Linkages with General Health
tongue appears smooth in pernicious anemia. Group 1995, Ramos-Gomez et al. 1996) and has been
B vitamin deficiency is associated with oral mucositis demonstrated to proceed to esophageal candidiasis, a
and ulcers, glossitis, and burning sensations of the sign of overt AIDS (Saah et al. 1992). Both the pseudo-
tongue. Scurvy, caused by severe vitamin C deficien- membranous and the erythematous forms of candidi-
CY is associated with gingival swelling, bleeding, asis appear to be important predictors of progression
ulceration, and tooth loosening. Lack of vitamin D in of HIV infection (Dodd et al. 1991, Klein et al. 1984,
utero or infancy impairs tooth development. Enamel 1992).
hypoplasia may result from high levels of fluoride or Like oral candidiasis, oral hairy leukoplakia in
from disturbances in calcium and phosphate metab- HIV-positive persons heralds more rapid progression
olism. which can occur in hypoparathyroidism, gas- to AIDS (Glick et al. 1994a, Greenspan et al. 1987,
troenteritis, and celiac disease. The mouth also can Lifson et al. 1994, Morfeldt-Manson et al. 1989). Oral
reflect the effects of tobacco use, perhaps providing hairy leukoplakia is an oral lesion first reported in
the only visible evidence of its adverse effects. the early days of the AIDS epidemic (Greenspan D et
al. 1984, Greenspan JS et al. 1985). Since its discov-
ery, hairy leukoplakia has been found in HIV-negative
Oral Manifestations of HIV Infection and persons with other forms of immunosuppression,
of Osteoporosis such as organ or bone marrow recipients and those
The mouth can serve as an early warning system, on long-term steroid therapy (Epstein et al. 1988,
diagnostic of systemic infectious disease and predic- Greenspan et al. 1989, ltin et al. 1988, King et al.
tive of its progression, such as with HIV infection. In 1994, Zakrzewska et al. 1995), and less frequently
the case where oral cells and tissues have counter- among immunocompetent persons (Eisenberg et al.
parts in other parts of the body, oral changes may 1992, Felix et al. 1992).
indicate a common pathological process. During rou- In a comprehensive review of periodontal condi-
tine oral examinations and perhaps in future screen- tions, Mealey (1996) noted that linear gingival ery-
ing tests, radiographic or magnetic resonance imag- thema and necrotizing ulcerative periodontitis may
be predictive of progression of HIV infection.
ing of oral bone may be diagnostic of early osteo-
Necrotizing ulcerative periodontitis, a more serious
porotic changes in the skeleton. The following sec-
tions provide details. periodontal condition observed in HIV-infected per-
sons, is a good predictor of CD4+ cell counts of
under 200 per cubic millimeter, and in one study was
a strong predictor of rapid progression to death
The progressive destruction of the body‘ immune (Glick et al. 1994a,b, Winkler and Robertson 1992,
system by HIV leads to a number of oral lesions, such Winkler .et al. 1988). In addition, the numerous
as oral candidiasis and oral hairy leukoplakia, that ulcerative and nonulcerative conditions that affect
have been used not only in diagnosis but also in the oral cavity (Aldous and Aldous 1991, Coates et
determining specific stages of HIV infection (CDC al. 1996, Cruz et al. 1996, Gandolfo et al. 1991, Itin
1992, 1994, Montaner et al. 1992, Redfield et al. et al. 1993, Mealey 1996) may affect the biologic
1986, Royce et al. 1991, Seage et al. 1997). Oral can- activity of HIV and are affected by its treatments.
didiasis is rarely seen in previously healthy young Other oral conditions, unexpected in the oral
adults who have not received prior medical therapy cavity, have been noted in the early stages of HIV
such as cancer chemotherapy or treatment with other s
infection. The increased incidence of Kaposi’ sarco-
immunosuppressive drugs (Klein et al. 1984). It was ma among young men in New York and California
associated with AIDS as early as 1981 in the first was one of the earliest signs of the AIDS epidemic
report of the syndrome (CDC 1981a) and was fre- (CDC 1981b). In addition, some conditions create a
quently noted among otherwise asymptomatic HIV- problem for differential diagnosis. For example,
positive populations (Duffy et al. 1992, Feigal et al. because involvement of the gingiva is common, early
1991). Oral candidiasis may be the first sign of HIV s
non-Hodgkin’ lymphoma lesions are frequently mis-
infection and often occurs as part of the initial phase taken for common periodontal or dental infections
of infection-the acute HIV syndrome (Tindall et al. (Epstein and Silverman 1992).
1995). It tends to increase in prevalence with pro- The changing face of the HIV epidemic and
gression of HIV infection when CD4 lymphocyte changes in the therapies used to manage complica-
counts fall (Glick et al. 1994a, Lifson et al. 1994). It tions are reflected in changes in the oral manifesta-
also appears to be the most common oral manifesta- tions, which warrant continued surveillance and
tion in pediatric HIV infection (Kline 1996, Leggott research. The increasing resistance of microorganisms
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 101
Linkages with General Hdth
to antibiotics and antifungals is challenging. On the skeletal measures in osteoporotic women and that
other hand, the completion of the Candida albicans the height of the edentulous ridge is correlated with
genome may yield better treatments for this oppor- total body calcium and mandibular bone mineral
tunistic infection. density. Hirai et al. (1993) found that the presence of
skeletal osteoporosis strongly affects the reduction of
Osteoporosis and Oral Bone Loss the residual ridge in edentulous patients. A small
With growing numbers of Americans living longer, case-control study comparing older female patients
there have been concomitant increases in the num- with osteoporotic fractures and non-osteoporotic
bers affected by age-related chronic degenerative dis- women without fractures found greater periodontal
eases. Prominent among these conditions are bone attachment loss in the osteoporotic women than in
and joint diseases. It is likely, for example, that some the controls (von Wowern et al. 1994).
temporomandibular joint disorders are manifesta- Studies that have controlled for confounding fac-
tions of osteoarthritis, rheumatoid arthritis, or tors also have found correlations between oral bone
myofascial pain. Paget’ disease, characterized by
s loss and skeletal bone density. Controlling for pack-
enlarged and deformed bone, can be particularly years of smoking, education, body mass, and years
painful and debilitating when it affects the cranial since menopause, Krall et al. (1994, 1996) found a
and jaw bones. significant positive relationship between number of
Osteoporosis, a degenerative disease character- teeth and bone mineral density of the spine and the
ized by the loss of bone mineral and associated struc- radius. In a cohort of 70 postmenopausal women,
tural changes, has long been suspected as a risk fac- Wactawski-Wende et al. (1996) measured skeletal
tor for oral bone loss. In addition, measures of oral bone mineral density at the Wards triangle area of the
bone loss have been proposed as potential screening femur and compared it with periodontal disease
tests for osteoporosis (Jeffcoat 1998). Osteoporosis assessed by attachment loss and the height of alveo-
affects over 20 million people in the United States, lar bone measured by radiographs. After adjusting for
most of whom are women, and results in nearly 2 age, years since menopause, estrogen use, body mass
million fractures per year (National Institute of index, and smoking, the investigators concluded that
Arthritis, Musculoskeletal and Skin Diseases 2000). osteopenia (low bone mass) is related to alveolar cres-
The disease is more prevalent in white and Asian tal height and tooth loss in postmenopausal women.
American women than in black women. Methods used to measure oral and skeletal bone
Oral bone loss has been reported to be more loss have varied among investigators and have shown
prevalent in women than in men. Studies by,Ortman different outcomes. Kribbs (1990) found that
et al. (1989) found a higher percentage of women patients in an osteoporotic group had lost more teeth,
than men with severe alveolar ridge resorption. This had less mandibular bone, and had a thinner bone
finding parallels the findings of Humphries et al. measured at a part of the jaw (cortex at the gonion)
(1989), who showed that loss of bone mineral densi- than a comparable non-osteoporotic group. However,
ty with age in edentulous adult mandibles was more using periodontal attachment loss as an indicator of
significant in women than in men. Also, the associa- mandibular bone loss, they found no differences
tion between estrogen status, alveolar bone density, between the osteoporotic and the non-osteoporotic
and history of periodontitis in postmenopausal group. Mohajery and Brooks (1992) compared non-
women has been studied (Payne et al. 1997). osteoporotic postmenopausal women with women
Most of the studies in this area have examined with mild to moderate osteoporosis and found no
bone loss in women, and most investigators have correlation between mandibular and skeletal bone
reported a correlation between oral and skeletal bone mineral density This study raises questions about the
loss measured in a variety of ways. Studies of non- quantification of mild and moderate osteoporosis.
osteoporotic women by Kribbs et al. (1990) showed Defining healthy periodontal tissues as having no
that mandibular bone mass is significantly correlated periodontal pockets deeper than 5 millimeters,
with skeletal bone mass. Dual photon absorptiometry Hildebolt et al. (1997) studied postmenopausal
measurements of jawbone volume in women with women with healthy periodontal tissues and found
osteoporosis have shown that reduction in mandibu- no relationship between periodontal attachment
lar bone mass is directly related to the reduction in loss and postcranial bone mineral density. How-
total skeletal mass density (Kribbs and Chesnut ever, preliminary studies from the oral ancillary study
1984, Kribbs et al. 1983, von Wowem 1985, 1988, s
of the NIH Women’ Health Initiative report signi-
von Wowern et al. 1994). Kribbs et al. (1989) further ficant correlations between mandibular basal
showed that mandibular mass is correlated with all bone mineral density and hip bone mineral density
102 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
(I- = 0.74, P -C ,001) (Jeffcoat et al. in press). In this ulation of bone mineral density in men as well as in
study, digital subtraction radiography methods were postmenopausal women needs to be evaluated fur-
used for mandibular bone measurements, and dual- ther with reference to oral bone loss, tooth loss, and
energy X-ray absorptiometry (DXA) scans were used periodontal disease. Variables such as sex, race,
for the hip bone measurements. The authors of this dietary calcium and phosphorus, vitamin D intake,
study propose the possibility that high-quality intra- exercise, body mass index, smoking, genetics, med-
oral radiographs may be used in the future for screen- ication use, reproductive history, and psychosocial
ing osteopenia. factors need to be assessed in depth. In addition, reli-
Larger cross-sectional studies, as well as longitu- able and valid criteria and imaging technologies for
dinal and mechanism studies, are needed to better assessing osteoporosis and oral bone loss are needed
define the relationship between osteoporosis. to better elucidate the full relationship between
osteopenia. and oral bone loss, periodontal disease, skeletal and mandibular bone mineral density, peri-
and tooth loss. The role of factors involved in the reg- odontal disease, alveolar ridge resorption, and tooth
Saliva/oral fluids: sampled analytes and current Oral-fluid-based Diagnostics:
The Example of Saliva
Category Analytes Tests
FDA-Approved The diagnostic value of salivary secretions to detect
Drugsof abusea Alcohol Cannabinoids systemic diseases has long been recognized (Mandel
Amphetamines Cocaine 1990), and oral fluids and tissues (buccal cells) are
Barbiturates Cotinine increasingly being used to diagnose a wide range of
conditions. Saliva- and oral-based diagnostics use
readily available samples and do not require invasive
procedures. Researchers have detected antibodies in
Nicotine saliva that are directed against viral pathogens such
Opiates as human immunodeficiency virus (Malamud 1997)
PCP and hepatitis A virus (O’ Farrell et al. 1997) or B virus
AntibodieG HIV HIVantibodies (Richards et al. 1996). Saliva is being used to detect
HPV antibodies, drugs, hormones, and environmental tox-
HHV-8/KSH ins (Malamud and Tabak 1993) (Table 5.2). The sim-
C.parvum plest tests are those that detect the presence or
absence of a substance in the saliva, such as various
Hormones Cortisol Estriol drugs. Greater technical challenges are presented for
Progesterone tests that will be used for therapeutic monitoring
since accurate levels of a substance and/or its
Met-enkephalin metabolites are needed. In these instances the sali-
va/plasma concentration ratio must be determined
Lead experimentally (Haeckel 1993). Tests beyond those
Mercury listed in Table 5.2 are currently on the market, but do
Therapeutics? Antipyrine not yet have FDA approval. Saliva is also the fluid of
Carbamazepine choice to assess the integrity of the mucosal immune
Ciprofloxacin system (Mandel 1990).
lrinotecan Most recently, oral fluids have been used as a
source of microbial or host DNA. With the advent of
Phenytoin polymerase chain reaction methods, the DNA con-
Phenobarbital tained within a single cell is sufficient for detection of
viruses (e.g., Kaposi’ sarcoma-associated herpes
virus, Koelle et al. 1997; Epstein-Barr virus, Falk et
Yonrtantine et al. 1997. al. 1997; mumps virus, Afzal et al. 1997) or bacteria
(Dabbr 1993,Ellison1993. (e.g., Helicobacter pylori, Reilly et al. 1997). Similarly,
*Gonzalezet al.1997, Joselowet al.1968. DNA extracted from sloughed buccal epithelial cells
eWilsOn1993. can be used to genotype persons. This has found
Source:Constantme al. 1997.
application in forensics (Roy et al. 1997) and may be
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 103
Linkages with General Health
used for diagnostic purposes in the future (van Schie These microorganisms can induce extensive local-
and Wilson 1997). ized infections that compromise general well-being
Saliva has the potential of replacing blood, the in and of themselves. However, they also may spread
current standard for testing many diseases and to other parts of the body if normal barriers are
conditions (e.g., diabetes, infectious disease, breached. The oral mucosa is one such barrier that
Parkinson’ disease, alcoholic cirrhosis, Sjogren‘ s provides critical defense against pathogens and other
syndrome, and cystic fibrosis sarcoidosis). Important challenges (Schubert et al. 1999). Salivary secretions
goals for the future are the development of new are a second major line of defense. Damage to the
diagnostic tests for early disease detection, defining oral mucosa from mechanical trauma, infection, or
individual patient risk of adverse response to drugs, salivary dysfunction with resulting derangements in
monitoring therapeutic progress, and determin- lubricatory and antimicrobial functions of saliva, as a
ing outcomes of treatment. Key issues in the result of chemotherapy, radiation, and medications
development of a new generation of saliva diag- causing hyposalivation, allows a portal of entry for
nostics include their selectivity, sensitivity, response invading pathogens.
time, dynamic range (values of interest), rep-
resentative sampling, and, perhaps most important,
their reliability or stability as well their ability to Oral Infections and Bacteremia
assess multiple substances simultaneously Oral microorganisms and cytotoxic by-products
associated with local infections can enter the blood-
stream or lymphatic system and cause damage or
Conclusion potentiate an inappropriate immune response else-
For the clinician the mouth and face provide ready where in the body. Dissemination of oral bacteria into
access to physical signs and symptoms of local and the bloodstream (bacteremia) can occur after most
generalized disease and risk factor exposure. These invasive dental procedures, including tooth extrac-
signs and symptoms augment other clinical features tions, endodontic therapy, periodontal surgery, and
of underlying conditions. Comprehensive care of the scaling and root planing. Even routine oral hygiene
patient requires knowledge of these signs and symp- procedures such as daily toothbrushing, subgingival
toms, their role in the clinical spectrum of general irrigation, and flossing may cause bacteremia.
diseases and conditions, and their appropriate man- However, these distant infections have been seen
agement. Oral biomarkers and surrogate measures more often in high-risk patients such as those who
are also being explored as means of early diagnosis. are immunocompromised.
With further development and refinement, oral- Oral bacteria have several mechanisms by which
based diagnostics such as salivary tests can be- they invade mucosal tissues, perhaps contributing
come widely used and acceptable tools for individu- to their ability to cause bacteremias. For example,
als, health care professionals, researchers, and com- oral bacteria and their products may invade the
munity programs. The continued refinement of periodontal tissues directly. Actinobacillus actino-
imaging techniques also has the potential of using mycetemcomitans has been found in gingival
oral imaging to identify early signs of skeletal bone connective tissue in patients with localized juvenile
degeneration. periodontitis (Christersson et al. 1987a,b, Meyer et
al. 1991, Riviere et al. 1991). Invasion of tissue by
Porphyromonas gingivalis has also been described in
THE MOUTH AS A PORTAL OF ENTRY vivo (Saglie et al. 1988) and in vitro (Njoroge et al.
FOR INFECTION 1997, Sandros et al. 1993, 1994, Weinberg et al.
Chapter 3 provides an overview of the effects of oral 1997). Although oral bacteria can enter the blood
microbial infections with viruses, bacteria, and fungi. through injured or ulcerated tissue, bacterial
More than 500 bacterial strains have been identified invasion of periodontal tissues represents another
in dental biofilm, and more than 150 bacterial strains possible mechanism.
have been isolated from dental pulp infections. More In the immunocompetent individual, bacteremia
recently, 37 unique and previously unknown strains originating from the oral cavity is usually transient
of bacteria were identified in dental plaque (biofilm) and harmless. However, if the individuals immune
(Kroes et al. 1999). Most oral lesions are opportunis- system is compromised, the normally harmless oral
tic infections, that is, they are caused by microorgan- bacteria may pose a significant risk. The morbidity
isms commonly found in the mouth, but normally and mortality associated with oral foci of infections
kept in check by the body’ defense mechanisms. are hard to assess. This is due to the formidable task
104 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
of tracking the source of an infection unless the Oral Infections as a Result of Therapy
responsible pathogen is indigenous to a specific
Viridans group streptococci (VGS) have a low
degree of virulence but can be associated with mor- Oral mucositis can be a major dose-limiting problem
bidity and mortality under certain circumstances. during chemotherapy with some anticancer drugs,
Increased pathogenicity of Streptococcus viridans is such as 5-fluorouracil, methotrexate, and doxoru-
most prominent in individuals with neutropenia (low bicin. It is estimated that approximately 400,000
blood counts of circulating white blood cells called patients undergoing cancer therapy each year will
neutrophils) and has been associated with a toxic- develop oral complications (NIH 1990). Infection of
shock-like syndrome (TSLS) or viridans streptococ- ulcerated mucous membranes often occurs after
cal shock syndrome (VSSS), as well as with adult res- chemotherapy, especially since patients are usually
piratory distress syndrome (ARDS) (Bochud et al. immunocompromised. Bacterial, fungal, and viral
1994). causes of mucositis have been identified (Feld 1997).
Although a high degree of morbidity is associat- The mechanism by which cancer-chemotherapy-
ed with viridans streptococcal bacteremia, a low inci- induced mucositis occurs is likely associated with the
dence of mortality has been reported (Heimdahl et al. rapid rate of turnover of oral epithelial cells. In addi-
1989). Several studies have shown that under tion, other components likely include upregulation
adverse circumstances oral flora and oral infections of pro-inflammatory cytokines and metabolic by-
are associated with increased incidence of morbidity products of colonizing oral microflora (Sonis 1998).
and even mortality (Engelhard et al. 1995, Lucas et Chemotherapy alters the integrity of the mucosa and
al. 1998, Martin0 et al. 1995, Ruescher et al. 1998, contributes to acute and chronic changes in oral tis-
Sparrelid et al. 1998, Sriskandan et al. 1995). sue and physiologic processes (Carl 1995). The
Reduction of oral foci of infection decreases systemic ulcerated mucosa is susceptible to infection by
complications, specifically in severely neutropenic microbial flora that normally inhabit the oral cavity,
patients undergoing chemotherapy (Heimdahl et al. as well as by exogenous organisms, and exacerbates
1984). In addition, hospital stays for patients with the existing mucositis. Further, these microflora can
oral mucositis undergoing autologous bone marrow disseminate systemically (Pizza et al. 1993, Rolston
transplants were longer than for those without oral and Bodey 1993). Compromised salivary function
mucositis (Ruescher et al. 1998). can further elevate risk for systemic infection of oral
Other cohorts identified at increased risk for sys- origin.
temic complications due to oral bacteria include hos- Both indigenous oral flora and hospital-acquired
pitalized patients unable to perform adequate oral pathogens have been associated with bacteremias and
hygiene, those receiving saliva-reducing medications, systemic infection (Schubert et al. 1999). Changes in
and those taking antibiotics that alter the oral flora. A infection profiles in myelosuppressed (immunosup-
positive dental plaque culture for aerobic pathogens pressed) cancer patients tend to occur in cyclic fash-
was significantly associated with the development of ion over many years. This evolving epidemiology is
hospital-acquired pneumonia and bacteremia in a caused by multiple factors including use of antibi-
study of individuals in an intensive care unit (ICU) otics. Gram-positive organisms including viridans
(Fourrier et al. 1998). streptococci and enterococci are currently associated
In addition, several case reports have been pub- with systemic infection of oral origin in myelosup-
lished implicating indigenous oral flora in the devel- pressed cancer patients. In addition, gram-negative
opment of brain abscesses (Andersen and Horton pathogens including I? aeruginosa, Neisseria spp., and
1990, Andrews and Farnham 1990, Baker et al. 1999, Escherichia coli remain of concern.
Gallagher et al. 1981, Goteiner et al. 1982, Saal et al. Cancer patients undergoing bone marrow radia-
1988). This serious condition is associated with a tion who have chronic periodontal disease may also
mortality rate of almost 20 percent and full recovery develop acute periodontal infections with systemic
in only slightly more than 50 percent of all patients complications (Peterson et al. 1987). The extensive
(Goteiner et al. 1982). These data are based on single ulceration of gingival sulcular epithelium associated
case reports and most probably represent rare events. with periodontal disease is not directly observable
However, they provide additional examples that clinically, yet may represent a source for disseminat-
point to the potential pathogenicity of the normal ed infection by an extensive array of organisms.
oral flora during special adverse circumstances. Inflammatory signs may be masked due to the under-
lying bone marrow suppression.
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 105
Linkages with General Health
Viruses are also associated with clinically impor- can require surgery to excise the dead tissue, which
tant oral disease in patients receiving chemotherapy can in turn leave the face badly disfigured as well as
(Ralston and Bodey 1993, Pizzo et al. 1993). functionally impaired (Field et al. 2000). The likeli-
Infections caused by herpes simplex virus, varicella- hood of ORN is increased with trauma to the bone,
zoster virus, and Epstein-Barr virus typically result including that caused by tooth extraction (Murray et
from reactivation of a latent virus, whereas al. 1980a, b). The risk is especially marked when the
cytomegalovirus infections can result via reactivation trauma occurs near the time of radiation (Epstein et
of a latent virus or a newly acquired virus. The sever- al. 1987). Management includes elimination of acute
ity of the infection, including fatal outcome, depends or potential dental and periodontal foci of disease,
on the degree of immunocompromise. increased patient participation in oral hygiene, use of
Many agents and protocols have been investigat- oral topical fluorides for caries prevention, and use of
ed to manage or prevent mucositis (Peterson 1999, antiviral, antifungal, or antimicrobial therapy for
Schubert et al. 1998). For example, various biologic management of infections associated with mucositis.
response modifiers, including transforming growth
factor p3 or keratinocyte growth factor, have been Combined Cancer Therapies
under recent study in randomized clinical trials.
Allopurinol mouthwash and vitamin E have been Rapid developments have occurred in the use of
cited as agents that can decrease the severity of blood cell growth factors for treatment of various
mucositis. although more extensive testing is neces- conditions, including the anemia of end-stage renal
sary. Prostaglandin E2 was not shown to be effective disease, the neutropenia occurring with cancer care,
in prophylaxis of oral mucositis following bone mar- and the bone marrow toxicity and mucositis that can
row transplant; however, more recent studies indi- follow aggressive chemotherapy or radiation therapy
cate possible efficacy when administered via a differ- (Sonis et al. 1997, Williams and Quesenberry 1992).
ent dosing protocol. Oral cryotherapy appears to be Sonis et al. (1997) found that topical application of
efficacious in reducing severity of oral mucositis transforming growth factor beta (TGF-8) in the ham-
caused by 54uorouracil and related compounds ster model of oral mucositis significantly reduced
(Rocke et al. 1993). basal cell proliferation and reduced the severity of
Local application of capsaicin preparations may mucositis associated with 5-fluorouracil treatment.
be effective in controlling oral mucositis pain as dis- Other growth factors considered for use in
tinguished from tissue injury itself (Berger et al. reducing mucositis include granulocyte-monocyte
1995). Capsaicin and its analogs are the active ingre- colony-stimulating factor and granulocyte colony-
dients in chili peppers. Capsaicin’ clinical potential stimulating factor. Bone morphogenetic proteins are
derives from the fact that it elevates the threshold for also in development for alleviating the toxicity and
pain in areas to which it is applied. mucositis that follow chemotherapy and radiation
therapy Other approaches to reducing mucositis and
Radiation Therapy adverse oral effects of chemotherapy and radiation
Radiation therapy disrupts cell division in healthy therapy include fractionating the dose of radiation,
tissue as well as in tumors and also affects the normal and combining chemotherapy with growth factors or
structure and function of craniofacial tissues, includ- with less toxic oncostatic agents. Although the oral
ing the oral mucosa, salivary glands, and bone. Oral- mucositis occurring in chemotherapy and in head
facial complications are common after radiation ther- and neck radiation patients shares many
apy to the head and neck. The most frequent, and characteristics, distinct differences also exist (NIH
often the most distressing, complication is mucositis, 1990, Schubert et al. 1998, Wilkes 1998). For
but adverse reactions can affect all oral-facial tissues example, in contrast to chemotherapy-associated
(Scully and Epstein 1996). lesions, radiation damage is anatomically site-
Radiation can cause irreversible damage to the specific; toxicity is localized to irradiated tissue
salivary glands, resulting in dramatic increases in volumes. The degree of damage depends on
dental caries. Oral mucosal alterations may become treatment-regimen-related factors, including the type
portals for invasion by pathogens, which may be life- of radiation used, the total dose administered, the
threatening to immunosuppressed or bone-marrow- fractionation, and field size. Thus, research involving
suppressed patients. A less common but very serious both cohorts of cancer patients remains essential to
adverse consequence is destruction of bone cells and enhancing patient management.
bone death, called osteoradionecrosis (ORN). ORN Development of new technologies to prevent
can result in infection of the bone and soft tissue and cancer-therapy-induced oral mucositis could
106 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
substantially reduce the risk for oral and systemic mucosal injury, or salivary compromise collectively
infections, oral pain, and the number of hospital promote the risk for clinical infection. In addition,
days. Improvement in quality of life and reduction in antibiotics and concurrent steroid therapy often alter
health costs are also likely and desirable outcomes. oral flora, thereby creating an environment for fungal
The new technologies could also provide a set- overgrowth. In high-risk cancer patients, fungal
ting in which novel classes of chemotherapeutic infection can cause severe morbidity and even death.
drugs, utilized at increased doses, could be imple-
mented. These advances in turn could lead to
enhanced cancer patient survival and lengthen the Infective Endocarditis
duration of disease remission. The purported connection between oral infection
and a specific heart disease, infective endocarditis,
Pharmaceuticals has a long history. Endocarditis is caused by bacteria
A number of medications used to treat systemic dis- that adhere to damaged or otherwise receptive sur-
eases can cause oral complications, ranging from faces of the tissue that lines heart valves (the endo-
xerostomic effects to alterations in the surface struc- cardium) (Weinstein and Schlesinger f974). Dental
ture of the enamel or mucosa. More than 400 over- and other surgical procedures may predispose sus-
the-counter and prescription drugs have xerostomic ceptible patients to infective endocarditis by induc-
side effects (Sreebny and Schwartz 1997). These ing bacteremias (Lacassin et al. 1995). However, bac-
include tricyclic antidepressants, antihistamines, and teremias from oral infections that occur frequently
diuretics. The dimensions and impact of these side during normal daily activities, coincidental even with
effects vary depending on the response of the indi- chewing food, toothbrushing, and flossing, con-
vidual patient and the duration of medication use. tribute more substantially to the risk of infective
Staining of the teeth or mucosa is associated with endocarditis (Bayliss et al. 1983, Dajani et al. 1997,
a variety of drugs, including tranquilizers, oral con- Strom et al. 1998). Oral organisms are common etio-
traceptives, and antimalarials. The antibiotic tetracy- logic agents of infective endocarditis (Bayliss et al.
cline can cause enamel hypoplasia when taken by the 1983). For example, strains of S. sanguis, as well as
mother during pregnancy and by children during gram-negative oral bacteria including Haemophilus
tooth development. The antimicrobial mouthrinse aphrophilus, A. actinomycetemcomitans, E. cormdens,
agent chlorhexidine also can stain the teeth, but this Capnocytophaga spp., and Fusobacterium nucleatum,
staining is external and can be removed by dental have been associated with bacterial endocarditis
prophylaxis. (Barco 1991, Geraci and Wilson 1982, Kaye 1994,
Other drugs have been associated with gingival Moulsdale et al. 1980).
overgrowth, including cyclosporin, which has been Infective endocarditis occurs with different incu-
used as an immunosuppressant in the United States bation periods, which differ in causative bacteria and
since 1984 to prevent rejection of transplanted signs and symptoms. For example, Staphylococcus
organs and bone marrow. This drug has also been aureus endocarditis may have a rapid onset and fatal
used in other countries for treatment of type 2 dia- course if it affects the left side of the heart. With a
betes, rheumatoid arthritis, psoriasis, multiple sclero- more indolent course, patients may often be unaware
sis, malaria, sarcoidosis, and several other diseases of infection and may experience fever, night chills,
with an immunological basis (Adams and Davies myalgia, and arthralgia for a considerable period of
1984). Other drugs that cause gingival overgrowth time before diagnosis. The infection is often curable
include calcium ion channel blocking agents used in if diagnosed and treated early
the treatment of angina pectoris and postmyocardial The classic risk factors for endocarditis include
syndrome, such as nifedipine and verapamil (Lucas cardiac valve disorders (valvulopathies) that include
et al. 1985>, and phenytoin (sodium 5,5-phenylhy- rheumatic and congenital heart disease, complex
dantoin), used in the treatment of epilepsy and also cyanotic heart disease in children, and mitral valve
for management of other neurological disorders. prolapse with regurgitation. Recent studies indicate
Treatment often consists of using an alternate drug, that the use of certain diet drugs (fenfluramine and
although this is not always possible. Conservative dexfenfluramine) has induced cardiac valvulopathy,
periodontal therapy can reduce the inflammatory which may in some cases be transient. Among at-risk
component of enlargement; however, surgery is often persons, bacteremias are more likely to occur in
required. Oral candidiasis is typically caused by those with periodontal disease (Silver et al. 1977).
opportunistic overgrowth of Candida albicans. Drugs However, the oral pathogens causing periodontitis
that cause systemic bone marrow suppression, oral have only rarely been shown to cause endocarditis.
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 107
Linkages Lvith General Health
Prevention of infective endocarditis from oral until the seventeenth century, when van Leewenhoek
bacteria depends on limiting the entry and dissemi- examined dental plaque using a microscope he
nation of bacteria through the bloodstream and lym- had constructed. In 1884, Koch demonstrated that
phatic circulation. Antibiotic prophylaxis for dental tuberculosis could be transmitted by airborne
procedures that are likely to provoke bacteremia has droplets from the mouth and respiratory tract. Since
historically been recommended (Dajani et al. 1997, that time, we have learned that many common respi-
Durack 1995). A recent study, however, suggests that ratory infections, such as influenza, the common
receiving dental treatment does not significantly cold, pneumonia, and tuberculosis, can be transmit-
increase the risk of infective endocarditis, even in ted from oral secretions. Before the development of
patients with valvular abnormalities (Strom at al. effective vaccines, orally transmitted diseases such as
1998). Further research is necessary to determine chickenpox, measles, mumps, polio, and diphtheria
whether some heart or valvular conditions or certain were a major source of morbidity and mortality in
dental procedures, such as surgery or scaling, would childhood. Viral diseases such as hepatitis B, herpes
require coverage with pre-procedural antibiotics and labialis, acute herpetic gingivostomatitis, cyto-
others would be precluded. megalovirus, and infectious mononucleosis may also
originate from oral contact.
Disease-causing microorganisms can be spread
Oral Infections and Respiratory Disease by direct contact (with saliva or blood from the
Pathogens in the oral cavity can also gain access to mouth) or indirect contact (with saliva- or blood-
the airway, sometimes with serious consequences. In contaminated surfaces, including hands or lips),
adults, bacterial pneumonias are strongly associated droplet infection (from coughing, sneezing, or even
with aspiration of bacteria into the lower respiratory normal speech), or by aerosolized organisms. These
tract, which is normally sterile. Common respiratory organisms can be inhaled, ingested, or taken in
pathogens such as Streptococcus pneumoniae, through mucous membranes in the eyes, nose, or
Streptococcus pyogenes, Mycoplasma pneumoniae, and mouth or through breaks in the skin. A number of
Haemophilus inf7uenzae can colonize the oropharynx diseases can be spread via oral sexual contact, includ-
and the lower airway. In addition, oral bacteria ing gonorrhea, syphilis, trichomoniasis, chlamydia,
including A. actinomycetemcomitans (Yuan et al. and mononucleosis.
1992), Actinomyces israelii (Morris and Sewell 1994, As mentioned earlier, the oral mucosa and saliva
Zijlstra et al. 1992), Capnocytophaga spp. (Lorenz provide significant defense against disease transmis-
and Weiss 1994), Eikenella corrodens Uoshi et al. sion. Epidemiological and animal studies are provid-
1991), Prevotella inter-media, and Streptococcus con- ing evidence, however, that the oral cavity may be the
stellatus (Shinzato and Saito 1994) can be aspirated site for transmission of serious systemic infections
into the lower airways (Scannapieco 1998, 1999). despite the protective factors in saliva (see Chapter
Chronic obstructive pulmonary disease, charac- 2). Infection with HIV provides a case in point (Baba
terized by obstruction of airflow due to chronic bron- et al. 1996, Dillon et al. 2000, Pope et al. 1997,
chitis or emphysema and by recurrent episodes of Ruprecht et al. 1999, Stahl-Hennig et al. 1999, Baron
respiratory infection, has been associated with poor et al. 2000).
oral health status (Hayes et al. 1998, Scannapieco et Early in the 198Os, when AIDS was first identi-
al. 1998). A positive relationship between periodon- fied in the United States, concern was expressed
tal disease and bacterial pneumonia has been shown about casual (i.e., nonsexual) transmission of HIV
by Scannapieco and Mylotte (1996). (CDC 1983, 1985). Detailed household studies did
Although oral bacteria, including periodontal not demonstrate transmission of HIV, even when
pathogens, have the potential for causing respiratory family members shared eating utensils and tooth-
infections, the frequency and nature of such infec- brushes with an HIV-affected member (Fischl et al.
tions are not known and merit further study. 1987, Rogers et al. 1990, Sande 1986). Similarly, sur-
veillance data collected over time showed no evi-
dence of casual transmission (Ward and Duchin
Oral Transmission of Infections 1997).
Besides being a portal of entry for infections, the Only one nonoccupational episode of HIV trans-
mouth is an important source of potentially patho- mission has been attributed to blood-contaminated
genic organisms and is often the vehicle by which saliva (CDC 1997); this incident involved intimate
infection is delivered to the bodies of others. kissing between sexual partners. There have been a
Microorganisms were not discovered in the mouth few cases of HIV transmission from performing oral
108 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
sex on a person infected with HIV, and it is also pos- infection can cause acute pharyngitis, but is usually
sible to become infected with HIV by receiving oral asymptomatic. The transmission of pharyngeal gon-
sex. In the San Francisco Options Study of men who orrhea to sex partners had been thought to be rare.
have sex with men identified within 12 months of However, in one study, 17 of 66 men who had sex
HIV seroconversion, oral transmission represented with men who had urethral gonorrhea reported
7.8 percent of primary HIV infections (Dillon et al. insertive oral sex as their only risk factor in the past
2000). Rothenberg et al. (1998) reviewed epidemio- 2 months (Lafferty et al. 1997).
logic studies and reports of 38 cases of oral transmis-
sion of HIV in the literature. They concluded that
although oral-genital contact may be less efficient Conclusion
than needle-sharing or anal intercourse for the trans- The role of the mouth as a portal of entry for infec-
mission of HIV, its increased use by men who have tion presents ever-new challenges for study. Although
sex with men (Ostrow and DiFranceisco 1996, oral tissues and fluids normally provide significant
Schwartz et al. 1995) and in crack cocaine smokers barriers and protection against microbial infections,
(Faruque et al. 1996a,b) may increase its contribu- at times these infections can not only cause local dis-
tion to HIV transmission over time. Several studies ease but, under certain circumstances, can dissemi-
provide evidence that when the oral environment is nate to cause infections in other parts of the body.
compromised, the mouth can be a potential site of The control of existing oral infections is clearly of
transmission of infectious microbes. Data from intrinsic importance and a necessary precaution to
Faruque et al. (1996a,b) and Wallace et al. (1996) prevent systemic complications.
suggest that there is a positive association between
the presence of oral lesions resulting from crack co-
caine use, receptive oral intercourse, and HIV trans- ASSOCIATIONS AMONG ORAL
mission. A case report has documented the passage of INFECTIONS AND DIABETES, HEART
HIV from a partner who is HIV-positive to one who DISEASE/STROKE, AND ADVERSE
is HIV-negative in the presence of periodontal disease PREGNANCY OUTCOMES
but in the absence of other risk factors (Padian and Recent studies have reported associations between
Glass 1997). Because the type, duration, and fre- oral infections-primarily periodontal infections-
quency of oral contact in past studies may not have and diabetes, heart disease and stroke, and adverse
been specified, the risk could be somewhat higher for pregnancy outcomes, but sufficient evidence does
oral transmission of HIV than previously reported. not yet exist to conclude that one leads to the other.
The risk might also vary depending on factors such This section characterizes the nature of these associ-
as viral load, infectious dose, area of exposure, and
ations by describing the quality of the evidence sup-
presence or absence of oral lesions. Additional stud-
porting the reports. Both observational and experi-
ies are needed to evaluate the risk of oral-genital
mental studies were accepted as admissible evidence.
transmission of HIV; some are under way (J.
Table 5.3 presents the hierarchy of evidence used to
Greenspan, K. Page-Schafer, personal communica-
interpret these associations. Where there are opera-
tive mechanisms proposed that support an associa-
Other sexually transmitted diseases (STDs) can
tion between oral infectious agents and the systemic
occur through oral contact. For example, pharyngeal
conditions in question, they are introduced at the
infection with Chlarnydia trachornatis has been found
outset. These are followed by animal studies and then
in 3 to 6 percent of men and women attending STD
by epidemiologic or population-based studies. The
clinics. Most infections are asymptomatic (Holmes et
evidence for each association is presented in the table
al. 1999). Another common sexually transmitted
in rank order according to the rigor of the study
infection, herpes simplex virus, commonly infects
the pharynx and is seen in 20 percent of patients with
primary genital herpes. The painless chancre of pri-
mary syphilis can be found in the oral cavity; howev-
The Periodontal Disease-Diabetes
er, there are no data on the prevalence of this site of
infection for Treponema pallidurn. Among persons
with gonorrhea, pharyngeal infection occurs in 3 to 7 There is growing acceptance that diabetes is associat-
percent of heterosexual men, 10 to 20 percent of het- ed with increased occurrence and progression of peri-
erosexual women, and 10 to 25 percent of men who odontitis- so much so that periodontitis has been
have sex with men (Holmes et al. 1999). Gonococcal called the “sixth complication of diabetes” (L6e 1993).
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 109
Linkages with General Health
The risk is independent of whether the diabetes pe
Tq’ 1 Diabetes. Ten reports focused principally on
is type 1 or type 2. Type 1 diabetes is the children and adolescents with type 1 diabetes, com-
condition in which the pancreas produces little or no paring them with groups of similar ages without dia-
insulin. It usually begins in childhood or adoles- betes (Cianciola et al. 1982, de Pommereau et al.
cence. In type 2 diabetes, secretion and utilization of 1992, Faulconbridge et al. 1981, Firatli 1997, Firatli
insulin are impaired; onset is typically after age 30. et al. 1996, Goteiner et al. 1986, Harrison and Bowen
Together, these two types of diabetes affect an esti- 1987, Novaes et al. 1991, Pinson et al. 1995,
mated 15.7 million people in the United States and Ringelberg et al. 1977). All but one of the studies
represent the seventh leading cause of death (NIDDK (Goteiner et al. 1986) reported greater prevalence,
1999). The goal of diabetic care is to lower blood glu- extent, or severity of at least one measure or index of
cose levels to recommended levels. Some investiga- periodontal disease (e.g., gingival inflammation,
tors have reported a two-way connection between probing pocket depth, loss of periodontal attach-
diabetes and periodontal disease, proposing that not ment, or radiographic evidence of alveolar bone loss)
only are diabetic patients more susceptible to peri- among subjects with diabetes, even though these
odontal disease, but the presence of periodontal dis- investigations were conducted in a variety of coun-
ease affects glycemic control. This section explores tries across several continents.
the bidirectional relationship, beginning with the Another set of studies on the relationship
effects of diabetes on periodontal disease. between type 1 diabetes and periodontal disease
included subjects with and without diabetes between
Effects of Diabetes on Periodontitis Prevalence the ages of 15 and 35 (Cohen et al. 1970, Galea et al.
and Severity 1986, Guven et a1. 1996, Kjellman et al. 1970,
Rylander et al. 1987, Sznajder et al. 1978). All six
Several reviews have described candidate mecha- studies reported greater prevalence, extent, or sever-
nisms to explain why individuals with diabetes may ity of at least one measure or index of periodontal
be more susceptible to periodontitis (Grossi and disease.
Genco 1998, Manouchehr-Pour and Bissada 1983, A third set of studies conducted in Scandinavia
Murrah 1985, Oliver and Tervonen 1994, Salvi et al. looked at the relationship between periodontal dis-
1997, Wilton et al. 1988). These include vascular ease and type 1 diabetes (or diabetes reported as
changes, alterations in gingival crevicular fluid, alter- requiring insulin therapy without specification of
ations in connective tissue metabolism, altered host diabetes type) in adults between 20 and 70 years old.
immunological and inflammatory response, altered Three of the four studies were cross-sectional
subgingival microflora, and hereditary patterns. (Glavind et al. 1968, Hugoson et al. 1989,
Studies were classified by type of diabetes and age of Thorstensson and Hugoson 1993), and one was a
study population (see Table 5.4). treatment follow-up study (Tervonen and
Hierarchy of evidence used in analyzing and interpreting results
Quality of Evidence
I: Evidenceobtained from at least one properly randomizedcontrolled trial.
11-l: Evidenceobtained from well-designedcontrolled trials without randomization.
11-2: Evidenceobtained from well-designedcohort or case-controlanalytic studies,preferablyfrom more than one center or researchgroup.
11-3: Evidenceobtained from multiple time serieswith or without the intervention.Dramatic results in uncontrolled experiments(such as the resultsof the
introduction of penicillin treatment in the 1940s)could also be regardedas this type of evidence.
Ill: Opinionsof respectedauthorities, basedon clinical experience;descriptivestudies and casereports; or reports of expert committees.
Strength of Recommendation
A: Thereis good evidenceto support the recommendation.
B: There is fair evidenceto support the recommendation.
C: There is insufficient evidenceto recommendfor or against, but recommendations may be made on other grounds.
D: There is fair evidenceto support the recommendationthat the intervention be excluded.
Thereis good evidenceto supportthe recommendation the interventionbe excluded.
Source:Adaptedfrom U.S.Preventive Force 1996.
110 ORAL HEAL-I-H IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
Summary of studies of the association between diabetes and periodontal diseases, classified by strength of evidence, diabetes type,
and age group
Numberof Measure of
Subjects Agesb Periodontal Other
Study Diabetes a. Diabetes a. Diabetes DiseaseStatus: Diabetes-Related Evidence
Country Design Type” b.Control b.Control DiabetesEffect Considered
Firatli1997 Turkey Prospective 1 a.44 a. 12.2(mean) Ging:0s Glycemiccontrol II-2
b. 20 b.12.3 (mean) Ppd:Os Durationof diabetes
Cohenet al. 1970 USA Prospective 1” a.21 a.18,35 Ging:1s None II-2
b.18 b.18,35 Lpa:lr,ls
Tervonen and Finland Prospective 1 a.36 a.24,36 Ging:Oe Glycemiccontrol II-2
Karjalainen1997 b.10 b.24,36 Ppd:lr Durationof diabetes
Novaes al. 1996 Brazil Prospective 2 a. 30 a. 30,77 Ppd:ls,lr control
b.30 b. 30,67 Lpa,ls,lr
Nelsonet al. 1990 USA Prospective 2 a.720 a. 15,55+ XRBL:li,lp None II-2
b. 1,553 b. l&55+
Taylor al. 1998a USA Prospective 2 a.24 a. 1557 li,
XRBL: lr None II-2
Taylor al. 1998b
et USA Prospective 2 a.21 a. 15,49 li,
XRBL: lr Glycemic
b. 338 b. 15,49
Goteineret al.1986 USA Cross-sectional 1 a.169 a.schoolages Ging:Os None III
b. 80 b.518 Lpa:Op,OS
Harrisonand USA Cross-sectional 1 a. 30 a.4,19 Ging:1s control
Bowen1987 b.30 b.4,19 Lpa:lp
Novaes al. 1991
et Brazil Cross-sectional 1 a.30 a.5,18 Ging:1s None Ill
b.30 b.518 Ppd:Os
et USA Cross-sectional 1 a. 263 a.<10,>19 Ging:lp Durationof diabetes Ill
b. 208 b.<10,>19 Lpa:lp
de Pommereau France Cross-sectional 1 a.85 a.12,18 Ging:le Glycemiccontrol Ill
et al. 1992 b.38 b.12,18 Op,
Lpa:Oe, OS Durationof diabetes
Ringelberg USA Cross-sectional 1 a.56 a.10,16 Ging:1s None Ill
et al. 1977 b.41 b.lO,lZ MGI:1s
Firatliet al. 1996 Turkey Cross-sectional 1 a. 77 a. 12.5(mean) Ging:Os Durationof diabetes Ill
b. 77 b. 12.6 (mean) Ppd:1s
Pinsonet al. 1995 USA Cross-sectional 1 a. 26 a.7-18 Ging:1s Glycemiccontrol Ill
b.24 b.7-18 Ppd:OS Durationof diabetes
Faulconbridge England Cross-sectional 1 a.94 a.5,17 Ging:1s Durationof diabetes Ill
et al. 1981 b.94 b.5,17
Kjellmanet al.1970 Sweden Cross-sectional 1” a. 105 a.l5,24 Ging:le Glycemiccontrol Ill
b. 52 b.1524 Ppd:0s complications
Guvenet al. 1996 Turkey Cross-sectional 1 a.10 a.18,27 Ging:le None Ill
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 111
Linltagcs u-it11 General Health
TABLE 5.4 continued
Subjects Age+ Periodontal Other
Study Diabetes a.Diabetes a. Diabetes DiseaseStatus: Diabetes-Related Evidence
Country Design TYP@ b.Control b.Control DiabetesEffecF Variables
Rylander al. 1987 Sweden Cross-sectional 1 a.46 a.18,26 Ging:le, 1p Diabetes
b.41 b.19.25 Ppd:Oe
Sznajder al. 1978
et Argentina Cross-sectional 1” a.20 a.9,29 Ging:1s None Ill
b.26 b.9,29 Lpa:0s
Galeaet al. 1986 Malta Cross-sectional l* a.82 a. 5,29 Ppd:lp Glycemiccontrol Ill
b.unknown b.5,29 Durationof diabetes
Hugosonet al. 1989 Sweden Cross-sectional 1 a.154 a. 20,70 Ging:le Durationof diabetes Ill
b. 77 b.20,70 Ppd:le,lp,ls
Giavindet al. 1968 Denmark Cross-sectional lx a.51 a. 20,40 Ging:Os Durationof diabetes Ill
b.51 b. 20,4O Ppd:OS Diabetestomplications
and Sweden Cross-sectional 1 a.117 a.40,70 Ging:Oe Durationof diabetes III
Hugoson1993 b. 99 b.40,70 Ppd:le,ls Onsetage
Morton et al. 1995 Mauritius Cross-sectional 2 a. 24 a.26,76 Ging:lp None Ill
b.24 b. 25,73 Ppd:1s
Shlossman al. 1990 USA Cross-sectional 2 a. 736 a.5 45+ Lpa:lp None III
b. 2,483 b.5,45+ 1
Emrichet al.1991 USA Cross-sectional 2 a. 254 a. 15,55+ Lpa:lp,ls None Ill
b. 1,088 b.15,55+ lp,
Wolf 1977 Finland Cross-sectional 1,2 a.186 a.16,60 Ging:1s Glycemiccontrol III
b.156 b.l6,60 Lpa:1s Durationof diabetes
Benveniste USA Cross-sectional 1,2* a.53 a.5,72 Ging:0s None Ill
et al.1967 b.71 b.5,72. Ppd:Op,Os
and USA Cross-sectional 1,2* a. 189 a. 20,79 PI:‘
Is Glycemiccontrol Ill
Boorujy1967 b.64 b. 20,79 Durationof diabetes
Belting et al. 1964 USA Cross-sectional 1,2” a.78 a.20,79 PI:ls Diabetes
b. 79 b. 20,79
Oliverand Tervonen USA Cross-sectional 1,2 a.114 a.20,64 Ppd:le,lp None III
1993 b.15,132 b.20,64 Lpa:le, Op,Os
Yavuzyilmaz al. Turkey Cross-sectional 1,2 a.17 a.25,74 Ppd:ls None III
1996 b.17 b. 19,29
Bridgeset al. 1996 USA Cross-sectional 1,2 a.118 a. 24,78 Ging:OS Glycemiccontrol ill
b.115 b. 24,78 Ppd:0s Durationof diabetes
Sandlerand Stahl USA Cross-sectional 1,2* a.100 a.20,69 le
PDR: None Ill
1960 b. 3,894 b. 20,69
Bacicet al. 1988 YugoslaviaCross-sectional 1,2 a.222 a. <20,6D+ Ppd:le,lp,ls Glycemiccontrol Ill
b.189 b. <20,60+ Durationof diabetes
Hoveand Stallard USA Cross-sectional 1,2” a. 28 a. 20,40+ Ging:Os Durationof diabetes III
1970 b. 16 b.20,40+ Ppd:OS Diabetesseverity
112 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages \vith General Health
Numberof Measure of
Subjects Age+ Periodontal Other
Study Diabetes a. Diabetes a. Diabetes DiseaseStatus: Diabetes-Related Evidence
Country Design TYP@ b.Control b.Control DiabetesEffect< Variables
Mackenzie and USA Cross-sectional 9 a. 124 a. 32,78 XRBL:Os None Ill
Millard 1963 b.92 b.32,78
Sznajder al. 1978
et Argentina Cross-sectional 9 a.63 a. 30,49 Ging:1s None Ill
b. 39 b. 30,50 Lpa:1s
Dolanet al. 1997 USA Cross-sectional 9 Weighted a.45,75+ Lpa:le,lp,ls None Ill
a. 107 b.45,75+
Grossi al. 1994
et USA Cross-sectional 9 a. 1,426 All:25,74; Lpa:Is, lp None Ill
Tervonen and Finland Cross-sectional 9 a.50 a. <30,40+ Ging:le control
Knuuttila 1986 b.53 b.<30,40+ Ppd:le, lp
Campbell1972 Australia Cross-sectional 9 a. 70 a.17,39 PI:lp,ls None Ill
Albrechtet al. 1988 Hungary Cross-sectional 9 a. 1,360 a. 15,65+ Ging:1s None Ill
b. 625 b. 15,65+ PI:OS
Szpunar al. USA Cross-sectional 9 a.474 a. 6,65+ PI:1s None Ill
1989(NHANES I) b. 15,174 b.6,65+
et USA Cross-sectional 9 a. 322 a. 15,65+ PI:1s None III
1989(HHANES) b.8,040 b. 12,65+
‘ type:1 = type 1 diabetes 2
mellitus; = type 2 diabetes
mellitur;1,2= bothtype 1 andtype 2 diabetes
mellitus;9 diabetes not specified not clearly
= type and ascertaina-
ble fromotherinformation the report; = diabetes not specified ascertained by reviewer from other information in the report.
in l type but
bAges:subjects’ agespresented as minimum, maximum reported for those with diabetes and controls unless otherwise specified.
(Measure of periodontal diseasestatus. Measuresused include Ging = girigivitis or gingival bleeding; Ppd = probing pocket depth; Lpa = loss of periodontal attachment; XRBt =
radiographic bone loss;JPS= juvenile periodontal score;MGI = modified gingival index; PI = Russell’periodontal index; PDR= periodontal diseaserate (proportion of teeth affected
by periodontal disease).Thenumber following the measure correspondsto greater diseasein those with diabetes (1) or no difference between those with diabetes and controls (0).
The letter followmg the number correspondsto the parameter(s) assessedin the study:e = extent;i = incidence;p = prevalence;s = severity; r = progression.
dlevels of evidence are delineated in Table5.3.
Karjalainen 1997). All four studies reported greater Taylor et al. 1998a,b). All seven studies reported
prevalence, extent, or severity of at least one measure greater prevalence, extent, or severity of periodontal
of periodontal disease. disease among subjects with diabetes for at least one
measure of periodontal disease. Three of these stud-
Type 2 Diabetes. There are fewer reports on the rela- ies were longitudinal (Nelson et al. 1990, Taylor et al.
tionship between type 2 diabetes and periodontal dis- 1998a,b) and showed that the progression of peri-
ease, particularly where type 2 diabetes is explicitly odontal disease was greater in diabetes patients than
identified or discernible from the ages of subjects. in individuals without diabetes.
Seven studies limited to subjects with type 2 diabetes In addition to finding significant differences in
included a comparison group without diabetes. Two various measures of periodontal status between sub-
of these studies included only adult subjects (Morton jects with and without type 2 diabetes, a number of
et al. 1995, Novaes et al. 1996); the remaining five these reports also provide estimates of association
were large population-based studies of diabetes and and risk. Using periodontal attachment loss as the
periodontal disease in Pima Indians, a group with the measure, Emrich et al. (1991) estimated that people
highest known prevalence of type 2 diabetes in the with type 2 diabetes were 2.8 times more likely to
world. The Pima Indian studies included subjects have destructive periodontal disease (odds ratio, 2.8;
aged 5 years and older (Shlossman et al. 1990) or 15 95 percent CI, 1.9 to 4.1). When they used radi-
and older (Emrich et al. 1991, Nelson et al. 1990, ographic bone loss as the measure and controlled for
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 113
Linkages with General Health
other important covariates, the estimate rose to 3.4 childhood to older adulthood (Albrecht et al. 1988,
(odds ratio. 3.4; 95 percent CI, 2.3 to 5.2). Nelson et Campbell 1972, Szpunar et al. 1989). Szpunar et al.
al. (1990) quantified the increased risk of advanced (1989) presented analyses of two separate national
periodontal disease in Pima Indians with and without surveys (the National Health and Nutrition
type 2 diabetes, finding the prevalence of periodontal Examination Survey, NHANES I, conducted between
disease in subjects with diabetes to be 2.6 times 1971 and 1974, and the Hispanic Health and
greater (95 percent CI, 1.0 to 6.6) than that of sub- Nutrition Examination Survey, HHANES, conducted
jects without diabetes. Taylor et al. (1996), in anoth- between 1982 and 1984).
er analysis of data from the Pima Indians, reported All seven studies found subjects with diabetes to
that type 2 diabetes was a significant risk factor for have increased prevalence, extent, and severity of
more severe alveolar bone loss progression (odds periodontal disease. The statistical significance of the
ratio, 4.2; 95 percent CI, 1.8 to 9.9), in addition to diabetes effect was markedly diminished in the final
being a significant risk factor for the prevalence of linear regression model used by Szpunar et al. (1989)
alveolar bone loss. in analysis of the NHANES I data: Two of the popu-
lation-based surveys, Grossi et al. (1994) and Dolan
Studies of individuals with Type 1 or Type 2 Diabetes. et al. (1997), provided epidemiologic estimates of the
Twelve reports included analyses in which subjects association of diabetes and attachment loss severity
with type 1 and type 2 diabetes were not separated. with odds ratios of 2.3 (95 percent CI, 1.2 to 4.6) and
All of these studies were cross-sectional and included 1.9 (95 percent CI, 1.3 to 3.0), respectively, while
adults; two studies included children or adolescents controlling for other covariates.
as well (Benveniste et al. 1967, Wolf 1977). Nine of
the 12 studies reported greater prevalence, extent, or Conclusion. Diabetes is a risk factor for the occur-
severity of periodontal disease among the diabetic rence and prevalence of periodontal diseases.
subjects for at least one measure or index of peri- Although there is insufficient evidence of a causal
odontal disease (Bacic et al. 1988, Belting et al. 1964, association, the findings of greater prevalence, sever-
Bridges et al. 1996, Finestone and Boorujy 1967, ity, or extent of at least one manifestation of peri-
Hove and Stallard 1970, Oliver and Tervonen 1993, odontal disease in individuals with diabetes is
Sandler and Stahl 1960, Yavuzyilmaz et al. 1996, remarkably consistent in the overwhelming majority
Wolf 1977). of studies. Furthermore, there are no studies with
Hove and Stallard (1970) and Benveniste et al. superior design features in the literature to refute this
(1967) did not find significant differences in peri- assessment. The studies were conducted in distinctly
odontal disease between subjects with and without different settings, with subjects from different ethnic
diabetes. The Hove and Stallard report included 28 populations and of different ages, and with a variety
subjects with diabetes and 16 without diabetes and of measures of periodontal status. This inevitable
may not have had enough statistical power to detect variation in methodology and study populations lim-
clinical differences, although they were able to detect its the possibility that the same biases apply in all the
a significantly higher prevalence of gingival vascular studies. There is a need for further research using
changes in subjects with diabetes. Benveniste et al. stronger designs that also control for confounding
(1967) commented that their results may have been variables such as socioeconomic status.
influenced by use of relatives without diabetes as the
comparison group and that the subjects with diabetes Glycemic Control
were all under reasonably good control with either Several lines of evidence support the plausibility that
insulin or dietary regulation. Both factors may have periodontal infections contribute to problems with
minimized differences between the groups. glycemic control, thus compromising the health of
diabetic patients. It has been reported that the chron-
Diabetes Type Not Specified. The final set of reports on ic release of tumor necrosis factor alpha (TNF-o) and
the association between diabetes and periodontal dis- other cytokines such as those associated with peri-
eases consists of seven cross-sectional studies in odontitis interferes with the action of insulin and
which the type of diabetes was not specified and was leads to metabolic alterations (Hotamisligil et al.
not easily determined from other information pro- 1993, Flier 1993). Other studies have noted relation-
vided. Four of the seven studies included only adults ships between insulin resistance and active inflam-
(Dolan et al. 1997, Grossi et al. 1994, Mackenzie and matory connective tissue diseases (Hallgren and
Millard 1963, Tervonen and Knuuttila 1986). In the Lundquist 1983, Svenson et al. 1987), other clinical
other three studies, subjects ranged in age from diseases (Beck-Nielsen 1992, Beisel 1975), acute
114 ORAL HEALTH IN AMERIC4: .4 REPORT OF THE SURGEON GENERAL
Linkages with General Health
infection (Drobny et al. 1984, Sammalkorpi 1989), impaired glycemic control is varied in the strength,
and periodontal disease (Grossi et al. 1999). Grossi quantity, breadth, and consistency of evidence pre-
and Genco (1998) have proposed a model whereby sented. The preliminary evidence, while encourag-
periodontal infection contributes to hyperglycemia ing, does not support a clear-cut conclusion that
and complicates metabolic control in diabetes. treating periodontal infection can contribute to man-
agement of glycemic control in type 1 or type 2 dia-
Clinical Studies. The effects of periodontal infection betes. As the table indicates, only studies using sys-
on glycemic control have been investigated in a small temic antibiotic treatment affected glycemic control
number of clinical studies that looked at metabolic favorably. The results suggest that infections other
control at baseline and following various periodontal than periodontitis may be implicated or that inten-
treatments (see Table 5.5; Aldridge et al. 1995, sive treatment of periodontal infections with sys-
Christgau et al. 1998, Grossi et al. 1996, 1997, Miller temic antibiotics is necessary to affect glycemic con-
et al. 1992, Seppala and Ainamo 1994, Seppala et al. trol favorably. Further rigorous controlled studies in
1993, Smith et al. 1996, Westfelt et al. 1996, Williams diverse populations are warranted.
and Mahan 1960, Wolf 1977). One report is based on
an epidemiological cohort study (Taylor et al. 1996).
The randomized controlled trials of Grossi et al. The Oral Infection-Heart Disease and
(1997) involving populations with type 2 diabetes Stroke Connection
found that use of the systemic antibiotic doxycycline During the past decade, infectious agents have
to treat periodontitis patients with diabetes resulted become recognized as causes of systemic diseases,
in a transient (3 to 6 months) improvement in without fever or other traditional signs of infection.
glycemic control. On the other hand, the two con- Helicobacter pylori is associated with peptic ulcers
trolled trials conducted in London by Aldridge et al. and, along with Chlamydia pneumoniae and
(1995) involving patients with type 1 diabetes found cytomegalovirus, is now thought to be associated
no effect. Taken together, these three studies provide with increased risk for cardiovascular disease as well
inconsistent results and are limited in how well they as malignancies (Wu et al. 2000). Studies investigating
generalize to broader populations. A small uncon-
the relationship between oral and dental infections
trolled study of 10 patients by Miller et al. (1992)
and the risk for cardiovascular disease suggest that
also reported an improvement in glycemic control of
there is potential for oral microorganisms, such as
diabetic patients whose periodontal disease was
periodontopathic bacteria, and their effects to be
treated with mechanical therapy and systemic doxy-
linked with heart disease.
cycline. Five of the above-mentioned studies did not
include control groups (Miller et al. 1992, Seppala et
al. 1993, Smith et al. 1996, Williams and Mahan Mechanisms of Action
1960, Wolf 1977), and four were not specifically Infectious agents are thought to affect the risk of
designed to address the relationship between peri- heart disease through several possible mechanisms.
odontal therapy and glycemic control (Grossi et al. Bacteria or viruses originating in tissues such as the
1996, Seppala et al. 1993, Smith et al. 1996, Westfelt lungs or oral mucosa may directly infect blood vessel
et al. 1996), although the data collected allowed the walls. Such infection may be largely asymptomatic,
investigators to address the issue. One nonrandom- but may cause local vascular inflammation and
ized but controlled clinical trial of nonsurgical peri- injury, which would contribute to the development
odontal therapy found no significant influence on of lipid-rich plaques and atherosclerosis. Bacteria or
medical data for the diabetic patients (Christgau et al. viruses may also interact with white blood cells or
1998). A clear relationship between improvement in platelets, both of which integrate into the developing
periodontal health and glycemic control has not been atherosclerotic plaque. Cells of the blood vessel wall
shown. The studies seem to suggest that antibiotic and white blood cells and platelets can release
treatments may help in glycemic control. A recent prostaglandins (especially PGE,), interleukins (espe-
longitudinal study indicates inflammation may be a cially IL-l), thromboxane B2 (TBX,), and tumor
precursor to the onset of type 2 diabetes (Schmidt et necrosis factor alpha (TNF-ok). Bacterial products in
al. 1999). Thus periodontal infection may contribute the blood may also stimulate liver production of
to that inflammation. other pro-inflammatory or pro-coagulant molecules
such as C-reactive protein and fibrinogen. Microbes
Conclusion. The body of literature concerning the may also stimulate expression of tissue factor, which
relationship between periodontal infection and would activate coagulation. During the process of
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 115
Linkages with General Health
Effects of periodontal disease and its treatment on glycemic control: clinical and epidemiological evidence
Number subjects Metabolic
Study Diabetes a.Treatment(ages) Follow-up Control Evidence
Designa Type b.Control(ages) Time Periodontal
Therapy Outcome on Control
Effects Metabolic Levelb
Aldridge RCT Type1 a.16(16-40) 2 months Experimental group:oral Glycated Periodontaltreatment had no I
et al. 1995, b.15 (16-40) hygieneinstruction,scaling, hemoglobin, effect on changein glycated
Study1 adjustmentof restoration fructosamine hemoglobin.
after 1 month;control group:
Aldridge RCT Type1 a. 12 (20-60) 2 months Experimental group:oral Glycated Periodontaltreatwnt had no I
et al.1995, b. 10 (20-60) hygieneinstruction,scaling hemoglobin effect on changein glycated
Study2 and root planing,extractions, hemoglobin.
Grossi et RCT Type2 a.89 (25-65) 12 months Experimental groupsreceived Glycated Thethree groupsreceiving I
al. 1996, b.24 (25-65) either systemicdoxycycline or hemoglobin doxycyclineand ultrasonic
1997 placeboand ultrasonic bacterialcurettageshowed
bactericidalcurettagewith significant reductions
irrigation using either water, (P < 0.04) in mean glycated
or hemoglobinat 3 months.
Christgau Treatment Type1 a.20 (30-66) 2 months Scaling/rootplaning; Glycated No effecton glycatedhemoglobin. II-1
et al. 1998 study,non- andtype 2 b.20 (30-66) subgingivalirrigation with hemoglobin
Westfelt Treatment Type1 a. 20 (45-65) 5 years oral
Baseline hygiene Glycated “Themeanvalueof HbAlc II-1
et al. 1996 study,non- andtype 2 b. 20 (45-65) and
instruction,scaling root hemoglobin and
betweenbaseline 24 months
RCT planingfollowedby periodic differentfrom
was not significantly
prophylaxis,oralhygiene that between24 and 60 months.”
surgery siteswith bleeding
on probingand a periodontal
probingdepth of >5 m m
Smith Treatment Type1 a. 18 (26-57) 2 months and
Scaling root planingwith Glycated Foundno statistically or clinically II-1
et al. 1996 study,non- b.0 ultrasonics curets;
and oral hemoglobin significant changein glycated
RCT hygieneinstruction hemoglobin.
Taylor Historical Type2 Notreatmentor 24 years Notapplicable Glycated Those periodontitis
with severe II-2
et al. 1996 prospective controlsubjects hemoglobin were -6 timesmorelikelyto have
cohort 49 (severe poorglycemic controlat follow-up.
Miller Treatment Type1 a. 10 (not given) 8 weeks and
Scaling root planing, Glycated Founddecrease glycated
et al. 1992 study, b.0 systemic
doxycycline hemoglobin, and
hemoglobin glycated albumin
RCT glycated in patientswith improvement in
albumin gingivalinflammation(P < 0.01).
Patients no improvement in
no changeor increase glycated
coagulation, platelets would become trapped in the the lumen of the coronary blood vessels narrows and
growing clot or thrombus. Microthrombus formation the blood supply to the heart muscle becomes
is one of the key factors in the development of ather- reduced. A frank heart attack or myocardial infarc-
osclerotic plaques. As atherosclerotic plaques enlarge, tion results when a larger part of the coronary artery
!!6 OR4L HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
Study Diabetes a.Treatment(ages) Follow-up Control Evidence
DesigV Type b.Control(ages) Time Therapy
Periodontal Outcome on
Seppala Treatment Type1 a. 38 for 1 year; 2 years Scaling root planing,
and Medical an of
Reported improvement the
et al. 1993, 22 for 2 years’ periodontalsurgery,and historyfor and
HBAl levelsof the PIDD CIDD
and 26 PIDD-ly(48 + 6) extractions baseline subjects < 0.068, r-test).
Ainamo 12 CIDD-lv(43 k 51 controlstatus;
1994 16 PIDD-2; glycosylated
6 CIDD-2y hemoglobin
b.0 Al and blood
Williams Descriptive Not speci- 3-7 scaling
Extractions, and Insulin had’
7 of 9 subjects kignificant”
and Mahan clinical fied a.9 (20-32) gingivectomy,
months curettage, in
requirement; reduction insulinrequirements.
1960 study b.0 systemicantibiotics diabetes
Wolf1977 Treatment Type1 and B-12 and
Scaling homecare Bloodglucose, 23
Compared subjects with
study,non- type 2 a. 117 (16-60) months instruction,
surgery, 24-h urinary improved infections
oral with 23
RCT b.0 extractions,endodontic glucose, who had no improvement after
restorations, insulindose treatmentfor oral infectionand
or inflammation.The subjects with
improved inflammation and
(P < O.l).However,Wolf statesin
tal inflammation periapical
lesions. . doeslittle to improve
the controlof diabetes.”
2 RCT randomizedcontrolledtrial.
b Levelsof evidenceare delineatedin Table5.3. Notethat because body of literatureis small,this reviewdoesnot distinguishbetween”well-designed”studies
otherwisein assigningthe evidencelevels.
( PIDD poorly controlledinsulin-dependent =
diabetes;ClDD controlledinsulin-dependent diabetes.
lumen becomes occluded. Failing to receive enough tral event in stopping blood flow. When an experi-
blood, the heart muscle dies, resulting in an infarct. mental bacteremia was created with a strain of S. san-
guis that carried the collagen-like protein, rabbits
Animal Studies showed changes in blood pressure, electrocardio-
Bacteria originating in the oral cavity may also con- gram readings, heart rate, and cardiac contractility
tribute to platelet clotting or thrombosis, as proposed (Herzberg and Meyer 1996, 1998). Platelets also
by Herzberg et al. (1983, 1994). These investigators aggregated in the circulation, resulting in significant
have suggested that the association between peri- declines in platelet counts. From the electrocardio-
odontal disease and cardiovascular disease may be graphic tracings, rabbit heart muscle also appeared co
due in part to the potential for oral bacteria such as have suffered ischemic damage. The investigators
S. sanguis and F?gingivalis to induce platelet aggrega- concluded that oral bacteria carrying the collagen-
tion. Platelets aggregate in response to these bacteria like protein induced platelet aggregation or clotting
as a result of mistaken identity: a protein structure on in the bloodstream. These clots were of sufficient size
the surface of certain common strains of S. sanguis to obstruct coronary arteries and produce ischemic
and I? gingivalis mimics the platelet-interactive heart damage, an early warning sign of a heart attack
regions of collagen molecules (Erickson and or an infarction. Because S. sanguis is present in large
Herzberg 1993, Herzberg et al. 1994). Exposure of numbers in dental plaque and is a causative agent in
flowing blood to collagen triggers clotting, the cen- infective endocarditis, it is likely that these bacteria
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 117
Linkages with Gencrnl Health
have an opportunity to induce platelet clotting dur- in this study. Periodontal disease was measured at
ing human bacteremias from oral sources. Bacteria- baseline, and the incidence of cardiovascular disease
induced platelet clotting could contribute to was followed over the next 10 years. When the analy-
microthrombosis during the development of athero- sis was restricted to individuals under age 60, the risk
sclerotic plaques and occlusive thrombus formation of cardiovascular disease was 2.7 times higher in sub-
with occasional myocardial infarction. jects with periodontal disease than in those with lit-
tle or no periodontal infection. This association was
Population-based Studies seen even after adjusting for other risk factors for
Any study investigating the possibility of a unique cardiovascular disease or periodontal disease such as
role for oral pathogens as risk factors for cardiovascu- age, sex, cholesterol, weight, high blood pressure,
lar disease, including atherosclerosis and the forma- diabetes, and insulin use. The investigators conclud-
tion of a blood clot in a coronary artery of the heart, ed that periodontal disease is an important risk fac-
which typically precedes myocardial infarction, must tor for cardiovascular disease for individuals under
take into consideration such known risk factors as 60 in this group, second only to the presence of
smoking, hypertension, obesity, diabetes, genetic sus- long-term diabetes. Further analysis of death due to
ceptibility, and elevated cholesterol. Genco (1998) cardiovascular disease is needed in this population to
and Beck et al. (1998) have recently reviewed studies complete the study.
examining the associations between oral conditions Mattila and coworkers have conducted both
(including pe rro d ontitis) and atherosclerosis and prospective and retrospective studies. A prospective
coronary heart disease, the latter of which affects 12 study (Mattila et al. 1995) showed that new episodes
million people in the United States and is the leading of myocardial infarction occurred more frequently in
cause of death. These are summarized in Table 5.6. subjects with more extensive “dental” disease. The
Of the ten studies cited in the table, six are authors used a measure of dental disease that includ-
prospective cohort studies, in which oral health sta- ed a composite index that assessed caries, periodon-
tus was established at the outset (baseline) of the titis, pericoronitis, and periapical lesions. The com-
study period and the subjects were followed at peri- posite index estimates the combined infectious load
odic intervals to a previously defined endpoint, for that contributes to many possible oral infections.
example, diagnosis of coronary heart disease or an After combining the prospective study data with data
acute myocardial infarction, or death. Beck et al. from an earlier retrospective study (Mattila et al.
(1996) combined data from the \ieterans 1989) and adjusting for age, triglyceride levels, cho-
Administration Dental Longitudinal Study and its lesterol, C-reactive protein, smoking, social class,
parent longitudinal study, the Normative Aging diabetes, and hypertension, the investigators found a
Study, for a total of 203 cases and 891 noncases, to significant association between dental infections and
determine whether periodontal disease, judged by acute myocardial infarction in men under age 50 (P <
measuring alveolar crestal bone, is a risk factor for 0.01). A more recent study (Mattila et al. 2000) com-
cardiovascular disease. After adjusting for age, blood pared 85 patients with proven coronary heart disease
pressure, cholesterol, and body mass index, the and 53 matched controls. This case-control study
investigators found that subjects with periodontal showed that dental indices were higher among coro-
disease were 1.5 times more likely to develop coro- nary heart disease patients than controls, but the dif-
nary heart disease over a 2%year period than controls ferences were not statistically significant. Participants
(odds ratio of 1.5). Similarly, after adjusting for age, in the study were older, which the authors believed
smoking, and blood pressure, the investigators found was the most likely reason for the results. In the first
that veterans with periodontal disease were I.9 times National Health and Nutrition Examination Survey,
more likely to develop fatal coronary heart disease 9,670 subjects were followed for over 14 years.
(odds ratio of 1.9). DeStefano et al. (1993) found that there was a 25 per-
In a longitudinal study to eliminate the potential cent increased risk of cardiovascular disease in indi-
confounding effects of smoking, Genco et al. (1997) viduals with periodontitis compared with those with
measured the incidence of periodontal disease and minimal periodontal disease. The strongest associa-
cardiovascular disease in 1,372 American Indians of tion was seen in men under 50 (relative risk, 1.7). A
the Gila River Indian Reservation. Although diabetes limitation of this study, which the authors acknowl-
is prevalent in this population, cigarette smoking is edge, was the lack of baseiine data on smoking, a
rare in these individuals (a fact confirmed in this major risk factor for both periodontal and cardiovas-
study), so it was considered not to be a risk factor for cular disease. Morrison et al. (1999) evaluated a ret-
either cardiovascular disease or periodontal disease rospective cohort study using participants in the
118 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages uTith General Health
Summary of studies assessing the association between oral conditions, atherosclerosis, and coronary heart disease
Study (cases/ (oddsratio or Evidence
Designd controls) OralCondition Outcome
Cardiovascular Adjustment+ relativerisk) Level<
OeStefano Prospective 1,786/7,974 Russell’
s heart disease Age,sex,race,education,poverty, 1.72 (1.1-2.68) II-2
et al. 1993 index to
(admission hospitalor BMI,
marital status,cholesterol, (only for men
death) diabetes,smoking under age 50)
Mattila Prospective 521162 Dental index (caries, New acute myocatdial Smoking, hypertension, sex,
age, Yes,P-c 0.01 II-2
et al.1995 periodontaldisease, infarctionor death socioeconomic
pulpal infection) status,diabetes,lipids,BMI,
Joshiputa Prospective 757/44,119 Periodontaldisease New coronaryheart Age,BMI,exercise,smoking, 1.67 (1.03-2.71) II-2
et al. 1996 (self-reported), disease alcohol,vitaminC,familyhistory,
tooth lossdue to Ml
Beck Prospective 203/891 Alveolarctestalbone New coronaryheart Age,BMI,total cholesterol, 1.5 (1.04-2.14) II-2
et al. 1996 10% disease,fatal
coronary socioeconomic LDL,
status,DBP, 1.9 (1.0-3.43)
heart disease,stroke smoking,cholesterol 2.8 (1.45-5.48)
Genco Prospective 68/1,304 Alveolarcrestalbone New coronaryheart Age,sex,smoking,BMI,diabetes, 2.68 (1.35-5.60) II-2
et al. 1997 IO% disease hypertension
Morrison Retrospective 10,000 Severegingivitis; New coronaryheart Age,sex,setumtotal cholesterol, 1.37 (0.80-2.35) II-2
et al. 1999 petiodontitis; hypertension for petiodontitis
edentulousness deaths 1.90 (1.17-3.10)
for fatal CHD
Joshiputa Prospective 42,151 Numberof teeth lost lschemic
stroke Age,smoking,obesity,alcohol, 210 teeth 1.75 II-2
et al. 1999 aspirin,family history,
profession, ll-15reeth 1.95
Dental index (caries, (1.02-2.13)
Mattila Case-Control 100/102 periodontaldisease, Acutemyocatdial HDL,smoking,C-reactive
Yes, < 0.01 II-2
et al. 1989 pulpal infections) infarctions age,
Gtau Case-Control 166/166 periodontaldisease, Stroke Diabetes, preexistingvascular Oddsratio 2.6
et al. 1997 petiapical
infections) disease,socioeconomic status, (1.18-5.70)
Dentalindex (caries, smoking
Mattila Case-control 85153 periodontaldisease, New coronaryheart Age,sex,smoking,socioeconomic it-2
et al. 2000 pulpal infections) disease hypertension,
teeth, serumlipid levels
“Farthe prospective the of in
studies, totalnumber rubjects the cohortisthesumof thetwo numbersgiven,the number whichrepresents subjects
first of the to For
followed the endpoint.
the case-control the the and the
represents cases, the second controls.
bBMl bodymass MI
index; = myotardialinfarction; = low-density
LOL HDL lipoproteins.
lipoproteins; = high-density
of are in
[Levels evidence delineated Table 5.3.
1970-72 National Canada Survey. In the younger dence. This pattern of higher risk observed among
cohort, those under age 69, they found that gingivi- younger subjects may, to some extent, reflect the rel-
tis, periodontitis, and edentulousness were related to ative instability of risk estimates. However, it is also
fatal coronary heart disease in a statistically signifi- possible that periodontal disease, like other co-mor-
cant manner. However, in analyzing those over age bid relative risks for coronary heart disease, general-
70, none of these dental conditions was associated ly declines with age (Semenciw et al. 1988).
with fatal heart disease. These results were adjusted Wu et al. (1999) found periodontal disease to be
for age, sex, serum total cholesterol, smoking status, a potential factor for coronary heart disease and
diabetes SWUS, hypertension status. and province of resi- stroke based on an analysis of the first National
ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL 119
Linkages 11.ith Gencrd Health
Health and Nutrition Examination Survey and its 21- cular disease or stroke. The methods used to measure
year follow-up. In this analysis, periodontitis was or identify periodontal disease ranged widely from
found to be a significant risk factor for cerebrovascu- self-report, to composite indices that included dental
lar disease, in particular nonhemorrhagic stroke. caries experience, to precise measures of periodonti-
Compared with no periodontal disease, relative risk tis severity. Nevertheless, there were consistent find-
(95 percent CI) for incident nonhemorrhagic stroke ings of increased odds ratios and significant proba-
was 2.11 (1.30 to 3.42) for periodontitis. There was bility (P) values pointing to an association of peri-
no significant relationship for gingivitis or edentu- odontal and other oral infections with an increased
lousness, which were 1.24 (0.74 to 2.08) and 1.41 risk for cardiovascular disease. Further studies are
(0.96 to 2.06), respectively. The increased relative needed to determine whether periodontal disease
risk for total cerebrovascular disease and nonhemor- alone or in the presence of other oral infections is an
rhagic stroke was not seen for hemorrhagic stroke. independent risk factor for cardiovascular or cere-
Similar relative risks for total cerebrovascular disease brovascular disease. Research to elucidate the under-
and nonhemorrhagic stroke associated with peri- lying pathological mechanisms is also essential.
odontitis were seen in white men and women and Studies must also clarify the potentially confounding
African Americans. A conclusive statement about a effects of sex, age, socioeconomic level, and race/
cause-and-effect relationship between periodontitis ethnicity.
and the risk of developing cerebrovascular disease, in
particular nonhemorrhagic stroke, cannot be made at
this time. The consistency of the findings in different Periodontal Disease and Adverse
racial groups and the strength of the association war- Pregnancy Outcomes
rant further examination of the potentially important Preterm birth and low birth weight are considered
association between these two clinical conditions, the leading perinatal problems in the United States
which are highly prevalent in the adult population. (Gibbs et al. 1992). Although infant mortality rates
In the largest cohort studied, Joshipura et al. have decreased substantially over the past genera-
(1996) found that among a group of male health pro- tion, the incidence of low birth weight (just under
fessionals who were relatively homogeneous socio- 300,000 cases in 1995) has not shown a comparable
economically and who self-reported preexisting peri- decline (Institute of Medicine 1985, USDHHS 1984).
odontal disease, those with 10 or fewer teeth were at Over 60 percent of the mortality of infants without
increased risk of new coronary heart disease, com- structural or chromosomal congenital defects can be
pared with those with 25 or more teeth (relative risk, attributed to low birth weight (Shapiro et al. 1980).
1.67). These results were adjusted for sta’ ndard car-
diovascular disease risk factors. Mechanisms of Action
In a case-control study of 166 patients with acute
cerebrovascular disease and I66 age- and sex- Periodontal disease may contribute to adverse out-
matched controls, Grau et al. (1997) found that comes of pregnancy as a consequence of a chronic
“poor dental status” was independently associated oral inflammatory bacterial infection. Toxins or other
products generated by periodontal bacteria in the
with cerebrovascular ischemia. These results were
mother may reach the general circulation, cross the
based on a subgroup of patients and controls who
placenta, and harm the fetus. In addition, the
completed the dental examination. A modified form
of the Total Dental Index was used to measure dental response of the maternal immune system to the
infection elicits the continued release of inflammato-
status. In an 8-year follow-up of 42,151 male health
professionals who were free of cardiovascular disease ry mediators, growth factors, and other potent
cytokines, which may directly or indirectly interfere
at baseline, Joshipura et al. (1999) reported that
with fetal growth and delivery
edentulousness was associated with an increased risk
Evidence of increased rates of amniotic fluid
of ischemic stroke after adjusting for age, smoking,
infection, chorioamnion infection, and histologic
obesity, alcohol, exercise, aspirin, family history of
cardiovascular disease, profession, hypertension, and chorioamnionitis supports an association between
hypercholesterolemia. preterm birth, low birth weight, and general infection
during pregnancy It is noteworthy that the largest
proportion of such infections occurred during the
pregnancies of the most premature births (Hillier et
None of the studies reviewed to date achieves the al. 1988, 1995). The biological mechanisms involve
level of rigor that can unequivocally establish peri- bacteria-induced activation of cell-mediated immuni-
odontitis as an independent risk factor for cardiovas- ty leading to cytokine production and the synthesis
120 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
and release of prostaglandins, which may trigger preterm labor; or preterm, premature rupture of
preterm labor (Hillier et al. 1988). Elevated levels of membranes. Controls were all normal-birth-weight,
prostaglandin as well as cytokines (interleukin-1 (IL- full-term infants. In a case-control study of 124 sub-
I), interleukin-6 (IL-6), and tumor necrosis factor jects, the mean clinical periodontal attachment level
alpha (TNF-a)) have been found in the amniotic for the mothers of low-birth-weight babies was 3.10
fluid of patients in preterm labor with amniotic fluid + 0.74 (SD) millimeters (mm) per site (93 subjects)
infection (Romero et al. 1993), compared with levels versus 2.80 + 0.61 (SD) mm per site (31 subjects) for
in patients with preterm labor without infection. mothers of normal-weight infants (P = 0.038 for all
cases and controls). For a subset of mothers for
r\nimal Models whom this was the first child, the mean clinical peri-
odontal attachment level for those with low-birth-
;\ variety of studies have used the pregnant hamster weight babies was 2.98 + 0.84 (SD) mm per site (46
model. Some investigators have examined the effects subjects) versus 2.56 + 0.54 (SD) mm per site for
of lipopolysaccharide, produced by oral gram-neg- controls (20 subjects) at P = 0.041 (Offenbacher et al.
ative pathogens, on cytokine production (Collins et 1996). This subset was analyzed separately to avoid
al. I994a). In other studies, hamsters have been
the confounding effects of mothers %ith periodontal
infected with I? gingivalis, with or without prior
disease who had previously given birth to low-birth-
immunization. Collins et al. (1994b) challenged the
weight infants but who later had normal-weight
animals with nondisseminating, low levels of P gingi-
\aaIis, introduced in a subcutaneous chamber at a Logistic regression models demonstrated that
dorsolumbar site. Although the doses were insuffi-
severe periodontal disease was associated with a sev-
cient to induce fever or wasting, the hamster litters of
enfold increase in risk of low birth weight, after con-
the infected animals showed a significant reduction
trolling for known risk factors such as smoking, race,
in fetal weight (24 percent) in comparison with con-
alcohol use, age, nutrition, and genitourinary tract
trol animals (P < 0.0001). This suppressive effect on
infection. This study suggests an association between
fetal weight was accompanied by a proportional
periodontal disease and prematurity
intrachamber rise in tumor necrosis factor alpha
In a subsequent case-control study of 44 sub-
(TNF-(-w) and prostaglandin E2 (PGE,) (P < 0.0001).
jects, additional biochemical and microbial parame-
Immunization prior to mating did not provide pro-
ters of periodontal disease status were studied to
tection from a challenge during pregnancy, but rather
assess the relationship of current periodontal status
potentiated the effects, indicating the potential
to current pregnancy outcome (Offenbacher et al.
strength of a chronic infection.
1998). Results indicate that PGE, levels in gingival
In another series of hamster studies, researchers
crevicular fluid were significantly higher in mothers
observed the effects of experimental periodontitis on
of low-birth-weight infants than in controls (131.4 +
pregnancy outcomes and amniotic fluid mediators
21.8 (SE) versus 62.6 + 10.3 (SE) nanograms per mil-
(Offenbacher et al. 1998). The investigators noted a
liliter), respectively (at P = 0.02). Furthermore, with-
20 percent decrease in fetal weight (P = 0.002).
in the group of mothers of low-birth-weight infants
Periodontal infection in the pregnant hamster also
there was a significant inverse association between
was associated with a significant rise in intra-amniotic
birth weight, gestational age, and gingival crevicular
PGEz from 3.31 + 1.1 to 13.5 f 4.1 micrograms per
fluid PGE, levels (at P = 0.023 for current births).
milliliter (P = 0.03). These data suggest a link be-
These data suggest that the level of PGE, in gingival
tween oral infection and changes in the fetal envi-
crevicular fluid, serving as a marker of current peri-
odontal disease activity, varies inversely with birth
weight; that is, the higher the PGE, level, the lower
Epidemiologic Studies the birth weights. In this study the periodontal dis-
Human case-control studies have demonstrated that ease was more severe in mothers with adverse preg-
mothers of low-birth-weight infants born as a result nancy outcomes, as determined by biochemical and
of either preterm labor or premature rupture of microbial biomarkers, but the difference in clinical
membranes tend to have more severe periodontal dis- attachment levels did not reach statistical signifi-
ease than mothers with normal-birth-weight infants cance (P = 0.11).
(Offenbacher et al. 1996, 1998). A case was defined Studies also have been reported in other coun-
as a mother whose baby weighed less than 2,500 tries. In the United Kingdom a preliminary analysis
grams and who had one or more of the following fac- of 167 cases and 323 controls did not show an asso-
tors: gestational age of infant of less than 37 weeks; ciation between periodontal disease and pregnancy
ORAL HEALTH 1N AMERICA: A REPORT OF THE SURGEON GENERAL 121
Linkages with General Health
outcomes (Davenport et al. 1998); however, the IMPLICATIONS OF THE LINKAGES
investigators did not control for confounding factors. This review of oral health linkages with general
Dasayanake (1998) conducted a matched case-con- health reveals implications for the clinical practice of
trol study with 55 cases in Thailand. Gingivitis was both medicine and dentistry The recognition of well-
associated with a higher risk of having a growth- known and established signs and symptoms of oral
restricted infant (odds ratio = 0.3; 95 percent CI, 0.12 diseases may assist in the early diagnosis and prompt
to 0.72), controlling for mothers height, prenatal treatment of some systemic diseases and disorders,
care, dental caries status, and the infant’ gender. The presence of these signs also may lead to the insti-
Smoking was not controlled for in this study. tution of enhanced disease prevention and health
promotion procedures. All health professionals, and
Conclusion the public, should be aware of these signs and symp-
As a remote gram-negative infection, periodontal dis- toms. Individuals, practitioners, and community pro-
ease may have the potential to affect pregnancy out- grams may also benefit from the accelerated develop-
come. Not all the obstetric risk factors that result in ment and testing of readily accessible, acceptable,
babies being born too soon and too small have been and simple oral-based diagnostics.
fully identified (Gibbs et al. 1992, McCormick 1985). A better understanding of the role of the oral cav-
Oral infections have been investigated as a potential ity and its components in protecting against infection
risk factor for preterm labor or premature rupture of is needed. This information should permit the devel-
membranes, which are major obstetric antecedents to opment of interventions to enhance these compo-
spontaneous preterm births. .4lthough the findings nents. For example, research is under way investigat-
from animal research and case-control studies are ing how to augment some of the natural antimicro-
promising, additional work, including longitudinal bial molecules that are present in saliva and how to
studies, research on mechanisms, and intervention use oral and nasal vaccination routes to enhance
trials, is needed to determine whether periodontitis is immunity Also, host susceptibility factors contribut-
a risk factor and what the mechanisms of action may ing to the dissemination of oral infections to other
be for adverse pregnancy outcomes. In the United parts of the body should be investigated, especially in
States, longitudinal and intervention studies are populations at high risk for disease and infection. In
under way. addition, further studies are needed to elucidate the
role of the mouth as a means of transmitting infec-
tious microbes. This in turn will allow the develop-
Conclusion ment of interventions to prevent transmission and
This critical look at the emerging associations among curb .the progression of infections once established.
oral infections and specific conditions establishes the The associations between oral infections and dia-
need for an aggressive research agenda to better betes, heart disease and stroke, and adverse pregnan-
understand the specific aspects of these associations cy outcomes warrant a comprehensive and targeted
and the underlying mechanisms. Prospective and research effort. If any of these associations prove to
intervention studies are under way and should pro- be causal, major changes in care delivery and in the
vide additional and stronger evidence of the presence training of health professionals will be needed.
and direction of an association. It is essential for such Awareness of the oral complications of medica-
studies to include populations at known risk for the tions and other therapies for disease management
underlying conditions as well as the general popula- and for health promotion needs to be enhanced
tion. Of the conditions reviewed, the relationship of among health care professionals, the public, drug
periodontal disease and diabetes has the strongest manufacturers, and the research community. For
evidence, demonstrating that the risk of periodontitis some of these therapies, known interventions exist
is higher in individuals with diabetes. However, the and should be followed before initiating the therapy
effect of periodontitis on glycemic control is less to minimize or modulate its side effects. To prevent
clear, a reflection of the difficulty of controlling for the oral complications of other therapies, new
the effect of systemic antibiotic treatments used to approaches are needed. Ultimately, and ideally, the
manage periodontal disease in diabetic patients in side effects of therapies should be considered in the
clinical trials. development of new drugs and biologics.
122 ORAL HEALTH IN AMERICA: A REPORT OF THE SURGEON GENERAL
Linkages with General Health
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