pain
assessments are then needed throughout the
period of cancer treatment. A staged approach
to pain relief, ranging from topical anesthetics,
doxepin, and fentanyl through nonopioid and
opioid systemic analgesics, can be implemented
as needed. It is also essential to monitor side
effects of the pain therapeutics, particularly
with the opioid classes of drugs.
Mucosal injury caused by targeted
cancer therapy
The use of targeted cancer therapies has escalat-
ed in recent years, following their introduction
into clinical oncology practice approximately
a decade ago.28,30,31 These agents are designed
to selectively inhibit a molecular target that
is abnormal in malignant cells versus cells in
normal tissue.32 These agents have a number
of safety and efficacy benefits over convention-
al high-dose chemotherapy, including reduced
toxicity profiles as well as enhanced cancer pa-
tient survivorship in selected cohorts.
These agents have, however, resulted in the
emergence of unique oral mucosal lesions,
such as the mammalian target of rapamycin
(mTOR) inhibitors33 (Fig 13-8). These lesions
mimic recurrent aphthous ulcerations in
clinical appearance and in selected patients
respond well to topical, intralesional, and/or
systemic corticosteroid therapy.28,34–36 These
lesions are thus quite different from oral
mucositis caused by conventional chemother-
apy or head and neck radiation with regard
to mucosal distribution, clinical appearance,
and response to steroid management. Further
research on the molecular pathobiology of
these lesions is needed to enhance understand-
ing of their causation as well as the potential
for prediction of incidence and severity on a
patient-by-patient basis.
Unlike high-dose chemotherapy patients,
patients receiving targeted cancer therapies
such as inhibitors of the mTOR are not mye-
losuppressed. These mTOR inhibitory agents
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13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

a b

Fig 13-8  |  Selected mammalian target of rapamycin (mTOR) inhibitors can cause oral mucosal lesions that clin-
ically resemble recurrent aphthous ulceration and often respond to topical, intra­lesional, or systemic corticoste-
roid management. (a) Lesion on the tongue after a patient received three 21-day cycles (63 days) of ridaforolimus.
(b) Inner lips of a patient who developed mTOR inhibitor–associated stomatitis within 10 days after initiation of
treatment with everolimus (10 mg once daily) in combination with figitumumab. (Courtesy of Dr Nathaniel Treister,
Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, Massachusetts.)

are directed to reducing the hyperactivity of • Topical, intralesional, or systemic steroids

mTOR observed in several oncogenic path-
ways.30 However, patients receiving selected
targeted agents can experience a unique clinical
expression of mucosal injury not previously
documented prior to the advent of these agents.
Key points associated with oral mucosal
injury caused by mTOR inhibitors are the
following28:
• Incidence varies widely (2% to 78%).
• Grade 3 and grade 4 toxicity occurs in up to
9% of patients.
may be useful for treatment, in contrast to
mucosal injury caused by conventional che-
motherapy or head and neck radiation.
• Based upon the current state of the science,
clinicians cannot typically predict a priori
which patients will or will not develop the
lesions.
New research is needed, including risk pre-
diction, pathobiology, and the molecular basis
of pain (Fig 13-9), in order to enhance preven-
tion at the clinical level in the future.

280
 Oral Mucositis

Fig 13-9  |  Integration of the molecular modeling of oral mucosal pain into the current inflammation biology par-
adigm for oral mucositis caused by cancer therapy. Development of novel pain therapeutics targeting key neural
pathways could strategically enhance management of oral mucositis in the future. (Reprinted from Peterson et
al29 with permission.)

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13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

Box 13-3  |  Oral complications of hematopoietic stem cell transplantation

Phase I: Preconditioning
• Oral infections: dental caries, endodontic infections, periodontal disease (gingivitis or
periodontitis), and mucosal infections (ie, viral, fungal, or bacterial)
• Gingival leukemic infiltrates
• Metastatic cancer
• Oral bleeding
• Oral ulceration: aphthous ulcers and erythema multiforme
• Temporomandibular dysfunction
Phase II: Conditioning neutropenic phase
• Oropharyngeal mucositis
• Oral infections: mucosal infections (ie, viral, fungal, or bacterial) and periodontal
infections
• Hemorrhage
• Xerostomia
• Taste dysfunction
• Neurotoxicity: dental pain and muscle tremor (eg, jaws or tongue)
• Temporomandibular dysfunction: jaw pain, headache, and joint pain
Phase III: Engraftment hematopoietic recovery
• Oral infections: mucosal infections (ie, viral, fungal, or bacterial)
• Acute graft-versus-host disease (GVHD)
• Xerostomia
• Hemorrhage
• Neurotoxicity: dental pain and muscle tremor (eg, jaws or tongue)
• Temporomandibular dysfunction: jaw pain, headache, and joint pain
• Granulomas/papillomas
Phase IV: Immune reconstitution late posttransplant
• Oral infections: mucosal infections (ie, viral, fungal, or bacterial)
• Chronic GVHD
• Dental and skeletal growth and development alterations (pediatric patients)
• Xerostomia
• Relapse-related oral lesions
• Second malignancies
Phase V: Long-term survival
• Relapse or second malignancies
• Dental and skeletal growth and development alterations

(Adapted from the National Cancer Institute.37 )

Acute and Chronic Graft-
Versus-Host Disease
The HSCT patient represents a unique cohort
among immunocompromised patients, with a
broad scope of acute and chronic oral toxic-
ities that may develop1,37,38 (Box 13-3). This
uniqueness is characterized by a conceptual
framework that includes stem cell rescue
of bone marrow injury that is caused by a
conditioning regimen of high-dose chemother-
apy and/or radiotherapy for treatment of the
malignancy. This rescue is achieved by post-
conditioning infusion of hematopoietic cells
that are harvested in advance from one of the
following donor sources:

282

• Autologous: Patient’s own hematopoietic
stem cells (human leukocyte antigen [HLA]
identical).
• Syngeneic: Patient’s identical twin or triplet’s
hematopoietic cells (HLA identical).
• Allogeneic: Typically a sibling or donor
relative who is genetically similar based
on matching at the HLA locus. In some
instances, the donor can be unrelated to the
patient (HLA identical, haploidentical, or
mismatched).
Patients who undergo allogeneic HSCT may
develop moderate to severe oral mucositis
caused by the conditioning regimen.29
In addition, graft-versus-host disease
(GVHD) can be clinically significant in these
patients as well.39,40 For example, at least
50% of patients develop chronic GVHD
within about 1 year of the transplant proce-
dure.37 Risk for development of this condition
is directly influenced by the extent to which
there is genetic disparity at the HLA locus with
either a related or unrelated donor. The reac-
tion is in part mediated via alloreactive donor
lymphocytes that recognize and bind to anti-
gens associated with salivary glands and oral
mucosa. The resultant cytotoxicity can lead to
irreversible oral tissue injury. The oral mucosal
lesions associated with chronic GVHD are typ-
ically lichenoid in appearance, with an erosive
or ulcerative component in selected cases. As
such, they mimic naturally occurring mucosal
diseases, such as ulcerative lichen planus, pem-
phigus, and pemphigoid. Oral chronic GVHD
is considered a risk factor for the development
of potentially malignant and malignant oral
mucosal neoplasms over time. Clinically sig-
nificant salivary hypofunction and xerostomia
can develop as a result of chronic GVHD as
well, with a potentially highly adverse impact
on the dentition, periodontium, and mucosa.37
Considerations for topical management of
the mucosal lesions include steroids,41 immuno-
suppressants,42 photobiomodulation,43 and/or
oral psoralen and ultraviolet A therapy.37 Sys-
temic immunosuppression is usually warranted
Infection
in severe cases, particularly if multiorgan
involvement is present.
Infection
The dentition, periodontium, and periradicu-
lar sites represent potential sources of acute
local and systemic infection during myelo-
suppression.1 The following preexisting oral
lesions can represent clinically significant risk
to the patient during the subsequent period of
myelosuppression:
• Advanced and/or symptomatic dental caries
• Periapical pathoses symptomatic within the
past 90 days
• Severe periodontal disease for which prog-
nosis of the dentition is poor
• Mucosal lesions secondary to trauma from
prosthetic or orthodontic appliances
Many of these acute infectious flare-ups can
be prevented by stabilization of the oral cavity
prior to initiation of the chemotherapy. Unfor-
tunately, there is no definitive prechemotherapy
oral care protocol that clearly delineates risk
for infectious flare-ups in relation to degree and
duration of myelosuppression. For example, a
recent study reported that oral health status
was not associated with risk of bacteremia
of potential oral source either at the time of
acute myelogenous leukemia consolidation or
in association with allogeneic transplant.44 Fur-
thermore, chronic oral foci of infection present
prior to, for example, initiation of high-dose
chemotherapy are not necessarily likely to
flare during the subsequent period of intense
myelosuppression.44 Clinicians must therefore
incorporate clinical judgment in their preche-
motherapy decision making. The history of
symptoms within the previous 90 days can
serve as a useful guide in this regard.
The oral assessment should occur as early as
feasible in relation to the upcoming chemother-
apy. Clear communication of the oral findings
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13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

a b

Fig 13-10  |  Chronic inflammatory periodontal disease represents a potential site for acute infection in the my-
elosuppressed chemotherapy patient. (a) Patient who does not have cancer presenting for periodontal surgical
management of severe chronic periodontal disease. (b) Intraoperative clinical photograph of the patient in part
a. The extensive ulceration provides a direct portal for systemic dissemination of colonizing microflora. In the
chemotherapy patient with profound neutropenia (eg, neutrophil count of less than 100/mm3), this systemic
dissemination can result in morbid or fatal infections.

a b

Fig 13-11  |  (a) Acute periodontal infection in a neutropenic cancer patient with a neutrophil count of less than
500/mm3. Classic inflammatory signs, including erythema and purulence, are not clinically prominent because
the number and function of neutrophils are suppressed. (b) Acute periodontal infection in a chemotherapy pa-
tient with a neutrophil count of less than 1,000/mm3. Classic signs of inflammation are more evident because the
neutrophil response is more robust.

among the oncology team is essential, with a
focus on the extent of preexisting oral disease
in relation to the potential for acute infectious
exacerbation during myelosuppression.
Acute periodontal infections
Chronic periodontal disease can undergo
acute infectious exacerbation during neutro-
penia (Figs 13-10 and 13-11). Acute flare-ups
are infrequent despite the widespread occur-
rence of the predisposing chronic inflammatory
condition. The microbiologic flora has been
historically reported as comprising both peri-
odontopathic organisms as well as acquired
pathogens associated with morbidity and mor-
tality in the neutropenic cancer patient.45 When
it does occur, the classic signs of inflammation
may be diminished because of the myelosup-
pressed condition of the patient. Culturing
of the attached gingiva, as opposed to direct
subgingival culturing, may not produce mi-
crobial specimens reflective of the causative
microflora.

284
 Infection

a b

Fig 13-12  |  (a) Reactivated HSV is typically a self-limiting clinical infection in the immunocompetent patient.
This patient’s lesion has been present for 8 days and is now in the stages of resolution. (b) Reactivated HSV can
be extensive and fatal in a patient who is immunocompromised following HSCT. The compromised mucosal and
circulating immune defenses result in a rapidly progressing, painful, and sometimes fatal systemic viral infection.
(Part b courtesy of Dr Mark M. Schubert, Fred Hutchinson Cancer Research Center, Seattle, Washington.)

Treatment typically consists of oral rinses immunocompromised patients such as those

with 0.13% chlorhexidine digluconate, irri-
gation of the periodontal pocket with 3%
hydrogen peroxide, gentle and supervised
dental brushing and flossing, and use of sys-
temic broad-spectrum antibiotics if indicated
medically.
Herpes simplex viral infection
The mucosa can also become primarily or sec-
ondarily infected during this myelosuppression.
Examples of clinical infection with herpes sim-
plex virus (HSV) and Candida are discussed,
using the HSCT setting as the prototype. Addi-
tional detailed guidelines for the prevention of
infectious complications among these patients
have been provided by Tomblyn et al.46
The immunocompromised cancer patient is
at risk for either reactivation of latent viruses or
activation of newly acquired viruses.47 Latent
HSV, varicella zoster virus, and Epstein-Barr
virus can be reactivated, while cytomegalovirus
infection can result from either reactivation of
latent virus or newly acquired virus.
Unlike the self-limiting recurrent HSV
infections in otherwise immunocompetent
individuals, reactivation of latent HSV in
undergoing HSCT can be life-threatening (Fig
13-12). Fortunately, antiviral prophylaxis or
treatment with thymidine kinase inhibitors
such as acyclovir or its derivatives is highly
efficacious. Drug-resistant HSV is an infre-
quent occurrence. The infection can codevelop
in the setting of oral mucositis and/or acute
GVHD.38 This concurrent lesion development
not only confounds the diagnostic process
but also intensifies the severity of the mucosal
injury.
As with all infections in this population, early
diagnosis is key to instituting prompt measures
directed to cure. Viral culturing remains the
gold standard, while other testing such as direct
immunofluorescence, immunoassay, and shell
vial testing may be useful in generating more
rapid results.
The development of antiviral medications
such as acyclovir, valacyclovir, and their
derivatives means that the infections in pre-
chemotherapy and pre-HSCT patients who are
seropositive for HSV and varicella zoster virus
can essentially be prevented. Breakthrough
infections, should they occur, are typically
highly responsive to increased doses of the
antiviral medications, because viral resistance

285
13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype

a b

Fig 13-13  |  Pseudomembranous candidiasis can occur in oncology patients secondary to myelosuppression
and/or compromised salivary defense mechanisms. (a) Clinically documented pseudomembranous candidia-
sis in an allogeneic HSCT patient with chronic GVHD involving the major salivary glands. (b) Cytologic smear
demonstrating the dimorphic candidal organism and hyphae.

Box 13-4  |  Characteristics of candidiasis As with herpetiform infections, the risk and
severity of the human papillomavirus lesion
Risk factors are influenced by the duration and depth of
• Myelosuppression the immunocompromised state. While laser
• Mucosal injury removal or cryotherapy may be implemented,
• Salivary compromise the lesions often regress on immune recovery.
• Antibiotics
• Steroids
• Increased length of hospital stay Candidal infection
Diagnosis
• History Opportunistic infections such as candidiasis
• Assessment of risk factors are common in cancer patients experienc-
• Examination ing chemotherapy-induced myelosuppression,48
• Culture as needed including those patients undergoing HSCT47
Treatment (Fig 13-13). In addition to the patient’s im-
• Nonmedicated oral rinse paired immune response, additional risk
• Topical antifungal (systemic therapy if factors include oral mucositis as well as phar-
indicated) macologic- and/or GVHD-induced salivary
• Removal of dentures
gland hypofunction (Box 13-4). The resultant
compromised salivary flow and composition
(eg, lactoferrin, salivary immunoglobulin A,
histatins, transferrin, and mucins) can lead to
pseudomembranous candidiasis and other op-
is rare. Persistent clinical infection is less likely portunistic infections.
to be due to viral resistance than to less than Diagnosis of candidiasis is typically based on
optimal dosing and/or impaired gastrointesti- history and clinical examination. Smear testing
nal absorption of orally administered agents or culturing can be performed if clinically war-
such as acyclovir. ranted (see Fig 13-13b).
Other nonherpes viral infections such Topical oral antifungal therapy with nystatin
as human papillomavirus can occur in the and clotrimazole can be instituted, although the
immunocompromised HSCT patient as well. yeast infection will likely recur on cessation of

286
 Medication-Related Osteonecrosis of the Jaw

a b

Fig 13-14 |  MRONJ. (a) Exposed oral bone involving the lingual aspect of the left mandible. (b) Periapical
radiograph 4 months later demonstrating continuing evidence of an osteolytic process. (Courtesy of Dr Cesar A.
Migliorati, University of Florida College of Dentistry, Gainesville, Florida.)

the medication unless the underlying risk factors Medication-Related

are successfully addressed as well. The follow-
ing regimen of topical therapy (7 to 14 days’
treatment) was recommended by Lerman et al49:
• Clotrimazole troche (10 mg), four to five
times per day
• Nystatin oral suspension (100,000 U/mL),
five mL, four times per day
• Nystatin pastilles (200,000 U), four to five
times per day
• Fluconazole solution (eg, 10 mg), swished
and expectorated, three times per day
• Amphotericin B, oral suspension (100 mg/
mL), 1 mL, four times per day
Systemic antifungal management with agents
such as fluconazole is typically indicated for
treatment of persistent oral infection as well as
for patients with profound immunosuppression.
In addition to candidal infection, other types
of fungal infection can occur, including lesions
caused by Aspergillus, Mucor, and Rhizopus
species. Culturing is essential for diagnosis,
because these lesions may mimic the clinical
appearance of nonyeast toxicities in HSCT
patients.
Osteonecrosis of the Jaw
Bone-stabilizing agents have high clinical effi-
cacy relative to reducing risk of skeletal bone
fractures in patients with metastatic bone
disease. In addition, the agents can exert anti­
tumor effects in selected cancer cohorts as
well.
However, medication-related osteonecrosis
of the jaw (MRONJ) is a key toxicity associ-
ated with their use and is unique to the oral
cavity50–52 (Fig 13-14). These lesions can occur
in cancer patients who have been exposed over
many months to one or more of the following
three classes of bone-stabilizing agents, which
are in turn associated with three different
molecular mechanisms:
• Bisphosphonates, osteoclast inhibitors via
mevalonate pathway
• Denosumab, an inhibitor of the receptor
activator of nuclear factor κ B (RANK)–
RANK ligand (RANKL) pathway
• Angiogenesis inhibitors, including vaccular
endothelial growth factor (VEGF) inhibitors

287
13 Oral Complications in the Immunocompromised Patient: The Oncology Prototype
Despite the three uniquely different molecu-
lar mechanisms, the incidence as well as clinical
prevention and management of MRONJ in
cancer patients are comparable, regardless of
type of bone-stabilizing agent being utilized.
MRONJ is defined as the unexpected devel-
opment of necrotic bone anywhere in the oral
cavity of a patient who has been exposed or
is currently taking a bone-modifying agent, an
angiogenesis inhibitor, or both and who has
not received radiation therapy to the head
and neck. MRONJ is persistent and does
not respond within 6 to 8 weeks to standard
therapy.
Current guidelines for prevention and
management are based upon several key prin-
ciples.52 Oral disease should be eliminated
or stabilized prior to initiation of the bone-
stabilizing therapy, whenever possible. Cancer
patients receiving these agents should be evalu-
ated by a dentist based on a systematic timeline
developed in collaboration with the patient’s
medical oncologist. In addition, daily mainte-
nance of optimal oral hygiene by the patient is
essential. MRONJ staging is important in order
to provide a basis for appropriate level of oral
management (see Table 12-5).
If MRONJ should occur, the lesion should
be managed by health professionals with expe-
rience in managing such lesions. For MRONJ
stages 1 and 2, conservative treatment with
periodic clinical evaluation of the progress of
disease in MRONJ is typically recommended.
Use of systemic antibiotics is recommended for
patients with active infection and/or clinical
paresthesia. Oral rinses with 0.12% or 2.0%
chlorhexidine digluconate two to four times per
day should be considered to enhance wound
care. For MRONJ stage 3, more aggressive
surgical intervention may be necessary. Top-
ical or systemic pain management should be
implemented if clinically appropriate to do so.
288
Conclusion
Oral complications can adversely affect the
quality of life of myelosuppressed cancer pa-
tients. This impact can range from mild and
easily tolerated to severe and debilitating. In
some cases, the toxicities can decrease the can-
cer patient’s chances of survival. In addition to
the prototypic modeling of oral complications
associated with myelosuppression resulting
from conventional high-dose chemotherapy,
the increasing use of targeted cancer therapies
in recent years has led to the emergence of new
toxicity profiles. This latter toxicity expression
includes a unique form of oral mucosal injury
for which the clinical phenotype is distinctly
different from that of oral mucositis caused
by conventional chemotherapeutic regimens.
Treatment of the conditions can be expen-
sive, including the cost of prolonged hospital
stays and supportive care interventions such as
infection management and nutritional support.
Fortunately, substantial and innovative
research in recent years has provided new
insights into molecular-based causation.
These discoveries are setting the stage for the
development of novel preventive and ther-
apeutic technologies for future use in the
clinical setting. Researchers and clinicians
from dental medicine are taking the lead
role in these scientific advances for the pre-
vention and management of some toxicities,
such as mucositis. In recent years, interdisci-
plinary collaborations promoted via national
and international organizations of health
professionals have contributed to the trans-
lation of clinically applicable outcomes into
high-quality, evidence-based guidelines for
oncology practice.
The presentation of this oncology paradigm
has been designed to highlight these issues in
the context of dental medicine research and
clinical care. Insights and lessons learned from
this modeling may well be applicable to other
patient cohorts in whom disease and/or its
treatment has led to immunocompromise.

Clinical Considerations: What You Can Take Back to Your Practice
Is there a biologic plausibility for an association
between acute and/or chronic oral disorders and
systemic health?  An intact immune response
is an essential component of maintaining ho-
meostasis that is necessary for oral health. The
oncology patient experiencing chemotherapy-
induced myelosuppression serves as a key pro-
totype for how compromised host defenses can
lead to the emergence of clinically significant
oral toxicities. There is thus a profound bio-
logic plausibility regarding the association be-
tween oral health and the immunosuppressed
oncology patient.
Are oral infections independent risk factors for
the development of adverse systemic outcomes
in the immunocompromised cancer patient?  tologic trajectory including maximum nadir of
Acute oral mucosal infections can occur as a
result of the compromised immune surveillance
and function. Immunosuppression can thus be
viewed as an independent risk factor in these pa-
tients. The infections can be caused by preexist-
ing colonizing microorganisms, newly acquired
pathogens, and/or reactivation of latent viruses.
Can treatment of selected oral infections and
related disorders prior to immunocompro-
mise reduce the risk for the development of
adverse systemic outcomes during the immu-
nocompromised phase of patient treatment?
Similarly, can prompt diagnosis and early
treatment of acute oral infection during im-
munocompromise reduce risk for subsequent,
more severe oral infection during this phase?  care to these patients.
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291

Oral-Systemic Health:
The Genomic Connection
John R. Shaffer, phd
Robert J. Weyant, ms, dmd, drph
The interdisciplinary field of human genomic
science has grown rapidly over the last two
decades as key technologic developments have
led to landmark projects and a newfound ca-
pacity to generate vast quantities of biologic
data. In turn, these developments have led to
the birth of new fields of study and accelerated
the pace of biomedical research. We find our-
selves in a world where whole genomes can
be quickly and cheaply sequenced. Dynamic
cellular processes such as gene transcription,
translation, and protein-protein interactions
can be assayed; three-dimensional structures of
the genome and protein products can be exper-
imentally and computationally modeled; and
epigenetic modifications such as DNA meth-
ylation can be measured and studied, all at
the scale of the genome. To accommodate the
immensity of the data generated, information
storage systems have been stretched to the
point where the cost of storing these data may
in some cases exceed the cost of simply regen-
erating the data from a stored biologic sample.
And despite the numerous computational and
bioinformatics tools that have been developed
to manage, analyze, and interpret these data,
our current capacity to produce genomic data
far outstrips our ability to make sense of it.
How will this “tsunami of data” impact bio-
medical science? How will genomic data be
harnessed to inform clinical care? The specific
292
CHAPTER 14
answers to these questions are difficult to pre-
dict, in part because of how rapidly the state
of the science has evolved. The overwhelming
trend in genomic science is one of increasing
complexity, with new genomic discoveries of-
ten revealing that the gap between basic science
and clinical application is wider than previ-
ously thought. The reality in dentistry is that
genomic science has of yet not contributed in
substantial ways to direct improvements in
routine patient care, but this will not always
be so. We are confident that the benefits that
come from the precision medicine initiative will
ultimately contribute in important ways to im-
proved dental care as well.
As we approach the study of the genetic basis
of oral disease and its possible linkage with
systemic disease, it should be kept in mind that
almost all diseases arise through some inter-
action of environmental (eg, social, chemical),
behavioral (eg, smoking, exercise), and biologic
(eg, genetic) mechanisms. It is important not to
limit our thinking about common risks among
various diseases to only one domain or mech-
anism. In this chapter we review genetic risk,
but in most cases, genetic risk can be highly
variable based on interactions with environ-
mental and behavioral factors.
In this chapter we focus on issues of impor-
tance to clinical dentists and patient care. We
start with the current state of genomic science

by describing the technologies, research meth-
odologies, and conceptual approaches used to
investigate the genetic basis of disease. Next,
we briefly review our understanding of the
genomic basis of selected oral diseases and
where genetic research may suggest that oral
and systemic disease share a common patho-
physiology or causal relationship. Finally, we
touch on how our growing understanding
of the genetic basis of oral diseases will play
an expanding role in clinical dentistry in the
future.
State of Genomic Science
It was not long after the initial research on
DNA sequencing in the late 1950s that the
genes responsible for many diseases began to
be identified.1 This early research focused on
identifying monogenic diseases (ie, those de-
rived from mutations in a single gene), and now
over 4,000 such disease genes have been identi-
fied. Most of these diseases are associated with
serious morbidity but also tend to be rare in
the general population. It took several more
decades for the technology to mature and allow
for the study of polygenic (ie, contributions of
many genetic variants of small individual ef-
fects) disease.
The diseases that carry the most social con-
sequences due to their high prevalence in the
general population are polygenic diseases, often
referred to as common complex diseases. The
National Institutes of Health (NIH) describes
common complex disease as disease thought to
be caused by many, often hundreds, of genes
in conjunction with behavioral and environ-
mental factors.2 These diseases tend to be
major causes of morbidity and mortality in the
general population and include heart disease,
certain cancers, stroke, and diabetes, to name
a few. Dental caries and chronic periodontitis
also fit into this category.
To shed light on the current state of genomic
science, consider some seminal projects that
State of Genomic Science
have formed the foundation of the field. Among
these formative works include the Human
Genome Project, the International HapMap
Project, the 1000 Genomes Project, and the
Encyclopedia of DNA Elements (ENCODE).
The Human Genome Project
Launched in 1990 based on plans formed in
the mid-1980s, this international initiative to
sequence the human genome was audacious in
scope and difficulty given the technology of the
time. Completion of the first rough draft3,4 of
the human genome sequence was announced
with much fanfare in 2000 by US President Bill
Clinton and British Prime Minister Tony Blair.
A more comprehensive (ie, covering 99.7% of
the euchromatic genomic regions) and greatly
improved draft of the human genome sequence
was completed in 2004.5 This reference provid-
ed the foundation for seminal discoveries in
many areas, including shaping our understand-
ing of the composition and structure of the
human genome itself, advancing our knowledge
of genetic variation across human populations,
revealing new insights into human evolution,
and greatly forwarding our understanding of
how specific genetic variants impact human
health and disease. These far-reaching impli-
cations are all based on the creation of a fairly
simple information resource: the reference se-
quence of approximately 3 billion nucleic acid
base pairs in the human genome.
The International HapMap and
1000 Genomes projects
With the human reference genome complete,
the International HapMap Project6,7 (2002 to
2009) was conceived to map the haplotype
(ie, inheritance of multiple genetic variants to-
gether as a group from a single parent) and
correlational structure of the human genome,
representing important patterns of human ge-
netic variation. Eleven ancestry groups from
across the world were represented, including
293
14 Oral-Systemic Health: The Genomic Connection
European Americans, African Americans,
Chinese Americans, Mexican Americans, and
Gujarati Indians from the United States, as well
as people from China, Japan, Nigeria, Kenya,
and Italy. Whereas the Human Genome Proj-
ect provided an initial reference point for the
genomic sequence, the International HapMap
Project provided detailed information about
the differences in this sequence between indi-
viduals and between populations, and it greatly
expanded (by many millions) the list of known
polymorphic sites in the human genome.
Comprehensive knowledge of such common
human genetic variants was instrumental
in informing strategies for conducting unbi-
ased, whole-genome scans to identify variants
associated with human disease, which came to
be known as genome-wide association studies
(GWASs). A key advancement provided by the
International HapMap Project was its utility
as the first “imputation base”—that is, a ref-
erence of the correlation across polymorphic
sites, which allowed researchers to impute al-
leles of unobserved genetic loci based on the
loci genotyped in an experimental sample. In
practice, this allowed researchers to determine
genotypes for 2.5 to 5 million genetic poly-
morphisms based on the data experimentally
observed by genotyping 200,000 to 500,000
polymorphisms. In other words, genotyping
projects could leverage the HapMap reference
data to collect much higher-resolution genet-
ic data based on lower-resolution genotyping.
Thus, the resource provided by the Interna-
tional HapMap Project helped make GWASs
feasible, allowing for hypothesis-free associ-
ation scans for genetic variants influencing
human health and disease.
As a successor to the International Hap-
Map Project, with a similar goal of cataloging
human genetic variation, the 1000 Genomes
Project8,9 was launched in 2008 and employed
newly developed high-throughput sequencing
technologies to sequence the genomes of over
a thousand people across multiple ethnicities.
This project yielded deeper understanding of
the genetic variation of humans, helped refine
294
the human reference sequence, and, along with
some later large-scale sequencing initiatives,
provided the imputation base for many contem-
porary GWASs. The major contribution of the
1000 Genomes Project was to provide a more
comprehensive catalog of human genetic varia-
tion than previously known, which has proved
to be a valuable resource for disciplines such
as genomics, bioinformatics, human evolution,
genetic epidemiology, and pharmacogenomics.
ENCODE
Another important follow-up to the Human
Genome Project is the ENCODE project,10
an ongoing initiative to catalog the function-
al elements of the genome—that is, all of the
non–protein-coding content of the genome
involved in regulating gene activity. DNA ele-
ments include gene promoters, transcriptional
regulatory sequences such as transcription
factor binding sites, and regions affecting
chromatin structure and histone modifica-
tions, all of which can be cell type specific.
An array of methods, many based on recent
advancements in high-throughput sequencing
technologies, have been used to identify these
elements (Fig 14-1). ENCODE and its ancil-
lary projects, as well as other similar initiatives
such as the Function Annotation of the Mam-
malian Genome (FANTOM)11 and Roadmap
Epigenomics projects,12 have provided founda-
tional insights into the regulatory structure of
the human genome and have provided needed
tools for designing genetic studies and anno-
tating and interpreting their results.
Advances in the field
These seminal projects and others have rap-
idly reshaped our current understanding of
the human genome and its roles in health and
disease. For example, prior to the Human
Genome Project, most estimates for the num-
ber of human protein-coding genes ranged
from 100,000 to 200,000, whereas the initial
reference sequence suggested this number was
 State of Genomic Science

Hypersensitive sites CH3

CH3

RNA polymerase

CH3CO

Hi-C DNase-seq ChlP-seq WGBS ENCODE RNA-seq eCLIP

ChlA-PET ATAC-seq –TF RRBS Encyclopedia RAMPAGE Bind-n-Seq
Repli-seq –Histone methyl array –Registry of cREs miRNA-seq
–SCREEN

Genes

Long-range regulatory elements Promoters

(enhancers, repressors/silencers, insulators) Transcripts

Fig 14-1  |  The ENCODE project aims to catalog the functional elements of the human genome. The organi-
zational structure of the genome is depicted from chromosome to double helix. The blue boxes represent the
methods and tools, mostly based on high-throughput sequencing technologies, used to collect multiomics data
on functional elements. Black arrows represent the correspondence between method, target of the assay, and
functional element. (Reprinted from Daryl Leja and Michael Pazin [National Human Genome Research Institute],
Ian Dunham [European Bioinformatics Institute], and the ENCODE Consortium with permission.) Inclusion of
this figure does not imply endorsement by the NIH, the National Human Genome Research Institute, or EN-
CODE for any particular viewpoint expressed in this chapter. Methods: Hi-C, high-throughput chromosome
conformation capture, a method for determining the three-dimensional architecture of chromatin; ChIA-PET,
chromatin interaction analysis by paired-end tag sequencing, a method for determining long-range chromatin
interactions; Repli-seq, a method for determining replication timing of genomic regions; DNase-seq, DNase I
hypersensitivity sites sequencing, a method for determining the location of regulatory regions; ATAC-seq, assay
for transposase-accessible chromatin sequencing, a method for determining chromatin accessibility; ChIP-seq,
chromatin immunoprecipitation sequencing, a method for determining the binding sites for a protein of interest
such as a transcription factor (TF) or for determining histone modifications; WGBS, whole genome bisulfite se-
quencing, a method for determining the DNA methylation status of cytosines across the whole genome; RRBS,
reduced representation bisulfite sequencing, a method for determining the DNA methylation status of cytosines
for regions of the genome (comprising about 1% of the genome) with high CpG content; methyl array, a method
for determining the DNA methylation status of cytosines for a predetermined list of CpG sites (currently about
850,000); cREs, candidate regulatory elements cataloged in the ENCODE encyclopedia; SCREEN, a web inter-
face for searching near-acting cREs derived from ENCODE data; RNA-seq, RNA sequencing, a method for de-
termining gene expression based on the presence and quantity of RNA molecules; RAMPAGE, RNA annotation
and mapping of promoters for analysis of gene expression, a method for determining transcription start sites;
miRNA-seq, microRNA sequencing, a method for determining the presence and quantity of small regulatory
RNA molecules; eCLIP, enhanced crosslinking and immunoprecipitation, a method for determining RNA-binding
protein targets; Bind-n-Seq, a method for determining protein-RNA interactions.

closer to 30,000 to 40,000 protein-coding genes comprising only 1.5% of the genome.
genes. Further work has shown that even this In addition, we now believe that the genome
estimate was high, as there is currently believed contains about 11,000 pseudogenes (ie, DNA
to be approximately 20,000 protein-coding sequences related to and resembling genes but

295
14 Oral-Systemic Health: The Genomic Connection

CH3 CH3 CH3 CH3 CH3

O = C  O = C  O = C  O = C  O = C 
Active
Active
chromatin
chromatin

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

Inactive
chromatin

CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3

Fig 14-2  |  Transcription is regulated, in part, by the state of the chromatin. The nucleosomes comprise DNA
(blue) wrapped around eight histone proteins (orange). Transcription is possible for active (open) chromatin (top),
characterized by unmethylated cytosines (white circles) and acetylated histones. Transcription is impeded for in-
active (silent) chromatin (bottom), characterized by methylated cytosines (red circles) and deacetylated histones.
Histone methylation (not depicted) also differs between active and inactive chromatin.

having lost some functionality) and 30,000 to
60,000 noncoding RNAs (ie, transcribed and
putatively functional sequences that are not
translated into protein; sometimes referred to
as RNA genes). We now know that the rest of
the genome, which does not code any genes
and had traditionally been regarded as “junk
DNA,” is filled with functional sequences. In
fact, 80% of the noncoding sequence of the
genome is functional in the sense that it is
involved in biochemical activities relevant to
biomedical sciences.13 Many of these sequences
have importance roles, such as providing the
landing sites for regulatory proteins involved
in determining when and where genes are
expressed. Other sequences affect the pack-
aging of the genome within the nucleus of
the cell, which is itself a major modality of
gene regulation. For example, epigenetic DNA
modifications, such as histone methylation, his-
tone acetylation, and DNA methylation, are
associated with “switching on” regions of the
genome by activating the chromatin (ie, open-
ing the conformation of the DNA so that it is
physically accessible to the cellular machinery)
to make transcription possible, or conversely,
“switching off” regions of the genome by
silencing the chromatin (ie, tightly packaging
the DNA in a closed conformation) to prevent
transcription (Fig 14-2).
These insights into the composition and
structure of the human genome have also
reshaped our understanding of the genetic
basis of human disease. Whereas genetic dis-
ease had traditionally been viewed as the result
of a disruption of a protein-coding gene that
was passed on through families under rela-
tively simple inheritance models (eg, dominant,
recessive, sex-linked), we now know that the
contributions of genetics to human disease also
operates through regulatory variants and epi-
genetic modifications. Under this perspective,

296

$100,000,000
$10,000,000
Cost per genome (US $)
$1,000,000
$100,000
$10,000
$1,000
2001 2003 2005
Fig 14-3  |  The cost of sequencing a human genome has decreased substantially over the last 15 years, far
outstripping Moore’s law, originally postulated as a doubling of the number of transistors on a computer mi-
crochip every 2 years; it is shown here as cutting the cost in half every 2 years (orange line). These data were
provided by the National Human Genome Research Institute.14
many common complex diseases, including
dental caries and periodontitis, have been
studied to identify the specific genetic variants
contributing to disease susceptibility. In fact,
an important theme that has emerged from
genomic studies is that the majority (about
90%) of disease-associated variants are reg-
ulatory in nature rather than protein-coding.
These studies have been made possible through
the use of high-throughput genotyping and
sequencing technologies, many of which were
developed or honed via the seminal genomics
projects described earlier.
Among the most important genomic technol-
ogies of the last decade was the development
of high-throughput sequencing methods,
also known as massively parallel sequencing
or next-generation sequencing. These terms
are usually intended to refer to any of a few
separate technologies, which, in contrast to
traditional Sanger sequencing developed in the
1970s, can be used to sequence larger amounts
of DNA faster and at much lower cost per
nucleotide. Most of these methods are “short
read” sequencing methods, meaning that they
State of Genomic Science
Moore’s law
2007 2009 2011 2013 2015 2017
Year
generate relative short (ie, up to a few hun-
dred base pairs), partially overlapping, snippets
of DNA sequence. Billions of these snippets,
known as reads, must then be assembled into
one continuous sequence guided by their partial
overlap, which is a computationally intensive
task made possible by concurrent advance-
ments in computing power. Improvements in
sequencing technology have caused the cost of
sequencing a whole human genome to plum-
met, from its initial price point of about $100
million at the end of the Human Genome
Project to about $1,000 in 2015 (Fig 14-3).
This drop in price put clinical applications
of next-generation sequencing on the table,
including applications targeting malignancies,
undiagnosed genetic syndromes, and prenatal
testing.
Next-generation sequencing technolo-
gies have also formed the basis for other
high-throughput assays employed in bio-
medical research today. For example, RNA
sequencing uses next-generation sequencing
to assess gene expression by measuring the
presence and quantity of mRNA transcripts
297
14 Oral-Systemic Health: The Genomic Connection
in a biologic sample. Similarly, chromatin
immunoprecipitation (ChIP) sequencing uses
next-generation sequencing to assay the physi-
cal interactions of target proteins with DNA by
immunoprecipitating the target proteins after
crosslinking them to the DNA. The immuno-
precipitated DNA regions are then sequenced
to identify the binding sites of the target pro-
teins. Analogous methods have been developed
to use next-generation sequencing to identify
DNA methylation states and protein-RNA
interactions at the genome scale. Altogether,
these technologies have extended the field of
genomics into DNA-adjacent “-omics” are-
nas, such as transcriptomics, regulomics, and
epigenomics. These next-generation sequenc-
ing–based technologies have facilitated the
collection of vast quantities of data, which has
provided opportunities to pursue new scientific
questions and posed new challenges related to
data management, analysis, and interpretation.
In fact, based on the degree to which they have
impacted the operation of biomedical research,
DNA sequencing–based technologies have been
dubbed “the new microscope” in recognition
of their transformative role in allowing us to
“see” into the inner workings at the level of
the tissue and cell.
In addition to DNA sequencing technologies,
another important advancement in genomics
was the development of high-throughput geno-
typing technologies. In contrast to sequencing,
where all nucleotides are observed, genotyping
technologies target only the genetic variants
already known to differ between individu-
als, which are the sites of greatest interest in
explaining the differences in phenotype, such
as diseases, among people. Genotyping arrays
have been designed that simultaneously cap-
ture information on 200,000 to 5 million
single nucleotide polymorphisms (SNPs; ie,
differences in the nucleotide base—A, T, C,
G—at a given position in the sequence) for low
cost (roughly $50 to $200 per DNA sample).
Development of these “SNP chips” was made
possible by advancements in the genotyping
technology itself, as well as knowledge of the
298
common genetic variation in humans obtained
through the seminal genomics projects such
as the International HapMap Project and
similar efforts to catalog human genetic vari-
ation. These SNP chip technologies, together
with public reference data sets necessary for
imputing unmeasured genetic variation, made
GWASs possible, which have become the most
widely used genomic approach and have been
employed to study the genetics of a great many
human traits and diseases; approximately
15,000 genetic associations have been observed
to date, as reported in the GWAS Catalog.15
GWASs have become a preferred approach
for studying human genetics because it is
hypothesis free. That is, GWASs do not require
any a priori assumptions about the genetics
of a trait of interest, such as which genes are
involved or how the trait is inherited. Instead,
the GWAS approach is to scan the whole
genome by testing each genetic variant indi-
vidually for statistical association with a trait
of interest, with careful interpretation of the
results given the fact that many tests were
performed. Typically, GWAS efforts focus on
the contributions of common genetic variants
occurring at frequencies greater than 1% in the
population under study. The goal of GWASs is
to identify genetic variants that are associated
with the trait in order to nominate genes and/
or regulatory elements for further study. To
date, GWASs have been performed for several
oral health conditions, including dental caries,
chronic periodontitis, aggressive periodontitis,
periodontal pathogen colonization, temporo-
mandibular disorder, and nonsyndromic
orofacial clefts. Likewise, GWASs have been
used to study most systemic human diseases.
Genetics and Oral Disease
The fact that certain oral diseases covary
with certain systemic diseases has motivated
research to identify common underlying patho-
physiologic mechanisms. Identifying a shared

pathophysiology, it is hoped, could lead to a
common treatment and improved efficiencies
in patient care, including improved patient out-
comes and reduced health system costs. Below
we discuss the genetics research related to den-
tal caries and periodontal disease.
Genetics of dental caries
There have been a number of GWASs seek-
ing to identify the specific variants influencing
susceptibility to decay. These efforts were mo-
tivated by the cumulative evidence from prior
twin- and family-based studies going back nine
decades that overwhelmingly demonstrated
the heritability of dental caries. Heritabili-
ty estimates differ across populations, and
it is difficult to generalize the exact degree
by which caries liability derives from genet-
ic causes. One unresolved issue that concerns
all genetic research, including caries and peri-
odontal disease research, is the concern over
missing heritability. This concern relates to the
fact that standard genetic approaches, such as
was used before high-throughput technology
was available, often provided large heritability
estimates for many (disease) traits. However,
the application of subsequent GWASs and oth-
er high-throughput technologies that identified
individual genes associated with the trait fail,
in many cases, to account for a substantial
portion of that predicted heritability. Debate
continues on how to interpret this discrepancy.
Genomic studies of dental caries have typ-
ically considered the primary dentition in
pediatric samples and the permanent denti-
tion in adults separately. The first GWAS of
dental caries16 simply contrasted the genomes
of caries-affected versus caries-free white chil-
dren and did not identify any loci meeting the
strict statistical threshold of “genome-wide sig-
nificance” (ie, the P value needed to declare a
finding statistically significant given the large
burden of multiple comparisons). Later studies
looked at dental caries in adult populations and
expanded the list of dental caries phenotypes in
both children and adults to include quantitative
Genetics and Oral Disease
caries scores in addition to affected/unaffected
status.
These efforts were fruitful in identifying
significantly associated genetic variants. And
while the majority of GWASs of dental caries
have focused on white populations, the largest
study to date was performed in a US Latino/
Hispanic population,17 identifying a genetic
variant in NAMPT—a gene with roles in mul-
tiple biologic processes including periodontal
healing—that is not present in white popula-
tions. Altogether, these studies have identified
several genetic variants statistically associ-
ated with dental caries and have generated a
growing list of genes to follow up in addi-
tional studies. However, few of these genetic
associations have been robustly replicated in
independent samples, which may be due to the
presence of genetic heterogeneity (ie, that the
variants contributing to dental decay differ
across populations), environmental differences
across studies that moderate the genetic effect,
or the low statistical power of these studies to
detect genetic variants of small effects. It is also
likely that some of these genetic associations
were spurious. Efforts are currently underway
by the Gene-Lifestyle Interactions and Dental
Endpoints (GLIDE) Consortium, an interna-
tional collaboration with the goal of leveraging
existing genetic studies with data on dental phe-
notypes, to combine GWAS results across many
independent cohorts via meta-analysis. Simi-
lar meta-analyses have been very fruitful for
other complex diseases; therefore, results from
the GLIDE Consortium are likely to further
advance our understanding of the genetic archi-
tecture of dental caries. Altogether, GWASs of
dental caries have demonstrated the polygenic
nature of dental caries but have not yet led to
discoveries that would impact clinical care.
Genetics of periodontal disease
By far the most research in the genetics of
oral diseases has focused on periodontal dis-
eases. Genetic factors are reported to explain
around 50% of the variance in the liability for
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14 Oral-Systemic Health: The Genomic Connection
periodontitis, and the basis for the heritabili-
ty of periodontitis appears to be biologic and
not behavioral in nature.18 Periodontal dis-
eases are a family of biofilm-related diseases
that vary by clinical presentation but share an
underlying inflammatory basis.19 Van Dyke20
describes the disease process as an overgrowth
of commensal organisms creating a “dysbiotic”
microbiome, where the initiation and progres-
sion of the disease is largely modulated by the
host inflammatory response. As Sima and Van
Dyke21 remind us, a pathogenic biofilm is a
necessary but not sufficient cause of periodon-
tal disease. At a minimum it appears that an
impaired host inflammatory response is also
required for tissue damage to occur, the nature
of which is under substantial genetic control.
Periodontal medicine, as described by Wil-
liams and Offenbacher,22 is the branch of
periodontology focusing on the relationship
between periodontal disease and systemic
disease. In a review of the history of research
examining the association of periodontal dis-
ease with systemic disease, Monsarrat et al23
documented 57 systemic conditions that have
been hypothesized as having some linkage with
periodontal disease. Given that many of the
diseases associated with periodontal disease
are common conditions with high morbidity,
the advancement of further research can be
quite important from a patient and population
health perspective. Hypothesized mechanisms
linking periodontal disease and systemic dis-
ease consistent with the current evidence have
been described as falling into three categories:
metastatic infection, inflammation, and adap-
tive immunity.24 The literature detailing these
pathophysiologic mechanisms are described
elsewhere in this text. Relevant to genetic
research is the reality that the current litera-
ture suffers from substantial methodologic
shortcomings. A particular concern, as with
caries, is the variability across studies in the
case definition or phenotypic description used
to determine if individuals have disease. Linden
et al25 said this was a serious concern across
studies, concluding in most cases that it was
300
“doubtful whether the criteria applied could
be realistically taken to unequivocally identify
periodontitis.” They also noted a generalized
failure to address the potential for serious con-
founding, particularly from variables such as
smoking and socioeconomic status. The poten-
tial for disease misclassification and residual
confounding are likely reasons for the large
degree of heterogeneity of results across studies
in this area.
Like dental caries, several GWASs have
investigated the genetic architecture of peri-
odontitis. One surprising result was that the
initial batch of GWASs of chronic periodonti-
tis, published in 2013 and 2014 and focusing
primarily on white populations, did not iden-
tify any associations meeting the statistical
criteria for genome-wide significance. Only
suggestive results were reported. This paucity
of genetic associations was unexpected given
the presumed genetic architecture of the dis-
ease. Most of the subsequent GWASs using
clinical definitions of chronic periodontal dis-
ease, which have been undertaken in various
racial and ethnic populations, have also yielded
few or no significant associations. However,
studies looking at innovative phenotypes, such
as periodontal pathogen colonization, or that
cleverly combined gene expression and genetic
association in multiphase study designs, have
been more successful. Likewise, studies of the
rarer aggressive form of periodontitis have
yielded several interesting genetic associations.
Overall, the genomic studies of periodontitis to
date have identified several potential genetic
loci but have not yet generated any knowledge
that has impacted clinical care.
GWAS lessons and other
genome-wide approaches
While genomic studies in the area of oral
health have not uncovered any smoking guns,
nevertheless, key insights have been obtained.
In particular, GWASs of many diseases and
complex phenotypes, including oral conditions,

have revealed some big-picture themes about
the role of genetics in complex disease. These
include the observation (which had been hy-
pothesized beforehand) that most complex
human diseases involve the contributions of
many genetic variants of small individual ef-
fect sizes. A consequence of this is that most
complex diseases, like dental caries and peri-
odontitis, can only be poorly predicted based
on our current knowledge of their genetic ar-
chitecture. Moreover, this observation casts
some doubt on the ultimate utility of targeting
individual genetic variants via pharmaceuticals
or gene therapies, as individual variants may
only contribute a small amount to total genet-
ic liability. It also reflects a need for genomic
studies to move past examining single variants
individually and instead to consider regulato-
ry networks operating within the cell. Other
themes that have emerged from the mountain
of GWASs performed to date include the obser-
vation that disease-associated genetic variants
often differ in frequency across ancestry (ie,
racial and ethnic) groups and that some genes/
genetic variants are involved in multiple sep-
arate diseases, a concept known in traditional
genetics as pleiotropy. In fact, pleiotropy is so
commonplace that study designs leveraging
giant data warehouses of electronic medical re-
cords have flipped the GWAS upside down by
investigating the association of a single genetic
variant of interest with hundreds to thousands
of different medical conditions, an approach
that has been dubbed the phenome-wide asso-
ciation study (PWAS or PhenWAS).
In addition to GWASs and PWASs, which
focus primarily on common genetic variants,
other genomic study designs have also been
developed and deployed to understand human
disease. For example, whole-exome sequenc-
ing studies are used to identify the coding
variants associated with disease, including
the rare variants that are not well captured in
GWASs. Similarly, whole-genome sequencing
studies can be used to identify all variants,
regulatory and coding, rare and common, that
contribute to disease. RNA sequencing can be
Genetics and Oral Disease
used to perform transcriptome-wide associa-
tion studies, which investigate tissue-specific
gene expression with respect to disease. Like-
wise, epigenome-wide association studies
(also known as methylome-wide association
studies) can be performed to investigate the
connection between tissue-specific patterns
of DNA methylation and disease. Few such
studies have been performed in the area of
oral health, although some pioneering work
includes an epigenome-wide association studies
by Langevin et al, who used DNA methylation
patterns to develop a classifier that could accu-
rately predict oral and pharyngeal carcinoma.26
In summary, the science of genomics has
come a long way in just a few decades, fueled
by technologic advancements facilitating swift
and economical collection of huge masses of
data. Despite the advancements pioneered in
the seminal genomics projects, the field still
has unmet needs in terms of understanding and
interpreting these data. For most clinical areas,
including oral disease, genomic information
has yet to be successfully translated to clinical
practice. However, with the amassing GWASs
and other genomic studies, our understanding
of the genetic basis of human disease contin-
ues to grow. Emergent themes from the field of
genomics suggests that as our understanding
of the genetic architecture of disease grows, a
genomic connection between oral and systemic
diseases is likely to be revealed.
Evidence of the genomic
connection between oral and
systemic disease
Recent results from the GLIDE Consortium
provide some of the most systematic and salient
evidence to date of the genomic connection
between oral and systemic disease.27 Statisti-
cal methods (ie, linkage disequilibrium score
regressions) were used to contrast GWAS re-
sults for dental caries and periodontitis with
those of various traits and diseases reported
in separate studies. This approach allowed the
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14 Oral-Systemic Health: The Genomic Connection
genetic correlations between dental outcomes
and a number of other human diseases and
traits to be quantified. In other words, separate
genomic studies were compared to estimate the
proportion of shared genetics between oral and
nonoral health measures. In total, genetic cor-
relations were estimated for both dental caries
and periodontitis with dozens of health-related
traits. For dental caries, significant shared ge-
netic etiology was observed with smoking
habits; measures of obesity; lipid levels; dia-
betes; autoimmune diseases such as systemic
lupus erythematosus and rheumatoid arthri-
tis; psychiatric conditions such as depression,
anorexia nervosa, and bipolar disorder; and
educational attainment. Weaker statistical ev-
idence was observed for the shared genetics of
dental caries with Alzheimer’s disease, atten-
tion deficit hyperactivity disorder, asthma, and
celiac disease. For periodontal disease, signifi-
cant shared genetic etiology was observed with
smoking habits, depression, measures of obesi-
ty, psychiatric disorders, subjective well-being,
and educational attainment. Weaker statistical
evidence of shared heritability was observed
for periodontitis and multiple sclerosis, atten-
tion deficit hyperactivity disorder, diabetes, and
lipid levels.27
These results indicate that the genetic etiol-
ogies of both dental caries and periodontitis
are shared with a variety of systemic diseases,
plus tobacco use and education. However,
the genetic correlations observed from these
genomic studies only provide a global indicator
of the degree to which genetic determinants
are shared between oral and systemic diseases.
These estimates of genetic correlation do not
indicate which genetic variants specifically are
involved, nor do they point to the biologic
mechanisms linking the genetic etiologies of
oral and systemic disease. Additional research
will be needed to identify these genetic variants
and elucidate these mechanisms. Like other
comorbidities, we expect that the shared genet-
ics of oral and systemic disease may operate
through a variety of mechanistic paradigms.
302
Paradigms for the shared genetics
of oral and systemic disease
An important point to appreciate is that many
of the genomic studies of human disease are ob-
servational in nature rather than experimental.
Such research leads to statistical associations,
and, as the axiom states, association is not
causation. That said, the constitutional ge-
nome of a person is determined at fertilization
and remains unchanged thereafter (ignoring
somatic mutations). Therefore, studies of the
constitutional genome are unaffected by the
problem of epidemiologic confounding due to
environmental exposures. Namely, a risk fac-
tor such as smoking, for example, does not
confound the relationship between a genetic
variant and a disease, such as periodontitis,
because a person’s genotype is not affected by
smoking (or any other external factor) even
though smoking is a risk factor for the dis-
ease. This detail can be helpful in interpreting
genomic studies. However, even though ge-
netic associations with disease are robust to
confounding by environmental factors, the
associations themselves often do not provide
much insight into the mechanisms, biologic
or otherwise, through which they impact dis-
ease. Follow-up studies, both observational and
experimental, are needed to glean knowledge
about these mechanisms. Likewise, when con-
sidering the genomic connection between oral
and systemic disease, the mechanisms through
which the comorbidities are coupled can be
challenging to determine. We will consider a
few paradigms (Fig 14-4) while acknowledging
that other connections are also possible.
The simplest paradigm for a genomic con-
nection between oral disease and systemic
disease is pleiotropy—the single gene connec-
tion. Traditionally, pleiotropy was taken to
mean that a genetic variant in a gene simultane-
ously affected two or more distinct phenotypes.
We see this phenomenon in a number of genetic
syndromes with both oral and systemic mani-
festations (see Table 14-1 for a non-exhaustive
set of examples). In these syndromes, disruption
 Genetics and Oral Disease

D1
Pleiotropy: Single gene
G
connection
D2

D1
G E
Gene-environment D2
correlation

G D1 E D2

Shared molecular D1
basis of complex
disease
D2

Mendelian ?
G D1 D2
randomization
(instrumental
variables) E

Fig 14-4  |  Paradigms for the shared genetics of oral and systemic disease. The node diagrams illustrate theo-
retical modalities by which two diseases can share a genetic basis. G, gene; E, environmental factor(s); D1 and
D2, oral or systemic disease or trait; arrows indicate causal relationships.

TABLE 14-1  |  Examples of single-gene syndromes with oral and systemic symptoms

Syndrome Gene(s) Oral manifestations Systemic manifestations

Waardenburg type 1 PAX3 Cleft lip and/or palate, tooth enamel Hearing loss, musculoskeletal anomalies,
malformations, and tooth agenesis hirschsprung disease, and other features

Jalili CNNM4 Amelogeneis imperfecta, dental caries, dentin Cone-rod dystrophy (vision loss, light
dysplasia sensitivity, poor color vision)

Marfan FBN1 Orthodontic anomalies, high palate, crowded Over 30 symptoms of skeletal,
teeth, fragility of the temporomandibular joint, cardiovascular, and nervous systems, lung,
periodontal disease and eye

Crouzon FGFR2 High palate, malocclusion, tooth agenesis, Craniosynostosis, pronounced facial features,
crowded teeth hearing loss

Rothmund-Thomson RECQL4 Tooth agenesis, microdontia, tooth dysplasia Skin manifestations such as sun-sensitive
rash, poikiloderma, telagiectasias, skeletal
defects, cataracts, risk of malignant disease

303
14 Oral-Systemic Health: The Genomic Connection
of the proper functioning of a key gene results
in signs and symptoms across separate tissues
or systems. These examples show that del-
eterious genetic variants can simultaneously
impact oral health and other biologic systems.
They also suggest the plausibility that other
not-quite-so-deleterious genetic variants may
simultaneously impact risk for chronic oral and
systemic diseases.
Though not due to a single gene, several
aneuploidies (chromosomal disorders) includ-
ing trisomies of chromosomes 9p, 12p, 13,
18, 21, and 22, exhibit craniofacial and oral
manifestations in addition to other systemic
manifestations. The same is also true for dele-
tion syndromes of chromosomes 13q and 18q,
as well as aneuploidies of the sex chromo-
somes (ie, multiple X [XXX+], Turner [X0],
Klinefelter [XXY], and XXY syndromes). Due
to the fact that these syndromes are caused by
chromosomal anomalies encompassing large
amounts of genomic content, it is likely that
distinct symptoms are due to the gain/loss of
different genes across the affected genomic
regions. That is, the gain/loss of genetic mate-
rial responsible for the oral manifestations may
differ from those causing other symptoms. Still,
these chromosomal disorders demonstrate the
shared genomic origins of both oral and sys-
temic maladies under a fairly simple paradigm
involving a single genetic aberration.
Other examples following the single gene
connection paradigm are ectodermal dyspla-
sias, a group of related disorders affecting
the ectodermal tissues such as teeth, salivary
glands, hair, nails, and sweat glands. Many of
these, such as Hay-Wells syndrome, Naegeli
syndrome, and hypohidrotic ectodermal dys-
plasia, result in overt tooth dysplasias alongside
other clinical features. Recent studies have also
observed the connection between ectodermal
dysplasias and chronic oral conditions, such as
dental caries. For example, mutations in keratin
genes KRT6A and KRT6B cause the condition
pachyonychia congenita, which is character-
ized mainly by hyperkeratosis lesions on the
hands and feet, nail dysplasia, and white plaque
304
oral lesions on the tongue and cheek. Recent
work28 has shown that common protein-coding
variants in the keratin genes associated with
pachyonychia congenita are also associated
with increased susceptibility to dental caries
in unaffected individuals. A similar single gene
connection has been observed for the hair ker-
atin gene KRT75. Variants in this gene cause
a mild hair disorder leading to skin inflamma-
tion after shaving known as pseudofolliculitis
barbae; recent work has shown that variants
in KRT75 also cause increased susceptibility
to dental caries and reduced enamel hard-
ness as well as subclinical enamel defects.29
These examples illustrate that variation in a
gene can impact chronic oral disease, such
as dental caries, while also impacting other
tissues/systems. Given that dental caries and
periodontitis are prevalent and exhibit a wide
range of disease severity in the general popu-
lation, it is plausible that many single genes
connecting these oral diseases to other systemic
maladies have gone unnoticed. Indeed, Offen-
bacher et al30 suggested that variation in disease
progression among patients could indicate sub-
classifications of disease based on genetic and
microbial-inflammatory signatures.
Another paradigm through which genom-
ics may act to connect oral and systemic dis-
ease is gene-environment correlation. This
occurs when an exposure to an environ-
mental condition is dependent on an indi-
vidual’s genotype. For example, genetic
variants in the nicotinic receptor gene clus-
ter CHRNA5-CHRNA3-CHRNA4 have
well-established effects on nicotine depen-
dence and smoking behavior. Smoking, in turn,
impacts risk for numerous diseases, including
periodontal disease. Therefore, periodontal
disease shares a genomic origin with cardio-
vascular disease, various cancers, and other
smoking-related diseases by way of the genetic
basis for nicotine dependence/smoking behav-
ior. Knowledge of the genetic basis for an envi-
ronmental exposure is not always of particular
interest. In instances where the environmental
exposure is known, the genomic connection

takes a back seat to the exposure itself. That
is, smoking per se is of greater interest in con-
necting periodontitis to other smoking-related
diseases than is the genetic underpinnings
of smoking status. Indeed, knowledge of the
genetic underpinnings of the exposure do not
add much, from a clinical perspective, in man-
aging disease beyond what can be obtained
by asking about the exposure itself. In some
cases, knowledge of a genetic predilection prior
to key environmental exposures may be help-
ful for gauging future risk of disease. Where
smoking status may turn out to be important
clinically is in risk estimation. As an example,
Divaris et al31 in a GWAS of the genetic basis
of chronic periodontitis showed that the esti-
mate of the heritability of severe chronic peri-
odontitis from all SNPs increased from 18% to
52% when they included an interaction term
between the genetic data and smoking.
The gene-environment correlation para-
digm may be of greater interest in situations
where the environmental exposure connect-
ing oral and systemic disease is theorized or
unknown. For example, several large studies
have reported a correlation between childhood
asthma and dental caries, but the reason for
this connection is not clear. Moreover, unpub-
lished family-based studies have indicated a
shared heritability of these two diseases, and
genetic associations have been reported for
variants in the mucin-coding gene MUC7 with
both asthma and dental caries. Nevertheless,
the exact mechanism by which these two dis-
eases are linked at the genetic level remains
unknown. One potential explanation for the
genomic connection between dental caries
and asthma is through the gene-environment
correlation with antiasthmatic medications,
such as albuterol. The proposed scenario is
that asthma-associated variants contribute to
asthma, which in turn leads to antiasthmatic
medication exposure. Albuterol, for exam-
ple, alters the oral microbiome and can cause
dry mouth, both of which may contribute
to increased dental caries. Other antiasth-
matic medications may include sweeteners
Genetics and Oral Disease
that increase risk of caries. Thus, asthma and
dental caries share a genetic underpinning in
that asthma-associated genetic variants lead
to caries-associated environmental exposures.
Knowledge of such environmental exposures
could provide an actionable point to intervene,
breaking the connection between diseases.
Another proposed gene-environmental cor-
relation involving oral and systemic traits is
the connection between anxiety disorders, pain
experience, and oral health. Dental fear, which
is anxiety or apprehension regarding receiving
dental treatment, is related to other anxiety
disorders and has shared heritability with fear
of pain.32 Specific genetic variants, including
variants in MCR1 (the “redhead” gene), are
associated with both dental fear and fear of
pain.33 (This observation fits with dental lore
that red-headed individuals may experience
pain differently.) Genetic variants predis-
posing to anxiety disorders or affecting pain
experience or pain-blocker metabolism may
contribute to dental fear, which in turn leads to
avoidance behavior. Patients who avoid dental
treatment experience poor oral health. Thus,
oral health conditions may share a genetic basis
with anxiety and pain phenotypes; the genomic
connection is due to the gene-environmental
correlation between anxiety and pain percep-
tion–related genetic variants and avoidance of
dental care. Incidentally, poor oral health may
lead to painful symptoms, thereby exacerbat-
ing the problem of dental fear and avoidance.
Knowledge of such gene-environment correla-
tions may be useful in breaking the cycle of
avoidance. That is, treating the anxiety could
improve oral health.
In summary, genetics may play a key role
in risk of exposures that impact oral health,
and these exposures may simultaneously affect
systemic disease. This genomic connection,
which is mediated by an environment, may be
less interesting from a clinical perspective than
the exposure itself. However, genomic connec-
tions following this paradigm may be helpful in
identifying environmental exposures that could
serve as targets for disease-prevention strategies.
305
14 Oral-Systemic Health: The Genomic Connection
Another paradigm for the oral-systemic
health genomic connection is through the
shared molecular basis of complex diseases.
A hallmark of complex disease is that numer-
ous biologic processes may impact etiology
and predilection. Diseases may partly share
signaling pathways and molecular networks,
and genetic variants impacting these biologic
processes may impact both diseases. Genomic
studies hold potential for uncovering such
shared genetics, although to date little research
has been conducted in this area linking oral
diseases to systemic diseases. The most studied
relationship is the possible genomic connection
for periodontal disease and cardiovascular dis-
ease. Twin studies suggest a shared heritability
of cardiovascular and periodontal diseases. A
recent review34 of the periodontal and cardio-
vascular GWAS literature indicated that though
few periodontitis-associated genetic variants
have been mapped, to date, three out of four
loci associated with periodontal disease are
also associated with cardiovascular disease.
These preliminary results support the notion
that cardiovascular and periodontal diseases
involve some common underlying biology
influenced by genetic variation.
The paucity of evidence for a shared molecu-
lar basis of complex oral and systemic diseases
reflects the current state of the field in that few
attempts to consider this area of investigation
have been made to date. Unlike most epidemi-
ologic studies, genomic studies can use separate
samples to investigate the shared heritability.
Using genomics as the link, researchers can
estimate the shared heritability of two dis-
eases using two separate samples, one having
data on each disease. A major limitation is that
these methods require large samples, preferably
10,000 or more individuals, and presently there
are few such samples in which to study the
genetics of oral diseases. As described earlier,
recent efforts by the GLIDE Consortium have
achieved such large sample sizes by combining
multiple independent studies26 and provided
some of the first evidence for the shared her-
itability of oral diseases and general health
306
measures. More work will be necessary to tease
out the specifics of these genetic underpinnings.
Genetics and “omics” data resources, combined
with bioinformatics and computational tools,
may provide a framework for understanding
the overlap in the genetic architectures of oral
and systemic diseases, complementing and
informing experimental work in model organ-
isms and in vitro.
In addition to explaining the connection
between oral and systemic disease, genetics
can be leveraged in order to assess the causal
relationships between oral and systemic dis-
ease using Mendelian randomization. This
approach simply employs the statistical method
of instrumental variables where genetic vari-
ants serve as the instrument. One application
of the method has been to use genetics to test
the causal relationship of adiposity and peri-
odontitis. A genetic risk score, which combined
multiple well-established genetic variants asso-
ciated with body mass index, was used as an
instrumental variable to test whether adipos-
ity caused periodontal disease. The combined
results of this analysis across many large stud-
ies showed that adiposity was not a causal
risk factor for periodontitis.35 This conclusion
is consistent with a PWAS showing pleiotro-
pic associations between obesity and chronic
periodontitis.36
Altogether, oral and systemic disease can
share a genomic connection through multi-
ple different paradigms. Understanding these
connections could lead to novel therapies,
improved risk prediction, and improved patient
outcomes.
Genetics and Clinical
Practice
The full benefit from genomic research will
only be realized when that knowledge is
brought into routine clinical practice. Although
we are not yet to the point where actionable ge-
netic information is available for use in general

dental settings, that day will eventually arrive.
Through its translational research programs,
the NIH is leading the way to ensure that the
substantial resources it is investing in genetic
research will pay practical dividends in im-
proved patient outcomes. One of the principal
mechanisms by which NIH supports trans-
lational research is through its Clinical and
Translational Science Awards program, initiat-
ed in 2006. NIH defines translational research
as follows:
Translational research includes two areas
of translation. One is the process of apply-
ing discoveries generated during research
in the laboratory, and in preclinical stud-
ies, to the development of trials and studies
in humans. The second area of translation
concerns research aimed at enhancing the
adoption of best practices in the commu-
nity. Cost-effectiveness of prevention and
treatment strategies is also an important part
of translational science.37
The goal of this program, as described by
Reis et al,38 is to “catalyze the transformation of
biomedical research at a national level, speed-
ing the discovery and development of therapies,
fostering collaboration, engaging communities,
and training succeeding generations of clinical
and translational researchers.” Over the now
more than 12 years of this program’s operation,
it has fostered major advances in genomic sci-
ence and is helping to ensure that genetics will
become central to the future of clinical practice,
including clinical dental practice.
The two areas where translational genomic
science is currently having a large impact on
clinical practice is through improved disease
prediction and through genomic targeting of
drugs in ways that optimize patient outcomes.39
Accurate prediction of the risk for future dis-
ease development allows at-risk patients to
be appropriately provided with prevention
interventions while sparing the inconvenience
and cost of such interventions for patients that
would not derive benefit. Presently, efforts to
Genetics and Clinical Practice
predict caries and periodontal disease rely
primarily on measures of social, behavioral,
and clinical parameters. Caries risk assessment
(CRA) tools include caries management by risk
assessment (CAMBRA)40 and the American
Dental Association41 risk assessment forms.
The predictive ability of CRAs tend to lack
proper validation through longitudinal stud-
ies and thus have unknown predictive value.
Another problem that limits the predictive
ability of CRAs is their failure to incorporate
genetic information in their risk model. As
noted previously, the heritability estimates for
both caries and periodontal disease suggest that
roughly 50% of the variation in disease liability
comes from genetic risk factors. But a valid
algorithmic approach to caries risk prediction
is still some ways off.
Periodontal risk predictors include the peri-
odontal risk calculator (PRC)42 and periodontal
risk assessment (PRA) model.43 Both risk pre-
dictors rely on clinically measured disease
parameters such as bone loss, pocket depth,
and bleeding and tend to suffer from similar
shortcomings as the CRAs. The PRA, however,
in its original version and through subsequent
modifications has endeavored to incorporate
genetic information, specifically by consider-
ation of interleukin (IL) 1 gene polymorphisms.
There have been some efforts to advocate for
the use of single gene markers such as IL-1
or IL-6 as the basis for treatment planning
and insurance reimbursement for periodontal
disease, but the clinical value of such a test
has been questioned.44 These single-gene tests
were developed based on science that has not
been replicated. In fact, large meta-analysis
has proven that the effects of these variants, if
any, are very small—much too small to be of
clinical utility.
Oral cancers, given their high incidence,
particularly in developing countries, and sub-
stantial morbidity and mortality attributed to
frequent late-stage diagnosis, would benefit
from early risk predictors. Although environ-
mental and behavioral risk factors (eg, tobacco,
alcohol) are considered the major determinants
307
14 Oral-Systemic Health: The Genomic Connection
of oral cancer disease liability, genetic and
epigenetic risks are under investigation45 and
may provide some additional early diagnostic
benefit. Unfortunately, the current microarray
technology is too expensive for broad-based
screening, particularly in low-income countries,
where the disease has its highest incidence.46
Pharmacogenomics is a rapidly growing
area. The US Food and Drug Administration
now provides a framework for pharmaceuti-
cal companies on their requirements around
genetic data submission. The requirements are
based on the intended use and data availability.
Presently there are several hundred drugs that
are required to provide product labeling text
regarding genetic indications or contraindica-
tions for their use. Kornman and Polverini47
reviewed the current state of the use of genetics
to stratify patients in ways that could improve
prevention and treatment of oral diseases.
As stated earlier, this review highlights that
methodologic issues—including disease mis-
classification, residual confounding, and small
sample size—prevent any clear guidance on
actionable genetic traits that would be of value
to clinicians.
Methodologic shortcomings notwithstand-
ing, given the rapid advances in genomic
science, it seems reasonable to assume that
some clinically actionable genetic informa-
tion will be available for use in routine dental
practice in the not-too-distant future. If this
information is to be fully exploited for patient
benefits, the implication is that this will neces-
sitate important changes in how we train
dentists, finance dental care, deploy relevant
technology, and ethically treat patients.
At present there is a perceived inability
for clinicians to understand and effectively
implement genetic or pharmacogenetic infor-
mation in routine patient care.48 If dentistry is
to respond to this, it will require substantial
changes to dental school curricula and con-
tinuing education offerings. This training will
need to allow dentists to develop a sophisti-
cated understanding of complex genetic data
and to have the skills necessary to meaningfully
308
discuss genetic information with their patients.
Storing and managing genetic data will require
changes in the electronic health records used
by dentists, as no electronic health records
today are equipped to store or make available
genetic information. Medicine has responded
to this challenge by deploying automated
decisions-support software that incorporates
genetic information and is designed to improve
diagnosis and treatment response. Moreover,
such stored information requires careful han-
dling as it carries substantial risk for patient
harm. If its confidentiality is not well guarded,
it could impact patient insurability and
employability. Finally, the cost-benefit ratio of
genetic testing will need to be fully documented
if insurance companies are to consider this as
part of a dental benefit plan.
The advantages of genetic research for the
routine practice of dentistry will continue to
grow and benefit dentists and patients. But
this coming wave of new genetic knowledge
requires that we start preparing for it now.
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47. Kornman KS, Polverini PJ. Clinical application of genet-
ics to guide prevention and treatment of oral diseases.
Clin Genet 2014;86:44–49.
48. Selkirk CG, Weissman SM, Anderson A, Hulick PJ.
Physicians’ preparedness for integration of genomic
and pharmacogenetic testing into practice within a major
healthcare system. Genet Test Mol Biomarkers 2013;
17:219–225.

Common Risk Factors:
The Link Between Oral and
Systemic Disease
David M. Williams, bds, msc, phd, frcpath, fds rcs (engl)
There is currently enormous interest in the
associations between oral diseases, particular-
ly dental caries and periodontal disease, and
the major noncommunicable diseases (NCDs)
such as cardiovascular disease (CVD), diabe-
tes, stroke, and cancer.1 The literature is replete
with reports of the association between these
NCDs and oral diseases, but despite extensive
research, the evidence for a causal relation-
ship between oral diseases such as periodontal
disease and systemic disease—particularly
CVD—is weak. By contrast, it is well estab-
lished that the major oral diseases and NCDs
share the same social determinants and com-
mon risk factors. Particularly important among
the latter are tobacco, alcohol, and dietary sug-
ar intake. It is imperative that all oral health
care professionals (OHCPs) understand the im-
portance of these associations because it is in
large measure based on this evidence that the
World Health Organization (WHO) has en-
couraged an integrated approach to chronic
disease prevention.2
This chapter considers the evidence that oral
and systemic disease share the same determi-
nants and common, modifiable risk factors and
makes the case that OHCPs have a significant
CHAPTER 15
role in advocating for the inclusion of oral
disease in wider strategies for the prevention
of the major NCDs that are the major kill-
ers of the 21st century. Not only will such an
approach have the potential to reduce the bur-
den of NCDs in general, but it will lead to the
more effective prevention of oral diseases and
the more cost-effective use of scarce financial
and human resources in their treatment. This
shift substantially expands the strategies and
resources available to address oral disease and
should lead to a breakdown in the unnecessary
silos that have kept oral health in a separate cat-
egory from general health. Such a transition is
also imperative because current strategies that
deal with the two most common oral diseases,
periodontal disease and caries, are focused
overwhelmingly on treatment rather than on
prevention and oral health promotion. These
approaches are too costly to remain viable,3–5
and the limitations of the traditional surgical
model of oral health care demonstrate the need
to change to an approach for the prevention
of oral diseases that will involve integrating
efforts with all health professionals to achieve
optimal oral and general health.3
311
15 Common Risk Factors: The Link Between Oral and Systemic Disease
The Challenge of the Global
Oral Disease Burden and
the Growing Problem of Oral
Health Inequality
Current approaches to improve oral health are
relatively ineffective yet very costly, and high-
income countries are facing a “dental crisis.”6
Oral and dental diseases afflict almost every-
one and leave a legacy of substantial morbidity
and functional deficits among older adults.7 Al-
though the oral health of children and young
adults has improved significantly in recent
decades,8 with falls in the prevalence of both
dental caries and periodontal disease, these
falls mask persistent inequalities. It has been
estimated that only 3% of the variation in car-
ies levels in 12-year-olds can be attributed to
dental services and that 65% is explicable on
the basis of socioeconomic factors.9 More re-
cent studies have confirmed the importance of
social determinants and environmental factors,
as exemplified by the work of Elani et al,10 who
showed that in the United States and Canada,
the overall prevalence of edentulism and untreat-
ed dental caries in adults reduced significantly
between 1970 to 1972 and 2007 to 2008. How-
ever, a persistent oral health inequality gradient
remained that was attributable to place of birth,
educational attainment, and level of income. In
the United States, the oral health of older adults,
currently one of the fastest-growing segments of
the population, “is in a state of decay.”11
From a global perspective, a more disturbing
and challenging picture of oral disease emerges,
particularly in low- and middle-income coun-
tries, with a major and growing overall bur-
den of oral disease accompanied by marked
inequalities both within and between countries.
Indeed, oral diseases constitute a “neglected
epidemic” in these countries, and rates are
increasing.12,13 The only comprehensive effort
to date to estimate global population health by
cause is the Global Burden of Diseases, Injuries,
and Risk Factors (GBD) Study, which reported
312
on 291 diseases—including oral diseases—in
21 regions. In a systematic analysis of the
global burden of oral diseases within the wider
GBD study, Marcenes et al14 reported that in
2010 oral diseases affected 3.9 billion people
worldwide. Untreated caries in the permanent
dentition was the most prevalent condition
in the entire GBD study (Table 15-1), with a
global prevalence of 35%. Additionally, severe
periodontitis in adults and untreated caries in
primary teeth were the 6th and 10th most prev-
alent conditions, respectively. The authors also
observed a 20.8% increase in the total burden
of oral disease between 1990 and 2010, attrib-
utable principally to population growth.
Not only is the prevalence of oral disease
high in relation to all other diseases, but there
are very marked inequalities in the distribution
of all major oral diseases, including oral cancer.
Figure 15-1 shows the global distribution of
dental caries, where it can be seen that there is
a gradient of prevalence with higher levels of
disease in low- and middle-income countries.
Similar gradients in disease prevalence are also
seen for periodontal disease and oral cancer.15
In addition to being highly prevalent, oral
diseases have a significant negative impact on
people’s quality of life. In children, they are the
most common causes of pain that disturb sleep
and retard growth. Caries is also responsible
for poor learning and school performance. In
adults and older people, dental pain, suffering,
and discomfort severely restrict dietary intake
and social functioning.6
From a global perspective, oral disease pre­
sents two major challenges: (1) how to address
the existing burden of disease and (2) how to
implement effective prevention that will lead
to sustainable improvements in oral health and
a reduction in oral health inequality. For the
first of these challenges, a restorative approach
is simply unsustainable. Yee and Sheiham5
have calculated that to restore one tooth per
6- to 18-year-old child would cost between
US $1,618 and US $3,513 per 1,000 children,
which is unaffordable on a global scale. Figure
15-2 is a map of the ratio between the burden
 The Challenge of the Global Oral Disease Burden and the Growing Problem of Oral Health Inequality

TABLE 15-1  |  Global prevalence of oral conditions in 2010 by sex

Overall Men Women
Rank Condition n° % n° % n° %

1 Untreated caries of 2,431,636 35.29 1,194,051 34.37 1,237,585 36.23

permanent teeth

2 Tension-type headache 1,431,067 20.77 655,937 18.88 775,131 22.69

3 Migraine 1,012,944 14.70 371,072 10.68 641,873 18.79

4 Fungal skin disease 985,457 14.30 516,167 14.86 469,291 13.74

5 Other skin and 803,597 11.66 417,129 12.01 386,468 11.32

subcutaneous diseases

6 Severe periodontitis 743,187 10.79 378,407 10.89 364,780 10.68

7 Mild hearing loss 724,689 10.52 386,147 11.11 338,543 9.91

8 Acne vulgaris 646,488 9.38 311,349 8.96 335,140 9.81

9 Low back pain 632,045 9.17 334,793 9.64 297,252 8.7

10 Untreated caries of 621,507 9.02 352,085 10.13 269,421 7.89

primary teeth

36 Severe tooth loss 158,284 2.3 67,264 1.94 91,020 2.66

°Numbers of cases reported in thousands. (Adapted from Marcenes et al14 with permission.)

ICELAND
TOOTH DECAY
WORLDWIDE
SWEDEN FINLAND
NORWAY

ESTONIA Average number

LATVIA
LITHUANIA of decayed (D), missing (M),
DENMARK
IRELAND
UK and filled (F) teeth (T)
NETH. BELARUS
GERMANY
POLAND
in 12-year-olds
BELGIUM UKRAINE RUSSI A
C A N A D A
LUX.
CZECH
REP. SLOVAKIA latest available data
MOLDOVA
FRANCE SWITZ. AUSTRIA HUNGARY
SLOV. ROMANIA
1994–2014
CROATIA B-H
BULGARIA
PORTUGAL
MONT. more than 3.5 high
ALBANIA FYROM
MONGOLIA
SPAIN
ITALY 2.6 – 3.5 moderate
U S A GREECE
UZBEK. JA PAN 1.2 – 2.5 low
TURKEY SOUTH
KOREA

MALTA
CYPRUS SYRIA C H I N A 0.0 – 1.1 very low
LEBANON IRAQ
MOROCCO TUNISIA ISRAEL I RA N
JORDAN
KUWAIT
no data
PAKIS TAN BHUTAN
MEXICO BAHAMAS
L I B YA BAHRAIN
NEPAL
CAYMAN IS. CUBA DOMINICAN QATAR Macau SAR
EGYPT UAE
REP.
BANGLADESH HK SAR
JAMAICA PUERTO RICO SAUDI ARABIA INDIA KIRIB ATI
HAITI ANGUILLA LAOS
BELIZE OMAN MYANMAR
ANTIGUA & BARBUDA VIET NAM TUVALU
GUATEMALA ST KITTS & NEVIS
HONDURAS DOMINICA
SENEGAL NIGER SUDAN ERITREA YEMEN
THAILAND TOKELAU
EL SALVADOR ST LUCIA PHILIPPINES
NICARAGUA GRENADA GAMBIA
BARBADOS BURKINA
FASO CAMBODIA
COSTA RICA TRINIDAD & TOBAGO SAMOA
B ENI N

NIGERIA
GHANA

VENEZUELA C‘TE
PANAMA GUYANA SOUTH ETHIOPIA SRI LANKA
DíIVOIRE
SURINAME SUDAN BRUNEI VANUATU
COLOMBIA
MALAYS I A FIJI
UGANDA
COOK ISLANDS
SINGAPORE
ECUADOR KENYA NIUE
GABON
TONGA
SEYCHELLES
PAPUA
PERU TANZANIA I N D O N E S I A NEW
GUINEA FRENCH POLYNESIA
BRAZIL
SOLOMON
ISLANDS

BOLIVIA
NAMIBIA
PARAGUAY MOZAMBIQUE
CHILE

SWAZILAND AUSTRALI A
SOUTH
AFRICA
URUGUAY

NEW
ZEALAND

From The
From The Challenge
ChallengeofofOral
OralDisease
Disease—A callforforglobal
– A call globalaction
actionbybyFDI
FDIWorld
WorldDental
DentalFederation.
Federation.
Maps and
Maps and graphics
graphics©©Myriad
MyriadEditions
Editions2015
2015

Fig 15-1  |  Global inequalities in the prevalence of dental caries. (Reprinted from FDI World Dental Federation15
with permission.)

313
15 Common Risk Factors: The Link Between Oral and Systemic Disease

ICELAND THE BURDEN OF

NORWAY
SWEDEN FINLAND
DISEASE/PROVIDER RATIO
ESTONIA The ratio between burden of
LATVIA
LITHUANIA
oral disease in DALYs
DENMARK
IRELAND
UK and number of oral health
NETH.
GERMANY
POLAND
BELARUS
personnel per country
BELGIUM UKRAINE
CZECH
SLOVAKIA
LUX.
REP.
HUNGARY
MOLDOVA
RUSSI A
highest ratio 500 or more
FRANCE SWITZ. AUSTRIA
SLOV. ROMANIA
CROATIA SERBIA 100 – 499
BULGARIA
MONT. KOSOVO
PORTUGALANDORRA
CA NADA FYROM 20 – 99
SPAIN
ITALY KAZAKHSTAN
GREECE MONGOLIA 2 – 19
U S A
AZERBAIJAN
UZBEK. KYRGYZSTAN JA PAN lowest ratio 2 or less
TURKEY ARMENIA TURKMEN.
TAJIKIS TAN
CYPRUS SYRIA
no data
MALTA
CHIN A
LEBANON IRAQ AFGHANISTAN
MOROCCO TUNISIA ISRAEL I R AN
JORDAN
KUWAIT PAKIS TAN BHUTAN
BAHAMAS NEPAL
ALGERIA LIBYA BAHRAIN QATAR
MEXICO CUBA
EGYPT UAE MARSHALL ISLANDS
DOMINICAN
JAMAICA REP. BANGLADESH
HAITI SAUDI ARABIA LAOS
BELIZE CAPE IN DI A MYANMAR KIRIB ATI
ANTIGUA & BARBUDA VERDE MAURITANIA MALI
OMAN
GUATEMALA HONDURAS DOMINICA NIGER SUDAN THAILAND
EL SALVADOR SENEGAL CHAD ERITREA YEMEN
NICARAGUA GRENADA GAMBIA PHILIPPINES
BARBADOS BURKINA
FASO DJIBOUTI CAMBODIA
TRINIDAD & TOBAGO GUINEA-
COSTA RICA
BISSAU GUINEA

B ENI N
SAMOA
GHANA
VENEZUELA NIGERIA
TOGO
PANAMA GUYANA CÔTE ETHIOPIA
SIERRA LEONE D’IVOIRE CENTRAL SRI LANKA
SURINAME AFRICAN REP. BRUNEI
COLOMBIA LIBERIA VANUATU
MALDIVES
EQUATORIAL CAMEROON SOMALIA MALAYSIA FIJI
GUINEA UGANDA
KENYA SINGAPORE
ECUADOR GABON
SÃO TOME DEM. REP. RWANDA
& PRINCIPE CONGO OF CONGO BURUNDI SEYCHELLES TONGA
PAPUA
PERU TANZANIA I N D O N E S I A NEW
GUINEA SOLOMON
BR A Z I L COMOROS ISLANDS
ANGOLA EAST TIMOR

ZAMBIA

BOLIVIA MAURITIUS
ZIMBABWE MADAGASCAR
NAMIBIA
BOTSWANA
PARAGUAY MOZAMBIQUE
CHILE
SWAZILAND AUSTRALI A
LESOTHO
URUGUAY

ARGENTINA

NEW
ZEALAND
From The Challenge of Oral Disease – A call for global action by FDI World Dental Federation.
From The Challenge of Oral Disease—A call for global action by FDI World Dental Federation.
Maps and graphics © Myriad Editions 2015
Maps and graphics © Myriad Editions 2015

Fig 15-2  |  Inequalities in the global distribution of oral health personnel: The burden of disease/provider ratio.
DALYs, disability-adjusted life years. (Reprinted from FDI World Dental Federation15 with permission.)

of disease in disability-adjusted life years and responsible. The understanding exists to

the number of oral health personnel by coun- prevent a very large proportion of oral dis-
try. This shows very clearly that in low- and eases, and community-based prevention
middle-income countries there is a major dis- generally is cost-saving compared with
proportion between the availability of personnel a treatment-focused approach, particularly
and the burden of disease. From this it is clear for communities and individuals at high risk
that a traditional high-income country model for disease.
of dental care, such as that seen in the United
States and Europe, is completely inappropriate It is clear that current approaches to pre-
to address the challenge of poor oral health. vention have not been effective at a global
Even if it were appropriate, financial constraints level, and it is imperative to understand the
in low- and middle-income countries mean that reasons for this and develop strategies that
there is no realistic prospect of addressing this could deliver effective disease prevention
human resource challenge in the short term. and sustainable improvements in oral health
This means that if the current burden of oral worldwide. In this regard, there are important
disease is to be managed effectively, particularly lessons to be learned from addressing the asso-
in low- and middle-income countries, very dif- ciations between oral and systemic disease and
ferent models of care will be required. understanding whether the approaches pro-
In a critique of the US dental care system, posed to reduce the global burden of NCDs
Tomar and Cohen16 summed up the situation could also result in improvements in global
worldwide thus: oral health.
However, it is not enough for oral health
A system focused primarily on treatment of professionals simply to observe the associations
disease in individuals is not economically between oral and systemic disease. As Garcia
sustainable, socially desirable, or ethically and Tabak17 have so presciently stated:

314
 Intervening to Improve Oral Health: The Common Risk Factor Approach

Fig 15-3 |  Downstream to up-

National and/or local policy initiatives stream: Options for oral disease
Legislation/regulation prevention. (Reprinted from Watt19
Fiscal measures
with permission.)
Upstream healthy
public policy Healthy settings–HPS
Community development
Training other professional groups
Media campaigns
School dental health education
Chairside dental health education
Downstream health Clinical prevention
education and
clinical prevention

Tackling global oral health inequalities will
require creativity, diligence and a strong
commitment to partner with the many play-
ers involved in global health. These include
research institutions, institutions of higher
education, private and public organizations,
professional associations, health officials,
corporations and foundations that promote
health. The oral health community must ‘be
at the table’ with these and other partners,
be willing to frame oral health needs in the
context of overall health, and develop clearly
articulated objectives driven by strong evi-
dence of the burden posed by oral diseases
and conditions. […] The oral health com-
munity needs to become more integrated
with the broader family of global health.
As a discipline, oral health has evolved
from the one-dimensional understanding of
health and disease to a more comprehensive
view. Individual risk and susceptibility to
oral diseases can no longer be understood
in isolation, but as part of a complex set of
influences that include individual, family,
community or neighborhood characteristics,
and health system factors. This broad con-
ceptual framework of oral health facilitates
interactions with other health professions
and with other sectors including education
and social services. Framing oral health as a
vital part of overall health will enable the in-
tegration of oral health as part of a broader
global health agenda that includes for exam-
ple, tobacco and alcohol control, clean water
and sanitation, maternal and child health,
and health systems research.
The evidence presented in this section sets
out the scale of the oral disease challenge that
all countries face, and it is clear from this that
the burden of disease falls disproportionately
on those countries least able to respond. The
sections that follow consider strategies to
reduce both the overall burden of disease and
the unjust inequalities in oral health.
Intervening to Improve Oral
Health: The Common Risk
Factor Approach
The failure of most approaches to improve
oral health and reduce inequalities in oral
health were cogently summed up by Kwan
and Petersen18:
Measures that focus on downstream factors
(Fig 15-3) only, such as lifestyle and behav-
ioral influences, may have limited success in
reducing oral health inequities. … Such ap-
proaches may be counterproductive as they
are often ineffective and costly and fail to

315
15 Common Risk Factors: The Link Between Oral and Systemic Disease
, (Reprinted from Whitehead and Dahlgren20 with
Poverty
Work
Unemployment
Tobacco Alcohol
Nutrition
Sugar
Education
address the wider social determinants that
cause people to get ill in the first place. Peo-
ple in more privileged social positions tend to
benefit from interventions more than those
in disadvantaged groups. Hence, inappropri-
ate interventions can widen inequities. It is
necessary to address the root causes, tackling
social determinants and the environment.
The social determinants of health are the cir-
cumstances into which people are born, grow,
live, work, and age (Fig 15-4). These circum-
stances, which largely determine the behaviors
people adopt and the choices they make, are
in turn shaped by a wider set of forces: eco-
nomics, social policies, education, politics,
and many more. The unequal distribution
of all these determining factors accounts for
the persisting and growing global differences
in health status and disease burden.20 These
inequalities in general and in oral health within
and between populations pose significant chal-
lenges for policy­makers and those in public
health.15
A major reason that oral diseases remain
a global problem is the absence of rational,
sustained, interlinked, multitargeted policies
directed at the proximal causes of dental caries
and periodontal disease and the determinants
of those causes. Increases in the numbers of
316
Fig 15-4 |  The social determinants of health.
permission.)
Water
Sanitation
Housing
Diet
Health care
decayed, missing, and filled teeth with age
result from dental caries caused by sugars and
periodontal disease associated with inadequate
oral hygiene and smoking.21–24 Consequently,
the priorities for oral disease prevention should
include controlling dietary sugar intake and
tobacco use and making healthy choices the
easier choices.25 These shared risk factors (Fig
15-5) provide the conceptual basis for the com-
mon risk factor approach (CRFA),26 which is
one of the most important concepts for oral
disease prevention. At the same time, it paves
the way for the close integration of oral health
into strategies addressing NCDs.
The key concept underlying the CRFA is that
controlling a small number of important clus-
tered risk factors should have a major impact on
a number of common chronic diseases, includ-
ing oral conditions, at a lower cost than narrow
disease-specific approaches.26–28 Interventions
to prevent NCDs on a population-wide basis
are not only achievable but also cost-effective.29
The WHO Global Strategy for Control of
NCDs stated: “We know what works, we know
what it costs, and we know that all countries
are at risk. We have an Action Plan to avert
millions of premature deaths and help promote
a better quality of life for millions more.” 29
Emphasis should therefore be on directing
actions at shared behavioral risks common
 Intervening to Improve Oral Health: The Common Risk Factor Approach

Tooth decay
Unhealthy
Tobacco
diet use
Periodontal disease

Stress Oral trauma Alcohol

Diabetes

Obesity

Lack of control Cancers

Lack of exercise

Cardiovascular disease

Respiratory disease

Poor hygiene From The Challenge of Oral Disease—A call for global action by FDI World Dental Federation. Injuries
Maps and graphics © Myriad Editions 2015

Fig 15-5  |  Common risk factors and their importance for oral health. (Reprinted from FDI World Dental Feder-
ation15 with permission.)

to NCDs.30 Such an approach would expand
the roles of oral health professionals and
strengthen collaborative linkages with other
professional cadres.31,32
Another reason why oral diseases remain
a major global problem is the dependence
on individualized “high-risk” approaches to
prevention and health education.19,33,34 These
approaches divert limited resources away from
upstream healthy public policies and blame
the victim35; they produce a lifestyle approach
to health policy instead of a social policy
approach to healthy lifestyles and overlook
the way behaviors are generated and struc-
turally maintained.36 Upstream interventions
are those directed at the proximal causes of
disease and operate at national and local lev-
els. National-level actions include encouraging
stronger legislation on food labeling and health
claims on products, supporting legislation on
water fluoridation, and supporting food and
nutrition standards for school meals and other
food and drink sold in schools. Examples of
local interventions include encouraging schools
to become part of the Health Promoting
Schools Network,37 encouraging commu-
nity action groups to engage in oral health
projects, and supporting the development of
local infant feeding policies that include oral
health messages19 (see Fig 15-3). Downstream
interventions operate at the individual level
and include such measures as chairside oral
health education and tertiary prevention.19
These latter interventions are of limited effec-
tiveness and are costly,36 so a shift is required
away from downstream efforts toward a more
appropriate whole-population upstream public
health approach to health policy. In general,
dentists principally work downstream or mid-
stream, but they do not address the upstream

317
15 Common Risk Factors: The Link Between Oral and Systemic Disease

From The Challenge of Oral Disease—A call for global action by FDI World Dental Federation.
Maps and graphics © Myriad Editions 2015

Fig 15-6  |  The global impact of NCDs. (Reprinted from FDI World Dental Federation15 with permission.)

determinants of oral disease. More effort of 56 million deaths worldwide, with nearly
needs to be focused on the upstream forces 75% of these NCD-related deaths occurring
that cause disease in the first place. Refocus- in low- and middle-income countries. They are
ing efforts upstream requires a healthy public now the major cause of premature death, with
policy approach that involves national and the overwhelming majority of these early deaths
local initiatives, legislation, fiscal measures, and occurring in low and middle-income countries
community development to increase healthy (Fig 15-6). In 2013, the WHO asserted:
settings.
Most of these premature deaths from NCDs
are largely preventable by enabling health
Systemic Disease: The systems to respond more effectively and eq-
uitably to the health-care needs of people
Growing Challenge of NCDs with NCDs, and influencing public policies
in sectors outside health that tackle shared
While deaths due to infectious diseases are de- risk factors—namely tobacco use, unhealthy
clining, NCDs are increasing and have now diet, physical inactivity, and the harmful use
become the leading cause of death and disabil- of alcohol.29
ity worldwide. The most significant of these in
terms of prevalence and severity are cancers, In 2014, the WHO stated that “the human,
CVD, chronic respiratory diseases, and diabe- social and economic consequences of NCDs
tes.1 In 2012, they accounted for 38 million out are felt by all countries but are particularly

318
 The WHO Global Action Plan for the Prevention and Control of NCDs 2013 to 2020
devastating in poor and vulnerable popula-
tions. Reducing the global burden of NCDs
is an overriding priority and a necessary con-
dition for sustainable development.”1 A key
entry point for the inclusion of oral disease
within the context of the wider agenda for the
prevention and control of NCDs arose from
a 2011 meeting of the General Assembly of
the United Nations.38 Addressing the threat
of NCDs, the United Nations recognized that
they “undermine social and economic devel-
opment throughout the world, and threaten
the achievement of internationally agreed
development goals.”38 The role of common
risk factors and social determinants in the
etiology of NCDs was acknowledged, and
the high-level declaration that followed the
meeting also stated “that renal, oral and eye
diseases pose a major health burden for many
countries and that these diseases share com-
mon risk factors and can benefit from common
responses to non-communicable diseases.”38
This single sentence in the declaration was a
highly significant recognition at the highest
policy level of the need for an NCD strategy
that includes oral disease.
The integration of oral and general health
should be the cornerstone of policy approaches
to improve prevention and control of oral dis-
eases, as was acknowledged in the Oral Health
Action Plan adopted by the 60th World Health
Assembly in 2007.2 This plan emphasizes “the
intrinsic link between oral health, general
health and quality of life” and identifies “the
need to incorporate programmes for promo-
tion of oral health and prevention of oral
diseases into programmes for the integrated
prevention and treatment of chronic diseases.”2
In the same document, the Ministers of Health
call for the creation of innovative workforce
models to integrate essential oral health care
into primary health care.2 This is also one of the
key strategies set out in FDI’s Vision 20203 and
is developed further later in this chapter (see
“Taking Action on Common Risk Factors and
the Social Determinants of Health”).
The WHO Global Action
Plan for the Prevention and
Control of NCDs 2013 to 2020
The stated goal of the WHO Global Action
Plan for the Prevention and Control of NCDs
2013–2020 published in 2013 is the following:
To reduce the preventable and avoidable bur-
den of morbidity, mortality and disability
due to noncommunicable diseases by means
of multisectoral collaboration and coopera-
tion at national, regional and global levels,
so that populations reach the highest attain-
able standards of health and productivity at
every age and those diseases are no longer
a barrier to well-being or socioeconomic
development.29
The key objectives of the action plan are
to raise the priority accorded to prevention
and control of NCDs in global, regional, and
national agendas; strengthen national capacity,
leadership, governance, multisectoral action,
and partnerships to accelerate country response
for the prevention and control on NCDs; reduce
modifiable risk factors for NCDs and under-
lying social determinants through creation of
health-promoting environments; strengthen
and orient health systems to address the preven-
tion and control on NCDs and the underlying
social determinants through people-centered
primary health care and universal health cover-
age; promote and support national capacity for
high-quality research and development for the
prevention and control on NCDs; and monitor
trends and determinants of NCDs and evaluate
progress in their prevention.29 A high priority
for all oral health professionals is to ensure that
all NCD action plans also address the global
burden of oral disease. This issue is addressed
in more detail later in this chapter (see “Oral
Health in All Policies”).
319
15 Common Risk Factors: The Link Between Oral and Systemic Disease
The Associations Between
Oral Diseases and NCDs:
Making the Case for an
Integrated Strategy
The importance of tobacco use, unhealthy
diet, physical inactivity, and the harmful use
of alcohol as common risk factors for CVD,
cancers, respiratory disease, and diabetes29 has
already been discussed (see “Systemic Disease:
The Growing Challenge of NCDs”), and the
role of these same risk factors in the etiology
of oral diseases is also the basis of the CRFA
discussed previously (see “Intervening to Im-
prove Oral Health: The Common Risk Factor
Approach”). Thus, it is not surprising that there
are associations of varying strength between
oral diseases and NCDs, as shown in Fig 15-5.
For example, there is high-level evidence that
individuals with periodontitis have a signifi-
cantly higher risk of various other problems,
including CVD, diabetes mellitus, respirato-
ry disease, and preterm delivery of low–birth
weight babies,39 but the evidence for these as-
sociations is of variable strength. There is also
intense debate in the literature as to whether
these associations are indicative of causal re-
lationships between oral and systemic disease.
This matter is addressed in detail in other chap-
ters in this publication.
There is good evidence from epidemiologic
studies for a moderate, positive association
between periodontal diseases and CVD,40
and evidence from systematic reviews with
meta-analyses indicates that patients with
chronic periodontal disease are at increased
risk of developing coronary heart disease41
and carotid atherosclerosis.42 This has led to
speculation about plausible biologic mecha-
nisms to implicate periodontal disease in the
etiology of CVD.43 However, in spite of intense
research, there is insufficient evidence for a
causal relationship between periodontal disease
and CVD.44,45 By contrast, it is well established
that the most important behavioral risk factors
320
for heart disease and stroke are unhealthy diet,
physical inactivity, tobacco use, and harmful
use of alcohol.46 This is the basis for the WHO
recommendation for the cessation of tobacco
use, reduction of salt in the diet, consump-
tion of fruits and vegetables, regular physical
activity, and avoiding harmful use of alcohol
to reduce the risk of CVD.
The relationship between diabetes and oral
diseases, particularly periodontal disease, has
been the subject of intense research. For exam-
ple, there is good evidence from meta-analyses
that type 2 diabetes is a risk factor for peri-
odontal disease.47,48 Furthermore, a separate
meta-analysis has shown that while diabetic
patients had the same prevalence of periodon-
tal disease as nondiabetic patients, this was of
significantly higher severity in the former.49
Over the last 20 years, consistent and robust
evidence has emerged that severe periodontitis
adversely affects glycemic control in patients
with diabetes and glycemia in patients without
diabetes. In diabetic patients, there is a direct
and dose-dependent relationship between
periodontitis severity and diabetes complica-
tions. Emerging evidence supports an increased
risk for diabetes onset in patients with severe
periodontitis.50 While there is some evidence
suggesting that periodontal disease adversely
affects diabetes outcomes, further longitudi-
nal studies are needed to test this assertion.
However, it is reasonable to conclude on the
basis of current evidence that patients should
be encouraged to adopt a healthy lifestyle to
reduce the risk of developing diabetes, one of
the complications of which is severe periodon-
tal disease. The presence of severe periodontal
disease should alert the oral health practitioner
to the possibility that the patient may have
undiagnosed diabetes. To this end, Chapple et
al50 have recommended that, given the current
evidence, it is timely to provide guidelines for
periodontal care in diabetic patients for medical
and dental professionals as well as recom-
mendations for patients and the public. These
guidelines include the specific recommendation
that patients who present without a diabetes
Taking Action on Common Risk Factors and the Social Determinants of Health: An Integrated Strategy for Oral Health
diagnosis but with obvious risk factors for type
2 diabetes and signs of periodontitis should be
informed about their risk for having diabetes,
assessed using a chairside hemoglobin A1c test,
and/or referred to a physician for appropriate
diagnostic testing and follow-up care.
In addition to the associations discussed
previously, there is also evidence for associa-
tions of varying strength between periodontitis
and caries with respiratory disease, particu-
larly chronic obstructive pulmonary disease
(COPD).51 In light of the foregoing discussion
about periodontal disease, it is important to
note that the most significant risk factor for the
development of COPD is cigarette smoking,52
with case-control studies also pointing to an
increased risk associated with passive smoking.
To summarize the evidence presented in
this section, there are associations of varying
strength between oral disease and NCDs, partic-
ularly diabetes and CVD. There is also evidence
for the importance of CRFA in these associa-
tions, to which should be added the importance
of tobacco and alcohol use as risk factors for
oropharyngeal cancer and other body-site can-
cers.15 The effects of common risk factors and
the social determinants of health are cumulative
over the life course, so many of the reported
associations occur in middle-aged and older
adults as the prevalence of NCDs increases.
The long latent period between initial expo-
sure and the development of frank clinical
disease means that intervention studies are
difficult to conduct, but there is good reason
to believe that upstream interventions directed
at reducing the effects of common risk factors
are effective. The most notable example is the
success of actions directed at reducing pre-
mature mortality due to CVD. The aging and
growth of populations has led to an increase
in the total number of cardiovascular deaths,
which accounted for almost one-third of all
deaths globally in 2013. However, while the
overall number of deaths has risen between
1990 and 2013, age-standardized death rates
for cardiovascular and circulatory diseases have
fallen in high-income and many middle-income
countries since 1990. Rapid decreases have
occurred in some countries. For example, five
countries (Israel, Denmark, Norway, South
Korea, and the United Kingdom) had at least
a 65% decrease in age-standardized death
rates for ischemic heart disease. Many other
countries have had decreases of 40% to 65%.53
These decreases coincide with the introduction
of policies to reduce exposure to risk factors for
CVD, specifically the cessation of tobacco use,
reduction of salt in the diet, increased consump-
tion of fruits and vegetables, regular physical
activity, and avoiding harmful use of alcohol.
The key conclusions arising from this sec-
tion are that actions to reduce the burden of
NCDs—including oral diseases—should (1)
address the common risk factors and the social
determinants of health, (2) be implemented
early in the life course, and (3) be directed
at upstream interventions operating at the
level of national policies, and they need to be
integrated.
Taking Action on Common
Risk Factors and the Social
Determinants of Health: An
Integrated Strategy for Oral
Health
A new model for oral health promotion is need-
ed.3,54 The traditional “vertical” approach to
public health, where individual diseases are ad-
dressed in isolation, should be replaced by the
“horizontal” approach that addresses a num-
ber of diseases at the same time and uses the
CRFA.55 Intersectoral action is necessary at all
stages of policy formulation and implementa-
tion because the major determinants of chronic
disease lie outside the health sector. Hence, pol-
icies and plans should focus on the common
risk factors and cut across specific diseases.
They should be population-wide, with indi-
vidual interventions being integrated with the
321
15 Common Risk Factors: The Link Between Oral and Systemic Disease

Box 15-1  |  Taking action on oral health equity: Things the oral health team should do

1. All members of the oral health team should acquire a thorough understanding of the importance that social
determinants play in oral as well as general health. They should have a thorough understanding of how the con-
ditions in which people are born, live, work, and age can affect their health and how they can act to tackle these.
2. Dentists and the oral health team should engage in partnership with communities to help them better understand
and tackle the social, economic, and environmental factors that determine oral health and increase inequalities.
3. Dentists and the oral health team should engage with colleagues such as primary health care professionals in
the development of cross-sectoral partnerships so that oral health promotion strategies become incorporated
into all strategies for health.
4. Dentists should become advocates for health, particularly oral health, with their patients and the wider community.
This should include an emphasis on acting as enablers, helping to make healthy choices the easier choices and
empowering people to take control of their own lives and health.

(Based on Williams et al.58 )

population approaches.56 If behaviors are to
change, the environment that predisposes people
to adopt health-compromising behaviors must
also be addressed. Health promotion to improve
social and physical environments supportive of
health is pivotal to improving health and should
redress the balance of influences away from pre-
scription to make healthier choices easier and
facilitate decision-making skills. This includes
combatting the upstream influences of those
who produce and profit from ill health and
points to a requirement for greater regulation
of the food, drink, and tobacco industries.
Integrated policy action across individual,
community, and societal intervention levels,
as well as across the life course, are needed
to tackle complex health problems such as
obesity, CVD, and caries effectively and to
reduce health inequalities.57 While it is clear
that physicians and other health professionals
have a role in promoting health equity, dental
teams are in an important position to actively
engage in promoting oral health equity, both
for their patients and the wider community58
(Box 15-1).
Given the close links between oral health
and other indicators such as family income
and educational attainment of children and
parents, a whole-systems approach to improv-
ing oral health in the context of general health
is required. Some of the principles that must
underpin action include the following:
• Tailoring the response to the level of oral
and general health need
• Building on community assets and
strengthening family competence to
self-manage health, including oral health
• Emphasizing the early years and early
intervention
• A family focus
• A personalized approach to delivering
services
All primary health care professionals should
tackle the needs of families in the context of
the environment and their experience. There is
a fundamental need to integrate initiatives to
improve oral health with more general inter-
ventions to support good physical and mental
health. Primary care is the first point of con-
tact with the health service and is the setting
in which most care—both general and oral—
is provided. Oral health teams, collaborating
with primary care teams, have the largely
unexploited potential to be important advo-
cates, enablers, and mediators for oral health.
Because the risk factors for oral and general
health are the same, such activities will also
promote good general health.

322

Primary medical care is increasingly appre-
ciating the pivotal importance of social
determinants in influencing health status and
health outcomes. If oral health care is to be
properly integrated with health care in general,
it is essential that all members of the oral health
team understand the importance of the social
determinants of oral health and integrate their
activities with other groups.
Oral Health in All Policies
Because oral diseases share social determinants,
common risk factors, and biologic pathways
with other NCDs, oral health belongs in a
“Health in All Policies” (HiAP) approach.59 This
integrative approach will require high-level pol-
icy initiatives that lead to an “Oral Health in All
Policies” (OHiAP) concept. The WHO Consti-
tution60 acknowledges that “enjoyment of the
highest attainable standard of health is one of
the fundamental rights of every human being,”
and the WHO Adelaide Statement on Health in
All Policies61 advocated for an HiAP approach
as an important strategy to advance this human
right. The acknowledgment of oral health as a
serious threat to overall health and well-being
and understanding that many oral disease share
common risk factors and biologic pathways
with other NCDs legitimizes the inclusion of
oral health in an HiAP approach and could
lead to new intersectoral partnerships and, as
suggested by Meier et al,62 shift the focus in
oral health from one of technical interventions
toward one based on social justice and consid-
eration of the social determinants of health. This
shift substantially expands the strategies and
resources available to address oral disease and
will lead to a breakdown in the artificial silos
that have for too long maintained oral health in
a separate category from general health policy.
Achieving parity in policy and full integra-
tion of oral health necessitates substantial
modifications of national (dental and non-
dental) health care delivery systems, which
Oral Health Professionals as Advocates for Oral Health
are often highly invested in the status quo and
resistant to change. Moreover, adding oral
health concerns to already overtaxed public
health and primary care systems requires a
redistribution of resources that needs to be
driven by a sustained political will. The exam-
ple of the US legislative battles to achieve
parity for mental health services gives reason
for optimism. As Hernandez and Uggen63 have
shown, important policy changes that include
integration of services and the redistribution
of scarce resources can be achieved, even when
organized resistance to policy change is wide-
spread and neoliberal ideology predominates.
But policy change depends on a well-organized
and consistent advocacy message from various
stakeholders who have the stability to sustain
their messaging throughout a policy-change
process that may take decades to achieve.
Oral Health Professionals as
Advocates for Oral Health
Oral health professionals have opportunities
to become strong advocates for upstream pol-
icy changes that can reduce health-harming
social conditions and close the inequality
gap in disease by working collectively at the
community and national levels through their
professional dental organizations. This is not
a role generally embraced by oral health pro-
fessionals, but national dental organizations
have it within their power to make their voic-
es heard and become advocates for policies
that will address these inequalities effectively.
Leaders within the dental profession need to
improve understanding among their members
of the central role that social determinants of
health play in creating these persistent inequal-
ities in oral disease. By shifting the policy focus
toward common risk factor reduction and up-
stream interventions, the dental profession can
significantly expand their alliances with other
chronic disease stakeholders and leverage that
collective influence as they seek to reduce sugar
323
15 Common Risk Factors: The Link Between Oral and Systemic Disease

Box 15-2  |  Recommendations on integrating oral health into the NCD agenda

• Improve access to health services and ensure more supportive social conditions for disadvantaged groups to
reduce social inequities.
• Adopt both an HiAP and OHiAP approach to minimize and manage risks to oral health, general health, and health
equity arising from policies in other sectors.
• Implement cost-effective evidence-based population-wide oral health promotion measures as a way of protecting
overall health and well-being.
• Strengthen interprofessional collaboration between oral health and other health professionals to improve prevention
and management of comorbidities, for example through shared health records.
• Include oral health in curricula for other health care professionals and ensure that oral health care professional
education addresses associated diseases and interdisciplinary care.
• In low and middle-income countries, integrate oral and NCD care into current programs, such as those for HIV/
AIDS, to improve collaboration and capitalize on existing systems.
• Integrate oral and NCD care into broader efforts to achieve universal health coverage.
• Include oral health and NCD workforce planning in overall planning for human resources for health.
• Strengthen health care professional education and collaboration to ensure that oral disease and NCD risks are
appropriately considered in maternal and pediatric care.
• Implement community-based initiatives, such as school education programs, to promote healthy behaviors from
an early age.
• Ensure healthy environments for children, for example through banning sugar-sweetened beverages and unhealthy
snacks in schools and ensuring that healthy food is available.
• Systematically include oral disease and NCD surveillance in epidemiologic monitoring, including surveillance of
common modifiable risk factors.
• Promote research into effective interventions for oral health and NCDs, focusing on what works in the area of
social and behavioral interventions to tackle the common modifiable risk factors.
• Integrate oral health perspectives into national NCD action plans and other relevant NCD governance mechanisms.
• Fully integrate oral health into sustainable development goals strategies and monitoring frameworks.

(Based on the policy brief from the FDI World Dental Federation and the NCD Alliance.64 )

consumption, increase access to healthy diets,
reduce tobacco and excessive alcohol consump-
tion, and address the other risk factors that
contribute to inequalities in oral and gener-
al health. Advocating for common risk factor
reduction and upstream interventions will al-
low dentistry to take part in championing the
value of health equity, create clarity of goals,
and further integrate oral health into general
health at all levels.
Consistent with the principle of integration
that runs throughout this chapter, if the oral
health community is to be effective in its advo-
cacy efforts, then it will be essential to develop
strategic partnerships with those engaged in
action against NCDs in general. Arguably the
most effective organization engaged in this
regard is the NCD Alliance. Founded in 2009,
the NCD Alliance is a network uniting 2,000
civil society organizations in more than 170
countries with the mission to combat the NCD
epidemic by putting health at the center of all
policies. Strategic partners include the United
Nations, WHO, and governments, and the
long-term goals of the organization are aligned
with the WHO Global Action Plan for the Pre-
vention and Control of NCDs 2013–2030.28
The FDI World Dental Federation has taken a
lead among dental organizations in joining the
NCD Alliance, and the most tangible output
from this partnership has been the publica-
tion of a joint FDI/NCD Alliance policy brief
titled “Accelerating Action on Oral Health and
NCDs: Achieving an Integrated Response.”64
This policy brief makes a number of practical
recommendations for action (Box 15-2) that
are consistent with the goals discussed else-
where in this chapter.

324

The Care Team:
Interprofessional Education
and Collaboration
The current training, service provision, and dis-
tribution of dental care teams responsible for
the delivery of the majority of clinical dental
services do not adequately address the needs of
most populations.6 Therefore, a change is re-
quired, and a first step is to change the existing
education model for oral health professionals
and give equal emphasis to preventive services
and risk reduction through use of a chronic
disease management approach. Risk reduction
through such a medical management ap-
proach to chronic diseases such as caries and
periodontal disease should provide immediate
improvements in patient outcomes while reduc-
ing costs. However, this will only happen if it is
accompanied by changes in the way dentists and
other oral health professionals are remunerated.
We need to move away from procedure-based
reimbursement and toward value-based
models that reward improvements in individu-
al- and population-level health status.
A second step is the expansion and integra-
tion of the dental care delivery system into
the broader general medical care infrastruc-
ture. Incorporating oral health services into
primary health care will improve access and
provide better coordination of overall health
care. To facilitate the necessary conceptual
change requires acknowledgement by schools
educating non–oral health care professionals
that oral health is integral to overall health.
Their curricula should change in line with
WHO recommendations on “Transforming
and Scaling Up Health Professionals’ Educa-
tion and Training,”65 with the goal of creating
an “Oral Health in All Training” approach
across all health professional education.
Oral health professionals can improve their
ability to contribute to the overall health care
mission by playing a stronger role in overall
health management through greater integration
Conclusion
into primary health care.66 Furthermore, in
their role as clinical service providers, they need
to adapt the chronic care model for manage-
ment of oral disease67 to that used for other
chronic systemic diseases. Thus, there needs
to be widespread implementation of health
promotion efforts that improve the ability of
patients to manage their own health.
Full implementation of the provision of
oral health services throughout the primary
care system will require changes in the over-
all care delivery infrastructure. The chronic
care model also emphasizes the provision of
clinical services that are evidence-based and
cost-effective. As stated earlier, a new model
for oral health promotion is needed3,54—one
that considers oral health as an integral part
of general health, addresses the needs and
demands of populations, and includes an
integrated upstream public health approach,
moving health from an individual lifestyle
choice model to one that tackles the social
determinants of chronic diseases.
Conclusion
The challenge that the burden of oral disease
presents is immense and will not be met ef-
fectively by the dental profession continuing
to work in a dental silo. It will require closer
engagement with the other health professions,
engagement with—and advocacy on behalf
of—civil society, and a high degree of leader-
ship. The leaders within the dental profession
must increase understanding among their
members of the central role that the social de-
terminants of health play in creating persistent
inequalities in oral disease. Advocating for re-
ductions in common risk factors will allow
dentistry to take part in championing the val-
ue of health equity, create clarity of goals, and
integrate oral health into monitoring of general
health. National dental organizations should
advocate for policies that will address inequal-
ities in oral and general health effectively. They
325
15 Common Risk Factors: The Link Between Oral and Systemic Disease
should advocate for much greater emphasis on
controlling dietary sugars and tobacco use, re-
ducing excessive alcohol consumption, and
making healthy choices the easy choices.
Current approaches to the control of oral
disease are of limited effectiveness and econom-
ically unsustainable. Oral diseases share the
same common risk factors and social determi-
nants as the major NCDs. Thus, to reduce the
growing global threat to society of poor oral
health, the focus must shift toward a greater
emphasis on health promotion and the inte-
gration of oral health with general health in
all strategies. The horizontal HiAP approach
that addresses a number of diseases at the same
time and uses the CRFA should be widened to
include oral diseases.
Acting alone, the dental profession is
unlikely to be effective in achieving good oral
health outcomes. Hence there is a need for a
“multi-sectoral approach to oral health, linking
the health sector with sectors of society such
as education, agriculture, trade, environment,
energy, social welfare, housing and others that
impact on oral health.”68
Acknowledgments
My views on the response of the dental pro-
fession to the global challenge of oral disease
have evolved during numerous discussions with
the late Professor Aubrey Sheiham, my mentor
and friend over many years. I also gratefully ac-
knowledge the contribution to development of
the principles set out in sections 8 and 9 by my
coauthors Sheiham A, Williams DM, Weyant
RJ, et al.6
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47. Chávarry NG, Vettore MV, Sansone C, Sheiham A. The
relationship between diabetes mellitus and destructive
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48. Borgnakke WS, Ylostalo PV, Taylor GW, Genco RJ.
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120S–121S.

Antibiotic Prophylaxis for
Patients at Risk for Infective
Endocarditis
Peter B. Lockhart, dds, fds rcsed, fds rcps
The ancient notion of an association between
oral and systemic disease has had a reviv-
al in the past 25 years, although these more
recent claims have not been confirmed by
clinical studies.1 However, scientific evidence
connecting oral bacterial pathogens and infec-
tive endocarditis (IE) is undisputed, and the
strength of the association between invasive
procedures and IE has a long history. Around
1940, with the advent of the first antibiotics,
it was proposed that people at risk for IE (eg,
history of rheumatic fever) might benefit from
the use of antibiotics prior to invasive proce-
dures. In 1955, the American Heart Association
(AHA) issued their first recommendations for
antibiotic prophylaxis,2 which included ad-
ministration of an intramuscular injection 30
minutes before the procedure. In a revised AHA
recommendation in 1957, oral antibiotics four
times per day for 2 days before, on the day of,
and for 2 days after the procedure were added
to the intramuscular dose. The trend since then,
however, has been a reduction in the number
of days of prophylaxis as well as the dose, to
eventually eliminate the intramuscular dose in
1990. These recommendations have evolved
to the present time, and the controversy about
CHAPTER 16
the efficacy for prevention of IE has increased
greatly in recent years.
Antibiotic Prophylaxis
to Prevent Distant Site
Infections
Antibiotic prophylaxis recommendations for
invasive dental procedures can be broken
into two types: primary and secondary. Pri-
mary prophylaxis involves giving antibiotics
during a procedure (ie, intraoperative) to pre-
vent infection at the operative site. For some
surgical procedures, such as placement of a
prosthetic joint or an aortic graft, it has been
shown that primary prophylaxis reduces the
incidence of infection at the site of surgery.
Secondary antibiotic prophylaxis is given pri-
or to an invasive procedure in order to reduce
a procedure-related bacteremia and thereby
prevent the development of an infection at a
distant site; the best-known example is IE. It is
unclear if or to what extent secondary prophy-
laxis prevents distant site infections.
329
 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis

80–

70– 67.2%

60–
Percent of respondents

50–

40– 36.9%
30.3%
30–
22.4% 22.1%
20– 13.8%
10–

0–
Mitral valve Congenital Rheumatic Aortic Bicuspid Other
prolapse heart heart or mitral valve
conditions* disease stenosis disease

*Such as ventricular septal defect, atrial septal defect, and hypertrophic cardiomyopathy

Fig 16-1  |  Cardiac conditions for which some patients continue to receive antibiotic prophylaxis although this
is no longer recommended by the 2007 AHA guidelines.4

What Do We Know About dermatologic, and other invasive procedures

may also cause a bacteremia of pathogenic
the Issues Surrounding species known to cause IE.
Antibiotic Prophylaxis? • Antibiotics given an hour prior to an inva-
sive dental procedure will likely reduce but
not eliminate the number of circulating oral
The following section lists what we know, what viridans group streptococci, and it is believed
we think we know, and what we need to know that this reduces the risk of IE.7
about antibiotic prophylaxis: • Antibiotic prophylaxis, both primary and
secondary, is being used for many patient
• Antibiotic prophylaxis compliance is poor populations in dental practice for reasons
for patients and clinicians in part because that lack a scientific basis.
of confusion and a lack of understanding • Antibiotic prophylaxis may be cost-effective
concerning the AHA recommendations as in certain situations, but only where it is suf-
well as a wide diversity of opinion among ficiently effective in preventing disease and
physician specialty groups about the need where the costs of developing the disease
for prophylaxis prior to dental procedures3–6 outweigh the costs of preventing it.8 This
(Fig 16-1). This confusion also arises because may be true in the case of antibiotic pro-
of conflicting evidence in the literature over phylaxis for IE in those patients at high risk9
time and a lack of definitive answers for the but not in other situations.
issue of efficacy. • Recent data suggest that a single dose of
• There is a long-standing assumption that amoxicillin prior to a dental procedure is
dental procedures are the main risk factor safe with regard to drug reactions,10 but clin-
for IE despite evidence that gastrointestinal, damycin may put patients at significant risk.

330

Fig 16-2  |  IE of the aortic valve. Note the vegeta-
tions on the valve leaflets (arrows).
• We need to know if single-dose use of anti-
biotics is contributing to the problem of
drug-resistant organisms.
• We need to know which dental procedures
put patients at risk.
• The risk of bacteremia following dental
extractions and other manipulations of
the gingival tissues comes from bacter­
emia studies, but the incidence and nature
of bacteremia from necrotic pulp tissue is
unknown. Although often referred to, there
are few data on bacteremia during chewing
food or flossing teeth.
• We need a definitive epidemiologic study to
determine if antibiotic prophylaxis prior to
dental procedures reduces the risk for IE.
• We need to know if those with poor oral
hygiene are really at significantly greater risk
of developing IE as a result of daily activities
compared to similar individuals with good
oral hygiene.
What Is Infective
Endocarditis?
IE is an uncommon if not rare infection of
the heart myocardium, particularly the heart
What Is Infective Endocarditis?
valves. There are about 40,000 to 50,000
new cases in the United States each year.11
The mechanism for these infections has sev-
eral steps. Briefly, a platelet plug forms on a
damaged heart valve and bacteria from the
bloodstream lodge in this platelet plug, which
grows to become a vegetation (Fig 16-2). Vege-
tations may obstruct the normal flow of blood
through the valve by perforating or obstructing
valve closure and may allow the backflow of
blood through the valve. Both mean the heart
becomes inefficient in pumping blood around
the body, resulting in heart failure. In a fur-
ther complication, fragments of vegetations
may break off and travel as infected emboli to
distant sites in the body, including the brain,
where they can cause a stroke. For these rea-
sons, patients with IE require urgent hospital
admission and high-dose intravenous antibi-
otics for up to 6 weeks. Complications are
common, and the prognosis includes a mortal-
ity rate of 15% to 20% during hospitalization,
and 40% to 50% will require valve repair or
replacement.11 Upward of 25% of patients will
die within the first year following the infection.
These patients are also at risk for IE in the fu-
ture, which carries a poor prognosis, and they
are at risk for developing heart failure and ad-
ditional long-term morbidity.
331
16 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis
Types of IE
There are two general types of IE: community-
acquired and medically related. Community-
acquired IE occurs in people with a heart valve
defect who acquire this infection from a bac-
teremia from a skin or mucosal surface either
during an invasive procedure or routine daily
activities (eg, tooth brushing). These infections
are often caused by the viridans streptococci
group of bacteria, some of which are very com-
monly found in the mouth. This is the group
of people who are targeted for antibiotic pro-
phylaxis prior to invasive dental procedures.
Medically related IE occurs in people who
have a medical condition or device that puts
them at risk. This includes people on renal
dialysis, with prosthetic heart valves, involved
with injection drug use, or with chronic der-
matologic conditions. These medically related
cases are not believed to be caused by bacteria
from the mouth, and therefore they are not
targeted for antibiotic prophylaxis prior to
dental procedures.
The AHA Recommendations
The AHA prophylaxis regimen in the mid- to
late 1950s was aggressive and difficult for den-
tists to accomplish. Since that time, the dose
and the duration of antibiotic prophylaxis has
been reduced to the current recommendation
of just one dose 30 to 60 minutes prior to the
dental procedure. More than 60 years later, sur-
veys suggest that the AHA recommendations
are the most recognized of any publication,
with a 98% awareness among dentists in the
United States.4
It should be remembered that these AHA
recommendations focus on two major groups
of people at risk: those in the “moderate risk”
group and those in the “high risk” group.12
The determination of patients that are in one
or the other of these two groups is based on
a consensus of both the risks from getting IE
332
(ie, morbidity and mortality) and the risk of
acquiring IE. The moderate-risk group is made
up of people with a history of rheumatic fever
or mitral valve prolapse, for example; in com-
parison, the high-risk group involves four
categories of cardiac patients, those with (1)
artificial heart valves, (2) a prior history of IE,
(3) certain congenital heart defects, and (4) a
previous heart transplant who now have a val-
vular defect. The moderate-risk group includes
about 90% of patients at risk for IE, and the
remaining 10% are considered high risk.8
The 2007 AHA recommendations are
generally well accepted by both dentists and
physicians involved in the care of patients with
cardiac conditions. These recommendations,
however, do not cover all scenarios of patients
who might be considered for antibiotic pro-
phylaxis. For example, there are patients in the
moderate-risk group with additional medical
problems (eg, immunosuppression) who may
be at increased risk either for and/or from IE.
There may need to be a discussion with the
patient’s primary care physician or cardiologist,
but it is important beforehand to have a clear
understanding of the current AHA recommen-
dations and of the information needed from the
physician. Otherwise, these recommendations
provide for the vast majority of the situations
that arise in community dental practice.
Changes in the current 2007 AHA
recommendations
The 2007 AHA recommendations underwent
significant changes from the prior 1997 rec-
ommendations. These changes included the
following:
• An increased focus on the existing science
in general.
• The moderate-risk group was dropped from
antibiotic coverage, leaving the high-risk
group, which has only approximately 10%
of all people at risk for IE.

Box 16-1  |  Medical conditions and devices reported to put patients at increased risk from a bacteremia
following invasive dental procedures
• Cardiac:
–– Prosthetic heart valves
–– Congenital defects (some)
–– Previous IE
–– Heart transplants (some)
–– Native heart valve disease
–– Pacemakers and defibrillators
–– Coronary stents
• Asplenism
• Autoimmune disease
• Debilitated patients
• An increased emphasis on the frequency of
bacteremia due to routine daily events (eg,
tooth brushing) and a stronger suggestion
that poor oral hygiene and gingival disease
may play a role in the incidence of naturally
occurring bacteremia and therefore the risk
for community-acquired IE.
• Prior AHA recommendations included a
table listing dental procedures that might
put patients at risk for bacteremia and IE.
The 2007 recommendations dropped this
list because of the lack of evidence base and
replaced it with a single sentence to guide
dentists on procedures most likely to cause
a bacteremia: “All dental procedures that
involve manipulation of gingival tissue or the
periapical region of teeth or perforation of
the oral mucosa.”13 There was concern that
by eliminating the list of dental procedures
the new definition in the 2007 recommen-
dations would not cover all procedures that
might result in a bacteremia. A comparison
of more than 21 million claims for payments
to dentists in a large provider network sug-
gested that there would be no difference in
the dental procedures covered in the 1997
versus the 2007 recommendations.
The AHA Recommendations
• Hereditary hemorrhagic telangiectasia
• Immunosuppression from drugs or disease
• Indwelling catheters
• Nondental implants: deep brain stimulator, breast,
penile, and others
• Prosthetic joints
• Shunts: cerebral spinal fluid, renal dialysis, and others
• Systemic lupus erythematosus
• Transplants: solid organs, bone marrow, and others
• Type 1 diabetes mellitus
• Vascular grafts
• The recommendation to consider an antibac-
terial mouthrinse prior to a dental procedure
was dropped due to conflicting data.14
• The reference to bleeding as an indicator of
risk for bacteremia was dropped for lack of
data to show that “visible bleeding during
the dental procedure is a reliable predictor
of bacteremia.”13
The reasoning behind some of these changes
is an increasing appreciation for the likelihood
that community-acquired IE from oral bacterial
species is far more likely to result from frequent
bacteremia from daily activities such as tooth
brushing than from dental office procedures.
Therefore, the maintenance of optimal oral
health and hygiene may be far more impor­tant
as prevention than prophylactic antibiotics.
AHA recommendations for cardiac con-
ditions have been adopted for a variety of
noncardiac patient populations as well, partic-
ularly in patients with prosthetic joints. Other
examples include patients with a variety of
shunts, central line catheters, and transplanted
organs. In fact, in the dental literature there
are suggestions or recommendations for over
25 different patient populations to receive sec-
ondary antibiotic prophylaxis prior to dental
procedures, usually opinion-based8 (Box 16-1).
333
16 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis
However, there is no proof of efficacy for any
of these purported indications for antibiotic
prophylaxis. In addition, there are other com-
mon uses for secondary antibiotic prophylaxis
that have little or no support from the scientific
literature. Examples include use of secondary
antibiotic prophylaxis prior to invasive dental
procedures to prevent local infection (eg, third
molar removal), to resolve failure of local anes-
thesia due to inflammation in the region, for
extractions following radiotherapy to the jaws,
and for toothache without signs or symptoms
of infection.15
Why Is There a Focus on
Dental Procedures for People
at Risk for IE?
Distant site infections from oral bacterial spe-
cies are rare, but people with specific cardiac
conditions are at risk for IE. The gingival sulcus
and periodontal pocket have a wide variety of
both pathogenic and nonpathogenic bacteria
within them. It has long been assumed that the
gingival crevicular tissue adjacent to the tooth
surface becomes ulcerated in the presence of
inflammation from plaque and calculus. The
scientific evidence for this is weak, but it is gen-
erally regarded that this greatly increases the
likelihood that a wide variety of bacteria may
enter the inflamed gingival tissues and capil-
lary blood vessels around the teeth following
any manipulation and that these bacterial spe-
cies may travel to and lodge themselves onto
damaged heart valves. Some of the bacterial
species in the dental plaque are of particular
concern with regard to IE, such as some of
the viridans streptococci group (Streptococcus
mitis, Streptococcus oralis, Streptococcus mu-
tans, and Streptococcus salivarius). Much of
what is known about dental procedures and
oral disease as well as IE comes from bacte-
remia studies.
334
What Do Bacteremia Studies
Tell Us?
There have been many studies of bacteremia
following various dental procedures. Most
focus on surrogate measures of risk for IE,
most commonly the incidence, duration, na-
ture (bacterial species), and magnitude of
bacteremia. It seems clear that bacteremia
may arise from any procedure that involves
gingival tissues adjacent to the teeth. A wide
range of incidence has been reported follow-
ing single- and multiple-tooth extractions,
scaling, endodontic procedures, and other pro-
cedures.14,16–21 However, it is not known if there
is a clinically significant difference between the
bacteremia caused by various invasive dental
procedures or the degree to which they put pa-
tients at risk for IE.
A large randomized study comparing tooth
brushing with single-tooth extraction reported
that the incidence and duration of bacteremia
from tooth brushing is not greatly different
from that of an extraction done with antibiotic
prophylaxis7 (Fig 16-3). This raises the question
of the relative risk between naturally occur-
ring bacteremia from daily activities such as
tooth brushing and invasive procedures in the
dental office. Given that individuals have far
more frequent bacteremia from tooth brushing
(and perhaps other oral hygiene measures and
chewing food) than they would ever have from
dental office procedures, we may need to focus
more on preventing bacteremia by improving
oral hygiene and eliminating dental disease.
This is especially important because we are
currently employing antibiotics for only the
approximately 10% of people who are at high
risk for IE. Improving oral hygiene is likely
to be an important prevention measure for all
people at increased risk of IE (both high risk
and moderate risk) and is the only prevention
method available for those at moderate risk
for IE who are not currently recommended for
antibiotic prophylaxis.
 Support For and Against Antibiotic Prophylaxis

60

50
Positive cultures (% ) 40

30

20

10 Extraction +
placebo
0 Extraction +
0 1.5 5 20 40 60 amoxicillin
Tooth
Minutes after extraction or brushing brushing

Fig 16-3  |  Size and duration of bacteremia following single-tooth extraction versus tooth
brushing.7 Note that tooth extraction with a placebo had the largest and longest duration
of bacteremia but that tooth brushing can also have a bacteremia duration of up to 1 hour.

Support For and Against
Antibiotic Prophylaxis
The support for antibiotic prophylaxis comes
from a variety of sources. The original source
could be considered a remnant of the focal
infection theory. In 1955, the intention for
prophylaxis was to reduce the incidence of IE,
which was fatal for virtually everyone with the
disease in the preantibiotic era. The emergence
of antibiotics in the early 1940s, along with
early animal studies where prophylaxis was
shown to be effective, resulted in the opinion
that patients might benefit by having antibiotic
prophylaxis before invasive procedures. This
support for prophylaxis also comes from the
following sources:
• Over 60 years of AHA recommendations
that advise prophylaxis and long-established
practice patterns that are deeply entrenched
with the belief that prophylaxis works.
• Antibiotic prophylaxis has been the primary
if not the only method for prevention of IE.
• Reports that upward of 35% of cases of
community-acquired IE come from oral
bacterial species.
• Viridans group streptococci were highly
susceptible to antibiotics at the time of the
original AHA recommendations.
• Bacteremia with IE-related bacterial species
frequently occurs during dental procedures.22
• There is an increasing number of cardiac and
noncardiac devices that put people at risk for
IE, and these people have high morbidity and
mortality from this disease.
• It is believed that the antibiotic will kill the
bacteria both in the bloodstream before they
can attach to a heart valve and after they
attach to a vegetation.
• A large epidemiologic study in the United
Kingdom reported a benefit from the use of
antibiotic prophylaxis, and its use may be
cost-effective as well.9,23

335
16 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis
• Data from a study of 3 million prescriptions
for antibiotic prophylaxis in the United
Kingdom focused on single-dose amoxicillin,
and the data suggest that amoxicillin is safe
for this purpose because the drug reaction
rate is very low.10 However, clindamycin, a
backup drug for amoxicillin, has a higher
incidence of drug reactions than anticipated,
and the study reported cases of Clostridium
difficile and death following administration
for dental prophylaxis.
There has been increasing support in the
last two to three decades to reduce the use of
prophylactic antibiotics in general and for IE
specifically. This support comes from the fol-
lowing sources:
• There are no well-documented cases of IE
from a dental procedure, although it is likely
that this does occur.
• Bacteremia studies rely on surrogate mea-
sures of risk for IE.
• In the absence of a randomized controlled
trial, there is no proof of efficacy for the use
of antibiotic prophylaxis, and the epidemi-
ology studies often have conflicting findings.
• There are many well-documented cases of IE
where prophylaxis failed to work.
• Even if prophylaxis is effective, a huge num-
ber of antibiotic doses may be required to
prevent a small number of cases of IE.
• There is long-standing concern about drug
reactions from antibiotics, especially for
clindamycin.
• There is an increasing concern across the
world about the development of drug resis-
tance and more virulent strains of bacterial
species and a conviction that we must elim-
inate any unnecessary use of antibiotics.10,24
• There are concerns about the cost-
effectiveness of antibiotic prophylaxis. The
2007 AHA recommendations suggest that
this practice may not be cost-effective, but a
large study in the United Kingdom reported
that it may be cost-effective for preventing
336
IE, particularly in those at high risk.9 There
are a variety of other costs associated with
this use of antibiotics, such as the cost asso-
ciated with a single dose of amoxicillin for
cardiac patients,8 and they increase greatly
if used for the other noncardiac patient
populations mentioned previously (see Box
16-1).
• Much of the confusion surrounding antibi-
otic prophylaxis stems from the conflicting
literature over the years, which is often based
on expert opinion and case reports. For
example, there have been well over 200 case
reports suggesting that a dental procedure
caused a case of IE, but none are documented
well enough to show even a strong associ-
ation.25 Most of the studies that purport to
show a causal relationship have flawed meth-
odologies, including small sample sizes and
follow-ups that are too short.
• Finally, there is often an exaggerated tem-
poral relationship between the time of the
dental procedure and the onset of IE. IE is
generally thought to occur within 1 to 6
weeks from the time of the bacteremia, but
this time frame can extend out to more than
3 months in unusual cases, usually those
caused by oral viridans group streptococci
and other less pathogenic bacterial species.
What Do Current Data Tell Us
About the Prevention of IE by
Prophylactic Antibiotics?
Since the original 1955 AHA recommenda-
tions, there has been increasing concern that
the benefit of antibiotic prophylaxis prior to
invasive procedures has been exaggerated, and
there is a strong need to get definitive data con-
cerning the extent to which prophylaxis might
prevent some of these cases. There is much lit-
erature on the subject, but there are no studies
robust enough to provide a definitive answer
 Do Oral Hygiene and Periodontal Diseases Matter for Patients at Risk for IE?
to this question. Of interest is the opportunity
that arose when a guidelines committee in the
United Kingdom decided in 2008 to stop anti-
biotic prophylaxis entirely.26 A study published
in 2011 suggested that although the prescribing
of antibiotics fell significantly soon after 2008,
there was no change in the incidence of IE.27
However, another study by the same group of
researchers with a longer follow-up period re-
ported a significant increase in IE after 2008,
suggesting that antibiotic prophylaxis may re-
duce the risk of IE following dental procedures,
especially for the AHA moderate-risk group
of patients.23 There has been much discussion
concerning this study and the importance of
determining any change in the incidence of IE
in the United States since the 2007 AHA rec-
ommendations. There have been several such
studies published since 200728–30; the signifi-
cance of these papers has been covered in a
recent review of this topic.31
What is clear is that most of these studies
failed to give strong evidence one way or the
other because they (1) are too small in size and
therefore underpowered, (2) have too short a
time period for follow-up after 2007, (3) do not
have data on the microbiology of these infec-
tions that would implicate the oral cavity, or
(4) do not have antibiotic prescribing data to
compare with a change in the incidence of IE.
There is an ongoing effort to get these data
and compare them with a likely decrease in
the use of prophylactic antibiotics since 2007.
At least one study suggests that oral disease
significantly increases the risk for a bacteremia
both from tooth brushing as well as a dental
extraction,7 and there is a large ongoing study
underway to determine if poor oral hygiene
and periodontal disease are more common in
patients with IE as opposed to people who are
simply at risk for IE. In the meantime, there is
an increased understanding of the likely greater
risk for community-acquired IE from poor oral
hygiene and periodontal disease.
Do Oral Hygiene and
Periodontal Diseases Matter
for Patients at Risk for IE?
The connection between oral hygiene and
gingival disease and the risk for IE was first
suggested well over a hundred years ago,32
and it is well documented that oral bacte-
rial species are responsible for many cases
of community-acquired IE. It has long been
assumed that dental plaque and calculus and
the resulting inflammation and periodontal
pocket formation cause ulceration of the mu-
cosal lining of the gingiva adjacent to the teeth
(Figs 16-4 and 16-5). This allows bacterial
species to enter the bloodstream with manip-
ulation of the gingiva during dental procedures
and daily activities (eg, tooth brushing).
A study of tooth brushing and single-tooth
extraction showed an eight-fold increased risk
of bacteremia from IE-related bacterial spe-
cies.33 This study found that bleeding following
brushing, mean plaque scores, and mean cal-
culus scores were highly associated with the
risk for bacteremia during tooth brushing. This
work also suggests that the incidence of bacter­
emia in patients with heavy calculus is similar
to that of a single-tooth extraction. However,
it is important to note that these measures of
oral hygiene and periodontal diseases and the
resultant bacteremia are only surrogate mea-
sures of the risk for IE.
Given that there is ample evidence that den-
tal procedures and tooth brushing often cause
bacteremia and because there is evidence that
oral hygiene and disease increase the risk of
bacteremia, it is entirely possible that this puts
some people at greater risk for IE33 (see Fig
16-5). Ongoing investigations are attempting
to determine the strength of the association
between oral hygiene and disease and IE. The
impact of demonstrating a strong association
would do the following:
337
16 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis

Fig 16-4 |  Comparison of oral hygiene and the periodontium in healthy (left side) and diseased (right side)
states.7

Poor oral hygiene Gingivitis Advanced periodontal

disease

Ulcerated
sulcus/pocket
Bacteremia
with IE bacterial
species

Evidence-
Infective endocarditis based
May reduce
risk for* Assumed
Poor oral hygiene No gingivitis/
Unknown
and periodontal periodontal
diseases Treatment and prevention diseases

*It is unknown if resolving poor oral hygiene and periodontal disease will reduce the risk for IE.

Fig 16-5 |  Associations between oral hygiene and periodontal disease and
IE.

338
 What Can We Expect from Current and Future Research Studies?
• Add greatly to our understanding of risk
factors for IE.
• Provide the opportunity to reduce the
incidence and the associated morbidity, mor-
tality, and cost for community-acquired IE.
• Give patients the opportunity to prevent this
disastrous infection by maintaining good
oral hygiene and avoiding periodontal dis-
ease and decrease the likelihood of IE from
naturally occurring activities such as tooth
brushing.
• Provide policymakers with specific informa-
tion for future recommendations concerning
the importance of oral hygiene and prevent-
ing gingival disease.
• Over time, reduce the need for dental
procedures that might require antibiotic
prophylaxis.
• Provide a rationale for reimbursement for
medically necessary dental care for patients
at risk for IE.
What Can We Expect from
Current and Future Research
Studies?
Although there have been attempts to fund a
large study that would give a more definitive
answer to this long-standing question, there
has never been a prospective randomized con-
trolled trial of antibiotic prophylaxis. Reasons
for this include (1) logistics and study design is-
sues that would require over 100,000 high-risk
patients in a multi-center, multiyear study
that might cost in excess of $60 million, and
(2) there are ethical and legal issues, such as
randomizing patients at high risk for IE to a
placebo. Because a randomized controlled tri-
al of prophylaxis is highly unlikely, an answer
to the question of causality will require one
or more large, well-designed epidemiologic
studies.
The results of the study done in the United
Kingdom that reported an increase in the
incidence of IE after stopping prophylaxis
altogether have been discussed at great length
among the authorities in this field, and we
await future studies that will either confirm
or revise these findings.23 There are studies
currently underway in the United States that
should help greatly to answer the following
key questions:
1. Has there been an increase, a decrease, or
no change in the incidence of IE as a result
of the 2007 AHA recommendations, when
the moderate-risk group was no longer rec-
ommended for prophylaxis? This should
help to resolve the fundamental question
concerning the efficacy of antibiotic pro-
phylaxis to prevent IE.
2. What is the strength of the association
between indexes of oral hygiene and peri-
odontal diseases for cases of IE that are
caused by oral versus nonoral bacterial
species?
3. Are we using antibiotic prophylaxis for
the most appropriate cardiac patient pop-
ulations and for the appropriate dental
procedures?
4. How well do dentists understand the cur-
rent AHA recommendations and the lack
of scientific data to support the use of pri-
mary and secondary antibiotic prophylaxis
in other patient populations?
Studies published in the last decade are
bringing clarity to some of the other more sig-
nificant unanswered questions with regard to
this interface between medicine and dentistry.
In the meantime, given the lack of proof of
efficacy for antibiotic prophylaxis, guidelines
committees are charged with sorting out con-
flicts and confusion with the literature and
creating recommendations on the risks and
benefits of this practice. Until these studies have
been completed, current data suggest that all
patients at risk for IE may benefit by eliminat-
ing oral disease and maintaining good hygiene.
Once answers to these questions are available,
we will want to know if people with specific
339
16 Antibiotic Prophylaxis for Patients at Risk for Infective Endocarditis
cardiac conditions are at risk from poor oral
hygiene and periodontal diseases. If so, does
treatment and prevention of caries and peri-
odontal disease decrease the incidence of IE in
people at risk?
It is also important to understand that there
are no official guidelines concerning the use
of primary or secondary antibiotic prophy-
laxis in dental practice for any other patient
population with the exception of patients
with prosthetic joints, a highly controversial
issue given the lack of association between the
nature of bacterial species typically found in
infected prosthetic joints by comparison with
the strong association for patients with IE. This
is an important distinction for several reasons,
including the increasing concern about the
abuse of antibiotics and the global problem of
drug-resistant strains of bacteria.
Following a period of decades during which
there were relatively minor changes in the gen-
eral thinking about antibiotic prophylaxis for
dental procedures, the last 15 years of research
have brought about significant changes in
our understanding of the people at risk for
this disease and those factors that put them
at increased risk. The increased number of
well-designed studies should result in better
prevention protocols for cardiac patients and
other patient populations for whom there has
been well over 100 years of debate.
References
1. Lockhart PB, Bolger AF, Papapanou PN, et al. Peri-
odontal disease and atherosclerotic vascular disease:
Does the evidence support an independent associa-
tion?: A scientific statement from the American Heart
Association. Circulation 2012;125:2520–2544.
2. Jones TD, Baumgartner L, Bellows MT, et al. Prevention
of rheumatic fever and bacterial endocarditis through
control of streptococcal infections. Circulation 1955; 11:
317–320.
3. Dayer MJ, Chambers JB, Prendergast B, Sandoe JA,
Thornhill MH. NICE guidance on antibiotic prophylaxis
to prevent infective endocarditis: A survey of clinicians’
attitudes. QJM 2013;106:237–243.
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4. Lockhart PB, Hanson NB, Ristic H, Menezes AR,
Baddour L. Acceptance among and impact on dental
practitioners and patients of American Heart Association
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Assoc 2013;144:1030–1035.
5. Lockhart PB, Brennan MT, Fox PC, Norton HJ, Jernigan
DB, Strausbaugh LJ. Decision-making on the use of
antimicrobial prophylaxis for dental procedures: A survey
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6. Lockhart PB. Antibiotic prophylaxis for dental proce-
dures: Are we drilling in the wrong direction? Circulation
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7. Lockhart PB, Brennan MT, Sasser HC, Fox PC, Paster
BJ, Bahrani-Mougeot FK. Bacteremia associated with
toothbrushing and dental extraction. Circulation 2008;
117:3118–3125.
8. Lockhart PB, Loven B, Brennan MT, Fox PC. The
evidence base for the efficacy of antibiotic prophylaxis
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9. Franklin M, Wailoo A, Dayer MJ, et al. The cost-
effectiveness of antibiotic prophylaxis for patients at risk
of infective endocarditis. Circulation 2016; 134:
1568–1578.
10. Thornhill MH, Dayer MJ, Prendergast B, Baddour LM,
Jones S, Lockhart PB. Incidence and nature of adverse
reactions to antibiotics used as endocarditis prophylaxis.
J Antimicrob Chemother 2015;70:2382–2388.
11. Cahill TJ, Baddour LM, Habib G, et al. Challenges in
infective endocarditis. J Am Coll Cardiol 2017; 69:
325–344.
12. Wilson W, Taubert KA, Gewitz M, et al. Prevention of
infective endocarditis: Guidelines from the American
Heart Association: A guideline from the American Heart
Association Rheumatic Fever, Endocarditis, and Kawa-
saki Disease Committee, Council on Cardiovascular
Disease in the Young, and the Council on Clinical Cardi-
ology, Council on Cardiovascular Surgery and
Anesthesia, and the Quality of Care and Outcomes
Research Interdisciplinary Working Group. Circulation
2007;116:1736–1754.
13. Wilson W, Taubert KA, Gewitz M, et al. Prevention of
infective endocarditis: Guidelines from the American
Heart Association: A guideline from the American Heart
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saki Disease Committee, Council on Cardiovascular
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Assoc 2007;138:739–760.
14. Lockhart PB. An analysis of bacteremias during dental
extractions: A double-blind, placebo-controlled study
of chlorhexidine. Arch Intern Med 1996;156:513–520.
15. Runyon MS, Brennan MT, Batts JJ, et al. Efficacy of
penicillin for dental pain without overt infection. Acad
Emerg Med 2004;11:1268–1271.

16. Lockhart PB, Brennan MT, Kent ML, Norton HJ, Weinrib
DA. Impact of amoxicillin prophylaxis on the incidence,
nature, and duration of bacteremia in children after intu-
bation and dental procedures. Circulation 2004; 109:
2878–2884.
17. Baltch AL, Schaffer C, Hammer MC, et al. Bacteremia
following dental cleaning in patients with and without
penicillin prophylaxis. Am Heart J 1982; 104:
1335–1339.
18. Debelian GJ, Olsen I, Tronstad L. Profiling of Propioni-
bacterium acnes recovered from root canal and blood
during and after endodontic treatment. Endod Dent
Traumatol 1992;8:248–254.
19. Giglio JA, Rowland RW, Dalton HP, Laskin DM. Suture
removal-induced bacteremia: A possible endocarditis
risk. J Am Dent Assoc 1992;123:65–70.
20. Erverdi N, Biren S, Kadir T, Acar A. Investigation of
bacteremia following orthodontic debanding. Angle
Orthod 2000;70:11–14.
21. Heimdahl A, Hall G, Hedberg M, et al. Detection and
quantitation by lysis-filtration of bacteremia after different
oral surgical procedures. J Clin Microbiol 1990; 28:
2205–2209.
22. Lockhart PB, Brennan MT, Sasser H, Noll J, Coleman
S, Ashar J, et al. Tooth extraction and tooth brushing
both produce bacteremia of endocarditis-related patho-
gens. J Am Coll Cardiol 2007;49(9 suppl A):301A.
23. Dayer MJ, Jones S, Prendergast B, Baddour LM, Lock-
hart PB, Thornhill MH. Incidence of infective endocarditis
in England, 2000–13: A secular trend, interrupted
time-series analysis. Lancet 2015;385:1219–1228.
24. Centers for Disease Control and Prevention. Antibiotic
Resistance Threats in the United States. Atlanta: U.S.
Department of Health and Human Services, 2013.
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25. Durack DT, Kaplan EL, Bisno AL. Apparent failures of
endocarditis prophylaxis. Analysis of 52 cases submitted
to a national registry. JAMA 1983;250:2318–2322.
26. Centre for Clinical Practice at NICE. Prophylaxis Against
Infective Endocarditis: Antimicrobial Prophylaxis Against
Infective Endocarditis in Adults and Children Undergoing
Interventional Procedures. London: National Institute
for Health and Clinical Excellence, 2008.
27. Thornhill MH, Dayer MJ, Forde JM, et al. Impact of the
NICE guideline recommending cessation of antibiotic
prophylaxis for prevention of infective endocarditis:
Before and after study. BMJ 2011;342:d2392.
28. Pant S, Patel NJ, Deshmukh A, et al. Trends in infective
endocarditis incidence, microbiology, and valve replace-
ment in the United States from 2000 to 2011. J Am Coll
Cardiol 2015;65:2070–2076.
29. Mackie AS, Liu W, Savu A, Marelli AJ, Kaul P. Infective
endocarditis hospitalizations before and after the 2007
American Heart Association Prophylaxis Guidelines. Can
J Cardiol 2016;32:942–948.
30. van den Brink FS, Swaans MJ, Hoogendijk MG, et al.
Increased incidence of infective endocarditis after the
2009 European Society of Cardiology guideline update:
A nationwide study in the Netherlands. Eur Heart J Qual
Care Clin Outcomes 2017;3:141–147.
31. Thornhill MH, Dayer M, Lockhart PB, Prendergast B.
Antibiotic prophylaxis of infective endocarditis. Curr
Infect Dis Rep 2017;19:9.
32. Horder TJ. Infective endocarditis: With an analysis of
150 cases and with special reference to the chronic
form of the disease. QJM 1909;2:289–324.
33. Lockhart PB, Brennan MT, Thornhill M, et al. Poor oral
hygiene as a risk factor for infective endocarditis-
related bacteremia. J Am Dent Assoc 2009; 140:
1238–1244.
341
 CHAPTER 17

Oral-Systemic Connection:
The Salivaomics and
Exosomics Connection
Taichiro Nonaka, dds, phd
Karolina Elżbieta Kaczor-Urbanowicz, dmd, phd, msc, msl
David T.W. Wong, dmd, dmsc

The oral-systemic connection is further creden-
tialed in the development and genesis of salivary
biomarkers for systemic diseases (Fig 17-1). The
three major pairs of salivary glands (parotid,
submandibular, and sublingual) together with
minor glands produce a liter of whole saliva dai-
ly per individual (see Fig 17-1a). The source of
the saliva fluid and its omics constituents (pro-
teome, genome, and transcriptome) are from
systemic circulation where passive, active, and

Capillaries

  1   2     3    4

    6
Blood    7

   8

   9

Capillaries

Trigeminal nerve (V) Na+

Facial nerve (VII)     5 K+

Parotid gland

Blood
Sublingual gland
a Submandibular gland b Saliva

Fig 17-1  |  (a) Major salivary glands: parotid, submandibular, and sublingual. (b) Transport of circulatory mole-
cules and fluid into salivary glands: (1) ultrafiltration; (2) active transport or passive diffusion across the cell mem-
brane; (3) simple diffusion through cell membrane pores; (4) transepithelial movement of water along a sodium
chloride (NaCl) gradient via channel proteins; (5) creation of hypotonic salivary solution via ductal Na+ reabsorp-
tion; (6) acinar cell membrane; (7) cell membrane pore; (8) intercellular space; (9) acinar cell. K+, potassium ion.

342

secretory mechanisms are in place to transfer
fluid and omics targets from the capillary bed
(see Fig 17-1b). This systemic-oral passaging
of omics constituents embodies a compelling
rationale for systemic-oral communication. Yet
the mechanistic underpinnings and scientific
data are only beginning to emerge. This chapter
focuses on the systemic-oral connection from
a biomarkers development perspective using
basic, translational, and clinical studies to un-
derpin the mechanistic rationale.
Saliva
Human saliva is a clear, slightly acidic (pH
6.0 to 7.0) heterogeneous biofluid composed
of water (99%), proteins (0.3%), and inorganic
substances (0.2%).1 On average, individual sal-
ivation can range from 0.3 to 0.7 mL of saliva
per minute,2 producing approximately one liter
daily. Saliva is multifunctional, not only serving
to facilitate digestion, swallowing, tasting, and
tissue lubrication but also acting as a protective
barrier against pathogens. Saliva is generated
within the salivary glands by acinus cells, col-
lected in small ducts, and subsequently released
into the oral cavity.3 There are three major and
numerous minor saliva-producing glands lo-
cated in and around the mouth and throat
(see Fig 17-1). Each gland is entirely innervat-
ed autonomically, subject to parasympathetic
and sympathetic stimulation, and exocrine in
function. The three major glands—the parotid,
submandibular, and sublingual glands—con-
tribute approximately 90% of total saliva,
while the minor glands—the labial, buccal, lin-
gual, and palatal glands—supply the remainder.
Each salivary gland is highly permeable
and enveloped by capillaries (see Fig 17-1),
allowing free exchange of blood-based mol-
ecules into saliva-producing acinus cells.
Blood-derived molecules can enter salivary
tissues via trans­ cellular (eg, passive and
active transport) or paracellular (eg, extra-
cellular ultrafiltration) routes4 that influence
Salivaomics
the molecular constituency of oral fluids.
This suggests that circulating biomarkers of
disease absorbed by the salivary glands can
alter the biochemical composition of salivary
secretions. Consequently, oral fluids contain
molecular information capable of communi-
cating an individual’s current state of health.
This constituted the theoretical rationale for
oral-systemic communication and connection
for biomarker development.
Salivaomics
Salivaomics was coined in 2008 to reflect the
rapid development of knowledge about the
“omics” constituents in saliva.5 The terms
salivary proteome, extracellular RNA (exR-
NA), microRNA (miRNA), metabolome, and
microbiome have since entered the scientific
lexicon.5 The metabolome is the complete set
of small molecular metabolites found within
a biologic sample (carbohydrate, lipid, amino
acid, nucleic acid, hormones, and other signal-
ing molecules). Translationally, these are the
diagnostic alphabets of saliva, and their discov-
ery poised saliva for translational and clinical
applications, including personalized medicine
and dentistry. These salivaomics constituents,
their discovery, annotations, and documenta-
tions are assembled at the Salivary Proteome
Knowledge Base (Fig 17-2).
The defining of salivaomics constituents pre-
sented tools that can permit, for the first time,
development of salivary biomarkers de novo
for the detection of oral and systemic diseases.
The outcomes of these studies represent trans-
lational evidence of oral-systemic connection.
Key examples are highlighted below.
Salivary proteomics
Comprehensive analysis of the salivary
proteome is critical for appreciating its full diag-
nostic potential. A consortium of three research
groups from the Scripps Research Institute; the
343
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection
Salivaomics Knowledge Base
Scientific
Saliva ontology
foundations
Point-of-care
technology
Fig 17-2  |  Salivaomics Knowledge Base. An assembly of the omics constituent databases, publications, and
point-of-care technologies (www.skb.ucla.edu).
University of California, San Francisco; and the
University of California, Los Angeles compiled
a comprehensive catalog of the salivary pro-
teome of healthy individuals, identifying 1,166
proteins in parotid and submandibular/sublin-
gual gland ductal saliva.6 The data set from this
study has been deposited into the Saliva Pro-
teome Knowledge Base for public access.7
Bandhakavi et al made a significant contri-
bution to expand our understanding of the
salivary proteome by using three-dimensional
peptide fractionation and generated the larg-
est whole saliva proteome data set, including
2,340 proteins that are involved in a variety
of biologic functions in the oral cavity.8 Com-
parative analysis of human saliva and plasma
proteome showed that distributions of salivary
proteins are enhanced in two gene ontology
categories (metabolic and catabolic processes)
compared with plasma, suggesting that saliva
may be advantageous over plasma, especially
for less abundant proteins involved in these
biologic processes.9 Unlike the serum protein,
344
Proteome
Transcriptome
microRNA
Metabolome
Saliva diagnostic Genome
atlas
salivary proteins appear to be more suscepti-
ble to degradation.10 Esser et al11 reported that
salivary protein can be degraded rapidly even
during saliva collection and handling, which
may hamper the downstream experiments and
application. We have established the methods
to stabilize the salivary protein using protease
inhibitors, enabling saliva samples to be stored
up to 2 weeks without significant degradation.12
The first attempt at cancer detection using
salivary protein was made by Hoerman et al
more than 50 years ago, in which they showed
that patients with prostate cancer exhibited
elevated acid phosphatase enzymatic activity
in parotid saliva.13 There has been a marked
advancement in protein analytical technologies
combined with bioinformatics, creating a new
revolution in salivary proteomics. Currently,
high-throughput mass spectrometry is the
core technology for salivary protein identifi-
cation, and salivary proteins were identified
as potential biomarkers for the detection and
monitoring of cancer (Table 17-1).14–29
 Salivaomics

TABLE 17-1  |  Salivary protein biomarkers for cancers

Cancer Sample Salivary protein biomarker Ref

Breast cancer Whole saliva EGF 14
C-erbB-2 15
CA15-3, C-erbB-2 15
VEGF, EGF, CEA 16
CA6 17
LRP 18

Squamous cell Whole saliva A1BG, CFB 19

carcinoma M2BP, MRP14, CD59, CAT, PFN 20
FGB, S100, TF, IGHG, CFL1 21
ADA 22
IL-8, M2BP, IL-1β 23
Salivary extracellular vesicles A2M, HPa, MUC5B, LGALS3BP, IGHA1, PIP, PKM1/M2, GAPDH 24

Gastric cancer Whole saliva 1472.78 Da, 2936.49 Da, 6556.81 Da, 7081.17 Da 25
CSTB, TPI1, DMBT1, CALML3, IGH, IL-1RA 26

Lung cancer Whole saliva HP, AZGP1, CALPR 27

Salivary extracellular vesicles Annexin A1, A2, A3, A5, A6, A11; NPRL2, CEACAM1, 28
HIST1H4A, MUC1, PROM1, TNFαIP3

Ovarian cancer Whole saliva CA125 29

EGF, epidermal growth factor; VEGF, vascular endothelial growth factor; CEA, carcinoembryonic antigen; LRP, lung resistance protein; CFB, complement
factor B; FGB, beta fibrin; S100, S100 calcium-binding protein; TF, transferrin; IGHG, immunoglobulin heavy chain constant region gamma; CFL1, cofilin-1;
ADA, adenosine deaminase activity; IL-8, interleukin-8; IL-1β, interleukin-1β; A2M, α 2-macroglobulin; HPa, haptoglobin α chain; MUC5B, mucin-5B;
LGALS3BP, galectin-3-binding protein; IGHA1, immunoglobulin α1 chain C region; PIP, prolactin-inducible protein; PKM1/M2, pyruvate kinase isozymes
M1/M2; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; NPRL2, nitrogen permease regulator 2-like protein; CEACAM1, carcinoembryonic antigen-
related cell adhesion model 1; HIST1H4A, histone H4; MUC1, mucin 1; PROM1, prominin-1; TNFαIP3, tumor necrosis factor α –induced protein 3.

Breast cancer under the curve [AUC] = 0.84). Furthermore,

Breast cancer is a well-studied cancer by salivary
proteomics. Significantly elevated epidermal
growth factor (EGF),14 C-erbB-2, and CA15-315
were identified in saliva of breast cancer pa-
tients compared to noncancer groups. Positive
correlation was found between serum and sa-
liva CA15-3 level, supporting the potential of
saliva as a diagnostic body fluid for breast can-
cer. We analyzed vascular endothelial growth
factor (VEGF), EGF, and carcinoembryonic an-
tigen (CEA) in saliva from breast cancer patients
to evaluate the predictive power of each protein
individually and in combination.16 The logistic
regression model revealed that the best combi-
nation was salivary VEGF and EGF, with 83%
sensitivity and 74% specificity, respectively (area
we identified CA6 and psoriasin as potential
salivary biomarkers for breast cancer and per-
formed validation using an independent cohort.
The results showed a significant difference in
salivary CA6 between breast cancer patients and
healthy controls (P = .0017).17 Recently, Wood
and Streckfus analyzed the concentrations of
lung resistance protein (LRP) in saliva of Stage I
breast cancer patients.18 The results showed that
the saliva of the patients had significantly higher
levels of LRP compared to healthy controls, sug-
gesting it is a novel biomarker for breast cancer.
Squamous cell carcinoma
Our prior salivary proteomic study discov-
ered five candidate markers (M2BP, MRP14,

345
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection
CD59, catalase, and profilin) associated with
oral squamous cell carcinoma (OSCC).20 A lo-
gistic regression model including five markers
achieved 90% sensitivity and 83% specificity
with a cross-validation prediction accuracy rate
of 85% (AUC = 0.93). Furthermore, by using
two additional independent cohorts, we have
validated the previously identified three salivary
protein markers for oral cancer (inter­leukin-8
[IL-8], M2BP, and IL-1β) and found IL-8 and
M2BP to be significantly different (P < .02)
between cancer and control groups.23 Ohshiro
et al analyzed whole saliva from three head
and neck SCC (HNSCC) patients using liquid
chromatography–mass spectrometry (LC-MS/
MS).19 Among 34 proteins detected in sali-
va from NHSCC patients, α1-B glycoprotein
(A1BG) and complement factor B (CFB) were
identified as unique proteins in cancer. Dow-
ling et al analyzed whole saliva samples from
HNSCC patients using two-dimensional dif-
ference gel electrophoresis (DIGE) analysis
and subsequent mass spectrometry.21 The re-
sult identified five proteins: Beta fibrin (FGB),
S100 calcium-binding protein (S100), transfer-
rin (TF), immunoglobulin heavy chain constant
region gamma (IGHG), and cofilin-1 (CFL1)
were increased in the saliva from HNSCC pa-
tients compared to the control group. Rai et al
assessed adenosine deaminase activity (ADA)
in saliva of tongue cancer and found signifi-
cant differences between cancer and control
groups, suggesting that ADA levels might be
useful as a diagnostic tool for early detection
of tongue cancer.22
Gastric cancer
Much effort has been made to develop serum
biomarkers for gastric cancer, and over 2,000
studies were reported in the past decade. The
most commonly used diagnostic biomarkers
are CEA and CA19-9. However, these bio-
markers are not widely acknowledged in early
detection of cancer because of their limited sen-
sitivity (< 21%), and the combination use of
CEA, CA19-9, CA125, and α-fetoprotein (AFP)
346
is suggested to improve the sensitivity for the
diagnosis of gastric cancer.30 Despite enormous
effort in serum biomarker discovery, there are
only a few studies related to salivary protein
biomarkers for detection of gastric cancer. Wu
et al identified four salivary proteins (1472.78
Da, 2936.49 Da, 6556.81 Da, and 7081.17 Da)
by mass spectrometry and found that these pro-
teins were significantly different between gastric
cancer and normal groups.25 Recently, we iden-
tified and quantified 519 proteins in the saliva
of gastric cancer patients using mass spectrom-
etry with tandem mass tag, among which 48
showed a significant differential expression pro-
file between cancer patients and controls.26 Five
proteins (CSTB, TPI1, DMBT1, CALML3, IGH,
and IL-1RA) were selected for initial verifica-
tion by enzyme-linked immunosorbent assay
(ELISA) and found to be downregulated in the
saliva of gastric cancer patients. The logistic re-
gression model using three biomarkers (CSTB,
TPI1, and DMBT1) in the prevalidation sample
set resulted in 85% sensitivity and 80% specific-
ity (AUC = 0.93). These findings provided the
proof of concept of salivary protein biomarkers
for the noninvasive detection of gastric cancer.
Lung cancer
We investigated salivary proteomic biomark-
ers in lung cancer patients and found that
the levels of three proteins (HP, AZGP1, and
CALPR) were significantly higher in lung can-
cer patients than in healthy controls. A logistic
regression model including the three proteins
achieved 88.5% sensitivity and 92.3% speci-
ficity (AUC = 0.90), suggesting that salivary
protein biomarkers have the potential for de-
tection of lung cancer.27
Ovarian cancer
Chen et al analyzed CA125 in saliva samples
from ovarian cancer patients and showed sig-
nificant differences in salivary CA125 levels
between the malignant and benign groups,
with 81.3% sensitivity.29 There was a linear

correlation between salivary and serum CA125
levels, suggesting the promising utility of saliva
for monitoring ovarian cancer. Using a sali-
va exRNA approach, we have discovered and
validated that five salivary exRNA biomarkers
(AGPAT1, B2M, BASP2, IER3, and IL-1β) can
significantly discriminate ovarian cancer pa-
tients (n = 21) from healthy controls (n = 35),
yielding a receiver operating characteristic plot
AUC value of 0.909, with 85.7% sensitivity
and 91.4% specificity.31
Salivary transcriptomics
A transcriptome is the complete set of RNA
molecules, including mRNA, miRNA, piwi-
interacting RNA (piRNA), and other small
RNAs such as transfer RNA (tRNA) and ribo-
somal RNA (rRNA). Salivary transcriptomics
has emerged as a powerful approach for ex-
ploring salivary biomarkers.32 Although the
genome is the same in all host cells, different
cells and body fluids show different patterns
of RNA composition; therefore, transcriptom-
ic analysis can provide valuable information
about disease states. In 2004, the human sali-
vary transcriptome was first discovered in our
laboratory using expression microarrays.33 We
characterized the salivary transcriptome as a
highly fragmented coding and noncoding gene
transcript derived from host and oral microbio-
ta.34,35 We also developed a method that allows
stable and direct saliva transcriptomic analysis
without further processing.36
We analyzed the salivary transcriptome in
cancer patients in attempts to improve early
diagnosis. Our prior transcriptomic studies dis-
covered seven mRNA biomarkers (IL-8, SAT,
IL-1β, OAZ1, H3F3A, DUSP, S100P) in the
saliva of OSCC patients.37,38 A logistic regres-
sion model including four markers (IL-8, SAT,
IL-1β, and OAZ1) achieved a prediction accu-
racy rate of 81%. We further validated these
oral cancer biomarkers using two additional
independent cohorts and demonstrated that the
AUC for prediction of OSCC ranges from 0.74
to 0.86 across the five cohorts.23 These findings
Salivaomics
suggested that salivary mRNA can be a poten-
tial biomarker for oral cancer detection and
opened a new avenue for salivary biomarker
discovery for other human cancers.
We found four salivary transcriptomic
biomarkers (KRAS, MBD3L2, ACRV1, and
DPM1) to be associated with resectable pan-
creatic cancer.39 A logistic regression model
demonstrated that the combination of four
markers could differentiate cancer patients
from control subjects with 90% sensitivity and
95% specificity (AUC = 0.971). The utility of
salivary mRNAs was further demonstrated for
the detection of breast cancer,17 ovarian can-
cer,31 and lung cancer.40 We profiled salivary
transcriptomes and proteomes of breast cancer
patients.17 Preclinical validation demonstrated
that the combination of eight transcriptomic
biomarkers (CSTA, TPT1, IGF2BPI, GRM1,
GRIK1, H6PD, MDM4, S100A8) and one
proteomic biomarker (CA6) could discriminate
between breast cancer patients and controls
with 83% sensitivity and 97% specificity. Tran-
scriptomic analysis of saliva in ovarian cancer
identified 4 upregulated and 16 downregulated
genes.31 The logistic regression model demon-
strated that the combination of five biomarkers
(AGPAT1, B2M, BASP1, IER3, IL-1β) showed
85.7% sensitivity and 91.4% specificity. Fur-
thermore, we found significant differences
in salivary mRNA between patients with
lung cancer and healthy controls.40 A logis-
tic regression model using the combination
of five markers (CCNI, EGFR, FGF19, FRS2,
and GREB1) could differentiate lung cancer
patients from controls with 93.75% sensitivity
and 82.81% specificity (AUC = 0.925). Hence,
salivary exRNA biomarkers could be useful for
screening for cancers.
Detection of miRNA from body fluids is
becoming increasingly important in liquid
biopsy. Many studies have shown that miRNAs
are frequently dysregulated in cancer.41 There-
fore, the changes in miRNA expression
patterns often correlate with disease and can
be promising diagnostic biomarkers for cancer.
Importantly, salivary miRNAs are more stable
347
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection
and discriminatory than salivary mRNA; thus,
circulating miRNAs are attractive potential
biomarkers. In 2009, we discovered miRNA
in saliva and characterized it as a possible
biomarker for oral cancer detection.42 Two
miRNAs (miR-125a and miR-200a) were sig-
nificantly reduced in the saliva of oral cancer
patients compared to the control group. Fur-
thermore, in the validation study for salivary
gland tumors, we demonstrated the combina-
tion of four miRNAs with 95% specificity and
69% sensitivity (AUC = 0.90).43
More recently, we reported piRNA in
saliva as an emerging potential biomarker
for cancers.44 We conducted high-throughput
sequencing of piRNA in human saliva from
healthy individuals, showing comparable
expression patterns and levels compared to
that in other body fluids. These findings opened
doors for further investigation of salivary
piRNA as a cancer biomarker.
It should be mentioned that while RNA has
been demonstrated in saliva since 2004, its
presence and authenticity has been challenged.
A defining moment in the field of exRNA came
in 2012 when the NIH Common Fund funded
“The NIH Extracellular RNA Communication
Consortium (ERCC)” to develop a commu-
nity of investigators to address the critical
issues and to generate fundamental scientific
discoveries and innovative tools and technol-
ogies in five key initiatives: (1) defining the
fundamental principles of exRNA biogenesis,
distribution, uptake, and function as well as the
development of the molecular tools, technol-
ogies, and imaging modalities to enable these
studies; (2) generating a reference catalog of
exRNAs present in the body fluids of normal
healthy individuals that would facilitate disease
diagnosis and therapeutic interventions; (3)
identifying exRNA biomarkers of disease; (4)
demonstrating the clinical utility of exRNAs
as therapeutic agents and developing the scal-
able technologies required for these studies;
and (5) developing the Data Management and
Resource Repository (DMRR), a community
resource to provide access to exRNA data,
348
standardized exRNA protocols, and other use-
ful tools and technologies generated by funded
projects. Investigators from all five initiatives
will form the ERCC with goals to discover
fundamental biologic principles about the
mechanisms of exRNA biogenesis, to develop
an exRNA catalog in normal human body
fluids, and to investigate the use of exRNAs
as therapeutic molecules or biomarkers of
disease. The NIH Common Fund ERCC initia-
tive included saliva extracellular RNA in both
biomarker development and reference catalog
development, firmly credentialing the salivary
exRNA scientifically and translationally. Figure
17-3 is an insert from “exRNA Atlas” depict-
ing contributions of RNA-sequencing data sets
from various bodily fluids. Saliva’s contribu-
tion stands at 248 small RNA libraries (http://
exrna-atlas.org).
Saliva-Exosomics
Discovery of salivary exosomes
Extracellular vesicles (EVs) are classified into
three subgroups (exosomes, microvesicles, and
apoptotic bodies) based on their size and bio-
genetic pathways.45 Exosomes are intraluminal
vesicles (ILVs) that are formed within multive-
sicular bodies (MVBs) and released upon fusion
of the MVBs with the cell membrane. Over 30
years ago, two independent groups observed
that MVBs in reticulocytes released small ves-
icles into the extracellular space.46 Then, the
term exosomes was coined in 1987 by John-
stone et al to describe that vesicles shed from
cultured cells retained enzymatic activity as a
remnant from the parent cells.47 It was later
determined that exosomes are EVs of endoso-
mal origin that are not degraded by lysosomes,
noting that exosome secretion is a way to ex-
crete unnecessary products from the cells.48
With the discovery that exosomes contain
RNA, exosomes acquired substantial interest
as mediators of cell-to-cell communication.48
Salivary exosomes were first described in 2008

Fig 17-3  |  exRNA Atlas.
Urine (293)
Sputum (15)
Serum (376)
Seminal fluid (8)
Saliva (256)
when Ogawa et al found that 30- to 130-nm
vesicles were present in human whole saliva.49
The stability of exosomes in the circulation and
body fluids has made exosomes attractive as
potential biomarkers. Typically, exosomes are
defined as vesicles ranging from 30 to 100 nm
in size and 1.13 to 1.19 g/mL in density and
are isolated through density gradient or sucrose
cushion by ultracentrifugation at 100,000 g.
However, the term exosome is now often used
in a less restrictive manner than Johnstone’s
original definition.50 For the nomenclature
and definition of extracellular vesicles, see the
websites of the International Society for Ex-
tracellular Vesicles (http://www.isev.org), the
American Society for Exosomes and Microves­
icles (http://www.asemv.org), and Vesiclepedia
(http://microvesicles.org).
Human saliva is an ideal fluid with distinct
advantages for oral cancer detection.23 The
isolation of exosomes from saliva has been
optimized, and the use of this small but highly
informative fraction may reduce the overall
complexity of saliva as a result of contribu-
tion from local and systemic sources.51 For
these reasons, the study of vesicles secreted by
cancer cells via exocytosis into saliva will be
a valuable clinical approach for the detection
Saliva-Exosomics
Biofluid
Amniotic fluid (10)
Bile (17)
Bronchoalveolar lavage
fluid (10)
Cerebrospinal fluid
(615)
Conditioned media (22)
Ovarian follicle fluid (10)
Plasma (4,118)
of novel biomarkers in cancer. We coined
the term saliva-exosomics to describe the
next-generation salivaomics that studies sal-
ivary exosomes through the application and
integration of advanced “-omics” technologies
to better delineate their specific functions and
for use as a source of noninvasive biomarkers
for disease diagnosis.52
Structure of salivary exosomes
Exosome characterization typically includes
morphologic analysis. Due to their nanoscale
size, morphologic analysis of exosomes had
solely been limited to electron microsco-
py (EM).53 While EM has been a standard
technique for exosome characterization, this
technique may not provide a representative
view of the exosomes due to the harsh sample
processing such as fixation. Indeed, transmis-
sion EM showed a cup-shaped appearance,
while cryo-EM showed the round shape of
the exosomes.54 We first applied atomic force
microscopy (AFM) and field emission scan-
ning electron microscopy (FESEM) to assess
the native salivary exosome structure and sub-
structural organization unresolvable in EM.55,56
We found the distinct substructure of single
349
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection
isolated 70- to 100-nm human salivary exo-
somes in the form of trilobed structures and
demonstrated their reversible elastic nano-
mechanical properties. High-resolution AFM
images correlated well with the exosome struc-
tures obtained from FESEM, where low-force
imaging resulted in round-shaped exosomes,
suggesting exosomes have spherical morphol-
ogy unless outside force is exerted on them.
In addition, AFM phase-contrast images of
salivary exosomes indicated a heterogeneous
surface, which was attributable to the presence
of proteins in the highly dense lipid membrane,
consistent with previous proteomic analysis of
salivary exosomes.57
Salivary exosomes are naturally occurring
bioparticles, parts of which are secreted from
the surfaces of oral epithelial cells into saliva.
Because exosomes released by normal and
tumor cells have been suggested to differ in
both functional and structural properties,58 oral
cancer–derived exosomes in saliva have great
potential as biomarkers for cancer detection.
To elucidate the structural differences between
the salivary exosomes derived from healthy
subjects and oral cancer patients, Sharma et
al investigated morphologic characteristics at
single-vesicle level using high-resolution AFM.59
AFM imaging displayed irregular morphologies
and higher intervesicular aggregation in cancer
exosomes than normal exosomes. Quantita-
tive analysis revealed that the size and CD63
surface density were significantly increased in
cancer exosomes (98.3 ± 4.6 nm) compared to
normal exosomes (67.4 ± 2.9 nm) (P < .05).
The structural and morphologic aberrations
in the exosomes indicated that these exosomes
are at least in part cancer-derived products that
were directly shed into saliva. Interestingly,
MVBs were identified in oral cancer salivary
exosome fractions. These multivesicular struc-
tures revealed the presence of ruptures and
elongated nanofilaments around the lumen of
these MVBs, suggesting these to be the sites
for the release of the exosomes as well as the
filamentous extension of nucleic acids.
350
Contents of salivary exosomes
In general, exosomes carry a unique cargo of
proteins and nucleic acids that can be relative-
ly distinct from those of the cell of origin. The
most commonly detected proteins are mem-
brane transport and fusion proteins such as
tetraspanins (eg, CD63, CD9, and CD81), heat
shock proteins (eg, Hsp70 and Hsp90), Rab
GTPases, major histocompatibility complexes
(MHC class I and II), and endosomal proteins
(eg, Alix and Tsg101) that are involved in the
biogenesis of exosomes from MVBs.60 Other
proteins found on exosomes include signaling,
cytoskeletal, metabolic, and carrier proteins. Of
note, MHC class I is ubiquitously expressed on
all exosomes, while MHC class II is confined
to exosomes derived from antigen-presenting
cells, including dendritic cells, macrophages,
and B cells.61 Proteomic studies on mammali-
an EVs have yielded extensive catalogs of the
proteins found in various types of EVs isolated
from cells, tissue, or body fluids. The databas-
es are publicly available at Vesiclepedia45 and
ExoCarta.62 Both databases include data on
proteins, nucleic acids, lipids, and the constit-
uents isolated from salivary exosomes.
The first comprehensive proteomic analysis
of human salivary exosomes was performed by
Gonzalez-Begne et al using a multidimensional
protein identification technology (MudPIT).57
The analysis identified 491 proteins in the exo-
some fraction of human parotid saliva, and
Gene Ontology analysis found that cytosolic
proteins comprise the largest category of the
proteins. Comparison between the parotid
salivary exosomes (491 proteins) and the
previously identified global parotid saliva pro-
teome (914 proteins6) showed a 23% overlap
between the parotid salivary exosomes and the
parotid saliva, whereas 20% were unique to
the parotid exosomes and 57% were unique
to the parotid saliva. Ogawa et al revealed the
presence of two different types of vesicles (exo-
somes I and II) with different mean diameter
(I: 83.5 nm, II: 40.5 nm) and protein constit-
uents.63 A total of 101 and 154 proteins were

identified in exosomes I and II, respectively,
and 68 proteins including common markers
(CD63, Alix, Tsg101 and Hsp70) were found
overlapped between the two groups. Approx-
imately 40% of the proteins identified were
extracellular (eg, immunoglobulin chain) or
secretory proteins (eg, serum albumin), indi-
cating that saliva contains vesicles originating
from circulating lymphocytes and intravascular
fluid. The presence of DPP IV (CD26) in the
vesicles and its enzymatic activity were also
demonstrated by showing DPP IV–dependent
degradation of substrates (substance P and
GIP), suggesting that the vesicles were biolog-
ically active.
We performed the proteomic profiling of
salivary microvesicles (MVs) with an average
diameter of 100 to 1,000 nm to investigate a
different type of EVs in saliva.64 LC-MS/MS
combined with gel electrophoresis identified
63 proteins in salivary MVs. Among these, 35
proteins were exclusively identified in MVs by
comparing parotid exosomes proteome, sug-
gesting that salivary MVs contained their own
unique proteins. The most striking finding was
that saliva triggers factor VII–mediated coagu-
lation of human plasma. Berckmans et al tested
the ability of saliva to induce clot formation
of autologous plasma and found that sali-
vary exosomes shortened the clotting time of
exosomes-depleted plasma. Western blot anal-
ysis and transmission EM with immunogold
labeling identified tissue factor, the initiator of
coagulation activation in salivary exosomes.
Moreover, the salivary exosomes-induced
shortening of the clotting time was completely
abolished in the presence of antifactor VII.
These results indicated that saliva facilitates
hemostasis as one of the first steps in the pro-
cess of wound healing.
Salivary exosomes are also known to contain
mRNA55 and small RNA65 including miRNA,65
piRNA, small nucleolar RNA (snoRNA), and
other small RNAs (rRNA and tRNA).44 Inter-
estingly, piRNA appears to be found at higher
abundance in exosomes compared to whole
saliva.44 We conducted high-throughput RNA
Saliva-Exosomics
sequencing (RNA-Seq) using human cell-free
whole saliva and found that the most abun-
dant types of small RNAs were piRNA (7.5%),
miRNA (6.0%), and snoRNA (0.02%), con-
sistent with prior study. Exosomes offer
protection from RNase, thereby inhibiting
RNAs from degradation and allowing them
to be taken up by the cells with subsequent
putative effects on gene expression in the target
cells.66 Indeed, prior studies have shown that
salivary exosomal RNAs are stable and can
be taken up and translated by recipient cells,
indicating that these RNAs are biologically
functional. Further saliva-exosomics studies
will provide important insight regarding the
mechanisms that control the epithelial cell
homeostasis in the oral cavity.
Salivary exosomes as biomarkers
for cancer
A breakthrough in the field of EVs was made
in 2008 when it was discovered that glioblas-
toma MVs carry cancer-specific mutant mRNA
(EGFRvIII).67 Strikingly, the tumor-specific
EGFRvIII was detected in the serum MVs
from glioblastoma patients, suggesting
that tumor-derived MVs may serve as cancer
biomarkers. Since this discovery, cancer-derived
exosomes have been recognized as an im-
portant diagnostic tool. A series of “-omics”
approaches has revealed that exosomal
miRNA, DNA, and protein signatures may
also serve as biomarkers to aid diagnosis. Se-
rum exosomal miR-21 and miR-141 levels
are significantly increased in the patients of
esophageal SCC and prostate cancer, respec-
tively.68 Mutated KRAS and p53 DNA were
detected by whole genome sequencing in the se-
rum exosomes of pancreatic cancer patients,69
and the membrane-anchored exosomal pro-
tein Glypican-1 (GPC-1) was identified as a
promising biomarker of pancreatic cancer.70
These findings indicate that serum exosomes
in cancer patients have great potential for can-
cer diagnosis.
351
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection

PBS Tumor (WT) Tumor (exosome secretion inhibited)

Control group (healthy) Tumor group #1 Tumor group #2

Control group Tumor group #1

Saliva Salivary gland Serum Saliva Salivary gland Serum Tumor

(Panel 1) ESTABLISHMENT OF TUMOR-SPECIFIC SALIVARY TRANSCRIPTOMIC BIOMARKER PROFILE

Daf2
mRNA
p < .0001
15

ΔCt (GAPDH)
10
Discovery of Verification/validation of 5
tumor-specific tumor-specific
salivary transcriptomic salivary transcriptomic 0
Microarray profile profile
–5

er
hy

nc
alt

Ca
He
qPCR

(Panel 2) DETERMINE ROLE OF TUMOR-DERIVED EXOSOMES IN TUMOR-SPECIFIC SALIVARY TRANSCRIPTOMIC BIOMARKERS

Daf2
p = .656
20
Control group #1 (PBS) Tumor group #1 (GFP) Tumor group #2 (DN-Rab11-GFP)
ΔCt (GAPDH) 10 p = .001
Determine whether established tumor-
specific salivary transcriptomic profile 0
is altered with the inhibition of exosome
secretion at the tumor source –10

FP
hy

-G
GF
Saliva Saliva Saliva –20
alt

11
He

ab
-R
DN
qPCR

Fig 17-4  |  Mouse pancreatic cancer model demonstrating that tumor-derived exosomes are responsible for
the transport of tumor-specific RNA biomarkers from the organ of pathology to salivary glands and saliva.71

We have focused our efforts on under- salivary transcriptome were the result of the
standing the mechanisms and roles of salivary changes in cancer-derived exosomes. This study
exosomes in cancer. To provide proof of demonstrated that cancer-derived mRNAs are
concept for the potential utility of salivary the cargo of exosomes and reach the salivary
exosomes for cancer detection, we developed gland via circulation, providing a mechanistic
a pancreatic cancer mouse model in which link between discriminatory salivary biomark-
a mouse pancreatic cancer cell line (Panc02) ers and distal tumor.
was orthotopically injected into the pancreas To further our understanding of the link
of syngeneic mice.71 We investigated the role between salivary exosomes and distal tumor,
of pancreatic cancer–derived exosomes in sal- we generated a xenograft lung cancer mouse
ivary biomarker development by inhibiting the model in which H460 human lung cancer cells
exosome biogenesis in Panc02 cells (Fig 17-4). that stably express hCD63-GFP were ortho­
Stable transfection of the dominant negative topically injected into immunocompromised
form of the GTPase Rab11 (DN-Rab11) effec- mice.72 We identified human GAPDH mRNA
tively inhibited the biogenesis of exosomes in in hCD63+GFP+ exosome-like MVs in mouse
Panc02 cells and resulted in the ablation of saliva, indicating that exosome-like MVs carry
discriminatory salivary biomarker signatures tumor cell–specific mRNA and travel to the cir-
between tumor-bearing mice and control mice, culation and reach the saliva where they have
suggesting that the observed changes in the a potential role as tumor biomarkers.

352

Our most recent animal study demon-
strated a role of salivary exosomes in immune
surveillance.73 To investigate an immunoregu-
latory effect of salivary exosomes, saliva from
Panc02-bearing mice was orally administered
to non–tumor-bearing control mice. Expres-
sion levels of NK activation markers CD69 and
NKG2D was significantly decreased by garage
feeding of tumor saliva, while these effects were
ablated by DN-Rab11–mediated inhibition of
exosome biogenesis in Panc02 cells. These
animal studies supported our hypothesis that
cancer-derived exosomes provide a rationale
for the development of salivary biomarkers
that are applicable to distal tumor.
Winck et al performed a proteomic analy-
sis of salivary EVs from OSCC patients and
healthy controls, and a total of 381 proteins
were identified in the EVs from the two groups
by mass spectrometry.24 Among the pro-
teins identified in salivary EVs, eight proteins
including α 2-macroglobulin (A2M), hapto-
globin α chain (HPa), mucin-5B (MUC5B),
galectin-3-binding protein (LGALS3BP), Ig α1
chain C region (IGHA1), prolactin-inducible
protein (PIP), pyruvate kinase isozymes M1/M2
(PKM1/M2), and GAPDH were differentially
expressed between the two groups (ANOVA,
P < .05). Gene Ontology analysis showed that
the salivary EVs proteome in OSCC patients
was enriched in proteins related to molecular
transport and cellular growth and prolifera-
tion, suggesting that the property of salivary
EVs may reflect the tumor of origin. Sun et al
analyzed the proteome of salivary EVs isolated
from lung cancer patients and identified 113
and 95 proteins in cancer patients and healthy
controls, respectively.28 Among the total 113
proteins identified in the cancer group, 63 pro-
teins were exclusively detected in this group.
The literature survey showed that 12 proteins
are lung cancer–related biomarkers, including
annexin family members (annexin A1, A2,
A3, A5, A6, A11), nitrogen permease regula-
tor 2-like protein (NPRL2), CEA-related cell
adhesion molecule 1 (CEACAM1), histone H4
(HIST1H4A), mucin 1 (MUC1), prominin-1
Acknowledgment
(PROM1), and tumor necrosis factor α–induced
protein 3 (TNFα IP3). These works thus open
up promising new lines of research that may
lead to the identification of new classes of can-
cer biomarkers. Further functional studies of
salivary exosomes will provide new clues to its
mechanism of action and simultaneously raise
fundamental questions about the coregulation
of serum and salivary exosomes on the progres-
sion of cancer.
Future Perspectives
In the past decade, salivaomics studies have
revealed the utility of saliva in identifying the
presence of diseases. Much progress has been
made in understanding the characteristics of
saliva, with significant advances on how the
salivary constituents relate to their biomark-
ers and functions. In addition, a growing body
of saliva-exosomics study is highlighting the
role of disease-derived exosomes in saliva.
The unique properties of exosomes in saliva,
which originate from organelles and then mi-
grate into saliva, are attracting the attention of
scientists as these could be used for diagnostic
biomarkers, potential surrogate markers for
other physical conditions, or novel immune
regulatory systems through the gastrointes-
tinal tract. These basic, translational, and
clinical research advancements of salivaomics
and saliva-exosomics support and credential
the mechanistic underpinnings of oral-systemic
connection and communication (Fig 17-5).
Acknowledgment
This work was supported by Public Health Ser-
vice (PHS) grants from the National Institutes
of Health (NIH)—UH3 TR000923 and R90
DE022734—and the Ronnie Dios Stand Up
and Shout Cancer Research Fund.
353
17 Oral-Systemic Connection: The Salivaomics and Exosomics Connection
Salivary gland
Cancer-derived Exosomes
exosomes
Pancreatic cancer
Fig 17-5  |  Oral-systemic connection: The salivaomics and saliva-exosomics connection.
Disclosures
David Wong is cofounder of RNAmeTRIX
Inc, a molecular diagnostic company. He
holds equity in RNAmeTRIX and serves as a
company Director and Scientific Advisor. The
University of California also holds equity in
RNAmeTRIX. Intellectual property that David
Wong invented and which was patented by the
University of California has been licensed to
RNAmeTRIX. Dr Wong is also a consultant
for GlaxoSmithKline, Wrigley, EZLife Bio,
and Colgate-Palmolive.
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The Economic Impact of
Periodontal Inflammation
Michael C. Alfano, dmd, phd
This chapter appears at the end of this sec-
ond edition of The Oral-Systemic Health
Connection because it is logical to consider
the economic effects of a biologic process, a
disease or set of diseases, or their various treat-
ments after the basic aspects of the processes
involved are clearly understood. Thus, I will
not endeavor to repeat the explanations of
specific biologic processes, treatments, and out-
comes addressed earlier in this text. However,
the various biologic processes and interactions
have been studied for several decades, more
than 10,000 papers have been written on these
topics, and tens of millions of research dollars
have been expended, all in the search for great-
er clarity in our understanding of the precise
interactions of oral and systemic diseases.1
While not every paper has shown a clear
relationship between oral infection, especially
periodontal disease, and systemic health, the vast
majority of the published literature supports a
claim that is now virtually universally accepted:
Periodontal infection is associated with a num-
ber of noncommunicable systemic inflammatory
diseases. The goal of this chapter is to take that
agreement and move the discussion from the
association of periodontal disease with a num-
ber of inflammatory-based systemic diseases to
the role of periodontal disease as a contributory
cause of several inflammatory-based noncom-
municable systemic diseases.2–4 Once causality,
CHAPTER 18
even partial or contributory causality, is estab-
lished, the dimensions of economic impact
expand substantially.
What is a contributory cause of a disease?
Bale et al2 define it as follows: “A contributory
cause does not require that all those who possess
the contributory cause experience the disease,
nor does it require that all those who are free
of the contributory cause be free of the disease.
It also means the contributory cause may not
be necessary to experience the disease.” We can
clarify this explanation by using the relation-
ship between smoking and lung cancer. A person
can smoke and never get lung cancer; another
person who has never smoked can get lung
cancer. But in the majority of the population
(80% to 90%, according to the American Lung
Association5), smoking becomes the cause—the
contributory cause—of their lung cancer.
I deliberately selected lung cancer as an
example because while there is no doubt that
smoking is a contributory cause of lung can-
cer, no randomized, double-blind, controlled
trial of smoking and lung cancer has ever
been performed. This is important because
most researchers today insist it is impossible
to say that periodontal disease is a contrib-
utory cause of noncommunicable systemic
inflammatory diseases such as cardiovascular
disease (CVD) or diabetes until a large, ran-
domized, well-controlled clinical trial confirms
357
18 The Economic Impact of Periodontal Inflammation
it. I submit that such a large, expensive, and
difficult-to-control study will never be done.
Indeed, based on what we have learned from
the private insurance sector on this topic, which
is described later in this chapter, I further submit
that such a large prospective study might be
unethical. Thus, by insisting on a study that will
likely never be performed, the research com-
munity is potentially denying society a huge
benefit from improved periodontal care driven
not only by an interest in oral health but also by
a desire to mitigate the effects of life-threatening
diseases such as diabetes and heart disease.
This benefit, as shown by the insurance stud-
ies described in the next section, consists of a
significantly lower chance of hospitalization
and complications from inflammatory-based
systemic diseases and a potential annual savings
of billions of dollars in the United States alone.
It is time to consider whether it continues to be
ethical to deny direct causal inference between
periodontal disease and systemic disease.
The Insurance Studies:
A Framework for Action
Several large, retrospective analyses of insurance
data have consistently shown that individuals
who receive periodontal therapy have signifi-
cantly lowered costs of health care, driven
primarily by fewer hospitalizations and emer-
gency department visits.6–9 For example, Mosen
et al6 reported significantly better hemoglobin
A1c (HbA1c) control, a 44% reduction in hospital
admissions, and a 38% reduction in emergen-
cy department visits in a population of diabetic
patients who received regular dental care com-
pared with a matched set of diabetic patients
who did not receive regular dental care. Using
data from United Concordia, Jeffcoat et al7
reported a strikingly similar reduction in hos-
pitalizations of 39.4% in a study of patients
with diabetes who received periodontal care
versus those who did not. The annual reduc-
tion in treatment costs for those who received
358
periodontal treatment versus those who did not
was also measured; the following systemic con-
ditions and associated savings were reported:
$2,840 annual savings with type 2 diabetes,
$5,681 annual savings with cerebrovascular
disease, and $1,090 annual savings with coro-
nary artery disease.
One criticism of this type of retrospective
study is that the subjects in the dental treatment
groups are simply more compliant with their
health care regimens. However, one of the cited
studies, conducted by United Healthcare, spe-
cifically controlled for this compliance effect,
and it showed the opposite effect of what might
be expected.8 Those individuals who received
periodontal care and were not compliant with
their medical treatment regimens had much
higher annual savings. Specifically, those who
received periodontal care and were not com-
pliant with medical recommendations saved
$1,849 per year compared to savings of $264
per year by those who received periodontal
care and were compliant with medical recom-
mendations. In short, both groups who had
the benefit of periodontal care showed medical
savings, with the noncompliant group show-
ing much greater savings. While this study is
not dispositive in proving periodontal care
reduces total health care cost, it is very sup-
portive of this relationship and mitigates the
most obvious objection to such retrospective
study designs. More definitive proof of the ben-
efits of periodontal care in reducing total health
care costs will be described in the next section.
All three studies cited earlier7–9 were sup-
ported by the dental insurance industry and
conducted on proprietary databases. Some
would devalue the importance of two of them,
though published in peer-reviewed journals,
because of the sponsorship of the research. This
makes the work of the team at the American
Dental Association (ADA) Health Policy Insti-
tute led by Marko Vujicic more meaningful.
In this study, Nasseh et al9 used a commer-
cially available database from Truven Health
MarketScan Research to explore the effect of
periodontal treatment on the health care costs

associated with newly diagnosed type 2 diabe-
tes. One might suspect that in cases of newly
diagnosed diabetes, some of the effects of the
diabetic process may not yet have taken hold,
potentially minimizing any salutary effect of
periodontal treatment. However, the authors
reported total health care savings in the peri-
odontal treatment group of $1,799, a figure
that is remarkably similar to what others have
reported, even though the study was conducted
on a different group of individuals at a differ-
ent time using different methodologies.
In an analysis of the earlier studies plus an
additional Cigna study,10 Chávez et al11 esti-
mated the potential savings nationwide for the
pool of Medicare patients. Their results were
remarkable: When they assessed the total sav-
ings available if all Medicare patients with a
history of stroke, congestive heart failure, or
diabetes received periodontal care each year, the
annual savings would be $19.0 billion based
on the Cigna study, $18.8 billion based on the
United Concordia data, and $20.4 billion based
on the United Healthcare dataset. Given the dif-
ferent approaches, timelines, investigators, and
populations used to generate these calculations,
the similarities in the numbers are amazing.
While the analysis by Chávez et al11 is
impressive, it assumes that everyone who is
eligible for periodontal care will receive it, and
this is not at all likely. Therefore, we should
look to another analysis, completed by the
respected consulting firm Avalere.12 The Avalere
study took data from three of the studies dis-
cussed earlier (Cigna,10 United Concordia,7 and
United Healthcare8) and added data generated
by Aetna to develop a model to determine the
impact of periodontal care on the cost of the
Medicare program if periodontal care was
made available through Medicare to anyone
with type 2 diabetes, CVD, or stroke. They esti-
mated the cost of periodontal care at $825 for
initial treatment (scaling and root planing) and
$250 for maintenance visits every 6 months
thereafter. In addition, they assumed that only
5% of eligible individuals would seek the care
in year 1 and that this number would only
The Economic Savvy of Dental Insurers
grow to 20% of eligible individuals seeking
care by year 10. Thus, over a 10-year period,
periodontal care would cost $7.2 billion. How-
ever, the projected savings, driven primarily by
fewer hospitalizations for the systemic condi-
tions during this same 10-year period, would
be $70.7 billion, for a net savings of $63.5
billion over 10 years. A year-by-year analysis
showed that the program generated net savings
of $500 million in year 1, growing to a net sav-
ings of $12.2 billion dollars by year 10. If more
people accessed the program, the savings would
go up, and Avalere estimated that these positive
effects would continue over the long term.
The remarkable similarity of the reports from
six different insurance studies, completed at six
different times by six different investigators on
six different populations using somewhat differ-
ent methods and definitions, makes a compelling
case that the minimization of oral inflammation
through periodontal care improves certain sys-
temic diseases so that total health care costs
are dramatically lowered. However, before we
can complete the case that periodontal care is
a contributory cause of systemic disease, some
prospective data is needed. The next section
reports on such prospective data. However, the
proprietary nature of the next level of support
requires the reader to accept the actions of the
insurance sector based on verbal reports. The
prospective data have not been published, most
likely in an effort to retain competitive advan-
tage in the marketplace.
The Economic Savvy of
Dental Insurers
Unencumbered by traditional academ-
ic norms, which would have required
large, well-controlled clinical trials of the im-
pact of periodontal care on systemic disease,
the insurance industry acted on its retrospec-
tive assessments of periodontal therapy on
the costs of treating systemic disease. To be
clear, the industry did not act in a vacuum
359
18 The Economic Impact of Periodontal Inflammation
based on its own studies alone; it consult-
ed the decades-long research enterprise that
showed numerous epidemiologic associations,
highly plausible biologic mechanisms, smaller
clinical trials, and surrogate endpoint analyses,
each of which, on balance, supported the con-
cept that oral inflammation is a contributory
cause of systemic diseases that are also driven
by inflammatory processes. So how exactly did
the insurance industry respond?
To answer this question requires indulgence
on the part of the reader, because the infor-
mation on which I base this discussion comes
from personal conversations with insurance
industry executives and direct observation of
presentations made by industry representatives
to the Centers for Medicare and Medicaid
Services (CMS) and the Congressional Budget
Office (CBO). In addition, due to the com-
petitive nature of the insurance business and
because the data presented can represent a
proprietary advantage to one company over
another, I feel obliged to protect the identities
of the various presenters. Indeed, they came
to the table in generous common cause with
several not-for-profit organizations, including
the Santa Fe Group, Oral Health America,
Pacific Dental Services Foundation, and the
Center for Medicare Advocacy, in an effort to
shed light on their actions vis-à-vis oral and
systemic health, so that the huge federal pro-
grams of Medicaid and Medicare might benefit
from their real-world experiences. In sum, these
individuals acted for the public good, and they
and the insurance industry per se should be
commended for this action.
Disclaimers aside, we can now answer the
question: How exactly did the insurance indus-
try respond? The industry responded by acting
on its retrospective studies and marketing its
periodontal insurance services not only for
their inherent benefits to oral health, which
include tooth retention, fresh breath, improved
mastication, and social confidence, but also
for the benefits to systemic health that include
markedly lower costs for the management of
diseases such as diabetes and heart disease.
360
As I am best able to determine, these mar-
keting actions took several shapes. First, the
dental insurers began to share their data with
large corporations to convince them of the out-
size value of dental insurance in terms of its
ability to save money in other areas of health
care. This argument resonates with corpora-
tions because most of them are self-insured,
and any savings derived from the addition of
periodontal services to the benefits mix delivers
savings directly to the bottom line by reducing
health care payments for employees who suffer
from one of the inflammatory-based systemic
diseases. Second, those dental insurers that
were a subsidiary of a larger health insurance
company began to work out reimbursement
arrangements from the general health side of
the parent company for cost benefits delivered
by the dental company to the general health
of the insured population, to be shared back
with the dental company in some appropriate
ratio. I am told that such funds only changed
hands after those insured individuals who suf-
fer from one of the noncommunicable diseases
actually received the requisite periodontal care.
Indeed, it is reported that the dental insurers
would actually recruit the affected insured indi-
viduals for periodontal care and would add
enticements such as waiving copayments and
deductibles to enhance the chances that the
affected people would seek periodontal care.
Finally, some dental insurers are reported to
have taken these various processes to the next
level by offering their dental/periodontal insur-
ance services to general health insurers that did
not have a dental insurer in their portfolios of
companies. These arrangements presumably
worked through contracts in which the gen-
eral health care savings were shared via some
appropriate formula between the two different
insurers.
This chapter could have been written
without the disclosures on insurance indus-
try practices included in this section. Indeed,
while everything to my knowledge about these
practices is legal, and although nothing was
told to me or observed by me in confidence,
 Challenge to the Dental Profession: Moving from Association to Causation
I take some risk in dispensing with the norms
of referencing for this section of the chapter
even through such means as named personal
communications. However, this information
was included because it is important that
individuals from the private insurance sector
continue to be forthcoming with their data and
practices so that the public insurance sector can
derive the same benefits. Even more important
is that the research, practice, and educational
communities know of these private insurance
practices because they constitute real-world,
prospective confirmation that the effects of
periodontal care to mitigate certain systemic
diseases are, in fact, valid.
Some of the dental insurers involved have
been acting in the way described earlier for
more than a decade. If the effect of periodon-
tal care to reduce total health care costs is
not real, their reimbursement practices would
have collapsed under their own weight because
they would have failed economically a long
time ago. In sum, I consider the six insurance
studies summarized in the prior section and
the prospective actions of the private insur-
ance industry described in this section to be
equal to or better than the proof that may
have been provided by a well-controlled, large
clinical trial. In a very significant way, these
real-world insurance studies and the current
insurance company actions are the equivalent
of a phase IV trial or an N of 1 clinical trial, as
eloquently defined by Curro et al.13 Finally, this
information provides the basis for the challenge
to the dental research, education, and practice
communities as described in the next section.
Challenge to the Dental
Profession: Moving from
Association to Causation
I cut my teeth in clinical research, both as an ac-
ademic researcher and as an industry executive,
on the value of the well-controlled clinical trial
as the gold standard of evidence required prior
to approving a new drug or device, accepting
a surgical technique, or changing a therapeutic
paradigm. Indeed, the well-executed clinical tri-
al creates a sort of safe space for researchers and
thought leaders, and in general it has served so-
ciety very well to protect against sham products
or outright scams through the years. However,
there are many scenarios of clinical trials not
serving society well. The best examples come
from drug development, where side effects often
go unnoticed until a given drug is delivered not
hundreds or even thousands of times but tens of
thousands of times; or perhaps the drug is not
given for weeks or months but for years. This
does not mean that clinical trials are of no use
but that they must be accompanied by continu-
ing surveillance as in the phase IV approach or
in real-world scenarios in people with comorbid
disease as in the N of 1 approach.
Further assault on the value of the clinical
trial can come in the form of the evidence-based
review system, which can devalue scores if not
hundreds of studies in a single analysis. Indeed,
while the evidence-based approach has done
wonders to enhance critical albeit retrospective
thinking on clinical design, we are regularly
confronted with the need to rethink norms of
clinical care because the evidence is weak. I
reiterate that the discipline of evidence-based
reviews has been a good thing, but I fear that
we are abusing the process and are in danger
of approaching a situation in which no study
is good enough to retrospectively pass muster.
Indeed, when was the last time you read an
evidence-based review that concluded that the
evidence is strong and consistent? Continuing
along the current path will have the insidious
effect of further debasing science in the minds
of the public, resulting in a situation in which
political opinion, folklore, religion, and such
are placed on an equal plane with science
(eg, creationism versus evolution). While not
directly related to the purpose of this chapter,
I urge all who are engaged in evidence-based
reviews to set their parameters and choose their
words carefully lest the very purpose for which
361
18 The Economic Impact of Periodontal Inflammation
the evidence-based process was created is mar-
ginalized, with the unintended consequence of
demeaning all scientific data on all subjects.
Finally, as noted previously, although there
never was a well-controlled human trial on
the effects of smoking on lung cancer, it is
virtually universally accepted that smoking is
a contributory cause of lung cancer and that
smoking affects 80% to 90% of all lung can-
cers. How did it become acceptable to blame
smoking for lung cancer? When did the data
become compelling enough to move the dia-
logue from association to causation? Was it
the report of the Surgeon General in 1964, as
referenced in chapter 1? Was it the work of
Hammond and Auerbach on smoking beagles
in early 1970?14 Or was it merely the constant
repetition of all of the observational data? I do
not know when the relationship tipped from
associative to causal, but it did tip, and it never
went back, despite the efforts of the Tobacco
Institute and the cigarette industry to malign
the causal relationship.
I submit that it is past time for the oral
health research community to tip the dialogue
on the relationship between oral and systemic
health from associative to causal. By clinging
to a messianic belief that we cannot speak of
causation until the large clinical trial is deliv-
ered, we are denying society the opportunity
to benefit fully from the decrease in hospital-
izations and emergency department visits that
results from periodontal therapy. In particular,
we are denying the large number of individuals
who are on public health insurance to benefit
in the way those insured by private entities are
benefitting. As noted previously, when society
loses the indirect systemic benefits of periodon-
tal care, it also loses the direct benefits of oral
care, including tooth retention, fresh breath,
improved mastication, and the enhanced social
acceptance derived therefrom.
Arguably no entity has done more to tip the
discussion from association to causation than
the Santa Fe Group. This group has published
a statement on the relationships of oral and
systemic health,3,4 which reads as follows:
362
Santa Fe Group Position Statement
on Oral-Systemic Interactions
After decades of research and thousands of
scientific papers, the relationships between
oral health, especially periodontal health,
and systemic health are well known. More-
over, during the past ten years, data analysis
by health economists, and public statements
and actions by several large, private dental
insurers have identified additional benefits of
oral health by revealing that insured individ-
uals who receive treatment for periodontal
disease show fewer hospitalizations and re-
duced cost of care for a number of systemic
diseases including diabetes, cardiovascular
disease, and stroke. Therefore, the Santa
Fe Group has concluded that sufficient ev-
idence now exists that periodontal disease
is a contributory cause to certain systemic
diseases, and the public should benefit from
this knowledge. Specifically, Medicare, Med-
icaid, and other public and private health
insurance programs should incorporate
oral health benefits as a component of com-
prehensive health insurance. These health
benefits will not only improve oral health
for its own sake, including speech, masti-
cation and social acceptance, but will also
produce substantial economic benefits and
total health improvement for the public.
This Santa Fe Group statement has been
published in two of the most widely read den-
tal journals in the United States, The Journal
of the American Dental Association3 and the
Compendium of Continuing Education in
Dentistry4; moreover, it has been presented to
senior leadership of the CMS and CBO. The
Santa Fe Group statement has been used to
solidify the importance of oral health to total
health, to galvanize support for oral health
from numerous not-for-profit organizations in
the health care segment, to motivate the global
periodontal research community to be more
forthcoming, and to endeavor to convince the
federal and state governments that it is foolish

to try to save money by cutting dental care
benefits.
To date, the Santa Fe Group statement has
generated great interest and surprisingly lit-
tle open criticism. While there is much work
to do, the dental, medical, and public health
communities—hopefully soon joined by crit-
ical governmental agencies—are poised to
promote the concept that periodontal disease
is a contributory cause to many systemic health
problems. Will you join this effort? Will you
accept the substantial real-world experience
described in the prior section? Or will you stay
in the safe place of waiting for the large clinical
trial that will probably never come?
What are the risks of stating that the rela-
tionship between oral and systemic health is
causal as opposed to merely associative? Are
we asking people to take new drugs? No. Are
we suggesting a different form of periodontal
therapy? No. Are there unintended conse-
quences of periodontal care? Very few (eg,
root sensitivity, rare anesthetic reactions) are
reported. Even if the thesis presented herein
should be disproved—and I submit that it will
not—the outcome of periodontal care will still
be positive. People will have better masticatory
function, less chance of painful inflammatory
flare-ups, fresher breath, less tooth loss, better
speech, and enhanced confidence in social set-
tings. Stated another way, there is no significant
downside to delivering periodontal care, and
the potential benefits, direct and indirect, in
terms of total health and in terms of finance
are enormous.
Reordering Priorities in
Medicare and Medicaid
Policy
One of the many idiosyncrasies of the historic
separation of the medical and dental profes-
sions is the belief that dental care is not really
health care. It is an elective service—a luxury, if
Reordering Priorities in Medicare and Medicaid Policy
you will, or even a cosmetic service that comes
in near last in any priority-setting exercise for
allocation of research dollars. We see this atti-
tude play out almost every day, as many states
choose not to exercise their right to provide
dental care under federal Medicaid rules. We
see it when states with public dental insurance,
even progressive states like California, decide
to eliminate dental care first as soon as there is
a financial crisis. We even see it in the fact that
dental infection is the only bodily infection that
Medicare does not routinely cover.
This historic separation has been made
worse by the dental profession’s aversion to
participating in public insurance programs.
Practicing dentists seem to perceive the rules
and guidelines that accompany programs like
Medicaid and Medicare as an unwieldy intru-
sion on their independence. This attitude was in
play even before the rise of Medicaid services,
with its flawed dental reimbursement model,
gave dentists good reason to resist the expan-
sion of such programs. Indeed, dentists were
opposed to Medicare when it was founded in
1965, well before they began to have difficult
experiences with Medicaid reimbursement.
Moreover, the ADA has had a resolution on
its dockets since 1993 to expand Medicare to
cover all medically necessary dental care, but
it has been unwilling or unable to advance this
cause for the past 25 years.
The resistance to these federal health pro-
grams is actually more principled than practical
or self-serving. Nevertheless, any principles
that oppose federal involvement in health care
delivery must be measured against the socie-
tal failure that occurs when low-income indiv
iduals are unable to afford health care. To be
sure, one-off events such as Missions of Mercy
and even Give Kids a Smile are worthy gestures
of the charitable nature of many in the dental
profession, but they do little to assist a person
with an off-cycle, painful dental health prob-
lem. The dental profession cannot simply resist
efforts to improve health care access; it needs
to bring viable plans to the table to sustain the
dignity of the profession.
363
18 The Economic Impact of Periodontal Inflammation
One potentially viable plan for a routine den-
tal benefit within Medicare has arisen as a joint
effort of the Santa Fe Group, the DentaQuest
Foundation, and Oral Health America. A key
element of this plan is to parallel reimburse-
ment practices of the private insurance sector
in the belief that it makes no sense to proffer a
poorly financed plan for dental coverage that
no clinical provider is interested in accepting.
Great credit is due to Judy Jones and her coau-
thors and colleagues for identifying the scope
of the need for oral health care in America’s
aged population and for framing out a realistic
approach to a dental benefit in Medicare.11,15–19
The work of Dr Jones and her colleagues
to add a dental care benefit to Medicare will
be referred to as the Jones approach. While
it is not the only approach, it is the one on
which the most information is published, and
it appears to be the broadest approach in that
34 collaborators from more than two dozen
agencies and institutions participated in some
way.15 Other efforts worthy of mention are the
joint effort to expand the definition of medi-
cally necessary dental care, driven primarily by
the Dental Lifeline Network and the Center for
Medicare Advocacy; the economic argument
articulated by Avalere12 and used by a large
coalition of health and social service orga-
nizations to foster change; and the effort of
the ADA facilitated through the work of PwC
Consulting, about which little is yet publically
known.
The Jones approach incorporates several
important principles, many of which were
articulated in the Santa Fe Group sympo-
sium on this topic.20 These principles include
the incorporation of the dental benefit for
all participants in Medicare; that any dental
benefit should be incorporated into Medicare
Part B (physician, outpatient hospital, home
health, and other services) and not developed
as a separate benefit; that providers should be
reimbursed at rates that are comparable to
private dental insurance; and that a primary,
global benefit should be provided to all par-
ticipants, along with an optional second-level
364
benefit. The primary global benefit in the Jones
approach has a specific focus to “prevent pain,
inflammation, and infection,” which was
designed specifically to ensure that all partici-
pants in the Medicare oral health benefit have
optimal ability to minimize the effects of oral
inflammation on systemic health.15
The Jones approach applies to a broad den-
tal benefit for all Medicare recipients, so it is
what could be called a net coster. In contrast, a
plan like that proposed in the Avalere report,12
whereby only selected periodontal services are
offered only to Medicare recipients who have a
diagnosis of diabetes, heart disease, or stroke,
is a net saver. Let’s explore the economic dif-
ferences in these approaches.
The Jones approach to a Medicare dental
benefit is biphasic. The first phase, Level 1, con-
sists of the core global benefit with a primary
goal of preventing pain, inflammation, and
infection. It therefore includes diagnostic, pre-
ventive, nonsurgical periodontal therapy and
nonelective oral surgery, reimbursed at 70% of
usual, customary, and reasonable fees with no
patient copayments to increase participation.
The estimated cost for this benefit is $32.01
per member per month (PMPM). Level 2 ben-
efits under the Jones approach would include
“restorative, removable, fixed, endodontic
and selected implant (ie, two implants under a
lower complete denture) as well as a spending
cap ($1,500).”15 Level 2 benefits would cost
$31.58 PMPM in addition to the costs of the
Level 1 benefits. The core global benefit would
cost $16.85 billion, not including any projected
savings (eg, $12.20 billion in year 10) as esti-
mated by the Avalere analysis described later
in this section. Thus, even assuming the full
benefit of cost reductions from reduced hos-
pitalizations and emergency room visits due
to the periodontal care provided, because the
global benefit proposed by Jones is available
to all seniors, it is a net coster of $4.65 bil-
lion in year 10 ($16.85 billion minus $12.20
billion). These net costs can be mitigated (or
not) based on additional premiums paid by
Medicare recipients as in the current system.

The initiative of the Dental Lifeline Net-
work and the Center for Medicare Advocacy
(DLN-CMA initiative) seeks expanded dental
care that is medically necessary for Medicare
recipients under the currently authorized
Medicare legislation. This initiative basically
argues that the CMS already has the authority
to expand the definition of medically necessary
dental care by simple administrative action. At
present, Medicare does pay for a very limited
amount of dental care, such as eliminating
oral infection in Medicare patients who are
undergoing organ transplants. This initiative
did not estimate the costs or the specific nature
of the expanded dental benefits that might be
provided, so the economic impact cannot be
discussed at this time. Moreover, the petition to
the CMS remains under review by the agency
many months after it was submitted.
The Avalere analysis12 is not actually an
initiative but rather a report on which other
initiatives are based, in full or in part. For
example, the Jones approach acknowledges that
the assessment by Avalere would substantially
reduce the total cost of the Medicare dental
benefits in her proposal. Like the DLN-CMA
initiative, the Avalere analysis limits benefits to
certain Medicare recipients with medical needs.
However, the Avalere analysis only provides
dental benefits to Medicare recipients with
three specific medical conditions (ie, diabetes,
heart disease, and stroke), while the DLN-CMA
initiative would presumably provide dental
benefits to any Medicare recipient with a med-
ically necessary dental treatment requirement.
By providing more limited dental benefits (eg,
diagnosis and nonsurgical periodontal care)
only to a more limited population , the Avalere
analysis easily has the best outcome from a
purely economic perspective. Simply, it is a net
cost saver, and a substantial one at that.
Using data on the effect of periodontal care
on the number of hospitalizations and emer-
gency department visits from the insurance
studies described earlier and data on Medicare
costs and the numbers of Medicare recipients
who have the three signature diseases (diabetes,
Reordering Priorities in Medicare and Medicaid Policy
heart disease, and stroke), Avalere estimated
the savings that could be provided if a basic
dental benefit consisting of nonsurgical peri-
odontal therapy was added to Medicare. Their
summary of the analysis was as follows:
We estimate providing a periodontal disease
treatment benefit will produce a savings of
$63.5 billion over the period of 2016–2025
and should continue long term. This savings
reflects new costs of approximately $7.2 bil-
lion from covering periodontal treatment for
Medicare beneficiaries with one of the three
target chronic conditions. This new spending
will be offset by an estimated $70.7 billion
reduction in Medicare spending, largely
related to fewer hospitalizations and emer-
gency room visits.
This analysis was actually quite conservative.
For example, it assumed only a 5% uptake of
the new periodontal benefit in the first year,
growing to a 20% utilization of the benefit in
year 10. Yet the financial outcome was a net
positive beginning in the first year with $500
million in savings and grew to a net benefit
of $12.2 billion in year 10. While some might
argue that the Avalere analysis would only ben-
efit a small portion of the senior population, the
number of people with periodontal disease and
one of the three systemic conditions is actually
quite large. Indeed, in follow-up to a meeting
with the CBO, it was estimated that a scenario
like the one proposed by Avalere would have
the potential to benefit 19 million people.
This is more people than have benefited from
either the Children’s Health Insurance Program
(CHIP) or the Affordable Care Act (ACA) insur-
ance pools. Therefore, efforts to characterize
the Avalere analysis as small in scope are inac-
curate. Moreover, the Avalere analysis based
the dental benefit on costs of $825 for initial
treatment and $250 for biannual maintenance
visits. Thus, the program delivers more than
two-thirds of a typical, private insurance dental
benefit in year 1 ($1,500 per year) and one-third
of a private dental benefit in subsequent years.
365
18 The Economic Impact of Periodontal Inflammation
The preventive techniques learned by seeking
the periodontal benefit will likely improve the
patient’s other oral health problems. In addi-
tion, patients could elect to have other oral
health problems treated out-of-pocket once
they develop a level of comfort with the den-
tist who provides the basic periodontal service.
What Comes Next?
At the time of this writing, a number of col-
laborative efforts are underway to affect “the
economic impact of periodontal inflammation”
as this chapter is titled. First, more effort must
be applied to educate the CMS and Congress. I
have had the privilege of participating in three
meetings with the CMS on this topic and one
meeting with the CBO. At each meeting, the
CMS participants, who sometimes represented
the highest levels in the agency, were attentive
and interested in the subject. In fact, it is not a
stretch to say that some of them were amazed
by the data set. That said, the administration
has changed, as has the leadership of the CMS,
and new efforts will be required to rekindle the
interest in the enormous savings that could ac-
crue to the Medicaid and Medicare programs
if the agency were to act to expand dental care
services, especially periodontal services.
Furthermore, as I write this, the CBO is
reported to be scoring the cost/savings of a new
dental benefit in Medicare. This benefit would
be similar to the one in the Avalere analysis
and has the potential, for example, to cover
most of the costs of the CHIP program, which
Congress is desperate to approve. By the time
you read this, we will know if this effort was
in fact successful.
To enhance the likelihood that Congress or the
CMS will act to add a dental benefit to Medicare,
the Santa Fe Group is funding a new program
to assess whether the Medicaid population in
New York State benefits from dental care in the
same way that those in the private insured pop-
ulation benefit. Confirmation that the data from
366
the public sector insured parallels that from the
private sector insured would provide substantial
evidence to prompt the federal government to
act on expanded oral care coverage.
Finally, and perhaps most importantly, a
large coalition of organizations guided by
Eric Berger, a principal in Liberty Partners in
Washington, DC, has developed a compelling
community statement on this issue.21 This
statement, which is supported by 70 signifi-
cant organizations from the medical, dental,
social sciences, and patient advocacy sectors,
is reprinted here:
Community Statement on Medicare
Coverage for Medically Necessary Oral
and Dental Health Therapies
The undersigned organizations are proud to
join in support of Medicare coverage for med-
ically necessary oral/dental health therapies.
It is well established that chronic dis-
eases disproportionately impact Medicare
beneficiaries and impose a substantial cost
on the federal government. It is also well
established that untreated oral microbial in-
fections are closely linked to a wide range
of costly chronic conditions, including di-
abetes, heart disease, dementia, and stroke.
In addition, oral diseases have been docu-
mented by researchers and medical specialty
societies as precluding, delaying, and even
jeopardizing medical treatments such as or-
gan and stem cell transplantation, heart valve
repair or replacement, cancer chemothera-
pies, placement of orthopedic prostheses,
and management of autoimmune diseases.
Despite these factors, most Medicare ben-
eficiaries do not currently receive oral/dental
care even when medically necessary for the
treatment of Medicare-covered diseases. In
fact, Medicare coverage extends to the treat-
ment of all microbial infections except for
those relating to the teeth and periodontium.
There is simply no medical justification for
this exclusion, especially in light of the broad
agreement among medical specialists that such

care is integral to the medical management of
numerous diseases and medical conditions.
Moreover, the lack of medically necessary oral/
dental care heightens the risk of costly medical
complications, increasing the financial burden
on Medicare, beneficiaries, and taxpayers.
At least six major insurance carriers
offering dental plans provide enhanced peri-
odontal and preventive coverage to targeted
enrollees with conditions such as diabetes,
heart disease, stroke, head/neck cancers,
and transplants. According to some reports,
such coverage has realized important bene-
fits, including markedly lower hospitalization
and emergency department admission rates
as well as substantial cost reductions. On a
further note, veterans getting care through
the Veterans Health Administration receive
medically adjunctive oral/dental treatment
in many instances when a dental diagnosis
affects their medical prognosis. These are
all important steps forward, and medically
necessary oral/dental healthcare including
periodontal treatment should be provided
in traditional Medicare as well.
The Medicare program and all its benefi-
ciaries should not be without the vital clinical
and fiscal benefits of coverage for medically
necessary oral/dental health therapies. Given
the significant potential to improve health
outcomes and reduce program costs, we urge
Congress and the Administration to explore
options for extending such evidence-based
coverage for all Medicare beneficiaries.
Signed by: AARP; Acuity Specialists;
American Academy of Maxillofacial Prosthet-
ics; American Academy of Periodontology;
American Association for Dental Research;
American Association of Clinical Endocri-
nologists; American Association of Hip and
Knee Surgeons; American Autoimmune Re-
lated Diseases Association; American Col-
lege of Emergency Physicians; American Col-
lege of Gastroenterology; American College
of Physicians; American College of Pros­tho­
What Comes Next?
dontists; American College of Rheumatology;
American Dental Association; American Den-
tal Education Association; American Dental
Hygienists’ Association; American Diabetes
Association; American Head and Neck Soci-
ety; American Kidney Fund; American Liver
Foundation; American Nurses Association;
American Parkinson’s Disease Association;
American Psychiatric Association; American
Public Health Association; American Society
for Radiation Oncology; American Society of
Clinical Oncology; American Society of Trans-
plant Surgeons; American Thoracic Society;
Arthritis Foundation; Association of Dental
Support Organizations; Association of State
and Territorial Dental Directors; California
Dental Association; Catholic Health Associa-
tion of the United States; Center for Medicare
Advocacy; Children’s Dental Health Project;
Crohn’s and Colitis Foundation of America;
Dental Lifeline Network; Dental Trade Alli-
ance; Eating Disorders Coalition; Epilepsy
Foundation; Families USA; Head and Neck
Cancer Alliance; Justice in Aging; Leukemia
and Lymphoma Society; Lupus Foundation
of America; Medicare Rights Center; Mental
Health America; National Alliance on Mental
Illness; National Association of Area Agen-
cies on Aging; National Association of Com-
munity Health Centers; National Association
of Dental Plans; National Council for Behav-
ioral Health; National Kidney Foundation;
National Multiple Sclerosis Society; Nation-
al Network for Oral Health Access; Nation-
al Osteoporosis Foundation; National Rural
Health Association; National Stroke Asso-
ciation; Oral Health America; Pacific Den-
tal Services Foundation; Parkinson’s Founda-
tion; PEW Dental Campaign; Renal Physicians
Association; Santa Fe Group; School-Based
Health Alliance; Society for Transplant So-
cial Workers; Support for Persons with Oral,
Head, and Neck Cancer; The Gerontological
Society of America; The Michael J. Fox Foun-
dation; The Society for Thoracic Surgeons
367
18 The Economic Impact of Periodontal Inflammation
This important statement, signed by an
almost unprecedented number of organizations
from across the health care spectrum, will be
used in the coming year in an effort to generate
an administrative solution that leverages the
power of periodontal care to reduce hospitaliza-
tions and emergency room utilization. Coupled
with many other efforts by these organizations
and other groups, there is reason for some opti-
mism even in a political environment that is
toxic, partisan, and struggling for resources. By
the time Dr Glick publishes the third edition
of this book, I hope we will be able to describe
a wonderful success story of improved health
complemented by favorable economics.
References
1. Lamster IB. Oral conditions and systemic health.
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2. Bale BF, Doneen AL, Vigerust DJ. High-risk periodontal
pathogens contribute to the pathogenesis of atheroscle-
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4. Alfano M. The seniors are coming! [editorial]. Compend
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Index
Page numbers followed by “f” denote figures; cost effectiveness of, 330, 336
“t” tables; and “b” boxes. distant site infection prevention with, 329, 334
for infective endocarditis
American Heart Association recommendations,
329–330, 332–336
A current data regarding, 336–337
drug resistance concerns, 336
ACA. See Affordable Care Act.
history of, 329
ACTH. See Adrenocorticotropic hormone.
research studies about, 339–340
Actinomyces naeslundii, 183
support for and against, 335–336
Activated partial thromboplastin time, 187
issues regarding, 330–331
Activities of daily living, 109
primary, 329–330, 340
Acute monocytic leukemia, 259, 259f
secondary, 329–330, 340
Acute myelogenous leukemia, 271, 272f
Antibiotics
Acute myocardial infarction, 3
bacteria control using, 77
Acute-phase proteins, 89
prophylactic uses of. See Antibiotic prophylaxis.
Acute-phase response, 171–172
Antifungal agents, for candidiasis, 256
ACVD. See Atherosclerotic cardiovascular disease.
Anti-inflammation, 97
Acyclovir, 250t
Antimalarial agents, 261
Addison disease, 262
Antimicrobial oral hygiene treatment, in pneumonia,
Adenotonsillar hypertrophy, 122
202–203
Adipocytes, 93, 106, 108
Antiviral medications, 250t, 285
Adipocytokines, 115
Anxiety disorders, 305
Adipokines, 93
Aortic valve, 331f
Adiponectin, 93, 108
AP. See Aspiration pneumonia.
Adipose tissue, 125
Aphthous-like ulcers, 244–246
Adiposity, 106, 306
Apical periodontitis, 51
Adjuvant therapy, 271
aPTT. See Activated partial thromboplastin time.
ADLs. See Activities of daily living.
Arachidonic acid, 89
Adolescent pregnancy, 224
Aristotle, 4
Adrenocorticotropic hormone, 262
Aspergillosis, 251
Advanced glycation end products, 93
Aspergillus flavus, 251
Affordable Care Act, 366
Aspergillus fumigatus, 251
AFM. See Atomic force microscopy.
Aspiration, 63–64
AGEs. See Advanced glycation end products.
Aspiration pneumonia, 194–195, 197, 204
Aggregatibacter actinomycetemcomitans, 51, 58, 63,
Associations
65, 70, 97, 237
Bradford Hill criteria for, 5–6, 6b, 12
AIDS-associated linear gingivitis, 258
causation and, 361–363
Albuterol, 305
cause-and-effect interpretation of, 13
Alleles, 18
in randomized controlled trials, 34
Allogeneic transplantation, 280, 282
α level, 26–27 Asymptomatic viral shedding, 75
Atherogenesis, 65f, 95
Alternate hypothesis, 25
Atherosclerosis
Alzheimer’s disease, 68–69
description of, 72–73, 95
Amalgam tattoo, 260
oral infections as contributing factor, 164–165
American Dental Association Health Policy Institute,
periodontal pathogens and, 166
359
Atherosclerotic cardiovascular disease
American Heart Association antibiotic prophylaxis
at-risk population, 172–173
recommendations, 329–330, 332–336
endothelial dysfunction and, 174
Amoxicillin, 330, 336
epidemiology of, 169
Amphotericin B, 286
intervention trials, 169–174
Amyloid-beta, 68
mechanisms of, 165–168
Angiogenesis, obesity and, 108–109
periodontal intervention effects on, 173–174
Angular cheilitis, 256
periodontitis and, 169, 175–176
Anthropometry, 102
risk factors for, 139, 169
Antiangiogenic agents, 266
Atherosclerotic plaque, 63
Antibiotic prophylaxis
Atherothrombogenesis, 168f
cardiac conditions requiring, 330f
Atomic force microscopy, 349–350
compliance with, 330

369
I Index

Attribution, 11 Body fluids, microbiome in, 41

Autologous transplantation, 280 Body mass index, 102–103, 104t, 109–110, 114,
Avalere, 359, 364–365 119–120, 157f
ACVD. See Atherosclerotic cardiovascular disease. Body weight, masticatory efficiency and, 121
Bone diseases, primary, 263–264
Bradford Hill criteria, 5–6, 6b, 12–13, 14f–15f
B Breast cancer, 345, 345t
Burket, Lester W., 3
Bacteremia
Burning mouth syndrome, 268
infective endocarditis and, 331, 333b, 334, 335f
oral hygiene as risk for, 337
pathogenesis of, 66–67
periodontal status and, 200 C
tooth brushing and, 67, 177, 200, 332–334, 335f, CA15-3, 345
337 CA19-9, 346
transient, 89 CA125, 346
Bacteria. See also specific bacteria. CAL. See Clinical attachment loss.
core set of, 46–47 CAMBRA. See Caries management by risk
fungi and, 61 assessment.
gram-negative, 42–43 Campylobacter rectus, 217–218
gram-positive, 42–43 CAMs. See Cell adhesion molecules.
interspecies interactions, 60f Cancer. See also Squamous cell carcinoma.
in intracellular spaces, 41 breast, 345, 345t
modifiable changes to decrease, 61–63 colorectal, 236
in oral plaque, 54f deaths caused by, 231
on orthodontic appliances, 52–53 early detection of, 237–238
in peri-implant space, 40 Fusobacterium nucleatum and, 233–234
periodontal breakdown and, 39–40 gastric, 346
periodontal therapy effects on, 61 genetic susceptibility to, 232–233
at phylum level, 46, 47f–48f head and neck, 234–235
on removable dentures, 53 lung, 232, 235–236, 346, 357
in saliva, 49–50, 58f, 62f MiRNA as salivary biomarker for, 347
in subgingival plaque, 39, 56, 65 obesity as risk factor for, 232
supragingival, 51f–52f oral infections and, 238
Bacterial DNA, 70 ovarian, 346–347
Bacteroides gingivalis, 45 pancreatic, 234, 236–237, 352f
Base pair, 43 periodontal disease and
Behavioral Risk Factor Surveillance System, 149 biologic plausibility for, 233–234
Behçet disease, 244–245 observational studies regarding, 234–237
Benzocaine, 243t shared risk factors for, 231–233
Bergeyella, 216 prevention of, 237–238
Betamethasone, 243t salivary biomarkers for
Betel nut chewing, 61 description of, 345t, 345–348
Bidirectional causal relationship, 4 salivary exosome as, 351–353
Binary outcome event, 10 salivary proteomics applied to, 344–347
Biologic plausibility smoking as risk factor for, 232
for cancer and periodontal disease, 233–234 type 2 diabetes as risk factor for, 232
for chronic kidney disease and periodontal disease, Cancer treatment
183–184 options for, 272, 273f
for end-stage renal disease and periodontal disease, oral toxicities associated with
183–184 graft-versus-host disease, 254, 280, 282b,
for oral infection correlation 282–283
with adverse pregnancy outcomes, 214–219, 216f mucositis, 275f–278f, 275–280
with systemic health, 289 overview of, 273t–274t
Biomarkers Candida albicans, 53, 67
cancer, salivary exosomes as, 351–353 Candidal infection, 285–286, 286f
clinical outcomes and, 18 Candidiasis
Bisphosphonates-induced osteonecrosis of the jaw. See characteristics of, 255–256
Medication-related osteonecrosis of the jaw. erythematous, 255
Bite marks, 70 hyperplastic, 255
Blastomycosis, 251 pseudomembranous, 255, 255f, 286f, 286t
Blinding, 33 CAP. See Community-acquired pneumonia.
Blood pigmentations, 262–263 Capsaicin, 268
BMI. See Body mass index. Carcinoembryonic antigen, 345–346
BMS. See Burning mouth syndrome. Cardiovascular disease
Body fat atherosclerotic. See Atherosclerotic cardiovascular
distribution of, 114 disease.
measurements of, 102, 114 deaths caused by, 231

370
 Index

diabetes mellitus as risk factor for, 137–138 Chloroquine, 261

diet and, 105 Chorioamnionitis, 70
inflammatory elements of, 95 CHRNA5-CHRNA3-CHRNA4, 304
oral infections and, 164–177 Chromatin, 296f
periodontitis and, 94–96 Chromatin immunoprecipitation sequencing, 298
risk factors for, 94, 320 Chromosomes, 43, 304
Caries management by risk assessment, 307 Chronic kidney disease
Caries risk assessment, 307 antibiotic therapy in, 187
Cariogenic bacteria, 70 definition of, 181
Carney complex, 262 dental management in, 186–188
Case reports, 36 end-stage renal disease progression of, 187
Case series, 36 estimated glomerular filtration rate in, 181
Case-control studies, 35–36 inflammatory burden in, 185
Cauliflower structure, 50, 55f periodontal therapy in
Causal relationships nonsurgical, 186
awareness of, 1 outcomes of, 186
bidirectional, 4 response of, 185–186
cyclic, 4 systemic outcomes of, 186
direct, 4 periodontitis in patients with
experimental studies for identifying, 11 biologic plausibility for, 183–184
hallmarks of, 2 conceptual model of, 184f
indirect, 4 epidemiology of, 181–182
necessary conditions for, 6–8, 7f, 8b–9b prevalence of, 182, 183t
reciprocal, 4 prevalence of, 181
reverse, 4 risk factors for, 182
sufficient conditions for, 6–8, 7f, 8b–9b, 15–16 summary of, 188
Causation. See also Cause. uremia in, 183–184
definition of, 3–5 Chronic obstructive pulmonary disease
frameworks for. See Causation frameworks. characteristics of, 195
instrumental variables and, 17f, 17–18 classification of, 196
Mendelian randomization and, 17f, 18–19, 19f description of, 164
reasons for caring about, 1–2 oral hygiene in, 203
studies on, 361–363 periodontal health in, 204
theories of, 4 periodontitis and, 201, 321
words that imply, 3 prevalence of, 195
Causation frameworks smoking as risk factor for, 195, 201, 321
Bradford Hill criteria, 5–6, 6b, 12–13, 14f–15f CI. See Confidence intervals.
contributory cause, 8 Cicatricial pemphigoid, 251
counterfactual, 10–11, 16, 18 CKD. See Chronic kidney disease.
description of, 5 CLASI-FISH. See Combinatorial labeling and spectral
Henle-Koch postulates, 5, 5b imaging fluorescence in situ hybridization.
necessary and sufficient conditions, 6–8, 7f, 8b–9b Clinical attachment loss, 141, 143, 185
probabilistic, 11 Clinical importance
sufficient-component, 8–9, 10f, 16 confidence interval and, 28–32
Cause. See also Causation. definition of, 24
contributory, 8 effect size and, 31
definition of, 3–5 evaluation of, 28–32
sufficient-component model of, 8–9, 10f, 16 minimal clinically important differences and, 24,
CBO. See Congressional Budget Office. 28, 31
CC chemokine receptor type 2, 107 Clinical outcomes, biomarkers and, 18
CEA. See Carcinoembryonic antigen. Clinical pathway programs, 150
Celiac disease. See Gluten-sensitive enteropathy. Clinical significance, 32
Cell adhesion molecules, 108 Clinical trials, 362
Cell-to-cell signaling, 77 Clobetasol, 243t
Centers for Medicare and Medicaid Services, 361 Clotrimazole, 256, 286
Cevimeline, 268 CMS. See Centers for Medicare and Medicaid
Chemokines, 88, 96 Services.
Chemotherapy, 275f–278f, 275–280 CMV. See Cytomegalovirus.
Children Coated tongue, 256f, 256–257
obesity in, 104, 119 Cohabitation, 59
physical activity in, 106 Cohort studies, 35, 37
pneumonia in, 194 Colony-forming units, 108
Children’s Health Insurance Program (CHIP), 365 Colorectal cancer, 236
Chlamydia pneumoniae, 184 Combinatorial labeling and spectral imaging
Chlorhexidine mouthwash fluorescence in situ hybridization, 50
for candidal infections, 256 Commensal-turned pathogen, 42
for medication-related osteonecrosis of the jaw, 287 Common complex diseases, 293
for oral hygiene in pneumonia patients, 202

371
I Index

Common risk factors approach, 316, 317f, 321–323, sugar-sweetened beverages as cause of, 118–119
326 systemic diseases and, 302
Community-acquired infective endocarditis, 332, 337 tooth loss secondary to, 148
Community-acquired pneumonia, 195 Dental examination, 149–150
Concurrent therapy, 271 Dental fear, 305
Confidence intervals, 28–32, 30t Dental health
Confounders, 4, 12, 14b–15b, 18, 32 acute myocardial infarction and, 3
Confounding, 33, 170b Medicare coverage for therapies, 366–367
Congressional Budget Office, 360, 366 Dental home concept, 223
Consolidation of Standards for Reporting Trials Dental implants, in diabetes mellitus, 40–41
(CONSORT) guidelines, 34 Dental Lifeline Network and the Center for Medicare
Continuous positive airway pressure, 122 Advocacy, 364
Contributory cause, 8 Dental plaque, gingivitis caused by, 257
Control group, 33 Descriptive studies, 36
COPD. See Chronic obstructive pulmonary disease. Desired effect size, 31
Corncob structures, 50, 55f Desquamative gingivitis, 251–252, 252f, 258
Coronary artery disease, 13 Destructive membranous periodontal disease, 260
Corticosteroids, for desquamative gingivitis, 251 Deterministic cause framework, 11
Corynebacterium, 54f–55f Dexamethasone, 243t
Counterfactual cause framework, 10–11, 16, 18 Diabetes mellitus
Counterfactual outcome, 10 burden of, 136–138
Cowden syndrome, 260 cancer risks associated with, 232
Coxsackievirus, 247 case definitions of, 137–138
CPAP. See Continuous positive airway pressure. complications of, 138
CRA. See Caries risk assessment. cost savings in, 151
C-reactive protein costs of, 138
coronary heart disease and, 18 criteria for testing for, 158b
description of, 89 definition of, 136–137
obesity and, 106, 115 dental examination referrals, 149–150
periodontal treatment effects on, 174 dental implants in, 40–41
periodontitis and, 94–95, 166t–167t diagnostic criteria for, 137t
preterm birth and, correlation between, 215, 219 economic burden of, 138
Crohn disease, 244 gestational, 137–138
Cross syndrome, 260 global prevalence of, 137
Cross-sectional studies, 35–36 glycemic control in, 143–144, 264
CRP. See C-reactive protein. guidelines for, 151–152, 152b–155b
CVD. See Cardiovascular disease. hemoglobin A1C test for, 93
Cyclic causal relationship, 4 hyperglycemia associated with, 137
Cyclic neutropenia, 245 interprofessional collaboration for, 150–152
Cyclooxygenases, 89 lifestyle changes for, 147
Cyclosporine-induced gingival hyperplasia, 259, 259f obesity and, 111
Cytokines office screening for, 146–148
in atherosclerotic plaque, 94–95 oral diseases and, 320
in inflammation, 88–89, 108, 215 periodontal disease and, association between
in periodontal infection, 218–219 description of, 138–139, 320
in periodontitis, 200 evidence for, 140–150
Cytomegalovirus, 68, 247 guidelines for, 151–152, 152b–155b
health care costs, 358–359
mechanisms linking, 139–140, 140f
D shared risk markers for, 139, 150
summary of, 152–155
Denosumab
periodontitis and, 92–94, 152b
medication-related osteonecrosis of the jaw caused
poorly healing extraction sockets in, 263
by, 266
prevalence of, 136–137
osteoporosis treated with, 266
risk assessment form for, 156f–157f
Dental care, in immunosuppressed patients, 289
screening for, 146–148
Dental care teams, 324
tooth loss and, 140–141, 148
Dental caries
type 2, 137, 139, 156f–157f, 232
in cancer therapy patients, 273t
Diabetic nephropathy, 182
caries management by risk assessment, 307
Diabetic neuropathy, 148–149
genetics of, 299, 302
Diabetic retinopathy, 138
genome-wide association studies of, 299–300
Diet
global prevalence of, 312, 313f
cardiovascular disease and, 105
metabolic syndrome and, 116
obesity and, 105
obesity and, 116–119
tooth loss effects on, 148
prevalence of, 312
Direct causal relationship, 4
risk assessment, 307
Disability, 109
socioeconomic factors, 312

372
 Index

Discoid lupus erythematosus, 254–255 Estrogens, 261

Disease(s). See also specific disease. Evidence-based review system, 361–362
cardiovascular. See Cardiovascular disease. Exosomes, salivary
contributory causes of, 357 as cancer biomarkers, 351–353
oral. See Oral diseases. contents of, 350–351
periodontal. See Periodontal disease. definition of, 349
systemic. See Systemic diseases. discovery of, 349
Distant site infections, 329, 334 mRNA in, 351
DLN-CMA. See Dental Lifeline Network and the structure of, 349–350
Center for Medicare Advocacy. summary of, 353
DNA mutations, 233 Experimental trials, 32–35
Docosahexaenoic acid, 90 ExRNA, 348
Dose-dependent relations, 11 ExRNA Atlas, 348f
Double blinding, 33 External validity, 33
Drug resistance, 336 Extracellular DNA, 59
Drug-induced gingival hyperplasia, 259, 259f Extracellular RNA, 343
Drug-induced oral pigmentation, 261 Extracellular RNA Communication Consortium, 348
Drug-induced oral ulcers, 245–246 Extraction sockets, 263–264
Drug-induced osteonecrosis of the jaw. See
Medication-related osteonecrosis of the jaw.
Dual energy x-ray absorptiometry, 120
Dyclonine hydrochloride, 243t
F
Fallacy of affirming the consequent, 4
Dysbiosis, 46–47
False negative, 26, 27f
Dysgeusia, 273t
False positive, 26, 27f
Famciclovir, 250t
E FANTOM. See Function Annotation of the
Mammalian Genome.
Ecchymoses, 262–263 FDI World Dental Federation, 324, 325
Edema, 86 FESEM. See Field emission scanning electron
Effect modifiers, 12, 14b–15b microscopy.
Effect size, 31 Fibromatosis gingivae, 260
Eicosapentaenoic acid, 90 Fibronectin, 200
Emphysema, 201 Fibrous cap, 94
ENCODE project, 294, 295f Field emission scanning electron microscopy, 349
Endothelial cells, 108 Filifactor alocis, 65
Endothelial dysfunction, 174 FISH. See Fluorescence In Situ Hybridization.
Endotoxins, 71 Fluconazole, 256, 286
End-stage renal disease Fluocinolone, 243t
antibiotic therapy in, 187–188 Fluorescence In Situ Hybridization, 50, 51f–52f, 56f
chronic kidney disease progression to, 187 Focal infection theory, 3, 87
description of, 182 Focus of infection, 2
inflammatory burden in, 185 Function Annotation of the Mammalian Genome, 294
periodontal therapy in Fungal infections, 250–251, 273t
nonsurgical, 186 Fungal microbiome, 49
outcomes of, 186 Fungemia, 67
response of, 185–186 Fungi, 61, 68
systemic outcomes of, 186 Fusobacterium, 216–217
periodontitis in patients with Fusobacterium nucleatum
biologic plausibility for, 183–184 antibiotics for, 65
epidemiology of, 182 cancer and, 233–234, 236
prevalence of, 182, 183t as commensal-turned pathogen, 42
summary of, 188 description of, 65
uremia in, 183–184 illustration of, 54f
Enterococcus faecalis, 56 in peri-implantitis, 51
Epidemiologic research, 32 in pneumonia, 198
Epidemiologic studies, 18 in pregnancy, 97
Epigenetics, 296
Epstein-Barr virus, 75–76, 247
Epulis, 213, 214f
ERCC. See Extracellular RNA Communication
G
Galen, 2
Consortium.
Gastric cancer, 346
Erythema areata migrans. See Migratory glossitis.
Gastritis, 76
Erythema multiforme, 248–250
Gastrointestinal mucositis, 277
Erythematous candidiasis, 255
GDM. See Gestational diabetes mellitus.
Escherichia coli, 56
Geisinger system, 110
ESRD. See End-stage renal disease.
Gene, 43
Estimated glomerular filtration rate, 181, 187

373
I Index

Gene-Lifestyle Interactions and Dental Endpoints Gram-negative bacteria, 42–43

Consortium, 299, 301, 306 Gram-positive bacteria, 42–43
Genetic variant, 18 Granuloma, pregnancy, 213, 214f
Genetics Graphite, 260
cancer risks associated with, 232–233 GWASs. See Genome-wide association studies.
clinical practice and, 306–308
data storage issues, 308
of dental caries, 299
oral diseases and, 298–306
H
Haemophilus influenzae, 195
of periodontal disease, 299–300
Hairy tongue, 256f, 256–257
Genome, 43–44
Hand, foot, and mouth disease, 247
Genome-wide association studies
HapMap Project, 293–294
of dental caries, 299–300
Hashimoto thyroiditis, 254
description of, 26, 232, 294, 298
Hay-Wells syndrome, 304
findings of, 300–301
HCAP. See Health care–associated pneumonia.
Genomic science
Head and neck squamous cell carcinoma, 277, 278f,
advances in, 294–298
346
ENCODE project, 294, 295f
Health care–associated pneumonia, 194
Human Genome Project, 43, 293–294
Health in All Policies, 323, 326
International HapMap Project, 293–294
Health Promoting Schools Network, 317
1000 Genomes project, 293–294
Health promotion, 322
oral disease and systemic disease connections,
Heart disease, 231
301–306
Heavy metal pigmentation, 261
overview of, 292–293
Hedgehog, 54f
Genotyping, 298
HeLa genome, 66f
Geographic tongue. See Migratory glossitis.
Helicobacter pylori, 52, 76–77, 233
Gestational diabetes mellitus, 137–138
Hematopoietic stem cell transplantation
Gingiva
autologous, 280
acute leukemia involvement of, 272f
graft-versus-host disease secondary to, 254, 280,
bleeding of, obesity and, 113
282, 282b
hyperplasia of
nonherpes viral infection after, 285
acute leukemia as cause of, 259f, 259–260
oral complications of, 282b
drug-induced, 259, 259f
oral mucositis secondary to, 275
hereditary causes of, 260
Hemoglobin A1C , 93, 144, 147
pathophysiology of, 258–259
Henle-Koch postulates, 5, 5b
plaque-induced, 259
Hereditary gingival fibromatosis, 260
syndromic causes of, 260
Hereditary hemochromatosis, 263
pregnancy-related inflammation of, 213
Herpangina, 247
Gingival crevicular fluid
Herpes simplex virus
inflammation and, 115, 334
antiviral agents for, 250t
oral microbiome in, 61
clinical presentation of, 248t
tumor necrosis factor α levels in, 112
description of, 75
Gingivitis. See also Periodontal disease.
in myelosuppressed patients, 284–285, 285f
Alzheimer’s disease and, 68
nerve pathways, 68
description of, 39
oral ulcers caused by, 246–247, 249
desquamative, 251–252, 252f, 258
recurrent, 249f
HIV/AIDS-associated linear, 258
HiAP. See Health in All Policies.
ligneous, 260
High-throughput assays, 297
necrotizing ulcerative, 258
High-throughput mass spectrometry, 344
plaque-induced, 257
High-throughput RNA sequencing, 351
plasma cell, 258
High-throughput sequencing, 348
pregnancy, 213
Hippocrates, 2, 86
Glaucoma, 69
Histoplasmosis, 250–251
Glioblastoma microvesicles, 351
HIV
Global Burden of Diseases, Injuries, and Risk Factors,
linear gingivitis associated with, 258
312
oral complications in, 245
Gluten-sensitive enteropathy, 244
HLA-B51, 244
Glycated hemoglobin, 52
Homeostasis, 90
Glycemic control
HOMINGS, 57
in diabetes mellitus, 263
Hospital-acquired pneumonia, 194–196, 206
nonsurgical periodontal treatment effects on,
Host-parasite interaction, 90
144–146, 145t
HSCT. See Hematopoietic stem cell transplantation.
periodontitis effects on, 143–144, 320
HSV. See Herpes simplex virus.
Glycemic status, 146
Human coronary artery endothelial cells, 64
Glypican-1, 351
Human genome, 43–44, 295f, 297f
Gonadal steroids, 212
Human Genome Project, 43, 293–294
Graft-versus-host disease, 254, 280, 282b, 282–283
Human herpesvirus 1, 68

374
 Index

Human herpesvirus 2, 68 oral hygiene in

Human herpesvirus 4, 75 description of, 334
Human herpesvirus 5, 247, 248t gingival disease and, 337–339, 338f
Human immunodeficiency virus. See HIV. oral infection and, 3
Human microbiome, 44–45 oral pathogens and, 329
Human Microbiome Project, 44–45, 45f, 77 time of onset, 336
Human Oral Microbiome Database, 45–46 types of, 332
Human papillomavirus, 66, 66f, 73–75, 235 vegetations, 331, 331f
Hunter, William, 87 Inflammation
Hydroxyeicosatetraenoic acids, 89 adiponectin in, 108
Hyperglycemia in chronic kidney disease, 185
in diabetes mellitus, 137 cytokines associated with, 108
hyposalivation caused by, 62 description of, 88–90
oral manifestations of, 148–149 in end-stage renal disease, 185
periodontal disease and, 139 macrophages in, 107
periodontal tissue affected by, 140 mediators of, in obesity, 115–116
periodontitis and, 139–141 in obesity, 106–108, 107f, 115–116
tooth eruption affected by, 140 periodontal. See Periodontal inflammation.
tooth loss affected by, 140 periodontal disease and, 97
Hyperplastic candidiasis, 255 in periodontitis, 139
Hypohidrotic ectodermal dysplasia, 304 in pneumonia, 194
Hyposalivation, 62, 266–268 systemic actions of, 92f
Hypothesis testing, 26–28, 27f Information bias, 33
Hypothetical condition, 10 Innate immunity, 88
Hypoxia, 109 Instrumental variables, 17f, 17–18
Hypoxia-inducible factor-1, 109 Insulin resistance, 112, 116
Insulin-like growth factor 2, 218
Insurance industry
I economic savvy of, 359–361
studies by, 358–359
IARC. See International Agency for Research on
Integrated oral health practice patient visit, 124f
Cancer.
Interferon- τ, 96
Immunoglobulin G, 216–217
Interleukin-1, 307
Immunoglobulin M, 216–217
Interleukin-2, 218
Immunosuppressed patients
Interleukin-6, 106, 108, 115, 214, 307
dental care for, 289
Interleukin-10, 218
oral complications in
Interleukin 1ß, 88, 97
herpes simplex viral infection, 284–285, 285f
International Agency for Research on Cancer, 232
infections, 283–286, 289
International HapMap Project, 293–294
mucositis, 275f–278f, 275–280
Interpersonal travel, 63
summary of, 288
Interprofessional education and collaboration,
oral health in, 289
324–325
Immunosuppressive agents, 243t
Intrauterine growth restriction, 211
Incidence, 35
IVs. See Instrumental variables.
Indirect causal relationship, 4
Infection. See also Oral infections.
in Alzheimer’s disease, 68
definition of, 42 J
diabetes mellitus as cause of, 263 Jaw
in immunosuppressed patients, 283–286 medication-related osteonecrosis of. See
in myelosuppressed patients, 283–286 Medication-related osteonecrosis of the jaw.
pathogen and, 42 metastatic tumor to, 266
Infective endocarditis Jones approach, 364
antibiotic prophylaxis for Junk DNA, 296
American Heart Association recommendations,
329–330, 332–336
current data regarding, 336–337
drug resistance concerns, 336
K
Keystone pathogen, 42
history of, 329
KRT75, 302
research studies about, 339–340
KRT6A, 302
support for and against, 335–336
KRT6B, 302
of aortic valve, 331f
bacteremia and, 334
community-acquired, 332, 337
definition of, 331
L
dental procedures, 334 Lateral gene transfer, 66
medically related, 332 Laugier-Hunziker syndrome, 262

375
I Index

Leptin Metagenomics, 43
adipocyte secretion of, 108 Metastatic tumors, to jaw, 266
in obesity, 115 Methotrexate, 246
skeletal growth affected by, 121 Methylome-wide association studies, 301
Leukemia Microbiome. See also Oral microbiome.
acute monocytic, 259, 259f in body fluids, 41
acute myelogenous, 271, 272f body site, 78f
gingival hyperplasia secondary to, 259f, 259–260 definition of, 44
Leukoplakia, 253, 253f description of, 44–45
Life expectancy, 180 functions of, 44
Ligneous gingivitis, 260 fungal, 49
Lipopolysaccharides, 71–72, 88, 107, 218 in saliva, 56–58, 57f
Lipoxins sampling sites for, 45f
A4, 98t smoking effects on, 41, 57, 61–62
description of, 90 Microvesicles, salivary, 351
Lipoxygenases, 89 Migratory glossitis, 257, 257f
Literature Mild periodontitis, 136t
assessment of, 24 Miller, Willoughby Dayton, 2
oral infection–systemic health link in, 25f, 357 Minimal clinically important differences, 24, 28, 31
Low birth weight, 211, 212b MiRNA, 347, 351
Low-density lipoproteins, 94 Mitral valve prolapse, 332
Lung cancer, 232, 235–236, 346, 357 Moderate periodontitis, 136t
Lung resistance protein, 345 MODY. See Maturity-onset diabetes of the young.
Lupus erythematosus, 254–255 Monogenic diseases, 293
Lymphonodular pharyngitis, 247 MRONJ. See Medication-related osteonecrosis of the
jaw.
mTOR inhibitors. See Mammalian target of
M rapamycin inhibitors.
MUC7, 305
Macrophages, 107, 109, 139
Mucopeptide, 43
MAGIC syndrome, 245
Mucormycoses, 250–251
Mammalian target of rapamycin inhibitors
Mucositis, oral, 245, 246f, 275f–278f, 275–280
description of, 246, 279–280, 280f
Mucous membrane pemphigoid, 251, 252f
stomatitis associated with, 246
Multidimensional protein identification technology
Maresin-1, 98t
(MudPIT), 350
Masking, 33
Murein, 43
Massively parallel sequencing, 297
Murray-Puretic-Drescher syndrome, 260
Masticatory efficiency, 121–122
Mycobacterium tuberculosis, 184
Matrix metalloproteinases, 95, 97
Mycobiome, 49
Maturity-onset diabetes of the young, 137
Myelosuppressed patients, oral complications in
McCune-Albright syndrome, 262
herpes simplex viral infection, 284–285, 285f
MCID. See Minimal clinically important differences.
infections, 283–286
Medicaid, 360, 363–366
mucositis, 275f–278f, 275–280
Medically necessary dental care, 364–367
Myocardial infarction, 3
Medically related infective endocarditis, 332
Medicare, 360, 363–366
Medication-induced oral pigmentation, 261
Medication-related osteonecrosis of the jaw N
antiangiogenic agents as cause of, 266 Naegeli syndrome, 304
bisphosphonates as cause of, 264–266 NAMPT, 299
clinical presentation of, 264–265, 265f, 265t National Cholesterol Education Program Adult
definition of, 262, 287 Treatment Panel III, 110
denosumab as cause of, 266 National dental organizations, 326
description of, 264–266, 273t National Health and Nutrition Examination Survey.
extractions in, 265 See NHANES.
illustration of, 265f, 287f National Institutes of Health, 293, 307
management of, 287–288 NCD Alliance, 324, 325b
prevention of, 265–266, 287 NCEP/ATPIII. See National Cholesterol Education
Prolia as cause of, 266 Program Adult Treatment Panel III.
staging criteria for, 288b Necessary and sufficient condition cause framework,
Melanin, 261–262 6–8, 7f, 8b–9b, 15–16
Melanotic macules, 262 Necessary conditions, 6–8, 7f, 8b–9b, 15–16
Mendelian randomization, 17f, 18–19, 19f Necrotizing ulcerative gingivitis, 259
Mendel’s law of segregation, 18 Neoadjuvant therapy, 27`
Metabolic syndrome Neonatal disorders
dental caries and, 116 low birth weight, 211, 212b
obesity and, 110–111 preterm birth, 210–211, 211f, 212b, 215, 219
periodontal disease risks, 116 Net coster, 364

376
 Index

Neurofibromatosis, 262 inflammatory mediators, 115–116

Neuroinflammation, 68 longitudinal studies of, 113–114
Neutropenia, 245 Mendelian randomization on, 17f, 19
Neutrophil extracellular traps, 77 treatment effects, 114–115
Neutrophils, 77 periodontitis and, 111–113, 112f, 123
Next-generation sequencing, 297 physical activity for prevention of, 106
NHANES, 120, 135, 141, 182, 192 prevalence of, 102, 103f, 104–105, 151
Nifedipine-induced gingival hyperplasia, 259, 259f skeletal maturation in, 121
Nikolsky sign, 251 sleep apnea associated with, 111, 122–123
95% confidence interval, 28–29 sugar-sweetened beverages as cause of, 105–106,
No effect, 29 118–119
Noncommunicable diseases summary of, 123–124
description of, 311, 314 tooth eruption and movement affected by, 119–121
global impact of, 318f, 318–319 tooth loss and, 121
interventions to prevent, 316 treatment of, 124
oral diseases and, 320–321 upper airway structure affected by, 122
World Health Organization and Observational studies
Global Action Plan for the Prevention and case-control studies, 35–36
Control of Noncommunicable Diseases cohort studies, 35, 37
2013–2020, 316, 319 cross-sectional studies, 35–36
statement by, 318–319 on dental health–acute myocardial infarction link,
Nonhealing extraction sockets, 263–264 3
Not-for-profit organizations, 360 description of, 1–2, 35
Nuclear factor κ B, 88 randomized controlled trials versus, 1–2
Null hypothesis, 25–27 Obstructive sleep apnea, 122–123
Null value, 29, 31 Odds ratio, 34, 36
Nutrition, tooth loss effects on, 148. See also Diet. OHiAP. See Oral Health in All Policies.
Nystatin, 286 Older adults
periodontal disease in, 180
pneumonia in, 198–199
O 1000 Genomes project, 293–294
Operational taxonomic units, 47, 48f
OAT. See Oral appliance therapy.
Oral appliance therapy, 122–123
Obesity
Oral cancer, 91, 307–308
angiogenesis and, 108–109
Oral cavity metastases, 266
assessment of, 102–104
Oral diseases
body mass index, 102–103, 104t, 109–110, 114,
challenges for, 312
157f
contributory causes of, 357
cancer risks associated with, 232
diabetes mellitus and, 320
in children, 104, 119
downstream interventions for, 317
chronic disease associated with, 110
genetics of, 298–306
clinical considerations regarding, 125
global burden of, 312–315, 313f
consequences of, 109–111
global prevalence of, 313f
definition of, 102
high risk approaches to, 317
dental caries and, 116–119
noncommunicable diseases and, 320–321
diabetes mellitus and, 111
prevention of, 315f, 316
diet and, 105
quality of life affected by, 312
disability caused by, 109
social determinants involved in, 323
disorders associated with, 102, 123
systemic diseases and
economic impact of, 110
common risk factors between, 311, 316, 317f,
ethnicity and, 104
321–323, 326
etiology of, 105–106
genomic connection between, 301–306, 303f
genetic predisposition, 105
shared molecular basis between, 306
gingival bleeding and, 113
summary of, 325–326
global prevalence of, 103f, 104–105
upstream interventions for, 317
inflammation in, 106–108, 107f
Oral dysesthesia syndrome, 268
insulin resistance in, 112, 116
Oral epithelial cells, 56
masticatory efficiency and, 121–122
Oral health
measures of, 113
common risk factors approach for, 316, 317f,
metabolic syndrome and, 110–111
321–323
morbidity and mortality of, 109–110
general health and, 319
obstructive sleep apnea associated with, 122–123
global
oral infections and, 125
inequalities in, 312–315, 314f
pathophysiology of, 106–109
interventions to improve, 315–318
periodontal disease and
in immunosuppressed patients, 289
conceptual analysis of, 123
integrated strategy for, 321–323
cross-sectional clinical studies of, 111–113
oral health professionals as advocates for, 323–324
description of, 111, 123

377
I Index

in pregnant adolescents, 224 future travels, 77–78

social determinants of, 316, 316f, 323 Helicobacter pylori, 76–77
Oral health care professionals herpes simplex virus, 75
description of, 311 human papillomavirus, 73–75
health management involvement by, 324 human transfer of, 69–71
oral health advocacy by, 323–324 indirect transfer of, 70–71
Oral Health in All Policies, 323 interpersonal methods, 69–71
Oral hygiene intrapersonal methods, 63–69
antimicrobial, in pneumonia, 202–203 nerve pathways, 68
in chronic obstructive pulmonary disease, 203 pacifier transfer of, 71
gingival disease and, 337 salivary transfer, 70
in infective endocarditis, 334 travel options, 63–71
periodontal disease and, 338f travelers, 71–77
Oral infections. See also Infection. Oral mucositis, 245, 246f, 275f–278f, 275–280
adverse pregnancy outcomes caused by, 226 Oral pain, 273t, 279
atherosclerosis and, 164–165 Oral sepsis, 87
cancer and, 238 Oral squamous cell carcinoma, 345, 353
cardiovascular disease and, 164–177 Oral ulcers
fungal, 273t aphthous-like ulcers, 243–245
in immunosuppressed patients, 289 deep fungal infections as cause of, 250–251
obesity and, 125 description of, 242
pulmonary diseases and, 205 drug-induced, 245–246
systemic diseases and, 165 erythema multiforme, 248–250
tumor growth and, 238 immunosuppressive agents for, 243t
viral, 273t recurrent aphthous stomatitis, 242–243, 244f
Oral infection–systemic health link. See also Oral- traumatic, 242
systemic connections. vesiculobullous disease as cause of, 251–253,
benefits of establishing, 20 252f–253f
Bradford Hill criteria applied to, 12–13, 14f–15f viral infections as cause of, 246–247, 248t, 250t
counterfactual cause framework applied to, 16 Oral-systemic connections. See also Oral infection–
history of, 2–3 systemic health link.
literature published regarding, 25f, 357 inflammation in. See Inflammation.
necessary and sufficient condition cause framework overview of, 86–88
applied to, 15–16 summary of, 99
position statements on, 362–363 Oropharyngeal cancer, 321
probabilistic framework applied to, 16 Orthodontic appliances, 52–53
research on, 2 Osteitis deformans. See Paget disease of bone.
salivaomics, 354f. See also Salivaomics. Osteonecrosis of the jaw, medication-related. See
salivary biomarkers, 342 Medication-related osteonecrosis of the jaw.
salivary-exosomics, 349–353, 354f Osteopetrosis, 264
sufficient-component cause framework applied to, Osteoporosis, 266
16 Osteoradionecrosis, 273t
Oral lichen planus, 253–255, 254f Ovarian cancer, 346–347
Oral microbiome Overweight, 104
core, 46–50
definition of, 38
distribution of, 50–59
dynamic nature of, 59–63
P
P value, 26–28, 28t, 30t
geographic diversity, 58–59
Paget disease of bone, 263–264
human, 45–46
Pain, oral
intraoral diversity of, 50–56
management of, 279
modifiable changes to, 61–63
topical medications for, 243t
periodontal pockets, 50
Palifermin, 277
phylotypes in, 47f
Panc02 cells, 352, 352f
tooth surfaces, 50
Pancreatic cancer, 234, 236–237, 352f
traveling
Parotid gland, 342f, 342–343
air transfer of, 71
Pathogen, 42
Alzheimer’s disease, 68–69
Pemphigus vulgaris, 252, 252f
antibiotics for, 77
Peptidoglycan, 43
aspiration, 63–64
Periapical periodontitis, 50–51
atherosclerosis, 72–73
Peri-implant space, 40
bloody entryways, 67
Peri-implantitis, 40, 51, 52f
bloody travel vehicles, 67
Periodic fever, aphthous stomatitis, pharyngitis, and
cell invasion, 64–66
adenitis syndrome, 245
destinations of, 63
Periodontal disease. See also Gingivitis; Periodontitis.
direct transfer, 66, 69–70
burden of, 135–136
fungi, 68
cancer and biologic plausibility for, 233–234

378
 Index

observational studies regarding, 234–237 during pregnancy, 222–224

shared risk factors for, 231–233
characteristics of, 92
description of, 90–91
destructive membranous, 260
diabetes mellitus and, association between
description of, 138–139, 146, 321
evidence for, 140–150
guidelines for, 151–152, 152b–155b
health care costs, 359–360
mechanisms linking, 139–140, 140f
shared risk markers for, 139, 150
summary of, 152–155
genetic component of, 232
genetics of, 299–300
historical descriptions of, 3
host-parasite interaction, 90
hyperglycemia and, 139
inflammation and, 97
lung cancer and, 235–236
in myelosuppressed patients, 284f
obesity and
conceptual analysis of, 123
cross-sectional clinical studies of, 111–113
description of, 111, 123
inflammatory mediators, 115–116
longitudinal studies of, 113–114
Mendelian randomization on, 17f, 19
treatment effects, 114–115
treatment effects of, 114–115
in older adults, 180
oral hygiene and, 338f
smoking as risk factor for, 112, 234
systemic conditions and, 92–97
treatment of
delivery of, 171–172
obesity effects on, 114–115
Periodontal infections, 283–284, 284f
Periodontal inflammation. See also Inflammation.
adverse pregnancy outcomes associated with, 216f
description of, 91, 95
economic impact of, 357–368
Periodontal medicine, 180, 300
Periodontal pathogenic bacteria, 39–40
Periodontal pockets, 50, 135
Periodontal risk assessment model, 307
Periodontal risk calculator, 307
Periodontal risk predictors, 307
Periodontal therapy
atherosclerotic cardiovascular disease affected by,
173–174
in chronic kidney disease
nonsurgical, 186
outcomes of, 186
response of, 185–186
systemic outcomes of, 186
C-reactive protein concentrations affected by, 174t
description of, 61, 124
in end-stage renal disease
nonsurgical, 186
outcomes of, 186
response of, 185–186
systemic outcomes of, 186
insurance studies regarding, 358–359
nonsurgical, glycemic control affected by, 144–146,
145t
periodontal pathogen dissemination during, 200
preterm birth affected by, 221t
Periodontitis. See also Periodontal disease.
Alzheimer’s disease and, 68
animal studies of, 98t
atherosclerotic cardiovascular disease and, 169,
175–176
atherothrombogenesis and, 168f
bacteria that cause, 46, 53f
cardiovascular disease and, 94–96
case definitions of, 135, 136t
chronic obstructive pulmonary disease and, 201,
321
contributory factors for, 193
costs associated with, 193
C-reactive protein and, 94–95, 166t–167t
cytokine levels in, 200
definition of, 135, 170b
description of, 39, 75, 90
diabetes mellitus and, 92–94, 152b
etiology of, 92
genetic causes of, 303
glycemic control affected by, 143–144, 321
hyperglycemia and, 139–141
inflammation in, 139
mild, 136t
moderate, 136t
obesity and, 111–113, 112f, 123
periapical, 50–51
pneumonia and, 197–201
pregnancy and, 96–97, 219–222
prevalence of, 135–136, 136f, 180, 193
pulmonary diseases and
epidemiologic association between, 196–197
mechanisms of, 197–201, 204
summary of, 204–206
risk factors for, 169, 176, 193
risk indicators for, 40
severe, 136t
systemic diseases and, 170b
tooth loss secondary to, 148
tumor necrosis factor α levels in, 115
waist circumference and, 113, 114f
Periodontitis and vascular events, 173
Periopathogens, 166–167
Peritonitis, 98t
Peroxisome proliferator-activated receptor gamma,
108–109
Petechiae, 262–263
Peutz-Jeghers syndrome, 262
PGN. See Progranulin.
Pharmacogenomics, 308
Phenome-wide association study, 301
Phenytoin-induced gingival hyperplasia, 259
Physical activity, for obesity prevention, 106
Pigmented lesions, 260–263
Pilocarpine, 267
Piwi-interacting RNA, 347–348, 351
Placebo group, 33
Placental growth factor, 218
Plaque
gingival hyperplasia caused by, 259
gingivitis caused by, 257
subgingival. See Subgingival plaque.
supragingival, 55f
Plasma cell gingivitis, 258
Platelet aggregation, 166

379
I Index

Platelet/endothelial cell adhesion molecules, 108 Probing pocket depth, 141, 143, 185, 196
Pleiotropy, 301–302, 303f Progranulin, 115
Pneumonia Proinflammatory cytokines, 89, 95
antimicrobial oral hygiene treatment in, 202–203 Prolia, 266
aspiration, 194–195, 197, 204 Prostaglandin E 2 , 89, 215
childhood, 194 Protectin D1, 98t
community-acquired, 195 Pseudogenes, 295
definition of, 194 Pseudomembranous candidiasis, 255, 255f, 286f, 286t
health care–associated, 194 Pseudomonas aeruginosa, 198–199
hospital-acquired, 194–196, 206 Psoralen and ultraviolet A therapy, 283
inflammation in, 194 Puberty, 119
in older adults, 198–199 Pulmonary aspiration, 63
pathogens that cause, 195, 198–200 Pulmonary diseases
periodontal health in, 204 chronic obstructive pulmonary disease. See Chronic
periodontitis and, 197–201 obstructive pulmonary disease.
ventilator-associated, 194, 198, 202–203, 206 clinical considerations regarding, 205
Polymorphonuclear leukocytes, 88, 93 definition of, 196
Poorly healing extraction sockets, 263–264 overview of, 193
Pores of Kohn, 195 periodontitis and
Porphyromonas gingivalis epidemiologic association between, 196–197
atherosclerosis and, 165–167 mechanisms of, 197–201, 204
bacteremia and, 67 summary of, 204–206
cell invasion/penetration by, 41, 64 pneumonia. See Pneumonia.
classification of, 45, 46b PWAS. See Phenome-wide association study.
illustration of, 46f Pyogenic granuloma, 213
nerve transport by, 68 Pyostomatitis vegetans, 244
pancreatic cancer and, 234
in peri-implantitis, 51
periodontitis caused by, 95, 198
in pregnancy, 97, 214
R
Radiation therapy
salivary transfer of, 70
hyposalivation caused by, 267
sleep pattern disturbances caused by, 69
salivary gland damage caused by, 267–268
Potential outcome, 10
Randomized controlled trials
PPD. See Probing pocket depth.
advantages of, 32–33
PRA model. See Periodontal risk assessment model.
association measures in, 34
PRC. See Periodontal risk calculator.
blinding in, 33
Preadipocytes, 108
control group in, 33
Precision medicine, 39
of dental treatment during pregnancy, 223–225
Prediabetes, 137t, 137–138, 146–147, 155
description of, 1
Preeclampsia, 211
disadvantages of, 33–34
Pregnancy
ethical concerns for, 34, 37
adolescent, 224
external validity issues, 33
adverse outcomes, oral infection correlation with
hallmark of, 32
biologic plausibility of, 214–219, 216f
limitations of, 1–2
description of, 210–211, 226
Mendelian randomization versus, 19f
indirect pathway of, 218–219
observational studies versus, 1–2
periodontal inflammation, 216f
randomization in, 32
gingival inflammation during, 213
statistical significance of, 31
granulomas during, 213, 214f
RCTs. See Randomized controlled trials.
oral infections during, 210, 226
Receptor activator of NFκ B ligand, 88
periodontal health during, 210, 226
Reciprocal causal relationship, 4
periodontal therapy during, 222–224
Recurrent aphthous stomatitis, 242–243, 244f
periodontal tissues affected by, 211–214
Relative risk, 34–35
periodontitis and, 96–97, 219–222
Removable dentures, 53
preterm birth, 210–211, 211f, 212b, 215, 219
Renal diseases
sex steroids during, 212–213
chronic. See Chronic kidney disease.
Pregnancy gingivitis, 213
end-stage. See End-stage renal disease.
Preterm birth
overview of, 181–182
C-reactive protein and, 215, 219
Renin-angiotensin blockers, 182
description of, 210–211, 211f, 212b
Research
periodontal treatment effects on, 221t
hypothesis-driven, 25
Prevotella intermedia, 198, 214
purpose of, 25
Prevotella nigrescens, 214
Resolution, of inflammation, 97
Primary antibiotic prophylaxis, 329–330, 340
Resolvin D1, 98t
Primary bone diseases, 263–264
Resolvin D2, 98t
Primary medical care, 322
Resolvin E1, 98t
Probabilistic cause framework, 11, 16
Retrospective cohort study, 35

380
 Index

Retrospective studies, 358 Skeletal-dental age, 120

Reverse causal relationship, 4 Sleep apnea, 111, 122–123
Rheumatic fever, 332 Small nucleolar RNA, 351
Rheumatoid arthritis Smoking
historical descriptions of, 2–3 cancer risks associated with, 232
leptin in, 108 chronic obstructive pulmonary disease caused by,
Ribosomal RNA, 39 195, 201, 321
Risk factors lung cancer and, 357
for atherosclerotic cardiovascular disease, 169 microbiome affected by, 41, 57, 61–62
for periodontitis, 169, 176 periodontal disease and, 112, 234
RNA genes, 296 “SNP chips,” 298
RNA sequencing, 301 Social determinants of health, 316, 316f, 323
Rutherford syndrome, 260 Sodium lauryl sulfate, 247
Spurious correlations, 11–12
Spurious relationships, 11–12
S Squamous cell carcinoma. See also Cancer.
head and neck, chemotherapy for, 277, 278f
Saliva
salivary proteomics and, 345–346
bacteria in, 49–50, 58f, 62f, 197
Staphylococcus aureus, 47, 195, 198–199
cancer biomarkers in, 345t, 345–348
Statistical analyses, 2
composition of, 343
Statistical significance testing
extracellular vesicles, 353 α level for, 26–27
factor VII–mediated coagulation triggered by, 351
confidence intervals for, 30t
functions of, 266, 343
definition of, 25–26
hyposalivation, 266–268
hypothesis testing for, 26–28, 27f
microbiome in, 56–58, 57f–58f
P value for, 26–28, 28t, 30t
oral microbe transfer via, 70
Stevens-Johnson syndrome, 249–250
xerostomia, 266–268, 274t
Streptococcus pneumoniae, 195
Salivaomics
Streptococcus salivarius, 183
definition of, 343
Streptococcus viridans, 332, 334
salivary proteomics, 343–347
Stromal-vascular component, 106
schematic diagram of, 354f
Study designs
Salivary exosomes
classification of, 32, 33f
as cancer biomarkers, 351–353
description of, 32
contents of, 350–351
evidential interpretations from, 34f
definition of, 349
experimental trials, 32–35
discovery of, 349
randomized controlled trial. See Randomized
mRNA in, 351
controlled trials.
structure of, 349–350
Sturge-Weber syndrome, 263
summary of, 353
Subgingival plaque
Salivary glands
bacteria in, 39, 56, 65
anatomy of, 342f, 343
microbiomes in, 50
hypofunction of, 274t
Sublingual gland, 342f, 342–343
radiation therapy–induced damage to, 267–268
Submandibular gland, 342f, 342–343
Salivary microvesicles, 351
Sufficient conditions, 6–8, 7f, 8b–9b, 15–16
Salivary Proteome Knowledge Base, 343, 344f
Sufficient-component cause framework, 8–9, 10f, 16
Salivary proteomics
Sugar-sweetened beverages, 105–106, 118–119
breast cancer applications of, 345
Supragingival bacteria, 51f–52f
description of, 343–345
Supragingival plaque, 55f
gastric cancer applications of, 346
Susceptibility, 11
lung cancer applications of, 346
Syngeneic transplantation, 280
ovarian cancer applications of, 346–347
Systemic diseases. See also specific disease.
squamous cell carcinoma applications of, 345–346
dental caries and, 302
Salivary transcriptomics, 347–349
oral conditions caused by
Salivary-exosomics, 349–353, 354f
candidiasis, 255f, 255–256
Sanger sequencing, 297
coated/hairy tongue, 256f, 256–257
Santa Fe Group position statement, on oral-systemic
diffuse gingival hyperplasia, 258–260
interactions, 362–363
gingivitis. See Gingivitis.
Scaling and root planing, 115, 144, 200
hyposalivation, 266–268
Secondary antibiotic prophylaxis, 329–330, 340
leukoplakia, 253, 253f
Selection bias, 33
medication-related osteonecrosis of the jaw. See
Severe early childhood caries, 116–117
Medication-related osteonecrosis of the
Severe periodontitis, 136t
jaw.
Sex steroids, 212–213
metastatic tumors, 266
Signature innate cytokines, 88
migratory glossitis, 257, 257f
Sink drain, 71
oral lichen planus, 253–255, 254f
16S rRNA gene, 43–44
Sjögren syndrome, 267

381
I Index

oral ulcers. See Oral ulcers. Trismus, 273t

overview of, 242–243 Tumor necrosis factor- α , 89, 93, 96, 106, 108, 112
pigmented lesions, 260–263 Tumor necrosis factor α-induced protein 3, 353
poorly healing or nonhealing extraction sockets, Type I error, 26, 27f
263–264 Type II error, 26, 27f
white/red lesions, 241t, 253–257 Tyrosine kinase inhibitors, for burning mouth
xerostomia, 266–268 syndrome, 268
oral diseases and. See also Oral infection–systemic
health link.
common risk factors between, 311, 316, 317f,
321–323, 326
U
Ulcers. See Oral ulcers.
genomic connection between, 301–306, 303f
Umbrella reviews, 144
shared molecular basis between, 306
Unfractionated heparin, 187
summary of, 325–326
Uremia, 183–184
oral infections and, 165
Uveitis, 69
periodontal disease and, 92–97
periodontitis and, 170b
salivary biomarkers for, 342
Systemic lupus erythematosus, 254–255
V
Valacyclovir, 250t
VAP. See Ventilator-associated pneumonia.
T Varicella-zoster virus, 247
Vascular endothelial growth factor, 345
T cells, 95–96, 107
Vascular lesions, 263
Tacrolimus, 243t
Vegetations, 331, 331f
Tacrolimus solution, 243t
Veillonella species, 72
Tannerella forsythia, 51
Ventilator-associated pneumonia, 194, 198, 202–203,
Targeted therapies, 279
206
Telangiectatic granuloma, 213
Vesiculobullous disease, 251–253, 252f–253f
Temporality, 2
Viral infections, oral ulcers caused by, 246–247, 248t,
Tetracycline, 261
250t
Th1 cells, 108
Visceral adiposity, 106
Th2 cells, 108
Viscous lidocaine, 243t
Tiffeneau-Pinelli index, 196
Vitamin D deficiency, 184
Toll-like receptors, 88
Tooth brushing
bacteremia after, 67, 177, 200, 332–334, 335f, 337
in diabetes mellitus patients, 154b
W
infective endocarditis and, 337, 339 Waist circumference, 104, 113, 114f
oral microbiome altered by, 61 Waist-height ratio, 104
Tooth eruption and movement Waist-hip ratio, 104
hyperglycemia and, 140 White/red lesions
obesity effects on, 119–121 leukoplakia, 253, 253f
Tooth extractions, 337 oral lichen planus, 253–255, 254f
Tooth loss Whole-exome sequencing, 301
causes of, 121 World Health Organization (WHO)
dental caries as cause of, 148 Global Action Plan for the Prevention and Control
diabetes mellitus and, 140–141 of Noncommunicable Diseases 2013–2020,
dietary effects of, 148 316, 319
hyperglycemia and, 140 noncommunicable diseases statement by, 318–319
nutritional effects of, 148
Toxic epidermal necrolysis, 249
Transcription, 296f X
Transcriptome, 347 Xerostomia, 148–149, 266–268, 274t
Transfer RNA, 347
Translational research, 307
Traumatic ulcers, 242
Traveling oral microbiome. See Oral microbiome,
Z
traveling. Z variable, 17f, 17–18
Triamcinolone, 243t Zimmerman-Laband syndrome, 260

382