Periodontal Medicine Periodontal Medicine

Louis E Rose, DDS, MD Professor of Surgery and Medicine MCP Hahnemann School of Medicine Philadelphia, Pennsylvania and Clinical Professor of Periodontics University of Pennsylvania School of Dental Medicine Philadelphia, Pennsylvania

Robert J. Genco, DDS, PhD Distinguished Professor and Chair of Oral Biology State University of New York Buffalo, New York

D. Walter Cohen, DDS Chancellor-Emeritus MCP Hahnemann University of Health Sciences Dean- Emeritus University of Pennsylvania School of Dental Medicine Philadelphia, Pennsylvania

Brim L. Mealey, DDS, MS Chief of Periodontics Chief of Dental and Professional Services US Air Force Hospital Eglin Air Force Base Fort Walton Beach, Florida

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Contributors

James D. Beck, PhD Michael Glick, DMD Kenan Professor Professor, Department of Oral Medicine Department of Dental Ecology Director, Programs for Medically Complex University of North Carolina at Chapel Hill Patients, University of Pennsylvania Chapel Hill, North Carolina Philadelphia, Pennsylvania

Sebastian G. Ciancio, DDS Sara G. Grossi, DDS, MS Professor and Chair, Department of Clinical Director, Periodontal Disease Periodontics and Endodontics Research Center Clinical Professor of Pharmacology, State Department of Oral Biology University of New York at Buffalo School School of Dental Medicine of Dental Medicine State University of New York at Buffalo Buffalo, New York Buffalo, New York

D. Wdter Cohen, DDS Car1 W. Haveman, DDS, MS Chancellor-Emeritus, MCP Hahnemann Staff, University Hospital University of Health Sciences Assistant Professor Dean-Emeritus, University of Pennsylvania Department of General Dentistry School of Dental Medicine The University of Texas Health Science Philadelphia, Pennsylvania Center San Antonio, Texas Joel Epstein, DDS, MSD Faculty of Dentistry, University of Palle Holmstrup, PhD, DrOdont British Columbia Professor of Periodontology Department of Oral Medicine, University of Copenhagen University of Washington, Seattle School of Dentistry Department of Dentistry, Department of Periodontology Vancouver General Hospital Copenhagen, Denmark Dentistry, B.C. Cancer Agency Vancouver, Canada Marjorie Jeffcoat, DMD University of Alabama School of Dentistry Robert J. Genco, DDS University of Alabama at Birmingham Distinguished Professor and Chair of Birmingham, Alabama Oral Biology, School of Dental Medicine, State University of New York at Buffalo University Dental Associates Buffalo General Hospital Buffalo, New York Vi Contributors

Kenneth S. Kornman, DDS, Ph.D. Louis F. Rose, DDS, MD University of Texas Health Science Center Professor of Surgery and Medicine at San Antonio MCP Hahnemann School of Medicine San Antonio, Texas Clinical Professor of Periodontics Harvard University University of Pennsylvania School of Boston, Massachusetts Dental Medicine Philadelphia, Pennsylvania Brim Medey DDS, MS Chief of Periodontics Terry D. Rees, DDS, MSD Chief of Dental Professional Services Periodontics Department US Air Force Hospital Baylor College of Dentistry Eglin Air Force Base, Florida Dallas, Texas Clinical Assistant Professor Department of Periodontics FrankA. Scannapieco, DMD, PhD University of Texas Health Science Center Department of Oral Biology San Antonio, Texas School of Dental Medicine Associate Professor Robert E. Mecklenburg, DDS, MPH State University of New York at Buffalo Coordinator, Tobacco and Oral Health Buffalo, New York Initiatives, Tobacco Control Research Branch, National Cancer Institute Harold C. Slavkin, DDS Potomac, Maryland Director, National Institute of Dental and Craniofacial Research Laboratory Michael G. Newman, DDS Chief, Craniofacial Developmental Biology University of California School of Dentistry National Institute of Arthritis, Section of Periodontics Musculoskeletal, and Skin Disease Pacific Palisades, California Bethesda, Maryland

Steven Offenbacher, DDS Barbara J. Steinberg, DDS Professor and Director Professor of Surgery and Medicine Center for Oral and Systemic Diseases MCP Hahnemann School of Medicine University of Carolina School of Dentistry Clinical Assistant Professor of Oral Medicine Chapel Hill, North Carolina University of Pennsylvania School of Dental Medicine Spencer W. Redding, DDS, MEd Philadelphia, Pennsylvania Staff, University Hospital Professor, Department of General Dentistry Edwin J. Zinman, DDS, JD The University of Texas Health Science Former Lecturer, University of California Center at San Antonio at San Francisco San Antonio, Texas San Francisco, California To my beautihl granddaughter, Cameron Sara, who has brought so much love and joy into my life. To my mother-in-law, Helen Aberbach, whose love and kindness will remain with me for- ever. And to my wife, Claire, and children, Michael, David, and Hedy, whose unconditional love and support have allowed me to pursue my professional dreams.

Louis F, Rose

To D. Walter Cohen, Henry Goldman, Nicholas Marfino, James English, Fred Karush, and Art Ellison. These mentors instilled in me their intense appreciation for the role of the host in modulating oral diseases, and for the effect of oral disease on the rest of the body.

Robert J. Genco

To the late Russell Ross, DDS, PhD, one of the most distinguished scientists of the Twentieth Century.

D. Walter Cohen

To my loving wife Carla, who has supported me in every endeavor and has given me the most beautifd family a man could ever have. I also devote this undertaking to the honor of my mother, Jeanne C. Mealey, who taught me the value of a challenge, who showed through her personal example the gains derived from sacrifice, and who demonstrated that love and devotion overcome all difficulties.

Brian L. Mealey Preface

Over the past 70 years, a number of astute clinicians in the field of dental medicine have observed and recorded the relationship between periodontopathies and systemic manifestations of disease. The influence of systemic conditions on the oral environment, and especially the periodontium, has long been recognized and supported by scientific evidence. However, an evidence base for the influence of periodontal diseases on overall systemic health has only recently begun to be established. Fascinating research has eroded the tradition-bound concept that oral infections such as periodontitis are simply local entities whose effects are limited to the oral tissues. While the clinical observations of many practitioners have long suggested that periodontal diseases can have widespread systemic effects, only recently has rigorous scientific investigation supported this concept. The information in this text has not been collected in this format previously, and one of the goals of the authors is to offer the material to physicians, dentists, and other health-care professionals collaborating in treatment of patients with periodontal disease who may also have systemic involvement. This will allow the practicing clinician to enhance the medical-dental interface when evaluating a patient and will contribute to a continuing dialogue between the dentist and physician. We are hopehl that this information will stimulate new collaborations between physicians and dentists and serve as a basis for hrther studies to help improve the total health of our society. This effort should also prove usehl to medical and dental students as well as those in residency training and post-doctoral studies. Bridging the gap between the dental and medical professions will provide better education, research and patient care. Our purpose is to provide existing evidence that supports and strengthens the association and relationships between periodontal diseases and systemic diseasedcondi- tions. The information presented will demonstrate the practical application in day to day practice. Our sincere gratitude to the many excellent contributors to this volume and sincere appreciation to their families who sacrificed to make this a timely and valuable publication. We applaud Mr. Brian Decker for inspiring the authors to assemble this material in an effective and expedi- tious manner and the support provided by his excellent editorial staff. Our heartfelt thanks to the various federal agencies, corporations and foundations, who had the courage and creativity to support the numerous studies that are reported in this volume. Dr. Genco would like to thank his colleagues at the University of Buffalo, School of Dental Medicine, who have supported and contributed to our efforts in this emerging science, particularly Lou Goldberg for unfailing support of our efforts in periodontal medicine. He thanks his wife, Sandra, for her patience with his hectic schedule which intensified during the editing of the text. She was a wonderhl sounding board for ideas about the importance of good health. He also wishes to thank Rose Parkhill for her unceasing efforts in preparing materials, editing, and performing other tasks that are so essential in making such a book possible.

The Editors August, 1999 Con tents

... Preface ...... viii

CHAPTER1 Periodontal Disease and Systemic Disease ...... 1 D. Wulter Coben, DOS, Hurold C. Shvkin, DDS

CHAPTER2 Risk Factors for Periodontal Disease ...... 11 Robert]. Genco, DOS, PbD

CHAPTER3 Clinical History and Laboratory Tests...... 35 Louis E Rose, DOS, MD, Burburu ]. Steinberg, DDS

CHAPTER4 Role of Genetics in Assessment, Risk, and Management of Adult Periodontitis ...... 45 Kennetb S. Kornmun, DDS, PbD, Micbuel G. Newmun, DDS

CHAPTER5 Cardiovascular Diseases and Oral Infections ...... 63 Robert]. Genco, DOS, PbD, Steven Offenbucber, DOS, Jumes Beck, PbD, Terry Rees, DOS, MSD

CHAPTER6 Relationships between Periodontal and Respiratory Diseases ...... 83 Frunk A. Scunnupieco, DMD, PbD

CHAPTER7 Tobacco Use and Intervention...... 99 Robert E. Mecklenburg, DOS, MPH, Surd G. Grossi, DOS, MS

CHAPTER8 Diabetes Mellitus ...... 121 Brim Meuley, DOS, MS

CHAPTER9 Periodontal Medicine and the Female Patient ...... 151 Joun Otomo-Corgel, DOS, MPH, Burburu ]. Steinberg, DDS

CHAPTER10 Osteopenia, Osteoporosis and Oral Disease...... 167 Surd G. Grossi, DOS, MS, Mugorie K Jeffcout, DMD, Robert]. Genco, DOS, PbD x Contents

CHAPTER11 HIV Infection and Periodontal Diseases ...... 183 Micbuel Glick, DMD, Pulle Holmstrup, PbD, Dr. Odont

CHAPTERI2 Periodontal Disease and Periodontal Management in Patients with Cancer...... 195 Joel B. Epstein, DMD, MSD, FRCD(C)

CHAPTER13 Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants...... 205 Terry D. Rees, DOS, MSD

CHAPTER14 Bleeding Disorders ...... 227 Spencer W Redding, DOS, MEd, Curl W Huvemun, DOS, MS

CHAPTER15 Pharmacotherapy ...... 243 Sebustiun G. Ciuncio, DDS

CHAPTER I6 Medicolegal Issues...... 273 Edwin J. Zinmun, DOS, JD CHAPTER1

PERIODONTALDISEASE AND SYSTEMIC DISEASE

D. Walter Cohen, DDS Harold C. Slavkin, DDS

Health sciences are in the midst of major transi- infected population. Health professionals use tions. The scientific and technologic paradigms of immunosuppressive drugs in patients to prevent the dentistry, medicine, nursing, and pharmacy are rejection of transplants, and patients can become changing as well as the management and financing immunosuppressed as a consequence of many of the of health care, the demographics of the United treatments for neoplastic and inflammatory diseases. States, the patterns of disease, and even the public’s Some infections, most notably those caused by the expectations for “quality of life.” Marked variations human immunodeficiency virus (HIV), immunoin disease occurrence and survival exist among dif- compromise the host in and of themselves. Lesser ferent subgroups of the population of the United degrees of immunosuppression are associated with States. Some of these are attributable to factors many other infections, such as influenza, viral such as age, gender, ethnicity, sexual orientation, meningitis, and a number of sexually transmitted geographic locations, and socioeconomic status. diseases, such as syphilis. The microenvironment of This chapter describes the scientific advances and immunosuppression can induce the prominence of responsibilities for health professionals, to help once obscure microbes, such as Pneumocystis curni, them revisit how we address the connections Cyptosporidiumpurvum, Mycobucterium uvium, and between a number of oral microbial infections and Cundidd ulbicuns. major systemic diseases and how we manage the There is growing evidence that a number of oral complications of systemic diseases. complex human diseases are caused or profoundly On a macro level, scientific and technologic influenced by opportunistic infections, such as in advances are defining new paradigms for dentistry, Legionnaire’s disease, Lyme disease, gastric ulcer medicine, nursing, and pharmacy to which tradi- and gastric cancers, a number of other malignan- tional theory may not apply. Improved under- cies, cardiovascular disease, low-birth-weight pre- standing of human biology at the molecular level is mature babies, and osteoarthritis. As a conse- rapidly advancing and may make invasive surgery, quence, there has been a resurgence of interest in intensive care units, and long-term home care, for oral microbial ecology, so-called “biofilms,” example, far less necessary in the not too distant mucosal immunity, and systemic diseases through- future. Costly and often clinically inadequate out the human lifespan. This renewed interest is interventions may soon be replaced by the postge- taking place at a time when advances in epidemi- nomic products of gene-based diagnostics and ology, microbiology, immunology, molecular biol- therapeutics, innovations from bioengineering and ogy and cell biology have enabled meaningful biomaterials, and progress toward understanding questions regarding oral infections and systemic individual, family, and community behaviors. diseases to be addressed. Advances over infectious diseases have been This chapter introduces the theme of oral hindered by changes in the patient population. infection associated with systemic diseases and Increasingly older and medically compromised highlights the rapidly expanding understanding of patients, including immunosuppressed ones, now microbial ecology, mucosal immunity, and com- constitute a significant proportion of the seriously plex human diseases. 2 Periodontal Medicine

ORAL INFECTIONAND SYSTEMIC and disorders) and also between systemic diseases DISEASE: A PARADIGM SHIFT (eg, arthritis, diabetes, HIV infection, and osteoporosis) and oral, dental, and craniofacial diseases The adult human body consists of 1013 somatic and disorders. cells, and 101* normal or commensal mirobes. Transmissible and opportunistic microorgan- These commensal bacteria reside on the surfaces of isms are responsible for dental caries. Transmissible teeth and/or prosthetic implants within complex and opportunistic microorganisms are also respon- ecosystems termed “biofilms,” and they reside on sible for periodontal diseases. In the case of peri- the surfaces of the mucosal epithelia that line the odontal diseases, the microbial-induced infection oral cavity, respiratory tract, esophagus, gastroin- presents a substantial infectious burden to the testinal tract, and urinary tract. Under a variety of entire body. Further, specific microorganisms with- conditions, some of these microorganisms become in the microbial ecology associated with the disease opportunistic and are associated with local or sys- process release toxins that invoke an inflammatory temic infections, such as Hemopbilus inJuenzu, response. Bacteria, bacterial toxins, localized tissue Streptococcus pneumonia, Neisseriu meningitis, and response cytokines, and other inflammatory medi- Stupbylococcus uureus infection. ators enter the vascular circulation and may acti- The oral cavity contains almost half the com- vate a systemic response. The subsequent patho- mensal bacteria in the human body; approximately genesis of the disease process reflects gene-gene 6 billion microbes representing 300 to 500 species and gene-environment interactions. Nested in a reside in the oral cavity. The oral microbial ecosys- complex interaction of host susceptibility, external tem is remarkably dynamic. During human devel- exposures, and life-style behaviors, the manage- opment, viruses, bacteria, and yeast are transmitted ment of health and disease will require interdisci- from mother to child and, in addition, microbes plinary education, strategies, and health-care deliv- are transmitted from caretaker to child, from ery. These scientific and technologic advances are spouse to spouse, and can be also acquired from creating new paradigms. the environment. The oral microbial ecology is extremely sensitive to the potential insults that confront the ANATOMIC PRIMER OF THE human hosts throughout their lifespan. From fetal PERIODONTIUM life through senescence, the oral cavity is continuously challenged by opponunistic infections on the The following provides an anatomic primer of the one hand and the oral complications of systemic periodontium to facilitate the reader’s understand- diseases and disorders on the other. These dynam- ing of this chapter and those to follow. The perio- ic interactions between hosts and pathogens are the dontium includes those tissues that invest and sup- essence of a paradigm shift in oral medicine. There port the tooth-the gingiva, the cementum cover- is growing evidence that oral bacteria contribute to ing the root surfaces of each tooth, the periodontal systemic disease. One of the best documented ligament that attaches the tooth root surface to the examples is the involvement of the gram-positive adjacent alveolar bone process that supports each Streptococcus sunguis and Streptococcus orulis in tooth, and the alveolar bone. The gingiva covers infective endocarditis. the structures that comprise the attachment appa- An association between oral infections and ratus (cementum, ligament, and adjacent alveolar systemic diseases has been suspected for centuries. bone). The gingiva is divided into free and The effect of oral health on the rest of the human attached gingiva. The free gingiva extends from the body was proposed by the Assyrians in the sev- base of the gingival sulcus to the gingival margin. enth century BC. In the 18th century, a Pennsyl- The tissues extending from the bottom of the sul- vania physician named Benjamin Rush was quot- cus to the mucogingival junction are those that ed as remarking that arthritis could be treated in comprise the attached gingiva. Apical to the some people after they had infected teeth extract- mucogingival junction, the alveolar mucosa is con- ed. Over the past decade, a growing body of sci- tinuous with the mucous membrane of the lip, entific evidence suggests an exquisite association cheek, and the floor of the mouth. between oral infection (eg, viruses, bacteria, yeast) The adult dentition presents the gingival mar- and systemic diseases (eg, atherosclerosis, cardio- gin located on the enamel surface approximately vascular disease, cerebrovascular disease, prematu- 0.5 to 2.5 mm corona1 to the cervical line of each rity and low birth weight, and pulmonary diseases tooth. The gingival margin is rounded and is adja- Periodontal Disease and Systemic Disease 3 cent to the opening of the gingival sulcus, which is The lining of the gingival sulcus is sulcular normally 2 to 4 mm in depth. Placing of a cali- epithelium which resembles the oral epithelium but brated instrument, such as a periodontal probe, is not keratinized. The base of the sulcus is formed into the gingival sulcus provides the clinician with by the junctional epithelium, which consists of a a measurement referred to as the probing depth. thin layer of epithelium that joins the gingival con- The term “pocket” is used to describe the nective tissue to the tooth surface (Figure 1-1). In histopathology in the soft and possibly the under- recently erupted teeth, the junctional epithelium lying bony tissues, reflecting an inflammatory extends from the bottom of the gingival sulcus to response to oral infection. “Pocket” is used to dif- the apical border of the enamel tooth surface. The ferentiate from the healthy gingival sulcus. The thickness of epithelial tissue varies from 15 to 30 gingival sulcus contains fluid. The gingival sulcus cells in the vicinity of the gingival sulcus to as few fluid in disease reflects inflammation as measured as I cell at its apical extension. The junctional by the levels of cytokines and tissue necrosis factor. epithelim is not keratinized. The sulcular and junc- Pocket depth and pocket levels of cytokine bio- tional epithelia form the critical anatomic location markers can be used to monitor health and disease. at which bacterial biofilms of the subgingival There are two major forms of periodontal dis- microbiota interact with host defense mechanisms. ease (Table 1-1). One is gingivitis, in which the most apical portion of the junctional epithelium is Su pra-alveolar Connective Tissue on the enamel, or at or near the cementoenamel junction (Table 1-2). Periodontitis occurs when The dermis of the gingiva coronal to the alveolar the periodontal ligament, the connective tissues crest comprises the supra-alveolar connective tissue that attach the tooth to the Alveolar Bone is and consists of fibers, cells, blood vessels, and destroyed by the inflammatory process. This is nerves, in a rich dense connective tissue. The princi- associated with apical migration of the junctional pal cell is the gingival fibroblast, which produces the epithelium onto the root surface beyond the main elements of the connective tissue. There are cementoenamel junction. Periodontal disease also undifferentiated mesenchymal cells, macro- occurs in the presence and absence of systemic phages, and mast cells. Types I and I11 collagen, conditions (Table 1-3). For example, gingivitis elastin, and fibronectin, along with proteoglycans, may occur simply associated with dental plaque, assemble into the reticular fibers that are observed in which case it is called marginal gingivitis. It beneath the basement membrane adjacent to the may also occur as a result of systemic involvement epithelium, and they are also seen in the connective such as gingivitis in AIDS patients and hyperplas- tissue stroma associated with blood vessels. The tic gingival conditions associated with intake of greatest part of the gingival connective tissue are the drugs such as phenytoin, cyclosporine, nifedipine, collagen fibers; some are arranged in distinct bun- and the dihydropyridines. dles with a definite orientation. There are bundles Periodintitis occurs as two major forms: adult that run around the tooth in a ring-like pattern and and juvenile or early onset. The adult form may are referred to as circular fibers. Interdentally, there occur in the presence or absence of systemic com- are bundles that run from the cementum of one plications. Juvenile forms are usually associated tooth to another and are called the trans-septal with abnormalities in neutrophil hnctions. fibers. Other fibers may not be in a distinct pattern. The dentogingival fibers are bundles that arise from Structure of the Periodontium

The gingival tissues are covered with keratinized TABLE I- I. Diseases of the PeriodontalTissues and parakeratinized epithelia. The gingival epithe- I. Gingival diseases and conditions lium has three components: oral, sulcular, and A. Gingivitis (no systemic involvement) j unctional. The underlying dermis or connective B. Gingivitis and gingival changes with systemic tissue beneath the gingival epithelium connects the involvement gingiva to the tooth root cementum and the adjacent alveolar process (Figure 1-1). The gingiva is 11. Periodontal Diseases and Conditions firm and is tightly attached to the tooth and the A. Periodontitis in adults (no systemic involvement) alveolar process by the supra-alveolar connective B. Periodontitis in juveniles tissue fibers. The gingival tissues are covered with C. Periodontitis with systemic involvement oral epithelium which is usually keratinized. D. Occlusal traumatism 4 Periodontal Medicine

TABLE 1-2. Gingival Diseases and the cementum and run parallel to the sulcus. Anoth- er group runs at right angles to the root surface; yet Conditions another group emerges from the cementum, passes A. Gingivitis over the alveolar crest, and blends with the mucope- 1. Marginal gingivitis riosteum of the gingiva, and these fibers are called 2. Acute necrotizing ulcerative gingivitis (ANUG) den to-per is teal fibers. B. Gingivitis and other gingival changes with systemic involvement of 1. Gingival changes associated with sex hormones Blood Supply Gingiva a. “Pregnancy” gingivitis The gingival tissues are rich in blood vessels, which b. Gingivitis associated with oral contraceptives have their origins from the supraperiosteal vessels c. Gingivitis associated with other hormonal originating from the lingual, mental, buccinator, and alterations (eg. Polycystic ovaries, puberty, palatine arteries. These vessels give off branches along and menopause) the hcial and oral surfaces of the alveolar process. 2. Gingival changes associated with diseases of the skin and mucous membranes Branches of the alveolar arteries may penetrate the a. Pemphigus interdental septa or from the coronal parts of the b. Cicatrical pemphigoid periodontal ligament. Numerous capillaries are seen c. Bullous pemphigoid immediately below the basement membrane of the d. Lichen planus sulcular, junctional, and oral epithelium. e. Psoriasis f. Desquamative gingivitis Clinical Criteria of Healthy Gingiva g. Lupus erythmatosus h. Erythma multiforme Healthy gingiva is usually pink in color, well adapt- i. Idiopathic gingival fibromatosis ed to the teeth, with a stippled surface texture, and j. Recurrent aphthous stomatitis bound tightly to the underlying alveolar process 3. Gingivitis in generalized systemic diseases and the roots of the dentition (Figure 1-2). The a. Diabetes gingival sulcus varies in depth from I to 3 mm and b. Acute leukemia shows no signs of bleeding when probed. Histolog- C. Thrombocytopenia ically, it has been shown that a small number of d. Hemophilia lymphocytes and plasma cells are observed in the e. Sturge-Weber syndrome connective tissue of the gingiva under the sulcular f. Wegener’s granulomatosis epithelium in health gingiva as elsewhere in the gas- g. Sclerosis trointestinal tract. h. Hypodrenocorticism 1. Vitamin C deficiency Attachment Apparatus j- AIDS k. Sarcoidosis 4. Infective gingivostomatitis Attachment of the tooth to the alveolus consists of a. Herpetic gingivostomatitis numerous bundles of collagenous tissue (principal b. Herpes zoster fibers) arranged in groups in between, which is c. Herpangina loose connective tissue together with blood vessels, d. Syphilis lymph vessels, and nerves. This attachment appa- e. Candidiasis ratus hnctions as the investing and supporting f. Actinomycosis mechanism for the tooth. It comprises the cemen- g. Histoplasmosis tum of the tooth, the periodontal ligament, and 5. Drug-associated gingival changes the alveolar process. The periodontal ligament is a. Systemic medications the tissue that surrounds the roots of the tooth and i. Phenytoin (Dilantin) attaches it to the bony alveolus. Cementum is the ii. Sodium valproate hard tissue covering the anatomic roots of the iii. Cyclosporine teeth. The alveolar process is made up of the alve- iv. The dihydropyridines: nifedipine olar bone and supporting bone and the outer cor- (Prodardia) and nitrendipine tical bone. The alveolar bone that lines the tooth b. Compounds with local effects socket is termed the lamina dura. In addition to its i. Caustic compounds supportive hnction, the dentoalveolar unit has ii. Heavy metals sensory, nutritional, and formative roles to play. Periodontal Disease and Systemic Disease 5

Cementum TABLE 1-3. Periodontal Diseases and Cementum is the calcified tissue that covers the Conditions roots of the teeth and is deposited during tooth A. Periodontitis in adults formation. There are two types of root cementum: AAJ? Classification I, 11, 111, IV acellular and cellular. The acellular type is clear and Epidemiologic; moderately and rapidly pro- structureless and is formed by cementoblasts, gressing periodontitis which do not become embedded in it as they do Clinical based on treatment; refractory and when the cellular type is formed. Those collagen recurrent fibers that become embedded in the cementum are Clinical based on history; recurrent acute necrotizing ulcerative periodontitis and postlo- known as Sharpey’s fibers (Figure 1-3). Most of calized juvenile periodontitis the root is covered by acellular cementum, with B. Periodontitis in juveniles cellular cementum forming on the apical portions 1. Localized juvenile periodontitis of the root. Cellular cementum is bone-like, with 2. Generalized juvenile periodontitis the cementocytes embedded in it. Cementum is C. Periodontitis with systemic involvement unlike bone in that it does not remodel throughout 1. Periodontitis in primary neutrophil disorders life. Incremental lines of cementum deposition are a. Agranulosytosis seen with the aging of the individual. These dark- b. Cyclic neutropenia staining lines also reflect the activities or function c. Chediak-Higashi syndrome d. NeutroDhil adherence abnormalities of the tooth, with cementoblasts continuing to line I the cemental surface throughout life and compen- e. Job‘s syndrome f. “Lazy leukocyte” syndrome sating for the physiologic movements of the tooth g. Neutrophil functional syndrome within the attachment apparatus. 2. Periodontitis in systemic diseases with secondary or associated neutrophil impairment Alveolar Process a. Diabetes mellitus type I b. Diabetes mellitus type I1 The alveolar process consists of osseous tissue, and c. Papillon-LeFevre syndrome the alveolar bone is the portion that lines the d. Down’s syndrome tooth socket. It is thin compact bone containing e. Inflammatory bowel disease: Crohn’s disease small openings through which blood vessels, f. Preleukemic syndrome nerves, and lymphatics pass. The alveolar bone g. Addison’s Disease contains the embedded ends of the connective tis- h. AIDS sue fibers of the periodontal ligament known as 3. Other systemic diseases associated with changes in the structures of the periodontal attachment Sharpey’s fibers (see Figure The supporting 1-3). apparatus bone is the cancellous bone between the alveolar a. Ehlers-Danlos syndrome (VIII) bone and the cortical plates. This supporting bone b. Histiocytosis (Cosinophilic granuloma) or spongiosa makes up the greatest part of the c. Sarcoidosis interdental septum but is much more active than d. Scleroderma cementum, showing areas of resorption and depo- e. Hypophosphatasia sition. It is composed of a network of osteocytes f. Hypoadrenocorticism and extracellular matrix. The calcified portion g. Hyperthyroidism consists of apatite crystals. Alveolar bone is D. Miscellaneous conditions affecting the periodontium deposited next to the periodontal ligament by the 1. Periodontal abscesses osteoblasts and is reinforced by the supporting 2. Periodontal cysts 3. Ankylosis bone. Larger vessels are found in the inter-radicu- 4. Root resorption lar bony process and branches from them to enter 5. Periodontal-pulpal communicating lesions the periodontal ligament through the numerous 6. Pericoronal abscesses openings in the cribiform plate. 7. Dentinal hypersensitivity 8. Retained roots Periodontal Ligament 9. Bony sequestration 10. Infections associated with fractured roots, or The fibers of the periodontal ligament that attach anatomic defects the tooth to the alveolar bone are arranged in 11. Neoplasms of the attachment apparatus groups according to their direction, with the alve- E. Occlusal traumatism 6 Periodontal Medicine olar crest fibers running from the alveolar crest to collagen in the ligament. It has been observed that the ccmcntum. The horizontal fibcrs pass in a pcr- the fibcrs on the ccmcntum side arc numerous and pendicular fashion from tooth to bone. Most of relatively thin; they tend to spread out and are the fibcrs arc in the oblique group, which run from interwoven into a network that makes up the the alveolus in an apical direction to the ceinen- greatest width of the ligament. On the bone side, tum. The apical fiber group surrounds the apex of the fiber bundles are fewer in number and are of the root. In multirooted teeth, the fibers running greater diameter than on the cementurn side. from the inter-radicular crest to the furcation are The liganient contains a network of blood ves- called the inter-radicular fibcrs. sels and lymph vcsscls as well as nerve bundles. The ligament is made up of collagen fibers, These vessels are closer to the alveolar side of the lig- which arc arranged in bundlcs (SCC Figure 1-3). amcnt and connect with larger vcsscls in the marrow Research suggests that there is a high turnover of spaces through the perforations in the alveolar bone. The cellular components of the periodontal ligament include fibroblasts, cementoblas ts, ostcoblasts, ostcoclasts, and cpithclial cell rests.

Regenerative Capacity

The attachment apparatus has been shown to regen- erate in certain surgical therapies. The periodontal ligament behaves as a double periosteum, giving rise to the cells that form cementum, bone, and connective tissue as well as numerous growth factors. This capability is of great value to the clinician who is seeking to restore lost supporting tissues.

ORAL INFECTION, SYSTEMIC DISEASE,AND THE GENETIC PARADIGM

The hos t7s reaction to invading microbes (viruses, bacteria, yeast) involves a rapidly amplifying polyphony of signals and responses that may spread beyond the invaded tissue. Fever or hypothermia, tachypnca, and tachycardia often herald the onset of the systemic response to microbial invasion and may bc described as bactcrcmia (viable bacteria in the blood), fungemia (viable yeast in the blood), or septicemia (systemic illness caused by the spread of microbes in the blood). Figure 1-1. Histology of the healthy periodontium. E = Commcnsal bacteria living on tooth and enamel; (; = cementilm of the root silrface; (:F>J = cemento- rnucosal epithelial cell surfaces create an interactive cnamcl junction; II = dcntin; OE = oral cpithcliuni; SE = system, in which the host synthesizes and secretes sulcular epithelium; JE = junctional cpithclium; GCT = gin- various irnmunoglobulins and antibacterial pep- gival corineclive hue; AB = alveolar bone; PDL = peri- tides that control this remarkable eucaryotic/ odontal ligament. In health, the junctional epithelium form- procaryotic ccosystcm, ing the base of the siilciis termiantes at or near the cemento- Molecular medicine and dentistry are defined enamel junction ((;EJ). (.iingival connective tissue fibers and as the use of genotypic analysis (DNA tcsting) to the fibcrs of the periodontal ligament insert into root surface enhance the quality of health care, including cementurn. In inflarnmalory periodorid disease, die con- presymptomatic identification predisposition to nective tissue attachment is destroyed, allowing the juction- of al epithelium to migrate apically. Alveolar bone is also disease, preventive interventions, selection of phar- destroyed. The overall effect is a deepening of the gingival lllaCotherdpY, and the design and of sulcus (“pocket”) and a loss of support for the tooth. gene-based diagnostics and thcrapcutics. Periodontal Disease and Systemic Disease 7

Genomic progress continues to change the practice of dentistry and medicine. Gene-based diagnostics for viral, bacterial, and yeast infections as well as the numerous clinical applications throughout the human lifespan are continuing to enhance health care. Gene testing for inherited diseases as well as for predisposition to diseases or disorders has enormous potential benefits to improve health care. During 1938, more than 30,000 human genes were isolated, seyuenced, and mapped to specific locations on one of the 23 pairs of human chromosomes. By the year 2003, the complete nucleotide Figure 1-2. (:linical appearance of healthy gingival tissue in sequence of the approximately 100,000 structural a 60 ycar old fcmalc. Thc gingival tissues arc pink and firm. and regulatory genes that comprise the human No arcas of rcdncss or inflammation arc sccn. The dcpth of genetic lexicon will be completed. In tandem, the die gingival sulcus ranges ayproximaiely from 1 to 3 mm gcnomcs of many significant microbes and animals and doeh not bleed following probing. are also being deciphered, including those of viruses, bacteria, yeast, parasites, plants, animals (eg, fruit fly zebrafish, mouse, rat), and data from these extremely sensitive to environmental “stress” and gcnomcs arc being used to revolutionize our think- can and do mutate or change resulting in multidrug ing about biology, health, and disease. Completion and/or antibiotic resistance. The gene tic variance of the microbial gcnomcs of opportunistic viral, within microbial gcnomcs, such as that of Candida bacterial, and yeast species (putative pathogens) as albicanr, may be closely aligned with the host well as the human genome may provide even fiister changes associated with immunologically compro- progress in the diagnostics and therapeutics related mised patients. The HIV viral genome is another to oral infections, systemic diseases, and the oral particularly usefll model for considering viral muta- complications of systemic diseases. tion frequency within the human population. Perhaps with the sole exception of trauma, Moreover, genes are also the foundation of essentially all human diseases are genetic. Genetic even more complex human diseases. First, multiple dentistry and medicine are based on the paradigm mutations that are acquired can produce cancers. that changes or mutations in individual genes or We now appreciate that all cancers are genetic and alleles result in inherited diseases. For example, that most cancers are not inherited but rather mutations in the amelogenin gene located on the result from acquired multiple mutations. Oropha- human X and Y chromosomes can produce X- linked dominant or recessive amelogenesis imperfecta; mutations in the fibroblast growth factor receptor 2 gene can produce Crouzon syndrome as well as other craniofacial syndromes with craniosynostosis; or mutations in a number of transcription factors that regulate development can produce craniofacial malformations. These and other scientific discoveries are rapidly defining single- gcnc mutations, mapping these individual genes in their precise posi tions on human chromosomes, and arc being used to diagnose inherited clinical pheno types throughout the human lifespan. More- over, these advances in human molecular genetics are identifjhg candidate genes for developing targeted gene-mediated therapeutic approaches to Figure 1-3. Pcriodotital liganicnt bctvvccn thc root surfacc many clinical problems. and lhe alveolar bone. Collagen fibers of Lhe periodorid ligament are arranged in bundles. These fibers (Sharpey’s Gene mutations define not only the virulence fibers) connect the cementiim on the root siirfnce to the alve- of microbes (viruses, bacteria, yeast, and parasitcs) olar hone. The collagen fibers are destroyed by proteases dur- but also the fidelity of the human immune system. ing inflammatory periodontal discasc, allowing thc cpithcli- Of course, microbial as well as human genes are um of‘ lhe poclcel 10 migrae apically. 8 Periodontal Medicine ryngeal cancer is the sixth most common neoplas- nity, and a variety of systemic diseases and disor- tic disease; one American dies every hour of oral ders. The following chapters will highlight the cancer. The major “risk factors” for oral cancer are many advances and opportunities for improved tobacco products and alcohol. health care in the 21st century. Second, we are beginning to understand that variations or polymorphisms in multiple genes confer susceptibility or resistance to chronic and dis- SELECTED REFERENCES abling diseases and disorders, such as osteoporosis, periodontal diseases, and temporomandibular dis- Oral Infections and Systemic Disease: eases and disorders. In these examples, multiple A Paradigm Shift genes and multiple gene-environment and gene- gene interactions are associated with the molecular Andrews WW, Goldenberg RL, Hauth JC. Preterm pathophysiology of the disease process. For example, labor: emerging role of genital tract infections. single nucleotide polymorphisms (SNPs) in such Infect Agent Dis 1995;4(4):196-211. genes as IL-la, IL-lp, IL-1 receptor, IL-2, IL-6, Drangsholt MT. A new causal model of dental diseases IL-10, IL-12, and TNF a in various combinations associated with endocarditis. Annals of Periodon- and in juxtaposition to a number of risk factors may tology 1998;3(1):184-196. explain genetic susceptibility to periodontal diseases Davenport ES, Williams ECS, Sterne JAC, Sivanpatha- and/or associations with cardiovascular diseases. sundram V, Fearne JM, Curtis MA. The east lon- The human genome consists of 100,000 genes, don study of maternal chronic periodontal disease and each gene is likely to be represented in the pop- and preterm low birth weight infants: study design ulation with 10 variant alleles. To comprehensively and prevalence data. Annals of Periodontology cover the entire human genome and have the capac- 1998;3(1)2 13-22 1. ity to identify SNPs, 1 million SNPs will be Herzberg MC, Meyer Mw. Dental plaque, platelets, required. The recent consortia by the federal gov- and cardiovascular diseases. Annals of Periodontol- ernment and the private sector in SNPs, sufficient to ogy 1998;3(1): 15 1-1 60. cover the entire human genome, will significantly Kinane DF. Periodontal diseases’ contributions to car- accelerate the progress toward defining the multiple diovascular disease: an overview of potential mech- genes associated with complex human diseases. anisms. Annals of Periodontology 1998;3(1): These microbial and human genomic databas- 142-1 50. es will provide remarkable opportunities for the Limeback H. Implications of oral infections on systemic identification, design, and production of a new diseases in the institutionalized elderly with a spe- generation of biomarkers for diagnostics and for cial focus on pneumonia. Annals of Periodontology the development of innovative therapeutics such as 1998;3(1)262-275. drugs and vaccines to improve human health and Loesche WJ, Schork A, Terpenning MS, Chen YM, advance periodontal medicine. Kerr C, Dominguez BL. The relationship between dental disease and cerebral vascular accident in elderly united states veterans. Annals of Periodon- SUMMARY tology 1998;3(1):161-174. Mealey BL. Periodontal implications: medically com- There is growing evidence that a number of compromised patients. Annals of Periodontology plex human diseases are associated with oppor- 1996;1(1)256-321. tunistic infections in periodontal medicine. As a Nishimura F, Takahashi K, Kurihara M, Takashiba S, consequence, there has been a resurgence of interest Murayama Y. Periodontal disease as a complication in oral microbial ecology, mucosal immunity, and of diabetes mellitus. Annals of Periodontology associations with systemic conditions, such as pre- 1998;3(1)20-29 maturity and low birth weight, pulmonary diseases, Offenbacher S. Periodontal disease: pathogenesis. Ann cardiovascular diseases, and cerebrovascular dis- Periodontol 1996;1(1):821-78. eases. This renewed interest in periodontal medi- Page RC, Beck JD. Risk assessment for periodontal dis- cine is taking place at a time when dramatic ease. Int Dent J 1997;47:61-87. advances in the fields of microbiology, immunolo- Petit MDA, Van Steenbergen TJM, Degraaff J, et al. gy, molecular biology, and cell biology have allowed Transmission of Actinobacillus actinomycetemcomi- in-depth exploration of microbial genomics, oral tans in families of adult periodontitis patients. infections, the human genome project, host immu- J Periodontal Res 1996;28:33545. Periodontal Disease and Systemic Disease 9

Salvi GE, Beck JD, Offenbacher S. Pgez, 11-la, and Page RC. The pathobiology of periodontal diseases may TNF-a responses in diabetics as modifiers of peri- affect systemic diseases: inversion of a paradigm. odontal disease expression. Annals of Periodontol- Annals of Periodontology 1998;3(l)lO8-120. ogy 1998;3(1)40-50. Scannapieco FA, Papandonatos GD, Dunford RG. Oral Infections, Systemic Disease, Associations between oral conditions and respirato- and the Genetic Paradigm ry disease in a national sample survey population. Annals of Periodontology 1998;3(1):25 1-256. Amer A, Singh G, Darke C, Dolby A.E. Association Slavkin HC. Infection and immunity. J Am Dent Assoc between HLA antigens and periodontal disease. 1996;127:1792-6. Tissue Antigens 1988;31 : 53-5 8. Slavkin HC. Emerging and re-emerging infectious dis- Backman B. Inherited enamel defects. In: Chadwick ease. J Am Dent Assoc 1997;128:108-13. DJ, Cardew G, editors. Dental enamel. London: Slavkin HC. And we all lived happily ever after: under- John Wiley & Sons Ltd; 1997. p. 175-96. standing the biological controls of aging. J Am Baum BJ, Atkinson JC, Baccaglini L, et al. The mouth Dent Assoc 1998;129:629-33. is a gateway to the body: gene therapy in 21st cen- Slavkin HC. Chronic disabling diseases and disorders. J tury dental practice. CDA J 1998;25:455-60. Am Dent Assoc 1997;128:1583-9. Bodrner W, McKie R The book of man: the Human Slavkin HC. Diabetes, clinical dentistry and changing Genome Project and the quest to discover our genet- paradigms. J Am Dent Assoc 1997;128:638-44. ic heritage. New York: Scribner Publishers; 1995. Slavkin HC. Notes on a silent disease. J Am Dent Assoc Boughman JA, Halloran SL, Roulston D, Schwartz S, 1996;127: 80 1-5. Suzuki JB, Weitkamp LR, Wenk RE, Wooten R, Slavkin HC. An update on HIV/AIDS. J Am Dent Cohen MM. Autosomal dominant form of juvenile Assoc 1996;127: 140 14. periodontitis: it’s localization to chromosome 4 and Slavkin HC. The war on oral cavity and pharyngeal can- linkage to dentinogenesis imperfecta and Gc. Jour- cer. J Am Dent Assoc 1996;127:517-20. nal of Craniofacial Genetic Development Biology Slavkin HC. First encounters: transmission of infectious 1986;6:341-350.Porter R The greatest benefit to oral diseases from mother to child. J Am Dent Assoc mankind. New York: W.W. Norton & Company; 1997;128773-8. 1997. Soskolne WA. Epidemiological and clinical aspects of Chambers DA. DNA: the double helix: 40 years, periodontal diseases in diabetics. Annals of Peri- prospective and perspective. New York: New York odontology 1998;3(1):3-12. Academy of Sciences; 1995. Von Troil-Linden F, Alahuusua S, Wolf J, et al. Perio- Cohen MM Jr. Molecular biology of craniosynostosis dontitis patient and the spouse: periodontal bacte- with special emphasis on fibroblast growth factor ria before and after treatment. J Clin Periodontol receptors. In: Cohen MM Jr, Baum BJ, editors. 19979:893-9 Studies in stomatology and craniofacial biology. Winn DM, Diehl SR, Horowitz AM, et al. Scientific Amsterdam: 10s Press; 1997. p. 307-30. progress in understanding oral and pharyngeal can- Field MJ. Dental education at the crossroads. Washing- cers. J Am Dent Assoc 1998;129:713-8. ton, D.C.: National Academy Press; 1995. Yuan A, Luh KT, Yang PC. Actinobacillus actino- Finch CE, Pike MC. Maximum lifespan predictions mycetemcomitans pneumonia with possible septic from the Gompertz mortality model. J Gernotol embolization (letter). Chest 1994;105:646. 1996;51(3):3183-94. Zijlstra EE, Swart GR, Godfroy FJM, Degener JE. Peri- Hart TC, Marazita ML, McCanna KM, Schenkein HA, carditis, pneumonia and brain abscess due to a Diehl SR. Reevaluation of the chromosome 4q combined actinomyces-actinobacillus actino- candidate region for early onset periodontitis. mycetemcomitans infections. J Infect 1992;25: Human Genetics 1993;91:416-422. 83-87. Kevles BH. Naked to the bone. New Brunswick, New Jersey: Rutgers University Press; 1997. Anatomic Primer of the Periodontium Kornman KS, Page RC, Tonetti MS. The host response to microbial challenge in periodontitis: assembling Armitage GC. Periodontal diseases: diagnosis. Annals of the players. Periodontology 2000 14:33-53, 1997 Periodontology 1996;1(1)37-215. Kornman KS, di Giovine FS. Genetic variations in Genco RJ, Goldman HM, Cohen DW. Contemporary cytokine expression: a risk factor for severity of periodontics. St. Louis, MO: The C.V. Mosby adult periodontitis. Annals of Periodontology Company; 1990. 1998;3(1)325-338. 1 O Periodontal Medicine

Mealey BL. Periodontal implications: medically com- Slavkin HC. Clinical dentistry in the 21st century. promised patients. Ann Periodontol 1996;1 (1): Compendium 1997;18(3):212-8. 256-321. Slavkin HC. Basic science is the fuel that drives the Schwartz WB. Life without disease. Berkeley: Universi- engine of biotechnology: a personal science transfer ty of California Press; 1998. vision for the 21st century. Tech Health Care 1996; Slavkin HC. Possibilities of growth modification: 4:249-53. nature versus nurture. In: MacNamara R, editor. Slavkin HC. Advice to coaches of students in one of the Ann Arbor, Michigan: University of Michigan youngest sciences. J Dent Edu 1998;62:226-9. Press. 1999. [In press] Toteson DC, Adelstein SJ, Carver ST. New pathways to Slavkin HC. Understanding human genetics. J Am medical education. Cambridge, Massachusetts: Dent Assoc 1996;127:266-7. Harvard University Press; 1994. CHAPTER2

RISKFACTORS FOR PERIODONTALDISEASE

Robert J. Genco, DDS, PhD

Periodontal diseases, now recognized as bacterial ETIOLOGY infections, are among the most common, chronic diseases of humans, affecting 5 to 30% of the adult Concepts of the etiology of periodontal disease population in the age group of 25 to 75+ years. have changed markedly in the last four decades. Periodontal diseases are also among the most Several specific subgingival oral bacteria including important causes of pain, discomfort, and tooth Po rp byro monus gingivulis, Actinobucillus uctino- loss in adults.lP3 While a significant portion of the mycetemcomituns, Prevo telh intermediu, Bucteroides population is susceptible to periodontitis, there are forytbus, and perhaps others such as Cumpylobucter those that are relatively resistant to the severe forms rectus, Fusobucterium nucleutum, and spirochetes are of periodontal disease. This leads to the hypothesis associated with severe forms of periodontal disease.8 that there are susceptibility factors or risk factors In addition, a group of pathogens not normally that modulate susceptibility or resistance of indi- found in the oral cavity, except as transients, has viduals to destructive periodontal disease. been associated with periodontal disease, including In addition to being a major cause of discom- Enterobucteriuceue, Pseudomonddceu, Klebsielh sp p fort, disfigurement, and tooth loss in the popula- and Acinetobucter as well as others such as Stupbylo- tion, emerging evidence suggests that periodontitis coccus uureus, and Cundidd ~lbicuns.~Periodontal increases the risk for certain systemic diseases such diseases, therefore, are infections in which severe as heart disease? low birth eight,^ respiratory dis- forms of the disease are often associated with spe- ease,' and possibly other condition^.^ It is clear cific bacteria that colonize the subgingival area in then that prevention and treatment of periodontal spite of the host's protective mechanisms. Many of disease are necessary to maintain periodontal these bacteria have potent virulence factors such as health; without periodontal health, general health cytotoxins for mammalian phagocytes produced by is often compromised. Present day concepts of A. uctinomycetemcomituns, a potent array of pro- management of periodontal disease include prima- teases produced by I? gingivulis, and the ability to ry and secondary prevention, treatment of existing invade epithelia1 cells exhibited by A. uctino- disease to resolve the periodontal infection, and mycetemcomituns and I? gingivulis.l0 Recently, I? gin- modification of adverse risk factors which increase givulis has also been shown to invade the endothe- susceptibility to initial or re-infection with peri- lid cells which may explain, in part, the link odontal organisms. The goals of this chapter, there- between periodontal disease and heart disease." fore, are to provide the reader with (I) an under- Studies have linked specific therapies to specif- standing of the microbial etiology and pathogene- ic infections in periodontal disease. For example, sis of periodontal infection, (2) detailed knowledge van Winkelhoffi2 found that amoxicillin with of factors which increase the risk of periodontal metronidazole was useful in controlling periodon- disease, and (3) information to be used in assessing tal infection when A. uctinomycetemcomituns was individual patients to determine their risk profile found in plaque samples. Further, microbiologic or risk level for development of periodontal infec- tests have been developed and are useful in the tion. Information on modification of risk is found assessment of periodontal infection and the selec- in other chapters of this book. tion of appropriate therapies. 12 Periodontal Medicine

PATHOGENESIS It is clear then that host factors play a major role in the pathogenesis of periodontal disease. The periodontal pathogens have virulence factors Exogenous factors such as smoking, which alter which cause direct damage. However, it appears immune hnction and tissue repair, or endogenous that a significant contribution to tissue destruction or intrinsic factors such as genetic predisposition to in periodontal disease comes from an imbalance in hyperproduction of cytokines, low production of host protective and destructive mechanisms antibody, or depressed neutrophils can lead to induced by periodontal infection. l3 Host hyper- marked changes in the disease process. These fac- responsiveness or reactivity is induced by peri- tors then modifi- the host response to periodontal odontal infection and includes activation of neu- infection, altering susceptibility to infection by trophils, which migrate to the area of periodontal periodontal organisms. infection, and induction of antibodies, both of which appear to be protective. On the other hand, extracellular matrix components of the gingiva and ASSESSMENT OF RISK FACTORS periodontal ligament are destroyed and alveolar bone is resorbed mainly through induction of A risk factor for periodontal disease is a character- matrix metalloproteinases.l4 This leads to connec- istic, an aspect of behavior, or an environmental tive tissue destruction and production of proin- exposure that is associated with destructive peri- flammatory cytokines, such as IL-1,15 resulting in odontitis. l7 Numerous factors are modifiable while alveolar bone resorption. These cytokines can others cannot be easily modified. The term “risk cause activation of fibroblasts, which then produce factor” often implies a modifiable condition; how- major metalloproteinases that destroy the extracel- ever, this is not always the case. Those risk factors lular matrix. In addition, proinflammatory that cannot be modified are often called determi- cytokines such as IL-1, IL-6, and TNF-a lead to nants or background factors. The term “risk indi- activation of osteoclasts, which leads to bone cator” is used to describe a possible or putative fac- resorption. A full description of cytokines and tor associated with the disease often identified prostaglandins in immune hemostasis and tissue from case-control or cross-sectional studies. True destruction in periodontal disease is reviewed by risk factors that are associated with disease are con- Gemmell and colleagues.16 firmed in longitudinal and interventional studies Briefly, the pathogenesis of periodontal disease and by the existence of a biologically plausible could be thought of as a pathway, including direct mechanism for their actions. l8 toxic effects on cells from proteases and toxins pro- There are several study designs that are useful duced by bacteria, to triggering of cells by mitogens in the assessment of risk factors for diseases that and antigens. This initially results in a wave of neu- are considered multifactorial diseases, such as peri- trophil chemotaxis and antibody production, odontitis. Table 2-119 presents a series of study which is protective, leading to reduction of the designs ranging from anecdote, to case reports, to infecting flora. However, several of the periodontal case series, to randomized controlled trials that bacteria can evade the neutrophil-protective constitute evidence of increasing strength for risk response by killing neutrophils, inhibiting their factors. The anecdotes, case reports, and case series function, or digesting antibody and complement. provide the weakest evidence for association of The next wave is the induction of mononuclear risk with disease; however, they are important cells such as resident macrophages and fibroblasts because they often provide the basis for generating to produce matrix metalloproteinases, reactive oxy- important hypotheses. gen species, and proinflammatory cytokines, which The next line of evidence concerning the results in connective tissue destruction and bone association between a potential risk factor or risk resorption. The organisms then eventually appear indicator and disease is provided by case-control to be controlled by antibodies that neutralize the studies. Case-control studies can identifi- risk toxins and by phagocytes that remove them from indicators but often are not able to assess the role the site of infection causing the disease to go into of important confounding factors. For this, cross- remission. Episodes of periodontal disease exacer- sectional, population-based studies are necessary bation and remission follow blooms of the organ- because they describe large populations and allow ism once the immune response subsides and allows a more rigorous assessment of confounders or co-risk the organism to propagate again, resulting in a factors by multivariate statistical analysis. Cross- repeat of the cycle and recurrence of periodontitis. sectional studies are important because they can Risk Factors for Periodontal Disease 13

TABLE 2-1. Hierarchy of Evidence for Risk Factors* Hypothesis Hypothesis Interpretation and Study Design Generating Testing Health Policy Implication 1. Anecdote X case report Suggests a relationship case series

2. Case control X X Evidence for risk indicator

3. Cross-sectional X X Evidence for risk indicator

4. Longitudinal (cohort) X Evidence for risk factor

5. Interventional X Evidence for risk factor modulation RCT of treatment effects in high vs. low risk groups RCT in which risk factor is X Strongest evidence for specific modified interaction to apply to population

*Adapted from Ibrahim M. Epidemiology and health policy. Rockville (MD): Aspen Systems Corporation; 1985. RCT = randomized controlled trial. Table reprinted with permission from the Journal of Periodontology lead to identification of risk indicators that are rea- surrogate variables for periodontal disease, such as sonable or plausible correlates of disease. estimate of alveolar bone destruction by measure- Longitudinal studies are necessary to provide ment of radiographs, clinical attachment loss, and strong evidence that a risk indicator or a putative gingival inflammation including bleeding on prob- risk factor is indeed a true risk factor. Risk indica- ing and probing pocket depth. In large scale clini- tors are not always confirmed as risk factors in lon- cal epidemiologic studies, relative attachment lev- gitudinal studies. Although longitudinal studies els are often measured from an arbitrary but fured provide strong evidence, they are often difficult to point, such as the cemento-enamel junction, and carry out for periodontal disease because periodon- are better indicators of destructive periodontitis titis is a slowly progressing disease, and the defini- than probing depths.20 Ideally, both attachment tion of a new case is by no means clear. However, loss and radiographic measurement of alveolar longitudinal studies are necessary to resolve the bone loss in epidemiologic studies are carried out. temporal sequence of putative risk factors as they Measurement of alveolar bone loss may be more are associated with disease. A true risk factor should sensitive than attachment loss in assessing risk fac- precede the development of disease. tors. This, in fact, has been observed by Grossi and Analysis of risk is ultimately directed to improv- co-workers .21 ,22 ing the health of the population. Evidence for effi- Establishment of a definition for a periodontal cacy of the elimination or suppression of a risk fac- case is often arbitrary. Various cut-off points for tor in modulating or reducing disease often is gained attachment loss, bone loss, and pocket depth have from randomized controlled trials in which inter- been suggested but none is universally agreed vention is rigorously tested. It is important that the upon. Perhaps the best approach would be to assess mechanism of action of risk factors is biologically the extent and severity of disease in the population plausible to understand how the risk factor exerts its and determine cut-off points or case definitions influence on the disease. Also, knowing the mode of appropriate for the population. Lack of a clear-cut action may allow development of effective risk inter- definition of a case of periodontitis has hindered vention strategies that intercept or modulate the longitudinal studies that attempt to define inci- effects of the risk factor on disease. dence or occurrence of new cases, and often pro- Accurate and precise measurement of peri- gression of periodontal disease is used. For exam- odontitis can be carried out by assessing several ple, the rate of periodontal attachment loss using 14 Periodontal Medicine repeated measures and the establishment of step- of the disease. It is the confluence of these multi- wise thresholds-based on factors that contribute ple experimental approaches that leads to confi- to error including pocket depth, tooth type, and dence in assigning a risk factor to a disease and tooth location-for each individual patient and for thereby taking the next step, which is implemen- examiners have also been used with success to tation of risk factor modification in practice and assess risk factors.23 in public health.

RISK ASSESSMENT STUDY DESIGN BACKGROUND FACTORS AND ANALYSIS OF DATA OR DETERMINANTS

Correlation or univariate analysis is often seen in older studies of risk, especially in case-control or small cross-sectional studies. The weakness of such Studies of periodontal disease prevalence, extent, analysis resides in the inability of a single correla- and severity show more disease in older age tion analysis to develop comprehensive models of groups compared with younger groups. 1,21,22,27-29 disease since only one or, at most, a few potential Several studies also show that there is greater risk factors can be analyzed at one time. Also, uni- dental plaque and more severe gingivitis in elder- variate analysis does not allow for adjustments for ly persons compared with younger individuals, confounding or co-risk variables or factors. Power- suggesting age-related effects.29 Most studies, ful, modern statistical analyses using multiple however, show that periodontal disease is more regression models, linear discriminate analysis, and severe in the elderly because of the cumulative multivariate logistic regression have provided the destruction over a lifetime, rather than an age- necessary tools to assess the role of risk factors in related intrinsic deficiency or abnormality that periodontal disease. These analyses often make affects susceptibility to periodontal infection. adjustments for confounding factors and are useful For example, an analysis of the epidemiologic in assessing risk. The unit ofstudy in epidemiolog- data from the National Health and Nutrition ic assessment of risk is necessarily the patient. Surveys (NHANES) in the United States con- However, data often come from multiple sites in cluded that when oral hygiene status was consid- the same patient and hence lead to complex statis- ered, age was not an important factor in deter- tical issues. For example, there is often a lack of mining periodontal disease.29 independence of multiple observations in the same A longitudinal study addressing the cumula- patient, and several approaches to the assessment tive nature of periodontal attachment loss suggests of relationships between site-specific variables and that, at least up to age 70 or 75 years, the rate of statistical models assessing risk of periodontal dis- periodontal destruction has been the same ease have been de~cribed.~~-~~Recently, general throughout ad~lthood.~'Several other longitudi- estimating equations that allow the use of a broad nal studies came to the same concl~sion.~~-~~How- range of regression models that take into account ever, Ismail and colleagues34 from the Tecumseh and adjust for the dependence between observa- study found that age was a significant factor in a tions in the same individuals have been described multivariate model relating greater attachment loss and are in wide use.27 to age. However, it is instructive to note that in this Ultimately, however, association studies for study, the age range of individuals was >65 or 70 risk usually require that there be a concordance of years, the maximum age in most of the other stud- several well-executed studies on different popula- ies. It appears that age, per se, is not an intrinsic tions. In addition, it is important that the risk risk factor, at least until the age of 70 or 75 years. factor show some type of dose response; the more It is still unknown whether the deterioration of the exposure to the risk factor, the worse is the host-protective mechanisms or the acceleration of disease. Furthermore, it is important that longi- host-destructive mechanisms affects susceptibility tudinal studies show that there is a logical occur- to periodontal disease beyond age 70 or 75 years. rence of the risk factor prior to the development Indeed, there may be an increased risk of perio- of disease. Finally, for decisions on the clinical dontal disease associated with advanced age; per se, importance of the risk factor, it is necessary for however, this does not appear to be manifested the intervention studies to show that modifica- before age 70 or 75 years. Further work is needed tion of the risk factor will result in modification to resolve this issue. Risk Factors for Periodontal Disease 15

Race opment and understanding and are probably best called risk indicators at this point. These include Assessment of risk factors related to race, socioeco- osteopenia and osteoporosis; stress, distress, and nomic status, and poverty have been unsuccesshl in coping; dietary factors including calcium and vita- making associations with periodontal disease. For min C; and genetic factors. There are also a group example, in recent studies where periodontal status of immune system diseases such as AIDS; primary was adjusted for oral hygiene and smoking, the asso- and secondary neutrophil disorders, such as con- ciation between lower socioeconomic status and genital neutropenia and drug-related agranulocyto- more severe periodontal disease was not seen.21,22 sis; and diseases affecting host response, such as In a study of risk indicators for Mican Ameri- Papillon-Lefevre syndrome, Ehlers-Danlos syn- can and Caucasian Americans, there were more indi- drome, and hypophosphatasia, which are associated cators related to socioeconomic status for the former with more severe disease in juveniles and likely sig- than for the latter. For example, PrevoteZh intermediu nificantly increase the risk for periodontal disease. was a risk indicator for African Americans, but not for Caucasian Americans. However, when persons Tobacco Use from both races belong to the same socioeconomic group, differences in periodontal disease often dis- In spite of the long history of the association Further studies are necessary to between tobacco smoking and periodontal dis- look at the relative role of race and ethnicity, which the observation that greater levels of may be tied to genetic factors in Asians, Native plaque and calculus in smokers may have account- Americans, Hispanics, and other racial and ethnic ed for the association failed to convince the com- groups in the American population. munity of the importance of smoking and periodontal disease risk. However, in 1983, Ismail and Gender co-workers analyzed smoking and periodontal disease and found that smoking remained a major risk Periodontal disease is regularly reported to be more indicator for periodontal disease after adjusting for prevalent or more severe in men than in women at potential confounding variables, such as age, oral comparable ages. 1,21,22,36 Men exhibit poorer oral hygiene, and socioeconomic hygiene and report fewer visits to the dentist than do In recent studies,21,22smoking was shown to women.37 However, when correcting for oral be a strong risk indicator for periodontal disease hygiene, socioeconomic status, visits to the dentist, with an odds ratio of 2.0 to 5.0 when using clini- and age, being male is still associated with more cal attachment loss as a measurement. Odds ratios severe disease when either attachment loss or bone of 1.5 to 7.0 were achieved when using alveolar height is used as a measure of periodontal disease.21>22 bone loss as a measure of periodontal disease in Assessment of the effects of hormones, partic- these studies. These studies were adjusted for age, ularly the female hormone estrogen, which likely gender, socioeconomic status, plaque, and calcu- protect against destructive periodontal bone loss, lus, and hence strongly implicate cigarette smoking may help us understand the small but definite per se as a major risk indicator for periodontal dis- increase in periodontal disease seen in men. ease. Grossi and co-workers21>22also found a direct and linear dose response between level of smoking (pack years) and destructive periodontitis, support- SYSTEMIC RISK FACTORS ing the contention that smoking is a risk factor for AND RISK INDICATORS periodontal disease (Figure 2-1). Longitudinal studies have confirmed that current smokers exhib- Two groups of systemic factors are associated with ited greater disease progression as compared with periodontal disease.38One group includes smoking nonsmoker^.^^ Attachment loss is also directly and diabetes mellitus, for which there is consider- related to serum cotinine levels.44 A longitudinal able evidence based on cross-sectional, longitudi- study of the association between smoking and nal, intervention, and mechanism studies, and it is tooth loss over a 10-year period was carried out in reasonable to call these true risk factors. Certainly, 273 individual^.^^ Younger individuals who modification of these factors is important in the smoked more than 15 cigarettes per day had the management of periodontal disease. highest risk. In this study, the odds ratio for asso- The second set of factors associated with peri- ciation of smoking with periodontitis, adjusted for odontal disease is related to an earlier stage of devel- age and gender, for current smokers relative to 16 Periodontal Medicine

epithelium and may exert deleterious effects on fibro bl Smoking also dccrcascs in tcsti nal absorption of calcium and may thereby affect oatcoblast function and increase bonc loss in othcr- wise healthy postmenopausal women.62,63Postsur- gical healing may be interfered with by absorption of thc toxic substances in tobacco smokc by the root surface^.^'-^^ Recently, two studies have shown the adverse effects of smoking on the subgingival flora."rG6 While there is no evidence that the use of smokeless tobacco increases susceptibility to peri- Figure 2-1. The relationship of more severe periodontal odontal disease, smokeless tobacco may affect gin- disease as assessed by increasing levels of probing attachment gival inflammation by affecting levels of IL-IP and loss, with increasing exposure to cigarette smoking PGE in gingival tisaucs.h"6x Although thcrc is no (expressed as packycars) is dcpictcd. (Figure is rcprintcd with direct evidence, it is likely that cigar and pipe permission Crom Grossi SG, Zambon JJ, Ho AW, ei al. smoking will have effects similar to cigarette smok- Asseshment of risk for periodontal disease. I. Risk indicators ing if the exposures are comparable. It is clear that Tor aiiachnient loss. J Periodontol 1994; 65;260-7.) thcrc are many mechanisms by which thc components of tobacco smoke can deleteriously affect periodontal tissues. those who never smoked, was 3.3, and for former smokcrs versus those who ncvcr smokcd, the odds Diabetes Mellitus ratio was 2.1. These longitudinal studies provide convincing evidence, along with other lines of evi- There is a large body of evidence supporting the dence, that tobacco use is a major risk factor for association between diabetes inellitus and peri- periodontal disease. odontal diseases. There is remarkable consistency Although dircct intcrvcntion studics of peri- in finding either greater prevalence, severity, or odontal disease in smokers who have quit smoking cxtcnt of at least one manifcstation of pcriodontal have not been carried out, other studies show that disease in the overwhelming majority of these pcriodontal thcrapics arc less effective in smokers studies. Studies of children and adolescents with than in nonsmokers, and recurrence of disease is typc 1 diabctcs and a group of similar agcs with- more likely in smokers after periodontal thera- out diabetes found greater periodontal disease in py."~'~ Also, smoking cessation appears to yield thc diabctics as comparcd to thc controls.63P" clinical benefits.21.22>52>54-56In these reports, the However, Goteiner and colleagues's did not find pcriodontal status of former smokers is comparable such a relationship. In another group of studies, with that of nonsmokers. In the study by Grossi subjects between the agcs of 15 and 35 years with and colleague^,^^ there was no relationship to time type 1 diabetes were assessed and, essentially, all of cessation of smoking (although cessation times thc studies found greater periodontal disease in of less than 1 year were not observed), which sug- the diabetic^.^'^^^ A set of studies of insulin- gests that smoking cessation for as little as 1 year dcpcndcnt diabctics, presumably mostly typc I, in results in healing after periodontal therapy conipa- adults 20 to 70 years of age, also found greater rablc with that in a nonsmoker. periodontal disease in diabetics as compared with

The mechanisms by which ciearetteU smokingU controls.s5Pss affects the periodontal tissues are quite diverse. A series of studies of type 2 diabetic subjects Smoking causes constriction of the blood vessels of also has bccn reported, and thc investigators the gingiva5' and has deleterious effects on leuko- reported greater periodontal disease in the diabet- cyte f~nction.~'Smoking also has been shown to ics than in the control^.^^-^^ In a longitudinal suppress serum antibody levels to certain periodon- study,x3the increased relative risk of advanccd pcri- tal ba~teria.'~-~'The effect may be specific since odontal disease in the diabetics was found to be 2.6 smoking suppresses production of the IgGz class of (95% CT 1 .O to 6.6). A further study of the same immunoglobulin both in patients with periodonti- population by Taylor and colleagues'16showed that tis and in those with normal period~ntium.~~-"" type 2 diabetes was a significant risk factor for pro- Smoking also may have dircct effects on tissues. For grcssion of alveolar bone loss with an odds ratio of example, cyto toxic substances can penetrate the 4.2 (95% CI 1.8 to 9.3). Risk Factors for Periodontal Disease 17

There are a series of studies that do not sepa- eral reviews of the oral manifestations of HIV rate type I and type 2 diabetes and, in general, infection have been published recently.'03-'05 these also support an association of diabetes with periodontal di~ease.~',~~,~~In the study by Grossi Oral Candidiasis and colleagues,2' the estimates of association Oral candidiasis is an infection of the oral tissues between diabetes and attachment loss severity had by yeasts of the genus Cundidd, and its association an odds ratio of 2.3 (95% CI 1.2 to 4.6). Hence, with severe underlying disease has been noted for it is clear from case-control, cross-sectional, and many years.'06 Oral candidiasis is rarely seen in longitudinal studies that diabetes is a significant previously healthy individualslo7 and is often seen risk factor for periodontal disease. as part of the acute HIV syndrorne.'O8 It can also Randomized controlled trials of the effects of be a common problem when CD4 lymphocyte therapy on both periodontal disease and diabetes counts fall.lo9 There are four clinical variants of status have also provided evidence that treatment oral candidiasis including pseudomembranous, of periodontal disease can be successfully carried erythematous, hyperplastic, and angular cheili- out in diabetics. Furthermore, resolution of peri- tis. ' 'O Both the pseudomembranous and erythema- odontal infections in diabetics can contribute to tous forms of candidiasis appear to be important the management of glycemic control in type I or predictors of progression of HIV infection. '07-" ' type 2 diabetes (see Chapter 8).52,99J00The study by Aldridge and colleaguesg9did not show a ben- Oral Hairy Leukoplakia eficial effect but the two studies by Grossi and col- Oral hairy leukoplakia is an oral lesion that was first 1eague~~~J~~did show a beneficial effect. Perhaps it reported in the early days of the AIDS epidem- is significant that in the Grossi studies, systemic ic. '12-' l3 In HIV-positive persons, oral hairy leuko- doxycycline was used. Miller and colleagues'" also plakia predicts more rapid progression to AIDS.lo9 used systemic doxycycline and mechanical therapy Oral hairy leukoplakia is associated with the and found an effect on glycemic control, pointing Epstein-Barr virus and generally occurs infrequent- to the possible effect of antibiotics in this benefi- ly among immunocompetent individuals.' 14' l5 cial response. Further rigorous, controlled studies of treat- Non-Hodglun's Lymphoma ment of periodontal disease in diabetics are needed Non-Hodgkin's lymphoma and Kaposi's sarcoma to confirm the extent to which treatment not only are two AIDS-associated malignancies that can resolves periodontal infection but enhances occur in the mouth. Because it involves the gingivae, glycemic control. Further studies also are needed non-Hod&n's lymphoma is frequently mistaken to assess the extent to which control of the diabetes for common periodontal or dental infections. '16 status is related to control of periodontal disease status. Case reports as well as clinical experience do Linear Gingival Erythema support this contention. However, randomized Periodontal disease in AIDS patients often pre- controlled trials are needed to fully assess the sents in several forms. A gingival lesion known extent to which glycemic control in diabetics will as linear gingival erythema (formerly known as prevent or minimize periodontal destruction. HIV-gingivitis) has been described in HIV-infected indi~iduals."~-"~It is characterized by a red Acquired Immune Deficiency Syndrome band on the marginal and attached gingiva, and and Other lmmunodeficiencies does not resolve with routine dental curettage and prophylaxis. log Systemic diseases, especially those that compromise the host's ability to fend off infections, often Necrotizing Ulcerative Periodontitis lead to more severe periodontal disease. There are Necrotizing ulcerative periodontitis (formerly studies that describe severe forms of destructive known as HIV periodontitis) also can occur in periodontal disease in acquired immune deficiency HIV-infected individuals. It is characterized by syndrome (AIDS) patients, resulting in necrotizing painful, ulcerative, bleeding lesions of the gingiva ulcerative lesions, often affecting the alveolar bone. which often are rapidly destructive and involve the Furthermore, a "linear" form of gingivitis has also deep periodontal tissues and alveolar bone. '09-' l9 been described in AIDS patients. A wide variety of Necrotizing ulcerative periodontitis may be gener- oral lesions have been described in persons infect- alized or localized and may lead to tooth loss and ed with HIV,lo2the etiologic agent for AIDS. Sev- bone sequestration. 18 Periodontal Medicine

Neu trop hi1 Disorders approximately two times greater in women than in men, and postmenopausal osteoporosis is a hetero- Severe periodontal disease may also occur in patients geneous disorder that begins after natural or surgi- with neutrophil abnormalities, and many of these cal menopause and leads to fractures within 15 to conditions are reviewed by Van Dyke and col- 20 years from the cessation of ovarian function. leagues. 120 Patients with neutrophil defects that are Cortical bone loss is, on average, 0.3 to 0.5% either quantitative (neutropenia) or qualitative per year until menopause. At menopause, 2 to 3% (adherence, chemotaxis, microbicidal hnctional loss per year occurs for the next 8 to 10 years. Tra- activity) often suffer from oral mucosal ulcerations, becular bone is lost at a greater rate, with 4.8% gingivitis, and periodontitis. Severe oral disease being lost per year in the 5 to 8 years following occurs with both primary and secondary neutrophil menopause. This loss occurs when an imbalance is abnormalities. The primary neutrophil disorders caused by more bone resorption than formation. characterized by severe periodontal disease include Calcium balance, vitamin D metabolism, estro- neutropenia (chronic or cyclic), leukocyte adhesion gens, and aging are interrelated factors in the cau- deficiency (LAD),and Chtdiak-Higashi syndrome. sation of osteoporosis. Neutrophil abnormalities that occur secondary to Osteoporosis has long been suspected as a sys- underlying systemic disease and those that are also temic risk factor for loss of oral bone, including associated with severe periodontal disease include loss of the alveolar process associated with peri- diabetes, Papillon-Lefevre syndrome, Down syn- odontal infection. From assessment of osteoporosis drome, hyperimmunoglobulin-E recurrent infec- in the jaws by dual photon absorptiometry,122-126it tion syndrome (HIE or Job's syndrome), inflamma- was found that reduction in total skeletal mass is tory bowel disease, Crohn's disease, preleukemic directly related to reduction in mandibular density syndrome, AIDS, and acute myeloid leukemia.121 in osteoporotic women. 127-128 Studies by Kribbs Drugs which induce agranulocytosis, including and Che~nutl~~and Henrikson and Walleni~sl~~ some drugs used to treat cancer, can result in showed that mandibular BMD correlated with mucositis or periodontal disease. Other conditions skeletal BMD. Ortman and ~olleagues'~'found a such as acatalasia, alpha- I antitrypsin deficiency, significantly higher percentage of women with and Ehlers-Danlos syndrome are also described in severe alveolar ridge resorption than men, which which periodontal disease is more severe, some of may be related to the findings of Humphries and which may well involve neutrophil abnormalities. colleagues132showing that age-related loss of BMD Hence, it appears that neutrophil disorders in an edentulous adult mandible is important in that are either primary neutrophil dyscrasias, sec- females but not in males. ondary to systemic diseases, or result from chemo- As shown by Danie11133 and Krall and col- therapy are often associated with severe periodon- league~,~~~who conducted a study of estrogen tal disease. Hence, neutrophil dyshnction is a risk replacement after menopause and tooth retention in factor for periodontitis, most likely as it lowers the 488 women, osteoporosis is clearly related to tooth host resistance to periodontal infection by subgin- loss. Estrogen users had more teeth than did gival microflora. nonusers, and the duration of estrogen use independently predicted the number of remaining teeth. Osteoporosis Several studies have shown a relationship between periodontal disease and osteoporosis. For Osteoporosis is one of the most important health example, Von W~wren,'~~in a case control study of concerns in the United States. It affects over 20 12 female patients with osteoporotic fractures com- million people, most of whom are women, and pared with 14 normal women, found significantly causes nearly two million fractures per year. Osteo- more loss of periodontal attachment in osteoporot- porosis is a physiologic, gender-, and age-related ic women than normal women. Groen and col- condition resulting from bone mineral content league~~~~found edentulism and severe periodontal loss. It is a disease characterized by low bone mass disease among 38 patients, who exhibited severe and fragility, which in turn may lead to increase in radiographic evidence of osteoporosis. Wactawski- fractures. Primary osteoporosis includes post- Wende and colleague^'^^ found a relationship menopausal osteoporosis, age-related osteoporosis, between alveolar crestal bone height as a measure of and idiopathic osteoporosis. Secondary osteoporo- periodontal disease and skeletal osteopenia. It sis is that caused by an identifiable agent or disease. appears that osteopenia, measured as BMD of the The rate of bone mineral density (BMD) loss is trochanter and total femur, was related to both Risk Factors for Periodontal Disease 19 greater probing attachment loss and greater alveolar serum calcium levels and that those with the lower crestal height loss. Although these studies point to serum calcium levels showed a significantly higher the possibility that osteopenia may be a risk factor risk of periodontal disease (odds ratio 6.1; 95% CI for periodontal disease, further studies are clearly 2.35 to 15.84). These analyses of over 12,000 sub- needed, especially large-scale studies in which mul- jects representative of the United States population tiple risk factors affecting both osteoporosis and suggest that reduced dietary calcium intake and periodontal disease are taken into consideration. reduced total serum calcium levels are associated Furthermore, longitudinal studies are necessary to with increased risk for periodontal disease. Fur- establish if skeletal bone loss and mandibular BMD ther studies on other populations carried out in a precede the development of periodontal disease. longitudinal fashion, with consideration for Finally, intervention studies are needed to evaluate dietary calcium supplementation, as well as inter- the extent to which reduction or prevention of vention studies, are necessary to fully determine if osteopenia-through nutritional supplements, low dietary calcium is indeed a true risk factor for estrogen use, or use of bone-sparing agents such as periodontal disease. alendronate-will affect periodontal disease. Vitamin C Dietary Factors Several studies suggest that vitamin C plays a role in maintaining the health of the gingiva.’38 In fact, Studies of diet and periodontal disease, based on severe forms of vitamin C deficiency can cause a our knowledge of the pathogenesis of periodontal gingivitis known as “scorbutic” gingivitis. disease and the role of bone metabolism in inflam- A recent analysis of the NHANES I11 (1988 to matory responses, may well lead to uncovering 1992) study assessed the relationship between other important dietary factors that increase the dietary vitamin C and periodontal disease.’39 In risk for periodontal disease or decrease the ability of this study, a representative sample of 12,419 indi- the periodontal tissues to heal. Clinical recommen- viduals in the United States, 20 to 90+ years of age, dations regarding diet or use of nutritional supple- were analyzed. Those taking less dietary vitamin C ments must be based on randomized controlled tri- showed an increased risk of periodontal disease, als of diet or nutritional supplements, and these especially among current tobacco users (odds ratio have not yet been done with respect to periodontal 1.28; 95% CI 1.04 to 1.59); the odds ratio for for- disease for calcium, vitamin C, or other nutrients. mer users was 1.21 (95% CI 1.02 to 1.43) compared with those who did not smoke. These results Calcium suggest that reduced dietary vitamin C intake, Nishida and co-workers evaluated the role of dietary especially in smokers and former smokers, increas- calcium intake as a contributing factor to the risk for es the risk for periodontal disease. Further studies periodontal disease.’37 They evaluated a large study are needed, especially longitudinal studies, to of the United States population from NHANES determine if lower dietary intake of vitamin C pre- data. In the NHANES I11 data set, which involved cedes the development of periodontal disease. subjects assessed from 1988 to 1992, it was found that both men and women in the younger age group Stress and Psychological Disorders (20 to 39 years) and men in the middle-age group (40 to 59 years) who ingested lower levels of calci- Stress and psychological disorders have been sug- um in their diet showed increased risk for periodon- gested to be related to oral diseases including tem- tal disease. The odds ratio for increased risk for peri- poromandibular disorders, dental caries, salivary odontal disease associated with lower dietary levels dysfunction, and periodontal disease in HIV infec- of calcium for those 20 to 39 years of age was 1.84 tion. Little definitive data exist, however, with (95% CI 1.36 to 2.48); for women aged 20 to 39 respect to the role of stress on oral diseases. An years, it was 1.99 (95% CI 1.34 to 2.97). For mid- evaluation of mental health, family interaction, dle-aged men, the odds ratio was 1.9 (95% CI 1.4 and life events of infants and toddlers with caries to 2.54). These odds ratios were obtained after by Wendt and c~lleagues’~~found that there was adjusting for gingival bleeding, tobacco consump- considerable stress in most of the families. Howev- tion including smoking cigarettes or cigars and er, there was not a typical family pattern in which chewing tobacco, and alcohol consumption. Nishi- infants developed caries. da and colleague^'^^ also showed that women in the In studies of acute necrotizing ulcerative gin- younger age group (20 to 39 years) had lower total givitis, stress and emotional factors have been iden- 20 Periodontal Medicine tified as risk indicators since the early 1950s.141-142 adjusting for age, gender, and cigarette smoking. Recently, the role of psychosocial factors in adult Hence, it appears that stress, likely chronic stress as periodontitis has been assessed. For example, would be associated with financial strain, is a risk Marcenes and Sheiham143showed that among the indicator for periodontal disease. 135 subjects studied, those who faced greater When coping behaviors were evaluated for work-related mental demand had greater peri- those with high financial strain, it was found that odontal disease as assessed by probing depth. Mon- those who were high emotion-focused copers, a teiro da Silva and colleagues14 carried out a case- form of inadequate coping, had a higher risk of control study comparing 50 patients with severe having more severe attachment loss and alveolar periodontitis, 50 patients with chronic adult peri- bone loss compared with those with low levels of odontitis, and 50 controls. They found that the financial strain. However, subjects with high levels subjects with severe periodontitis had higher levels of financial strain and reported high levels of prob- of psychosocial maladjustment than the other two lem-focused coping, a form of adequate or good groups. Specifically, the severe periodontitis group coping, have no more periodontal disease than presented increased depression and loneliness com- those with low levels of financial strain. From this pared with the other groups. Linden and col- study, it appears that psychosocial measures of stress league~~~~studied 23 dental patients over 5 years. associated with financial strain are significant risk They found that loss of periodontal attachment indicators for periodontal disease in adults. Fur- was greater in those with increasing age, lower thermore, this study suggests that adequate coping socioeconomic status, lower job satisfaction, and behaviors may reduce stress-associated risk for peri- type A personalities, suggesting a relationship odontal disease. Adjustment for oral hygiene status between progression of periodontitis and psy- and previous dental care did not change the associ- chosocial measures. These studies are interesting in ations significantly, suggesting that other at-risk that they suggest the hypothesis that periodontal health behaviors did not account for the findings. disease is associated with psychological stress. The mechanism(s) by which stress may moder- Recently, in a cross-sectional epidemiologic ate periodontal disease is presently unknown. How- study, 1,426 adults were evaluated for stress, distress, ever, there are at least two pathways that stress can and coping as related to periodontal disease severi- affect in infectious disease: the biologic model and ty.146147The large study group allowed for adjust- the behavior m0de1.l~~Stress effects on periodontal ment for presently known confounders, such as age, disease may be biologically moderated through the gender, smoking status, systemic health, dental care, hypothalamic-pituitary-adrenal (HPA) axis to pro- and oral hygiene practices. Furthermore, this study mote the release of corticotropic-releasing hormone addressed not only stress but also measures of dis- from the hypothalamus and glucocorticoids from tress and coping. To estimate stress, the Life Events the adrenal cortex. Glucocorticoids may inhibit or Scale148and the Daily Strain Scale149were used. To reduce periodontal destruction. The effects of psy- measure distress, the Brief Symptom Inventory of chosocial stress also may occur through behavioral Derogatis and Cleary was used.15' Coping styles changes which affect at-risk health behaviors such were assessed using the COPE In~entory.'~' as smoking, poor oral hygiene, and poor compli- The associations between psychosocial factors ance with dental care. Any evaluation of the role of and periodontal disease status were evaluated, and stress in periodontal disease should take into con- it was found that individuals who suffered from sideration at-risk health behaviors as well as the bio- high levels of clinical attachment loss had higher logic effects transmitted through the HPA axis. scores on the financial strain scales compared with periodontally healthy individuals, after adjusting Genetic Factors for age, gender, and cigarette smoking (p = .008). A similar significant difference was found for indi- Genetic factors affect most oral conditions. These viduals with high levels of financial strain and will be discussed as (I) abnormalities of the teeth, greater loss of alveolar bone height compared with affecting size, shape, and number of teeth, defects those in the low financial strain group. Stepwise in enamel and dentin, and abnormalities in the ordinal logistic regression analysis showed that dental pulp; (2) genetic abnormalities affecting the financial strain was associated with significantly orofacial complex; and (3) genetic factors associat- greater clinical attachment loss (odds ratio 1.70; ed with periodontal disease. 95% CI 1.09 to 2.65), and with alveolar bone loss Orofacial genetic abnormalities include cheru- (odds ratio 1.68; 95% CI 1.20 to 2.37), after bism, osteoporosis, osteogenesis imperfecta, cleido- Risk Factors for Periodontal Disease 2 1 cranial dysplasia, craniofacial dysostosis, man- polymorphism is found in most juvenile periodon- dibulofacial dysostosis, Pierre-Robin syndrome, titis patients and few normal controls. Wilson and Marfan's syndrome, Ehlers-Danlos syndrome, KalmaP2 found Fc receptor polymorphisms also Down syndrome, trisomy 2 I, hemifacial hypertro- associated with poor binding of IgG2 Fc to neu- phy, clefts of the lip and palate, and the fragile X trophils to be much more common in LJP patients syndrome. In some of these conditions, such as than in matched controls. Ehlers-Danlos syndrome and Down syndrome, The search for genetic polymorphisms in can- severe periodontitis may occur. didate genes has been successful in the two studies, reported above, in neutrophil chemotactic recep- Genetic Aspects of Localized Periodontal Disease tors and Fc opsonic receptors. Further studies of Localized juvenile periodontitis (LJP) has a familial candidate genes for polymorphisms may explain aggregation and hence has been long thought to be a some of the subjects' increased susceptibility to genetically determined condition. Melnick and col- periodontal infection in LJP league~'~~suggested an X-linked transmission; how- Attempts to associate human leukocyte anti- ever, Sa~kn,'~~Long and colleague^,'^^ and Beaty and gens (HLA) with juvenile periodontitis are con- colleague^'^^ proposed an autosomal mode of inher- flicting. For example, Cullinan and colleague^'^^ itance of juvenile periodontitis. Hart and col- showed that the segregation patterns of HLA in league~'~~and Sa~by'~~also proposed autosomal LJP were not conclusive. Similar findings were modes of transmission. Hart points out, however, reported by Saxkn and Ko~kimies.'~~However, in a that juvenile periodontitis may be a heterogeneous population-based study, Reinholdt and col- group of diseases and, indeed, some rare X-linked league~'~~showed that LJP patients have a higher forms may exist. Hart and colleague^'^^ convincing- prevalence of HLA-A9, HLA-A28, and HLA- ly argue that the predominance of evidence suggests BW15 than the general population, suggesting an that most cases of juvenile periodontitis are inherited association between HLA markers and the gene(s) in an autosomal manner. Additional studies are for localized juvenile periodontitis. needed to provide definitive evidence of the specific genetic contributions to juvenile periodontitis. Genetic Aspects of Adult Periodontitis Specific traits associated with juvenile peri- Periodontal diseases are common, with mild forms odontitis that may have genetic backgrounds affecting 75% of adults in the United States,' and include abnormalities in neutrophil hnction. For bacteria are generally thought to be the initiating example, Van Dyke and colleague^'^^ studied 22 etiologic agents. However, the host response trig- families in which the probands suffered from local- gered by pathogenic bacteria largely determines the ized juvenile periodontitis. The families included a course and severity of the disease. Host responses total of 44 affected individuals: 25 female and 19 may affect initial colonization and infection and the male patients, including the probands. Among the growth of the organisms. They may also affect the siblings, exclusive of probands, the proportion of immune and inflammatory response to the peri- affected females (0.41) was the same as that of odontopathic bacteria, which, in turn, determines males (0.41). In 19 of the 22 families, neutrophil the severity and rate of progression of the disease. abnormalities were observed while in the other 3 Three approaches to the study of genetic influ- families, there were no subjects with neutrophil ences have been carried out in adult periodontitis. abnormalities, suggesting heterogeneity. However, One approach is linkage analysis, that is, to associ- the predominant number of cases of juvenile peri- ate periodontal disease with inherited disease odontitis appear to have neutrophil chemotactic markers, such as blood groups or HLA. The second and possibly other disorders. Others have also approach is through twin studies, and the third and reported neutrophil chemotactic disorders in fam- most recent approach is to assess genetic polymor- ilies with juvenile periodontitis, in which the phisms in candidate genes. affected children have the neutrophil defect, but not the unaffected children.'" Human Leukocyte Antigen Associations Recent studies have shown genetic polymor- Early studies showed negative association of adult phisms to be associated with neutrophil hnction periodontal disease with HLA-A2. 167-169 Klouda in subjects with juvenile periodontitis. 161-162 For and c~lleagues'~~and Amer and colleague^'^' example, Gwinn and colleagues'6' found a poly- showed an increase in HLA-A9 in patients with morphism in the f-met-leu-phe receptor, a receptor periodontal disease, which may be related to the for chemotactic factors produced by bacteria. This reported increased frequency of HLA-A9 as well as 22 Periodontal Medicine other HLA types by Reinholdt and colleagues165in controls with no periodontal disease as well as pop- juvenile periodontitis. Further studies of HLA ulations of various racial and ethnic groups are linkage are needed to resolve the issue of HLA needed to fully evaluate polymorphisms. association in adult periodontal disease. Van Schie and colleague^'^^ report an Fcy receptor polymorphism pattern associated with Twin Studies periodontitis. They compared 105 adults with Twin studies were carried out on 26 sets of twins moderate to severe periodontitis with 132 age- and aged 12 to 17 years, in which 7 pairs were mono- race-matched controls without periodontitis. The zygotic and 19 di~yg0tic.l~~No differences were FcyRIIA-HIH13 1 and FcyRIIIB-NA2INA2 geno- found in gingival recession, gingival crevice depth, type was elevated in patients compared with con- gingival bleeding, calculus, or plaque. Michalowicz trols (18.8% versus 3.8%) while the combined and colleague^'^^ studied 120 pairs of adult twins, FcyRIIA-RIH 131 and FqRIIIB-NA2INA2 geno- including 62 pairs of monozygotic twins reared type was reduced in the periodontitis group together, 25 pairs of same-sex dizygotic twins (6.3%) compared with the controls (22.9%). This reared together, and 33 pairs of monozygotic twins association observed between the combined reared apart. They found that alveolar bone height FcyRIIA and FqRIIIB genotype and moderate to was significantly affected by genetic factors. A sec- severe periodontitis suggests that reduced ond study from this group17* studied 110 pairs of opsonization associated with this combined geno- adult twins, including 66 monozygotic and 33 type impairs phagocytosis of pathogenic bacteria in dizygotic twins reared together and 14 monozy- individuals carrying these receptors. This may be gotic twin pairs raised apart. They found a genetic an important risk factor in adult periodontitis. influence on gingivitis, probing depth, attachment However, further studies with different racial pop- loss, and plaque. These studies are provocative, ulations and with larger populations are needed to leading to hypotheses relating to genetic factors in better account for possible confounding factors to periodontal disease. However, the authors point hlly assess the role of this risk indicator. out that the data must be viewed cautiously. For Hence, it appears that candidate gene poly- example, changes in alveolar bone height may be morphisms are a useful approach in assessing genetic due to anatomic variation and may or may genetic factors in both adult and juvenile forms of not be related to periodontal disease per se. periodontal disease. Future efforts along these lines Corey and colleague^'^^ studied 116 monozy- may reveal a set of important genes in periodonti- gotic and 233 dizygotic pairs and compared their tis in which genetic polymorphisms affect the periodontal disease history. They found that the hnction of the molecules encoded for by these proband-wise concordance rates were 0.38 for genes and thereby increase susceptibility or resis- monozygotic twins, and only 0.16 for dizygotic tance to periodontal infections. It is likely that twins. These results provide hrther evidence that genetic polymorphisms will explain risk for peri- genetic factors make an important contribution to odontal disease in subsets of the population. In the adult periodontal disease. hture, a larger battery of such polymorphisms may be useful to understand genetic influences on risk Genetic Polymorphisms for periodontal disease. Genetic polymorphisms have been associated with adult periodontitis. For example, Kornman and colleague^'^^ studied genetic polymorphisms in the EFFECTS OF MEDICATIONS proinflammatory cytokines interleukin- I (IL- 1) AND PERIODONTAL DISEASE and tumor necrosis factor-alpha (TNF-a). They report a specific periodontitis-associated IL- I geno- Phenytoin type, comprising a variant in the IL-1B gene associated with high levels of IL- I production. This geno- Sodium 5,5-phenylhydantoin has been used for 50 type was associated with severe periodontitis only in years in the treatment of grand mal epilepsy and nonsmokers. In smokers, severe periodontal disease also has been used for management of other neuro- was not correlated with any of the tested genotypes. logic disorders. Overgrowth of the gingiva is one of Tests for this combined genotype are commercially the most troublesome side effects of ~henyt0in.l~~ available and may be of value in understanding risk A gross increase in gingival size is due to a dramat- for periodontal disease, especially in nonsmokers. ic expansion of the connective tissue component. Further studies with larger populations including The growth is not a true fibrosis but a gingival over- Risk Factors for Periodontal Disease 23 growth since it results from neither hypertrophy sulfides, are present in the body. Oral manifesta- nor hyperplasia. Treatment consists of replacing tions of mercury, lead, and bismuth intoxication phenytoin with an alternative drug such as carba- are well described; however, the presence of such mazepine or sodium valproate, conservative peri- manifestations has decreased significantly as expo- odontal therapy to reduce the inflammatory com- sure to heavy metals by way of occupational haz- ponent of enlargement, and surgery, if necessary. ards and metal-containing drugs has declined. Bis- muth line is seen as a blue-black, easily discernible, Cyclosporine difhse pigmentation of marginal gingiva. Lead poisoning results in a line with grayish pigmenta- Cyclosporine has been used in the United States tion typically located a few millimeters apical to since 1984 for the prevention of rejection phenom- the gingival margin. A mercury line on the gingiva ena following solid organ and bone marrow trans- resulting from deposition of mercurial salts, main- plantation. It is also used in other countries in the ly mercuric sulfide, may be deposited in the gingi- treatment of type 2 diabetes mellitus, rheumatoid va. Cases of true allergy to mercury present in the arthritis, psoriasis, multiple sclerosis, malaria, sar- silver amalgam dental restorations are rare. The coidosis, and some other diseases with an immuno- role of lead and other heavy metals in the risk for logic basis. Cyclosporine selectively suppresses sub- periodontal disease has not been studied but is pos- populations of T lymphocytes interfering with pro- sible since these metals have major biologic effects, duction of interleukins, especially interleukin- I. and their ingestion is increasing in our society. Gingival overgrowth has been associated with cyclosporine.179 Histopathologically, cyclosporine- induced gingival overgrowth is associated with LOCAL RISK FACTORS: apparent fibroplasia, redundant collagenous ele- PERIODONTAL MICROFLORA ments, epithelial thickening as well as secondary inflammation. Reduction of dental plaque and low There are over 400 genera and species of microor- drug dosages may discourage the gingival over- ganisms that have been identified in the oral flora growth associated with the use of cyclosporine. Fur- of man. Only a few members of the subgingival thermore, cyclosporine substitute drugs appear to periodontal microflora, however, have been identi- have little or no effect on the gingivae. fied as candidate pathogens for the initiation and progression of periodontal disease. In a large epi- Dihydropyridines: demiologic study, Grossi and co-workers21>22tested Nifedipine and Nitrendipine a panel of candidate pathogen microorganisms, many of which have been implicated as periodon- Nifedipine (Procardia) is a substituted dihydropro- tal pathogens from animal, virulence, and case- lidine widely used since 1978 in the treatment of control human studies. This panel included Acti- angina pectoris and postmyocardial syndrome. nobucillus uctinomycetemcomituns, Bucteroides Nifedipine is a calcium ion blocker which induces forsytbus, Cumpylobucter rectus, Cupnocytopbugu gingival overgrowth. 180 Histologically, there is species, Eubucterium suburreum, Fusobucterium thickened epithelium, elongation of epithelial rete nucleutum, Porpbyromonus gingivulis, and Prevotelh ridges, redundant connective tissue, and abundant intermediu. Of this panel, only two, I? gingivulis fibroblasts. Inflammation may be reduced with and B. forsytbus, were associated with increased risk good plaque control, and scaling and root planing; for attachment loss as a measure of periodontal dis- however, often periodontal surgery is required for ease, after adjustment for age, plaque, smoking, treatment. and diabetes.21The same two organisms were also Another commonly used calcium antagonist identified as risk indicators for periodontal alveolar in cardiology is verapamil hydrochloride (Calan). bone loss.22Epidemiologic studies of Beck and CO- Verapamil hydrochloride has not been associated workers182suggested that specific bacteria such as with gingival enlargement or fibrosis elsewhere in I? gingivulis and I? intermediu play a role in peri- the body. odontal disease in older adults. They found in their study of older adults that the difference in the Heavy Metals prevalence of periodontal disease between African Americans and Caucasian Americans is explained Pigmentation of the gingiva or other mucosa in part by the prevalence of I? gingivulis and I? results when heavy metals, primarily heavy metal intermediu. In a longitudinal study of 886 patients, 24 Periodontal Medicine

Wolff and colleague^'^^ found that I? gingivulis, Calculus and its relationship to periodontitis A. uctinomycetemcomituns, I? intermediu, Eikenelh is complex. Calculus developing in certain sites, corrodens and E nucleutum were found in higher such as the lower incisal areas, in patients receiv- numbers in areas of increasing probing depths with ing regular dental care does not result in signifi- relative risks between 2.7 and 4.0. A very strong cant periodontal disease.194On the other hand, association has been found between the presence of studies report a high correlation between measures A. uctinomycetemcomituns and periodontal disease of calculus and measures of periodontal disease in localized juvenile periodontitis. 184-185 and since they coexist, it is difficult to determine The presence and level of spirochetes have been that calculus per se is a risk factor for periodontal associated with increased risk of periodontal dis- disease. Calculus is likely a deposit that forms after ease;186however, this finding has to be tempered by periodontal disease develops and likely con- the observation that spirochetes are also elevated tributes to progression of periodontitis by provid- when patients have poor oral hygiene.187HafTajee ing a nidus for microbial plaque accumulation and and co-workers188found that I? intermediu, C rectus, persistence. B. forsytbus, and Peptostreptococcus micros were predictors of future periodontal progression in Bleeding on Probing patients who were already affected by adult periodontitis. Li~tgarten'~~found that the absence of Surprisingly, gingival bleeding on probing appears A. uctinomycetemcomituns, I? intermediu, and I? gin- to have weak predictive value for fbture periodontal givulis served as an indicator of periodontal health to breakdown. 195-196 However, the repeated absence of a greater extent than their presence being a marker bleeding upon probing is associated with no disease for future disease. He suggests that they have a high progre~sion.~~~-~~~In these studies, it was found negative predictive value. The importance of specif- that setting level of bleeding upon probing at 50% ic bacteria in periodontal destruction is highlighted is predictive for fbture periodontal disease with a by the finding that the quantity of total plaque accu- relative risk of 3, after adjusting for smoking, mulation is only correlated weakly with destructive microbial dental plaque accumulation, diabetes, periodontal disea~e.~~,~~J~'Further studies are neces- and baseline flora. sary to determine the extent to which other organisms (eg, A. uctinomycetemcomituns) may play a role Preexisting Periodontal Disease in juvenile forms of periodontal disease. Perhaps one of the most strongly associated risk Oral Hygiene, Plaque, and Calculus factors for fbture periodontal breakdown is presence and severity of periodontal disease assessed by Microbial dental plaques have been strongly asso- attachment loss or alveolar bone loss at base- ciated as causative agents for gingivitis; however, line.32>34J88-189J99-203In a study of 79 patients the association of supragingival plaque with peri- with established periodontitis who were monitored odontitis is not clear. For example, in the studies every 3 months for I year, Machtei and co-work- by Grossi and colleagues,21>22they are not found ers203 found that individuals with baseline pocket to be risk factors for periodontal disease. In treat- depth 23.2 mm were at greater risk for future bone ment studies, such as that by Axelsson and col- loss I year later (relative risk: 2.97; 95% CI 1.02 to league~,~~~it was shown that patients who main- 8.70). A multivariate analysis of this study also tain excellent hygiene measures and who undergo found that smokers were at increased risk for fur- scaling and root planing every 2 to 3 months for 9 ther attachment loss when compared to nonsmok- years, and twice annually for an additional 6 years, ers (relative risk: 5.41; 95% CI 1.50 to 19.5) and had very little clinically detectable periodontal that subjects who harbored B. forsytbus at baseline disease. Thus, it is clear that periodontitis can be were at seven times greater risk for increased pock- prevented and established periodontitis arrested by et depth (relative risk: 7.84; 95% CI 1.74 to 35.3). control of microbial deposits. Supragingival plaque This study confirms that pre-existing periodontal may provide a favorable environment for coloniza- disease is among the true risk factors for develop- tion with specific subgingival flora and indirectly ment of periodontal disease. affect the pathogenic subgingival flora. 192-193 Lack of regular dental therapy has also been Therefore, the association that has been docu- suggested as a risk factor for periodontal disease in mented above for the specific flora is a direct one studies using univariate analyses. However, with in terms of risk factors. multivariate analysis, most studies showed that pre- Risk Factors for Periodontal Disease 25 vious dental therapy is not a risk factor when one infection. More study of the role of occlusion considers existing levels of disease, such as existing in periodontal disease is needed. pocket depth or existing gingivitis in the mode1.21>22 CLINICAL APPLICATION OF Individual Tooth Risk Factors RISK FACTOR ANALYSIS Several factors have been proposed to affect the Table 2-2 lists important risk indicators and risk risk of further periodontal disease on individual factors for periodontal disease and summarizes teeth. These include their strength of association. On the basis of the I. occlusion, especially functional malocclusion strength of the association, those factors that such as bruxism; appear to be true risk factors for periodontal dis- 2. excessive occlusal stress, which may be prima- ease in adults include the subgingival periodontal ry if the tooth has excessive stress with inade- pathogens I? gingivalis and B. forytbus, diabetes quate support, or secondary if the tooth is mellitus, male gender, smoking, and pre-existing under even normal stress and has inadequate periodontal disease. Putative risk factors or risk support; and indicators at this time include genetic factors; 3. teeth with pulpal infections that show periapi- osteoporosis; stress, distress, and coping; and cal lesions; these have greater chance of future dietary factors such as low calcium intake. Further loss of attachment than those with no pulpal studies are necessary to determine the extent to

TABLE 2-2. The Strength of Association of Local and Systemic Factors with Destructive Periodontal Disease Case Rep0 rt Cme-Co n trol Cross-Sectional Longitudinal Factor Studies Studies Studies Studies Intervention Studies Specific bacteria I? gingivalis Yes Yes Yes Yes Yes B. forsytbus Yes Yes Yes Yes Yes I? intermedia Yes Yes Yes Yes Yes Gender Male Yes NR Yes NR NR Age Yes Yes Yes No (to 7th decade) NR Diabetes mellitus Type 2 Yes Yes Yes Yes Yes (treatment reduces glycosylated hemoglobin) Type 1 Yes Yes Yes NR NR Smoking NR Yes Yes Yes Yes (smokers heal poorly) Osteoporosis Yes Yes Yes NR NR Stress, distress, Yes Yes Yes NR NR coping PMN disorders Yes Yes NR Yes (case series) NR Genetic factors NR Yes NR NR NR (IL-1 polymorphisms) Dietary calcium NR Yes Yes NR NR Preexisting Yes Yes Yes Yes Yes periodontal d'isease

NR = not reported, or not relevant; PMN = polymorphonuclear. Adapted from Genco RJ. Current view of risk factors for periodontal diseases. J Periodontal 1996;67(Suppl):1041-9. 26 Periodontal Medicine which these risk indicators are true risk factors for Bethesda, MD: National Institute of Dental periodontal disease. Research; 1987. NIH Publication No. 87-2868. 2. Hugoson A, Jordan T. Frequency distribution of individuals aged 20-70 years according to sever- DETERMINING A PATIENT'S ity of periodontal disease. Commun Dent Oral RISK PROFILE Epidemiol 1982;10: 187-92. Determination of patient-based as well as site- Brown LJ, Loe H. Prevalence, extent, severity and based risk factors for periodontal disease is a neces- progression of periodontal disease. Periodontol sary component of the evaluation and diagnosis of 2000 1993;2:57-71. our patients. Identification of risk factors for each Genco RJ. Periodontal disease and risk for myocar- patient, and their management should be part of dial infarction and cardiovascular disease. Car- the treatment plan. diovasc Rev Rep 1998;19(3):34-40. Offenbacher S, Katz V, Gertik G, et al. Periodontal infection as a possible risk factor for preterm low RISK FACTOR MODIFICATION birth weight. J Periodontol 1996;67:1103-13. IN CLINICAL MANAGEMENT Scannapieco FA, Papandonatos GD, Dunford RG. Associations between oral conditions and respi- Periodontal diseases are infections and, by and ratory disease in a national sample survey popu- large, are treated with anti-infective therapy, and lation. Annals Periodontol 1998;3:251-6. residual defects are restored by regenerative therapy. 7. Scannapieco FA. Periodontal disease as a potential The third mode of therapy, modification of risk, is risk factor for systemic diseases [position paper]. becoming more and more important as indicated J Periodontol 1998;69:84 1-50. by studies that show that if risk factors are not mod- 8. Haffajee AD, Socransky SS. Microbial etiological ified, periodontal healing is compromised, especial- agents of destructive periodontal diseases. Peri- ly in patients who ~moke.~~>~'*It would seem that odontol2000 1994;5:78-1 l l. smoking cessation is indicated for optimal peri- 9. Slots J, Feik D, Rams TE. Age and sex relationships of odontal healing as well as for other general health superinfecting microorganisms in periodontitis reasons. Diabetics who respond successfully to peri- patients. Oral Microbiol Immunol 1990;5:305-8. odontal therapy also have a reduction in glycated 10. Njoroge T, Genco RJ, Sojar HT, et al. A role for fim- hemoglobin, particularly if they are treated with briae in Porphyromonas gingivalis invasion of oral tetracycline. loo Several other studies have shown epithelial cells. Infect Immun 1997;65:1980-4. similar results. Hence, management of periodontal 11. Genco CA, Odusanya BM, Potempa J, et al. A pep- disease, that is, modification of risk factors, is part tide domain on gingipain R which confers of contemporary treatment of periodontal disease immunity against Porphyromonas gingivalis infec- and is supported by intervention studies. tion in mice. Infect Immun 1998;66:4108-14. 12. van Winkelhoff AJ, Tijhof CJ, de Graaff J. Micro- SUMMARY biological and clinical results of metronidazole plus amoxicillin therapy in Actinobacillus actin- In this chapter, those factors associated with omycetemcomitans-associated periodontitis. J increased risk for periodontal disease, functioning Periodontol 1992;63:52-7. as systemic factors or as local factors, are described, 13. American Academy of Periodontology. The patho- and data supporting these factors as true risk fac- genesis of periodontal diseases [informational tors are provided. A model for the assessment of paper]. J Periodontol 1999;70:457-70. risk for the development of periodontal disease in 14. Reynolds JJ, Meikle MC. Mechanisms of connec- patients with no or moderate periodontal disease tive tissue matrix destruction in periodontitis. is provided. Furthermore, the concept of risk Periodonto12000 1997;14:144-57. management, that is, modification of risk factors 15. Honig J, Rordorf-Adam C, Siegmund C, et al. as part of periodontal therapy, in those at high Increased interleukin- 1p concentration in gingi- risk is presented. val tissue from periodontitis patients. J Perio- dontal Res 1989;24:362-7. REFERENCES 16. Gemmell E, Marshal1 R, Seymour G. Cytokines and prostaglandins in the immune hemostasis 1. Miller AJ, Brunelle JA, Carlos JC et al. Oral Health and tissue destruction in periodontal disease. of United States Adults: National Findings. Periodonto12000 1997;14:112-43. Risk Factors for Periodontal Disease 27

17. Last JM. A dictionary of epidemiology, 2nd ed. 33. Wennstrom JL, Serino G, Lindhe J, et al. Peri- New York, Ny: Oxford University Press; 1988. odontal conditions of adult regular dental care 18. Beck JD. Methods of assessing risk for periodonti- attendants. A 12-year longitudinal study. J Clin tis and developing multi-factorial models. J Periodontol 1993;20:714-22. Periodontol 1994;65:468-78. 34. Ismail AI, Morrison EC, Burt BA, et al. Natural 19. Ibrahim M. Epidemiology and health policy. history of periodontal disease in adults: findings Rockville, MD: Aspen Systems Corporation; from the Tecumseh periodontal disease study. 1985. 1959-1987. J Dent Res 1990;69:430-5. 20. Goodson JM. Selection of suitable indicators of 35. Russell AL. Geographical distribution and epidemi- periodontitis. In: Bader JD, editor. Risk assess- ology of periodontal disease. Geneva: World ments in dentistry. Chapel Hill, NC: University Health Organization; (WHO/DH/33/34), 1960. of North Carolina Dental Ecology; 1990. p. 69. 36. U.S. Public Health Service. National Center for 21. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of Health Statistics. Periodontal disease in adults, risk for periodontal disease. I. Risk indicators for United States 1960-1962. PHS Publication No. attachment loss. J Periodontol 1994;65:260-7. 1000, Series 11, No. 12, Washington, DC: 22. Grossi SG, Genco RJ, Machtei EE, et al. Assess- Government Printing Office; 1965. ment of risk for periodontal disease. 11. Risk 37. U.S. Public Health Service. National Center for indicators for alveolar bone loss. J Periodontol Health Statistics. Basic data on dental examina- 1995;66:23-9. tion findings of persons 1-75 years; United 23. Carlos Jc Wolfe MD, Kingman A. The extent and States, 1971-1974. DHEW Publication No. severity index: a simple method for use in epi- (PHS) 79-1662, Series 11, No. 214, Washing- demiologic studies of periodontal disease. J Clin ton, DC: Government Printing Office; 1979. Periodontol 1986;13:500-5. 38. Genco RJ. Current view of risk factors for peri- 24. DeRouen TA. Statistical methods for assessing risk odontal diseases. J Periodontol 1996;67(Suppl): of periodontal disease. In: Bader JD, editor. 1041-9. Risk assessments in dentistry. Chapel Hill, NC: 39. Pindborg JJ. Tobacco and gingivitis. I. Statistical University of North Carolina Dental Ecology; examination of the significance of tobacco in 1990. p. 239-44. the development of ulceromembranous gingivi- 25. Hujoel Pc Loesche WJ, DeRouen TA. Assessment tis and in the formation of calculus. J Dent Res of relationships between site-specific variables. J 1947;26:261-4. Periodontol 1990;61:368-72. 40. Frandsen A, Pindborg JJ. Tobacco and gingivitis. 26. DeRouen TA, Mancl L, Hujoel E Measurement of 111. Difference in action of cigarette and pipe association in periodontal diseases using statisti- smoking. J Dent Res 1949;28:464-5. cal methods for dependent data. J Periodontal 41. Solomon HA, Priore Bross IDJ. Cigarette Res 199 1;26:2 18-29. RL, smoking and periodontal disease. J Dent 27. Marshall-Day CD, Stevens RG, Quigley LF Jr. Am Periodontal disease prevalence and incidence. Assoc 1968;77:1081-4. J Periodontol 195526:185-203. 42. Ismail AI, Burt BA, Eklund SA. Epidemiologic pat- 28. Schei 0, Waerhaug J, Lovdal A, Arno A. Alveolar terns of smoking and periodontal disease in the bone loss as related to oral hygiene and age. J United States. J Am Dent Assoc 1983;106: Periodontol 1959;30:7-16. 6 17-23. 29. Abdellatif HM, Burt BA. An epidemiological 43. Machtei EE, Hausmann E, Dunford R, et al. Lon- investigation into the relative importance of age gitudinal study of predictive factors for peri- and oral hygiene status as determinants of periodontal disease and tooth loss. J Clin Periodon- odontitis. J Dent Res 1987;66:13-8. to1 1999;26:374-80. 30. Machtei EE, Dunford R, Grossi SG, Genco RJ. 44. Gonzalez YM, De Nardin A, Grossi SG, et al. Cumulative nature of periodontal attachment Serum cotinine levels, smoking and periodontal loss. J Periodontal Res 1994;29:361-4. attachment loss. J Dent Res 1996;75:796-802. 31. Papapanou PN, Wennstrom JL, Grondahl K. A 10- 45. Holm G. Smoking as an additional risk for tooth year retrospective study of periodontal disease loss. J Periodontol 1994;65:996-1001. progression. J Clin Periodontol 1989;16:404- 11. 46. Preber H, Bergstrom J. Occurrence of gingival 32. Albandar JM, Rise J, Gjermo Johansen JR. Radi- bleeding in smoker and nonsmoker patients. ographic quantification of alveolar bone level Acta Odontol Scand 1985;43:315-20. changes. A 2-year longitudinal study in man. J 47. Preber H, Bergstrom J. The effect of non-surgical Clin Periodontol 1986;13:195-200. treatment on periodontal pockets in smokers 2 8 Periodontal Medicine

and nonsmokers. J Clin Periodontol 1985;13: 64. Cuff MJ, McQuade MJ, Scheidt MJ, et al. The 319-23. presence of nicotine on root surfaces of peri- 48. Preber H, Bergstrom J. Effect of cigarette smoking odontally diseased teeth in smokers. J Periodon- on periodontal healing following surgical thera- to1 1989;60:564-9. py. J Clin Periodontol 1990;17:324-8. 65. Zambon JJ, Grossi SG, Machtei EE, et al. Cigarette 49. Kaldahl WB, Kalkwarf KL, Patil KD, Molvar ME smoking increases the risk for subgingival infec- Relationship of gingival bleeding, gingival sup- tion with periodontal pathogens. J Periodontol puration and supragingival plaque to attach- 1996;67( Suppl) : 105 0-4. ment loss. J Periodontol 1990;61:347-5 1. 66. MacFarlane G, Herzberg M, Wolff L, Hardie N. 50. Tonetti MS, Pini-Prato G, Cortellini E Effect of Refractory periodontitis associated with abnor- cigarette smoking on periodontal healing fol- mal polymorphonuclear leukocyte phagocytosis lowing GTR in infrabony defects. A prelimi- and cigarette smoking. J Periodontol 1992;63: nary retrospective study. J Clin Periodontol 908-13. 1996;22:229-34. 67. Poore TK, Johnson GK, Rheinhardt RA, Organ 5 1. Preber H, Linder L, Bergstrom J. Periodontal heal- CC. The effects of smokeless tobacco on clinical ing and periopathogenic microflora in smokers parameters of inflammation and gingival crevic- and non-smokers. J Clin Periodontol 1996;22: ular fluid prostaglandin Ez, interleukin- 1a, and 946-52. interleukin-1p. J Periodontol 1995;66:177-83. 52. Grossi SG, Skrepcinski FB, DeCaro T, et al. Respons- 68. Johnson GK, Poore TK, Rayne JB, Organ CC. Effect es to periodontal therapy in diabetics and smok- of smokeless tobacco extract on human gingival ers. J Periodontol 1996;67(Suppl):1094-102. keratinocyte levels of prostaglandin E2 and inter- 53. Kaldahl WB, Kalkwarf KL, Patil KD, et al. Long- leukin-1. J Periodontol 1996;67:116-24. term evaluation of periodontal therapy. 11: Inci- 69. Ringelberg ML, Dixon DO, Francis AO, Plummer dence of sites breaking down. J Periodontol RW. Comparison of gingival health and gingival 1996;67:103-8. crevicular fluid flow in children with and with- 54. Bergstrom J, Eliasson S, Preber H. Cigarette smok- out diabetes. J Dent Res 1977;56:108-11. ing and periodontal bone loss. J Periodontol 70. Faulconbridge AR, Bradshaw WC, Jenkins PA, 199 1;62:242-6. Baum JD. The dental status of a group of dia- 55. Haber J, Wattles J, Crowley M, et al. Evidence for betic children. Br Dent J 1981;151(8):253-5. cigarette smoking as a major risk factor for peri- 71. Cianciola LJ, Park BH, Bruck E, et al. Prevalence odontitis. J Periodontol 1993;64:16-23. of periodontal disease in insulin-dependent dia- 56. Haber J, Kent U. Cigarette smoking in a peri- betes mellitus (juvenile diabetes). J Am Dent odontal practice. J Periodontol 1992;63:100-6. Assoc 1982;104:653-60. 57. Baab DA, Oberg PA. The effect of cigarette smok- 72. Harrison R, Bowen WH. Periodontal health, den- ing on gingival blood flow in humans. J Clin tal caries, and metabolic control in insulin- Periodontol 1987;14:418-24. dependent diabetic children and adolescents. 58. Palmer RM. Tobacco smoking and oral health: Pediatric Dent 1987;9:283-6. review. Br Dent J 1988;164:258-60. 73. Novaes AB Jr, Pereira ALA, de Moraes N, Novaes 59. Haber J, Brinnell C, Crowley M, et al. Antibodies AB. Manifestations of insulin-dependent diabetes to periodontal pathogens in cigarette smoking. J mellitus in the periodontium of young Brazilian Dent Res 1993;72(SpecialIssue): Abstract 1126. patients. J Periodontol 199 1;62:1 16-22. 60. Tew JG, Zhang J-B, Quinn S, et al. Antibody of 74. de Pommereau V, Dargent-Pare C, Robert JJ, Brion the IgGz subclass, Actinobacillus actinomycetem- M. Periodontal status in insulin-dependent dia- comitans, and early-onset periodontitis. J Perio- betic adolescents. J Clin Periodontol 1992;19 dontol 1996;67(Suppl) : 3 17-22. (Pt. 1):628-32. 6 1. Raulin L, MacPherson J, McQuade M, Hanson B. 75. Pinson M, Hoffman WH, Garnick JJ, Litaker MS. The effect of nicotine on the attachment of Periodontal disease and type 1 diabetes mellitus human fibroblasts to glass and human root sur- in children and adolescents. J Clin Periodontol faces in vitro. J Periodontol 1988;59:318-25. 1995;22:118-23. 62. Gall EA, Dawson-Hughes B. Smoking and bone 76. Firatli E, Yilmaz 0, Onan U. The relationship loss among postmenopausal women. J Bone between clinical attachment loss and the dura- Min Res 1991;6:331-7. tion of insulin-dependent diabetes mellitus 63. Daniel1 HW. Osteoporosis of the slender smoker. (IDDM) in children and adolescents. J Clin Arch Intern Med 1976;136:298-304. Periodontol 1996;23:362-6. Risk Factors for Periodontal Disease 29

77. Firatli E. The relationship between clinical peri- 92. Morton AA, Williams RW, Watts RLE Initial study odontal status and insulin-dependent diabetes of periodontal status in non-insulin-dependent mellitus. Results after 5 years. J Periodontol diabetics in Mauritius. J Dent 1995;23:343-5. 1997;68:136-40. 93. Novaes AB Jr, Gutierrez FG, Novaes AB. Periodon- 78. Goteiner D, Vogel R, Deasy M, Goteiner C. Peri- tal disease progression in type I1 non-insulin- odontal and caries experience in children with dependent diabetes mellitus patients (NIDDM). insulin-dependent diabetes mellitus. J Am Dent Part I. Probing pocket depth and clinical attach- Assoc 1986;113:277-9. ment. Brazilian Dent J 1996;7:65-73. 79. Kjellman 0, Henriksson CO, Berghagen N, 94. Taylor GW, Burt BA, Becker ME et al. Non-insulin Andersson B. Oral conditions in 105 subjects dependent diabetes mellitus and alveolar bone with insulin-treated diabetes mellitus. Svensk loss progression over two years. J Periodontol Tandlakaretidskrift 1970; 63: 9 9- 11 0. 1998;69:76-83. 80. Sznajder N, Carraro JJ, Rugna S, Sereday M. Peri- 95. Taylor GW, Burt BA, Becker ME et al. Glycemic odontal findings in diabetic and nondiabetic control and alveolar bone loss progression in type patients. J Periodontol 1978;49:445-8. I1 diabetes. Ann Periodontol 1998;3(1):30-9. 81. Galea H, Aganovic I, Aganovic M. The dental 96. Taylor GW, Burt BA, Becker ME et al. Severe peri- caries and periodontal disease experience of odontitis and risk for poor glycemic control in patients with early onset insulin dependent dia- subjects with non-insulin-dependent diabetes betes. Intl Dent J 1986;36:219-24. mellitus. J Periodontol 1996;67:1085-93. 82. Rylander H, Ramberg E Blohme G, Lindhe J. 97. Dolan TA, Gilbert GH, Ringelberg ML, et al. Behav- Prevalence of periodontal disease in young dia- ioral risk indicators of attachment loss in adult betics. J Clin Periodontol 1987;14:38-43. Floridians. J Clin Periodontol 1997;24:223-32. 83. Guven Y, Satman I, Dinccag N, Alptekin S. Salivary 98. Szpunar SM, Ismail AI, Eklund SA. Diabetes and peroxidase activity in whole saliva of patients periodontal disease: analyses of NHANES I and with insulin-dependent (type 1) diabetes melli- HHANES [abstract 16051. J Dent Res 1989; tus. J Clin Periodontol 1996;23:879-8 1. 68 (Special Issue) :383. 84. Cohen MM. Transforming growth factor beta and 99. Aldridge JE Lester V, Watts TL, et al. Single-blind fibroblast growth factors and their receptors: studies of the effects of improved periodontal role in structural biology and craniosynostosis.J health on metabolic control in type 1 diabetes Bone Min Res 1997;12:322-31. mellitus. J Clin Periodontol 1995;22:271-5. 85. Glavind L, Lund B, Loe H. The relationship 100.Grossi SG, Skrepcinski FB, DeCaro T, et al. Treat- between periodontal state and diabetes dura- ment of periodontal disease in diabetics reduces tion, insulin dosage and retina1 changes. J Perio- glycated hemoglobin. J Periodontol 1997;68: dontol 1968;39(6):341-7. 713-9. 86. Hugoson A, Thorstenson H, Falk H, Kuylenstierna 101.Miller LS, Manwell MA, Newbold D, et al. The J. Periodontal conditions in insulin-dependent relationship between reduction in periodontal diabetics. J Clin Periodontol 1989;16:215-23. inflammation and diabetes control: a report of 9 87. Thorstenson H, Hugoson A. Periodontal disease cases. J Periodontol 1992;63:843-8. experience in adult long-duration insulin- 102.Clearinghouse on oral problems related to HIV dependent diabetics. J Clin Periodontol 1993; infection and WHO Collaborating Centre on 20~352-8. Oral Manifestations of the Immunodeficiency 88. Tervonen T, Karjalainen K. Periodontal disease Virus. Classification and diagnostic criteria for related to diabetic status. A pilot study of the oral lesions in HIV infection. J Oral Pathol Med response to periodontal therapy in type 1 dia- 1993;22(7):289-9 1. betes. J Clin Periodontol 1997;24:505-10. 103.Greenberg MS. HIV-associated lesions. Dermatol 89. Nelson RG, Shlossman M, Budding LM, et al. Clin 1996;14:3 19-26. Periodontal disease and NIDDM in Pima Indi- 104.Greenspan D, Greenspan JS. HIV-related oral dis- ans. Diabetes Care 1990;135336-40. ease. Lancet 1996;348 (9029):729-33. 90. Shlossman M, Knowler WC, Pettitt DJ, Genco RJ. 105.Phelan JA. Oral manifestations of human immun- Type 2 diabetes and periodontal disease. J Am odeficiency virus infection. Med Clin North Dent Assoc 1990;121:532-6. Am 1997;81:511-31. 91. Emrich LJ, Shlossman M, Genco RJ. Periodontal 106.Samaranayake LE Holmstrup E Oral candidiasis disease in non-insulin dependent diabetes melli- and human immunodeficiencyvirus infection. J tus. J Periodontol 1991;62:123-30. Oral Pathol Med 1989;18:554-64. 3 0 Periodontal Medicine

107.Klein RS, Harris CA, Small CB, et al. Oral can- associated infections. Littleton (MA): PSG Pub- didiasis in high risk patients as the initial mani- lishing; 1988. festation of the acquired immunodeficiency 120.Van Dyke TE, Levine MJ, Genco RJ. Neutrophil syndrome. N Engl Med J 1984;311(6):35-48. function in oral disease. J Oral Pathol 1985;14: 108.Tindall B, Carr A, Cooper DA. Primary HIV infec- 95-120. tion: clinical, immunologic, and serologic 121.Sofaer JA. Genetic approaches to the study of peri- aspects. In: Sande MA, Volberding PA, editors. odontal disease. J Clin Periodontol 1990;17(7 The medical management of AIDS. Philadel- Pt. 1):401-8. phia: WJ3 Saunders; 1995. p. 105-29. 122.Phillips HB, Ashley FE Relationship between peri- 109.Glick M, Muzyka BC, Lurie D, Salkin LM. Oral odontal disease and a metacarpal bone index. Br manifestations associated with HIV-related dis- Dent J 1973;134:237-9. ease as markers for immune suppression and 123.Von Wowren N. Dual-photon absorptiometry of AIDS. Oral Surg Oral Med Oral Pathol 1994; mandibles: in vitro test of a new method. Scand 77:344-9. J Dent Res 1985;93:169-77. 110. Daniels TE. Oral candidiasis and HIV infection. 124.Von Wowren N, Klausen B, Kollerup G. Osteo- In: Greenspan JS, Greenspan D, editors. Oral porosis: a risk factor in periodontal disease. J manifestations of HIV infection. Chicago, IL: Periodontol 1994;65:1134-8. Quintessence; 1995. p. 80-4. 125.Von Wowren N, Kollerup G. Symptomatic osteo- 11 1. Dodd CL, Greenspan D, Katz MH, et al. Oral can- porosis: a risk factor for residual ridge reduction didiasis in HIV infection: Pseudomembranous of the jaws. J Prosthet Dent 1992;67:656-60. and erythematous candidiasis show similar rates l26.Von Wowren N, Storm TL, Olgaard K. Bone min- of progression to AIDS. AIDS 1991;5(11): eral content by photon absorptiometry of the 1339-43. mandible compared with that of the forearm 112.Greenspan D, Greenspan JS, Conant M, et al. Oral and the lumbar spine. Calcif Tissue Int 1988; “hairy” leukoplakia in male homosexuals: evi- 42: 157-6 1. dence of association with both papillomavirus 127.Kribbs PJ, Smith DE, Chesnut CH. Oral findings and a herpes-group virus. Lancet 1984;2:831-4. in osteoporosis. Part I: Measurement of 113.Greenspan D, Greenspan JS, Lennette ET, et al. mandibular bone density. J Prosthet Dent 1983; Oral viral leukoplakia-a new AIDS-associated 5 0: 576-9. condition. Adv Exp Med Biol 1985;187:123-8. 128.Kribbs PJ, Smith DE, Chesnut CH. Oral findings 114.Eisenberg E, Krutchkoff D, Yamase H. Incidental in osteoporosis. Part 11: Relationship between oral hairy leukoplakia in immunocompetent residual ridge and alveolar bone resorption and persons. A report of two cases. Oral Surg Oral generalized skeletal osteopenia. J Prosthet Dent Med Oral Pathol 1992;74:332-3. 1983;50:719-24. 115.Felix DH, Watret K, Wray D, Southam JC. Hairy 129.Kribbs PJ, Chesnut CH, 111. Osteoporosis and leukoplakia in an HIV negative, nonimmuno- dental osteopenia in the elderly. Gerodontology suppressed patient. Oral Surg Oral Med Oral 1984;3:10 1-6. Pathol 1992;74(5): 563-6. 130.Henrikson Wallenius K. The mandible and 116.Epstein JB, Silverman S Jr. Head and neck malig- osteoporosis-a qualitative comparison between nancies associated with HIV infection. Oral the mandible and the radius. J Oral Rehab Surg Oral Med Oral Pathol 1992;73:193-200. 1974;1:67-74. 117.Lamster I, Grbic J, Fine J, et al. A critical review of 13l.Ortman LF, Hausmann E, Dunford RG. Skeletal periodontal disease as a manifestation of HIV osteopenia and residual ridge resorption. J Pros- infection. In: Greenspan JS, Greenspan E, edi- thet Dent 1989;61:321-5. tors. Oral manifestations of HIV infection. 132.Humphries S, Devlin H, Worthington H. A radi- Chicago, IL Quintessence; 1995. p. 247-56. ographic investigation into bone resorption of 118. Winkler JR, Robertson PB. Periodontal disease mandibular alveolar bone in elderly edentulous associated with HIV infection. Oral Surg Oral adults. J Dent 1989;17:94-6. Med Oral Pathol 1992;73:145-50. 133. Daniel1 H. Postmenopausal tooth loss. Contribu- 119.Winkler JR, Grassi M, Murray PA. Clinical tions to edentulism by osteoporosis and cigarette description and etiology of HIV-associated peri- smoking. Arch Intern Med 1983;143:1678-82. odontal diseases. In: Robertson PB, Greenspan 134.Krall EA, Dawson-Hughes B, Hannan MT, et al. JS, editors. Perspectives on oral manifestations Postmenopausal estrogen replacement and of AIDS: diagnosis and management of HIV- tooth retention. Am J Med 1997;102:536-42. Risk Factors for Periodontal Disease 3 1

135.Groen JJ, Menczel J, Shapiro S. Chronic destruc- coping strategies: a theoretically based approach. tive periodontal disease in patients with prese- J Pers SOCPsycho1 1989;56:267-83. nile osteoporosis. J Periodontol 1968;39:19-23. 152.Melnick M, Shields ED, Bixler D. Periodontosis. A 136.Wactawski-Wende J, Grossi SG, Trevisan M, et al. phenotypic and genetic analysis. Oral Surg Oral The role of osteopenia in oral bone loss and peri- Med Oral Pathol 1976;42:324 1. odontal disease. J Periodontol 1996;67:1076-84. 153.SaxCn L. Heredity of juvenile periodontitis. J Clin 137. Nishida M, Grossi SG, Dunford RG, et al. Role of Periodontol 1980;7:276-88. dietary calcium and the risk for periodontal dis- 154.Long JC, Nance WE, Aring et al. Early onset ease. J Periodontol 1999. [Submitted] periodontitis. A comparison and evaluation of 138.RubinoffAB7Latner PA, Pasut LA. Vitamin C and two proposed modes of inheritance. Genet Epi- oral health. J Canadian Dent Assoc 1989;55: demiol 1987;4:13-24. 705-7. 155.Beaty TH, Boughman JA, Yang et al. Genetic 139.Nishida M, Grossi SG, Dunford RG, et al. Dietary analysis of juvenile periodontitis in families vitamin C and the risk for periodontal disease. J ascertained through an affected proband. Am J Periodontol 1999. [Submitted] Hum Genet 1987;40:443-52. 140.Wendt LK, Svedin CG, Hallonsten AL,Larsson IV. 156.Hart TC, Marazita ML, Gunsolley JA, et al. No Infants and toddlers with caries. Mental health, female preponderance in juvenile periodontitis family interaction, and life events with infants after correction of ascertainment bias. J Perio- and toddlers with caries. Swed Dent J 1995; dontol 1991;62:745-9. 19(1-2): 17-27. 157.Saxby MS. Juvenile periodontitis: an epidemiolog- 14l.Moulton R, Ewen S, Thieman W. Emotional fac- ical study in West Midlands of the United King- tors in periodontal disease. Oral Surg Oral Med dom. J Clin Periodontol 1987;14:594-8. Oral Pathol 1952;5:833-60. 158.Hart TC, Marazita ML, Schenkein HA, Diehl SR. 142.Melnick SL, Roseman JM, Engel JD, Cogen RB. Re-interpretation of the evidence for X-linked Epidemiology of acute necrotizing ulcerative dominant inheritance of juvenile periodontitis. gingivitis. Epidemiol Rev 1988;10:191-211. J Periodontol 1992;63:169-73. 143.Marcenes WS, Sheiham A. The relationship 159.Van Dyke TE, Schweinebraten M, Cianciola LJ, et al. Neutrophil chemotaxis in families with local- between work stress and oral health status. SOC ized juvenile periodontitis. J Periodontal Res Sci Med 1992;35:15 1 1-20. 1985;20:503-14. 144.Monteiro da Silva AM, Oakley DA, Newman HN, 16O.Page RC, Vandesteen GE, Ebersole JL, et al. Clini- et al. Psychosocial factors in adult onset rapidly - cal and laboratory studies of a family with a progressing periodontitis. J Clin Periodontol high prevalence of juvenile periodontitis. J Peri- 1996;23(8):789-94. odontol 1985;56:602-10. 145.Linden GJ, Mullally BH, Freeman R. Stress and 161.Gwinn MR, Sharma A, De Nardin E. Sequence the progression of periodontal disease. J Clin analysis of chemotactic receptor DNA in LJP Periodontol 1996;23(7):675-80. [abstract 1301. J Dent Res 1998;77(Special 146.Genco RJ, Ho AW, Grossi SG, et al. Relationship Issue B):648. of stress, distress, and inadequate coping behav- 162.Wilson ME, Kalmar JR FcgNIa (CD32): a potential iors to periodontal disease. J Periodontol 1999. marker defining susceptibility to localized juvenile [In press] periodontitis. J Periodontol 1996;67:323-3 1. 147.Genco RJ, Ho AW, Kopman J, et al. Models to 163.Cullinan ME Sachs J, Wolf E, Seymour GJ. The evaluate the role of stress in periodontal disease. distribution of HLA-A and -B antigens in Ann Periodontol 1998;3(1):288-302. patients and their families with periodontitis. J 148.Dowrenwend BS, Drasnott L, Ashenasj AR, Periodontal Res 1980;15: 177-84. Dowrenwend BI? Exemplification of a method 164.SaxCn L, Koskimies S. Juvenile periodontitis-no for scaling life events: the PERT. life events scale. linkage with HLA-A antigens. J Periodontal Res J Health SOCBeh 1978;19:205-9. 1984;19:4414. 149.Pearlin LI, Schooler C. The structure of coping. J 165.Reinholdt J, Bay I, Svejgaard A. Association Health SOCBehav 1978;19:2-2 1. between HLA-antigens and periodontal disease. 150.Derogatis LR, Cleary PA. Confirmation of the J Dent Res 1977;56:1261-3. dimensional structure of the SCL-90: a study in 166.Kornman KS, Page RC, Tonetti MS. The host construct validation. J Clin Psycho1 1977;33: response to the microbial challenge in periodon- 981-9. titis: assembling the players. Periodontol 2000 151. Carver CS, Scheier MF, Weintraub JK. Assessing 1997;1433-53. 32 Periodontal Medicine

167.Kaslick RS, West TL, Chasens AI. Association Natural distribution of five bacteria associated between AB0 blood groups, HL-A antigens with periodontal disease. J Clin Periodontol and periodontal diseases in young adults: a fol- 1993;20:699-706. low-up study. J Periodontol 198051:339-42. 184.Dzink JL, Tanner ACR, Haffajee AD, Socransky 168. Kaslick RS, West TL, Chasens AI, et al. Association SS. Gram-negative species associated with active between HL-A2 antigen and various periodon- destructive periodontal lesions. J Clin Periodon- tal diseases in young adults. J Dent Res 1975; to1 1985;12:648-59. 5 4 (2): 424. 185.Mandell U. A longitudinal microbiological inves- 169.Teraski PI, Kaslick RS, West TL, Chasens AI. Low tigation of Actinobacillus actinomycetemcomitans HL-A2 frequency and periodontitis. Tissue and Eikenelh corrodens in juvenile periodontitis. Antigens 1975;5:286-8. Infect Immun 1984;45:778-80. 17O.Klouda PT, Porter SR, Scully C, et al. Association 186.Listgarten MA, Levin S. Positive correlation between HLA-A9 and rapidly progressive peri- between the proportions of subgingival spiro- odontitis. Tissue Antigens 1986;28(3):146-9. chetes and motile bacteria and susceptibility of 171.Arner A, Sing G, Drake C, Dolby AE. Association human subjects to periodontal deterioration. J between HLA antigens and periodontal disease. Clin Periodontol 1981;8:122-38. Tissue Antigens 1988;31:53-8. 187.DahlCn G, Manji G, Baelum V, Fejerskov 0. Puta- 172. Ciancio SC, Hazen SE Cunat JJ. Periodontal obser- tive periodontopathogens in “diseased” and vations in twins. J Periodontal Res 1969;4:42-5. “non-diseased” persons exhibiting poor oral 173.Michalowicz BS, Aeppli Dc Kuba RK, et al. A hygiene. J Clin Periodontol 1992;19:35-42. twin study of genetic variation in proportional 188.Haffajee AD, Socransky SS, Dzink JL, et al. Clini- radiographic alveolar bone height. J Dent Res cal, microbiological, and immunological fea- 199 1;70:143 1-5. tures of subjects with refractory periodontal dis- 174.Michalowicz BS, Aeppli D, Virag JG, et al. Peri- eases. J Clin Periodontol 1988;15:390-8. odontal findings in adult twins. J Periodontol 189.Listgarten MA, Slots J, Nowotny AH, et al. Inci- 1991;62:293-9. dence of periodontitis recurrence in treated 175.Corey LA, Nance WE, Hofstede Schenkein HA. patients with and without cultivable Actinobacil- Self-reported periodontal disease in a Virginia lus actinomycetemcomitans, Prevotelh intermedia, twin population. J Periodontol 1993;64:1205-8. and Porpbyromonas gingivalis. A prospective 176. Kornman KS, Crane A, Wang H-Y, et al. The inter- study. J Periodontol 1991;62:377-86. leukin-1 genotype as a severity factor in adult 190.Haffajee AD, Socransky SS, Dzink JL, et al. Clini- periodontal disease. J Clin Periodontol 1997; cal, microbiological, and immunological fea- 24: 72-7. tures of subjects with destructive periodontal 177.Van Schie RC, Grossi SG, Dunford RG, et al. Fcy diseases. J Clin Periodontol 1988; 15240-6. receptor polymorphisms are associated with 191.Axelsson Lindhe J, Nystrom B. On the preven- periodontitis [abstract 1291. J Dent Res 1998; tion of caries and periodontal disease: results of 77(Special Issue B):648. a 15-year longitudinal study in adults. J Clin 178. Hassell T. Epilepsy and oral manifestations of Periodontol 1991;18:182-9. phenytoin therapy. Basel, Switzerland: S. Karg- 192.Smulow JB, Turesky SS, Hill RG. The effect of er; 1981. supragingival plaque removal on anaerobic bac- 179.Adams D, Davies G. Gingival hyperplasia induced teria in deep periodontal pockets. J Am Dent by cyclosporine-A. A report of two cases. Brit Assoc 1983;107:737-42. Dent J 1984;157(3):89-90. 193.Muller H-c Hartmann J, Flores-de-Jacoby L. Clin- 18O.Lucas RM, Howell Le Wall BA. Nifedipine- ical alterations in relation to the morphological induced gingival hyperplasia: a histochemical composition of the subgingival microflora fol- and ultrastructural study. J Periodontol 1985; lowing scaling and root planing. J Clin Perio- 56:211-5. dontol 1986;13:825-32. 181.Finne K, Goransson K, Winckler L. Oral lichen 194.Anerud A, Loe H, Boysen H. The natural history planus and contact allergy to mercury. Intl J and clinical course of calculus formation in Oral Surg 1982;11(4):236-9. man. J Clin Periodontol 199 1; 18:160-70. 182.Beck JD, Koch GG, Zambon JJ, et al. Evaluation 195.Claffey N, Nylund K, Kiger R, et al. Diagnostic of oral bacteria as risk indicators for periodonti- predictability of scores of plaque, bleeding, sup- tis in older adults. J Periodontol 1992;63:93-9. puration and probing depth for probing attach- 183.Wolff LF, Aeppli DM, Pihlstrom BL, Anderson L. ment loss. J Clin Periodontol 1990;17:108-14. Risk Factors for Periodontal Disease 33

196.Badersten A, Nilveus R, Egelberg J. Scores of cal risk indicators for periodontal attachment plaque, bleeding, suppuration, and probing loss. J Clin Periodontol 1991;18:117-25. depth to predict probing attachment loss. 5 20 1.Axelsson E Lindhe J. Effect of controlled oral hygiene years observation following nonsurgical therapy. procedures on caries and periodontal disease in J Clin Periodontol 1990;17: 102-7. adults. J Clin Periodontol 1978;5:133-5 1. 197.Lang NE Adler R, Joss A, Nyman S. Absence of 202.Haffajee AD, Dzink JL, Socransky SS. Effect of bleeding on probing is an indicator of periodon- modified Widman flap surgery and systemic tal stability. J Clin Periodontol 1990;17:714-21. tetracycline on subgingival microbiota of peri- 198.Lang NE Clinical markers of active periodontal odontal lesions. J Clin Periodontol 1988; 15: disease. In: Johnson NW, editor. Risk markers 255-62. for oral diseases, Vol. 3. Periodontal Disease, 203.Machtei EE, Dunford R, Hausmann E, et al. Lon- Cambridge: Cambridge University Press; 199 1. gitudinal study of prognostic factors in estab- p. 179-202. lished periodontitis patients. J Clin Perio- 199.Grbic JT, Lamster IB, Celenti RS, Fine JB. Risk dontol 1997;24:102-9. indicators for future clinical attachment loss in 204.Grossi SG, Zambon JJ, Machtei E, et al. Effects of adult periodontitis. Patient variables. J Perio- smoking and smoking cessation on healing after dontol 199 1;62:322-9. mechanical periodontal therapy. J Am Dent 200.Haffajee AD, Socransky SS, Lindhe J, et al. Clini- Assoc 1997;128:599-607. CHAPTER3

CLINICALHISTORY AND LABORATORYTESTS

Louis E Rose, DDS, MD Barbara J. Steinberg, DDS

PAT1ENT EVALUAT10 N Little and King, in 1971,lO presented the reasons for an evaluation of general health in the den- Medical emergencies can occur in any patient; tal office, and these are summarized as follows: however, they are most prevalent in geriatric or medically compromised patients. There is a rapid- 1. To identify patients with undetected systemic ly growing segment of the population whose phys- disease that could be a serious threat to the life ical or psychosocial problems may complicate den- of the patient or whose condition could be tal treatment. The elderly or medically compro- complicated by dental treatment mised patient who is frequently taking one or more 2. To identifi- patients who are taking drugs or medications such as steroids, anticoagulants, car- medications that could adversely interact with diac drugs, or immunosuppressive agents may drugs prescribed, that would complicate den- require special consideration before undergoing tal therapy, or that may serve as a clue to an dental treatment. As ever-increasing numbers of underlying systemic disease the patient has such individuals seek dental care, it becomes the failed to mention responsibility of the dentist to avoid adverse thera- 3. To provide information for the dentist to peutic interactions and to deal with medical emer- modifi- the treatment plan for the patient in gencies when they occur.‘p5 light of any systemic disease or potential drug Carehl study has shown that the compromised interactions patient is actually in the majority, with more than 4. To enable the dentist to select and communi- 50% of 4,365 patients recently surveyed giving a cate with a medical consultant concerning the history of more than one significant medical prob- patient’s possible systemic problems lem.‘ Sophisticated surgical manipulation and 5. To help establish a good patient-doctor rela- medical intervention have made possible the ambu- tionship by showing patients the clinician’s latory treatment of patients with cardiovascular, interest in them as individuals and concern for endocrine, and degenerative diseases-disorders that their overall well-being just a few years ago would have meant confinement or death. Medical advances, along with increasing Information obtained from a comprehensive public awareness of dental health, probably explain health evaluation may prevent a medical emer- the increased numbers of elderly and chronically ill gency. A well-conceived evaluation of the patient patients seeking dental treatment. includes the following: (1) recording a complete With an increasing likelihood of medical emer- medical history; (2) recording appropriate findings gencies in this population, the practising dentist on physical examination; (3) when indicated, and auxiliary staff are responsible for identifying ordering and interpreting necessary laboratory patients with a potential for medical risk by obtain- studies; and (4) initiating medical consultation or ing a comprehensive pretreatment physical evalua- referral as needed.5 ti01.1.~~~This evaluation is performed to determine In addition, to detect changes in general patients’ physical and emotional status and how health that may affect dental treatment, the med- well they will tolerate a specific dental pr~cedure.~ ical evaluation must be updated every time the 3 6 Periodontal Medicine patient is seen during maintenance therapy (eg, history, allergies, medications, and pertinent famil- every 3 to 6 months) and at appropriate intervals ial and social history as well as conduct a review of during protracted active therapy. body systems. The following information may be elicited under each area of the medical history.’J’J2

MEDICAL HISTORY Present Health Status

History-taking is a technique for eliciting subjec- The patient should be asked the date and results of tive information. These data are organized logical- the last complete physical examination. If the ly to portray the patient’s physical and emotional patient states, for example, that they have diabetes, status. Diagnosis of a specific medical disorder may it is important to determine the date of the initial require consultation. Medical history puts physical diagnosis, the degree of success in controlling the examination into perspective by supplying infor- disease, and the therapeutic regimen as well as the mation that should alert the examiner to suspected date, type, and results of the last blood glucose abnormalitie~.~Even in a life-threatening situation, study. If the patient has not had a recent physical once the immediate threat has been contained, a examination, it may be advisable to make a recom- history should be obtained from the patient, if pos- mendation for an examination, especially if the sible, or from a relative or friend if the patient is patient is in a high-risk group. The patient’s per- unable to respond. ception of their present health status may be an Two basic methods for obtaining a medical his- important indication of their psychological make- tory are the questionnaire and the personal inter- up and potential compliance with treatment. view. At first, it might seem that a great deal of time and trouble could be saved if we were to have each Past Medical History patient complete a printed questionnaire and then have the answers coded. There are, however, several The date, diagnosis, and treatment rendered at sig- problems with this approach. For instance, a “no” nificant hospitalizations for illnesses during child- answer may mean the patient never had the symp- hood and adult life will help evaluate the patient’s toms or the disease or that the question is not past medical history and clearly indicate whether understood or is thought to be irrelevant since the their average state of health has been one of normal patient only wants to have a tooth restored or vigor or chronic illness. extracted. On the other hand, a personal history elicited through dialogue allows for observation of Allergies patients and their reactions to questions. This often provides more important information than the The patient should be asked about allergies or reac- answer itself. The personal dialogue allows the prac- tions to any foods, medications, or environmental titioner to evaluate the patient’s mental status in a factors. Specifically, aspirin, local anesthetics, antibi- nonthreatening atmosphere. The patient who is otics, and any other potential allergens that may be afraid or uninterested will respond quite differently used in dental therapy should be mentioned. from the one who is self-confident and truly concerned about oral health. Medications A questionnaire can be used in conjunction with the dialogue to obtain a more complete med- In questioning about medications, it is imperative ical history. The questionnaire may help a patient to determine the brand and/or generic name of recall frequently used medications and various the drug, why and by whom it was prescribed, the symptoms that indicate disease. It can also assist the dosage, and the length of time the medication has dentist in determining which areas to emphasize been taken. Patients may not include medications and hrther explore when conducting the dialogue. used for allaying anxiety or for inducing sleep, The questionnaire completed by the patient in pri- such as tranquilizers and sedative-hypnotic drugs. vacy can also alleviate embarrassment in answering An effective way of obtaining this information is questions concerning habits, addictions, or sexually to ask patients if they ever have to take anything transmitted diseases, all of which are important to help them rest, relax, or sleep. Also, some components of a complete medical history. women will not include oral contraceptives or A comprehensive medical history helps the supplemental hormones, either of which may dentist evaluate present health status, past medical affect oral tissues. Clinical History and Laboratory Tests 37

Review of Systems seizure disorders, mental disorders, and other diseases that may be familial. The review of body systems (see Table 3-1) is the main component of the interview approach to his- Social History tory-taking. It provides additional data about each system and reveals symptoms not already elicited Social history may assist in determining the patient’s that may indicate a previously treated or undiag- response to the demands and conflicts of modern nosed disorder. The review of systems helps to society. In addition, it may help explain untoward refresh the patient’s memory, thus preventing any reactions to health problems and to the therapeutic inadvertent oversight. recommendations. For example, the alcoholic patient may be unwilling to follow recommenda- Family History tions about diet and oral hygiene. Also, the alcoholic patient is an anesthetic risk and may develop pro- Family history is taken to determine if there is a longed and profound hypotensive episodes sec- familial predisposition to diseases or if there are ondary to certain anxiety and pain-control drugs. diseases in which inheritance is an important fac- Social history should include the patient’s occupa- tor. For example, a patient with a strong family his- tion and any associated health hazards, marital sta- tory of diabetes mellitus, with no apparent signs or tus, diet, and use of alcohol, tobacco, or other drugs. symptoms of the disease, should be evaluated peri- Possible exposure to various infectious diseases, such odically since clinical manifestations may appear as hepatitis B, herpes, or acquired immunodeficien- later in life. Also, those with a history of diabetes cy syndrome (AIDS), should be determined. Social may have a greater risk for developing infections history is therefore important in assessing whether a such as periodontal disease. The dentist should patient is in a high-risk group, for example, those inquire specifically about a family history of dia- with alcoholism, drug addiction, or contagious betes, cancer, heart disease, high blood pressure, infections such as herpes, hepatitis, tuberculosis, or

TABLE 3-1. Review of Systems Skin Itching, rash, ulcers, excessive dryness, pigmentary change, changes in hair or nails, hair loss Eyes Vision, inflammation, diplopia, blurring Ears, nose, throat Hearing, earache, epistasis, sore throat, hoarseness, sinus pain Respiratory Cough, sputum (describe quantity, color, odor, blood), wheezing, infections, exposure to system tuberculosis, prior chest radiographic examination Heart Chest pain, palpitation, dyspnea, orthopnea, swelling of ankles, history of rheumatic fever, rheumatic heart disease, “heart attack,” high blood pressure, murmur Gastrointestinal Appetite, nausea, vomiting, dysphagia, heartburn, indigestion, food intolerance, abdominal system pain, jaundice, hepatitis Genitourinary Dysuria, nocturia, polyuria, hematuria, frequency, difficulty starting stream, sexually transmitted system diseases, kidney infection For women: Menstrual history: last menstrual period and previous menstrual periods, dysmenorrhea Menopause: age of occurrence, hot flashes Obstetric history: pregnancies, miscarriages, living children Extremities Vascular: varicose veins, phlebitis Joints: pain, stiffness, swelling of joints Muscles: weariness, pain, tenderness, cramps Nervous system Syncope, convulsions, headache, lightheadedness, vertigo, tremor, paralysis, paresthesias, anesthesia Psychiatric “Nervousness,” irritability, depression, history of previous “nervous breakdown,” family history of mental illness Blood Bleeding tendency, excessive bruising, anemia, known exposure to radiation or toxic agents 3 8 Periodontal Medicine

AIDS. Direct confirmation of these conditions Hemoglobin often requires testing and consultation. Hemoglobin is the oxygen carrier of the blood. It is decreased in hemorrhage and anemias and Medical Summary and increased in hemoconcentration and polycythemia. Recommendations The normal range is 14 to 18 g/dL of blood in men and 12 to 16 g/dL of blood in women. Positive findings should be summarized and recommendations recorded. This will enable the dentist Hematocrit and the dental staff to quickly review a patient‘s med- Hematocrit reflects the relative volume of cells and ical status at each visit and hcilitate the diagnosis and plasma in the blood. In anemias and after blood treatment of any medical emergency that may arise. loss, it is lowered and is elevated in polycythemia Initially, the medical history form described and dehydration. The normal Hct range is 40 to here represents one of the most accurate methods 54% for men and 37 to 47% for women, or rough- for determining the physical and emotional status of ly three times the HgB value. the patient, the patient’s tolerance for specific procedures, and the presence of any medical risk factors. RBC count In essence, this form aids in the decision to proceed The RBCs contain HgB. An increase in RBCs may with dental treatment with relative safety or to seek indicate hemoconcentration or polycythemia. A medical consultation before beginning therapy. l3>l4 decrease in the number of RBCs may be indicative In conclusion, a comprehensive medical histo- of blood loss or one of the anemias. ry is an important procedure that dentists must adopt and routinely use to ensure that their WBC count patients are receiving the optimum benefit from all White blood cells are important in the bodily available health resources. A form for recording the defense against invading microorganisms. An medical history has been suggested by the Ameri- increase in the WBC count is seen in leukemias, can Dental Association. (Figure 3-1) bacterial infections, infectious mononucleosis, and certain parasitic infections as well as after exercise and emotional stress. A decrease in the WBC INTERPRETATION OF CLINICAL count is seen in aplastic anemia, lupus erythe- LABORATORY STUDIES matosus, acute viral infections, and drug and chemical toxicity. A normal WBC count is 5000 to On occasion, the patient’s medical history and phys- 10,00o/mm3. ical examination warrant laboratory tests to confirm There are several kinds of WBCs that can be a diagnosis or to uncover incidental findings sepa- identified microscopically; such identification is rate from the chief ~omplaint.’~-’~Depending on called the differential. It is important to know the dentist’s background and experience in inter- whether the proportions of these cells have preting such tests, the patient will be referred direct- changed since they may be indicative of a particu- ly to either a clinical laboratory or a physician for lar type of ailment. appropriate examination, tests, and opinion. With the first alternative, the dentist assumes responsibil- 1. Neutrophils (50 to 70%) are increased in most ity for the interpretation and then refers the patient bacterial infections. An increase in the number to a physician for confirmation and treatment, if of immature neutrophils is frequently found in indicated. With the second alternative, the physi- acute infections. This is the so-called “shift to cian assumes all responsibility for preparing the the left.” patient and evaluating the findings. Table 3-2 lists 2. Eosinophils (I to 4%) are increased in allergic some commonly used clinical laboratory tests. conditions and parasitic infections. 3. Basophils (0 to 1%) may be increased in some Complete Blood Count blood dyscrasias. 4. Lymphocytes (25 to 40%) are noted to be The complete blood count (CBC) will routinely increased in measles and in several bacterial or include hemoglobin (HgB), hematocrit (Hct), red chronic infections. blood cell (RBC) count, and white blood cell 5. Monocytes (4 to 8%) may be increased during (WBC) count, with a differential WBC count and recovery from severe infections and Hodgkin’s a statement on the adequacy of platelets. d’isease. Clinical History and Laboratory Tests 39

Medical History Form Date

Name LIR HomePhone ( 1 Fist Middle

Business Phone ( ) Address Numbcr.SMel

City State Zip Code

Occupation Social Security No.

DateofBirth mo ' Sex M F Height Weight Single - Married - day Yf Name of Spouse Closest Relative Phone ( )

If you are completingthis form for another person, what is your relationship to that person?

Referred by

For the following questions, circle yesorno, whichever applies. Your answers are for our records only and will be considered confidential. Please note that during your initial visit you will be asked some questionsabout your responsesto this questionnaire and there may be additional questions concerning your health. 1. Are you in good health? ...... Yes No 2. Has there been any change in your general health within the past year?...... Yes No 3. My last physical examination was on 4. Are you now under the care of a physician? ...... Yes No If so,what is the conditionbeing treated? 5. The name and address of my physictan(s) is

6. l-faveyou had any serious illness, operation, or been hospitalized in the past 5 years? ...... Yes No If so, what was the illness or problem? 7. Are you taking any medicine(s) including non-prescription medicine?...... Yes No If so,what medicine(s) are you taking? 8. Do you have or have you had any of the following diseases or problems? a. Damaged heart valves or artificial heart valves, including heart murmur or rheumatic heart disease ...... Yes No b. Cardiovascular disease (heart trouble, heart attack, angina, coronary insufficiency, coronary occlusion, high blood pressure, arteriosclerosis,stroke) ...... Yes No 1. Do you have chest pain upon exertion? ...... Yes No 2. Are you ever short of breath after mild exercise or when lying down?...... Yes No 3. Do your ankles swell? ...... Yes No 4. Do you have inborn heart defects? ...... Yes No 5. Do you have a cardiac pacemaker? ...... Yes No c.Allergy...... Yes No d. Sinus trouble ...... Yes No e. Asthma or hay fever ...... Yes No f. Faintingspells or seizures ...... Yes No g. Persistent diarrhea or recent weight loss ...... Yes No h. Diabetes ...... Yes No i. Hepatitis. jaundice or liver disease ...... Yes No j. AIDS or HIV infection ...... Yes No k. Thyroid problems ...... Yes No 1. Respiratory problems, emphysema, bronchitis. etc...... Yes No m. Arthritis or painful swollen joints ...... Yes No n. Stomach ulcer or hyperacidity ...... Yes No 0. Kidney trouble ...... Yes No p. Tuberculosis ...... Yes- No q. Persistent cough or cough that produces blood ...... Yes No r. Persistent swollen glands in neck ...... Yes No s. Low blood pressure ...... Yes No t. Sexually transmitted disease ...... Yes No U. Epilepsy or other neurologicaldisease ...... Yes No v. Problems with mental health ...... Yes No w.Cancer ...... Yes No x. Problems of the immune system ...... Yes No

(over)

Figure 3-1. Medical history form, side 1. 40 Periodontal Medicine

9. Have you had abnormal bleeding?...... Yes No a. Have you ever required a blood transfusion? ...... Yes No 10. Do you have any blood disorder such as anemia? ...... Yes No 11. Have you ever had any treatment for a tumor or growth? ...... Yes No 12. Are you allergic or have you had a reactionto: a. Local anesthetics ...... Yes No b. Penicillin or other antibiotics ...... Yes No c. Sulfadrugs...... Yes No d. Barbiturates, sedatives, or sleeping pills ...... Yes No e.Aspirin ...... Yes No f.lodine ...... Yes No g. Codeine or other narcotics ...... Yes No h. Other 13. Have you had any serious trouble associated with any previous dental treatment? ...... Yes No If so, explain

14. Do you have any disease, condition, or problem not listed above that you think I should know about? ...... Yes No

15. Are you wearing contact lenses? ...... Yes No 16. Are you wearing removable dental appliances? ...... Yes No

Women 17. Are you pregnant? ...... Yes No 18. Do you have any problems associatedwith your menstrual period? ...... Yes No 19. Are you nursing? ...... Yes NO 20. Are you taking birth control pills? ...... Yes No

Chief Dental Complaint

I certify that Ihave read and understandthe above. Iacknowledge that my questions, if any, about the inquiries set forth above have been answered to my satisfaction. I will not hold mydentist, or any other memberof hisiherstaff. responsible for any errors or omissions that Imay have made in-ttte completion of this form.

Signature of Patient

For completion by the dentist. Comments on patient interview concerning medical history:

Significant findings from questionnaire or oral interview:

Dental management considerations:

(Date) Signature of Dentist

Medical history update: Date Comments Signature

S500 8 American Dental Association 1988

Figure 3-1. Medical history form, side 2. Clinical History and Laboratory Tests 41

Blood Glucose TABLE 3-2. Normal Values Blood glucose tests are performed to evaluate glu- Test Normal vdlues" cose metabolism. Basic tests for disorders of blood glucose are the fasting blood sugar test, the glucose Blood chemistry tolerance test, and the random blood sugar test. The Albumin 3.8-5.0 g/dL Bilirubin normal range for blood glucose is to mg/dL 70 100 direct c0.3 mg/dL of serum. indirect 0.1-1 .O mg/dL total 0.1-1.2 mg/dL Blood Urea Nitrogen Calcium 9.2-1 1.O mg/dL 4.6-5.5 mEq/L Blood urea nitrogen (BUN) is used as a screening Creatinine 0.6-1.2 mg/dL test for kidney hnction; however, it is not entirely Glucose 70-1 10 IU/L specific. An increased value may be seen in exten- Lactate dehydrogenase 25-100 IU/L sive kidney disease, congestive heart failure, and Phosphatase, alkaline dehydration. Protein intake may also directly affect child 20-150 IU/L at 30°C BUN values. If renal disease is suspected, a more adult 20-90 IU/L at 30°C reliable assessment is the serum creatinine test. The Transferases ratio of BUN to creatinine is 1O:l. The normal aspartate amino 16-60 U/mL at 30°C (SGOT) range for BUN is 8 to mg/dL of blood. 23 alanine amino (SGPT) 8-50 U/mL at 30°C Urea nitrogen 8-23 mg/dL Se rology Hematology Leukocyte count (WBC) 5 000- 10 , 000/mm3 There are a variety of serologic tests for the screen- 5-10 x 103/~~ ing of syphilis. All are nonspecific tests and may neutrophils give both false-positive and false-negative results. - segmented 50-70% Interpretation of these serologic tests requires cor- - band 0-5% relation with the patient's history and clinical find- lymphocytes 2540% ings. Normally, results of these tests are negative; if monocytes 4-8% results are positive, confirmation with the fluores- eosinophils 1-4% cent treponemal antibody-absorption test (FTA- basophils 0-1% abs) or the microhemagglutination treponemal Erythrocyte count (RBC) male 4.5-6.2 million/mm3 pallidum test (M€-€A-tp) is indicated. 4.6-6.2 x 106/pL female 4.2-5.4 million/mm3 Screening Tests for 4.2-5.4 x 106/pL Hemorrhagic Disorders Hemoglobin male 13.5-18.0 g/dL Bleeding Time female 12.0-16.0 g/dL Bleeding time is the time required for hemostasis Hematocrit to occur in a standard wound of the capillary bed. male 40-54% Bleeding time varies with vascular and platelet female 3747% abnormalities. The normal range is I to 7 minutes. RBC indices mean corpuscular 27-31 pg Platelet Count hemoglobin Platelets are decreased in thrombocytopenic pur- mean corpuscular 80-96 pm3 volume pura. In myeloproliferative disease, platelets are mean corpuscular 32-36% increased. The normal platelet count is 150,000 to hemoglobin 400,000/mm3. concentration Platelet count 15 0, 0 0 0-40 0, 0 0 O/mm3 Prothrombin 150-400 x 103/pL The prothrombin (PT) test is an indirect test of Bleeding time (Ivy) 1-7 min the clotting ability of the blood. This test gives an Partial thromboplastin time s 45 sec (variable) indication of prothrombin deficiency arising from Prothrombin time 12-14 sec liver disease, fibrinogen deficiency, and lack of or *There may be interlaboratoryvariations. 42 Periodontal Medicine inability of the body to use vitamin K. The normal agement. It must be emphasized that the purpose range is 12 to 14 seconds, depending on the type of the INR is to monitor patients taking oral anti- of thromboplastin used. In treatment with coagulants; it is not intended to be used for initial Coumadin, the physician will attempt to keep the evaluation of the hemostatic system or thrombot- prothrombin time at 2 to 2 1/2 times the normal ic conditions. Anticoagulation to a target INR of value (see “Test to Monitor Oral Anticoagulants”). 3.0 should be made before patients with cardiac valve prosthesis undergo dental procedures involv- Partial Thromboplastin Time ing the risk of bleeding. The partial thromboplastin time (PTT) test is designed to help the clinician recognize mild to moderate deficiencies of the intrinsic clotting fac- MEDICAL RISK ASSESSMENT tors. This test is necessary because PT entirely bypasses the intrinsic clotting system. Another use Having completed all the components of the phys- for PTT is to demonstrate a circulating anticoagu- ical evaluation and a thorough oral examination, lant in plasma. The normal PTT is 45 seconds or the dentist must gather all the information and less; however, because there are wide variations in determine if the patient is capable, physiologically technique, the normal range for PTT varies some- and psychologically, of tolerating in relative safety what between laboratories. the stresses involved in the proposed dental treatment. Is there a greater risk (of morbidity or mor- Test to Monitor Oral Anticoagulants tality) than normal during the dental therapy? If the patient decides to go ahead with the treatment The international normalized ratio (INR) is the in spite of the risk of being medically compro- ratio of a patient’s PT to the mean PT value deter- mised, then appropriate modifications in the mined by using a given thromboplastin, and this planned dental treatment must be considered to ratio is raised to the power of the international minimize the risk.18 sensitivity index (ISI) that is provided by the To categorize dental patients from the stand- reagent manufacturer. By using the INR, the point of medical status, each patient should be degree of anticoagulation achieved by warfarin assigned an appropriate medical risk category rec- therapy may be compared, regardless of the ommended by the American Society of Anesthesi- thromboplastin used. Use of the INR allows PT ologists. This is commonly referred to as the ASA results to be compared among clinical laboratories physical status classification system and is summa- around the world, resulting in better patient man- rized in Table 3-3.

TABLE 3-3. Medical Risk Categories* ASA Classification Dental Consideration Physical status 1 A patient without systemic disease; Routine dental therapy without modification a normal healthy patient Physical status 2 A patient with mild systemic disease Routine dental therapy with possible treatment limitations or special considerations (eg, duration of therapy, stress of therapy, prophylactic consideration, possible sedation, and medical consultation) Physical status 3 A patient with severe systemic disease Dental therapy with possible strict limitations that limits activity but is not incapacitating or special considerations Physical status 4 A patient with incapacitating systemic Emergency dental therapy only with severe limitations or disease that is a constant threat to life special considerations

*Adopted in 1962 by the American Society of Anesthesiologists (ASA) Clinical History and Laboratory Tests 43

DENTAL HISTORY 6. Colton JA, Kafrawy, AH. Medications and health histories; a survey of 4,365 dental patients. J Am Significant items of the past dental history that Dent Assoc 1979;98:713. should be recorded at this visit include previous 7. Hendler BH, Rose LE Common medical emergen- restorative, periodontic, endodontic, or oral surgi- cies; a dilemma in dental education. J Am Dent cal treatment; reasons for loss of teeth; untoward Assoc 1975;91 : 575. complications of dental treatment; attitudes 8. Malamed SE Handbook of medical emergencies in toward previous dental treatment; experience with the dental office. St. Louis, MO: The CV orthodontic appliances and dental prostheses; and Mosby Publishing Co.; 1982. radiation or other treatment for oral or facial 9. McCarthy FM. Emergencies in dental practice. lesions. l9 General features of past treatment, rather 2nd ed. Philadelphia: W.B. Saunders Company; than specific, detailed, tooth-by-tooth descriptions 1972. are needed at this time. In the case of radiation or 10. Little JW, King OR. The significance of physical other treatment for oral or facial lesions, exact diagnosis, patient history, data and medical information regarding the date and nature of the screening in the dental office. Am Dent diagnosis, the type and anatomic location of treat- 1972;3:31. ment, and the name, address, and telephone num- 11. Bates G. A guide to physical examination. Philadel- ber of the physicians and/or dentists involved as phia: J.B. Lippincott Co.; 1974. well as the facility (hospital, clinic) where the treat- 12. Halsted CL, et al. Physical evaluation of the dental ment was given, must be recorded. Likewise, clear patient. St. Louis, MO: The CV Mosby Pub- details of any previous untoward complications of lishing Co.; 1982. dental treatment must be recorded. 13. Brasher WJ, Rees TD. The medical consultation: its role in dentistry. J Am Dent Assoc 1977;95:961. 14. Redding SW, Rose LE The consultation: a means REFERENCES of communication between dentists and physicians. Gen Dent 1979;Sept/Oct p.54. 1. Genco R, Goldman H, Cohen DW. Contempo- 15. Rose LE Hospital dental practice. Dent Clin North rary periodontics. St Louis, MO: The CV Am 1975;19(4). Mosby Publishing Co.; 1990. 16. Sonis ST, Sandinski JJ. Physical and laboratory 2. Rose LE Diagnosis and management of medical diagnosis. Dent Clin North Am 1974;18 (1). emergencies in the dental office. Univ PA 17. Zambito RF. Hospital dental practice: a manual. School Dent Med 1977;3. New York: Medical Examination Publishing; 3. Rose LE Medical history as a dental procedure. 1978. Dent Dimens 1977; Jan-March; 13. 18. Little JW, et al. Dental management of the med- 4. Rose LF, Hendler BH. Medical emergencies in ically compromised patient. 5th ed. St. Louis, dental practice. Chicago: Quintessence Publish- MO: The CV Mosby Publishing Co.; 1997. ing Co.; 1981. 19. Kerr DA, Ash MM, Millard DH. Oral diagnosis. 5. Rose LF, Steinberg BJ, Hendler BH. Physical eval- 6th ed. St. Louis, MO: The CV Mosby Publish- uation. Alpha Omegan 1984;77(4):17. ing Co.; 1983. CHAPTER4

ROLEOF GENETICS IN ASSESSMENT,RISK, AND MANAGEMENTOF ADULT PERIODONTITIS

Kenneth S. Kornman, DDS, PhD Michael G. Newman, DDS

PERIODONTAL DISEASE variation in clinical severity of disease may be explained by factors other than the bacterial chal- Periodontitis, a chronic multifactorial disease in lenge. It should be emphasized that this statement adults, is caused mainly by gram-negative microor- in no way means that bacterial plaque is unimpor- ganisms, such as Porpbyromonus gingivulis, Prevotel- tant-in fact, it is quite the contrary. Bacterial h intermediu, and Actinobucillus uctinomycetemco- plaque is absolutely essential for the initiation and mituns. The most common form of periodontitis is progression of periodontitis. However, it now adult periodontitis, which has been reported to appears that once the bacteria are present, the affect more than 30% of the population, with amount of periodontitis that a patient develops is severe disease reported in 7 to 13%.l Adult peri- due to factors related to the body's response to the odontitis is characterized by an interaction bacterial challenge. One reason for the differences between the host immunoinflammatory response in how patients respond to plaque, manifest dis- and gram-negative bacteria. With periodontal disease, and respond to treatment is that there are dif- ease, plaque microorganisms adjacent to the gingi- ferent types of plaque. Some types of plaque are va stimulate host cells, resulting in the production more virulent than 0the1-s.~~~Although a few labo- of molecules that play an important role in activat- ratories have offered microbial analysis of subgin- ing and regulating the immunoinflammatory gival plaque samples for many years, the value of response. Microbial substances such as lipopolysac- plaque sampling in nonresponding patients is of charide (LPS) activate host cells (ie, fibroblasts, growing interest as some research groups have macrophages, and polymorphonuclear leukocytes started to clariti- how the resulting information can [PMNs]) to secrete proinflammatory cytokines be integrated into clinical practice. such as interleukin-1 beta (IL-Ip) and tumor The presence of bacteria is necessary for peri- necrosis factor alpha (TNF-a).2 odontal disease to occur; however, this presence Clinical evidence has demonstrated that not alone does not predict the presence or severity of all individuals have the same response to similar periodontitis. The differences in disease severity amounts of plaque accumulation. There are observed among individuals cannot be explained patients with moderate and advanced disease who solely by the presence of different quantities or have very little plaque while other patients with lit- types of bacteria.' For the presence, absence, or tle disease have large amounts of plaque. Most level of specific microbes believed to be periodon- importantly, large studies that have assessed the tal pathogens, the correlation coefficients are in the relationship of plaque quantity, as well as the pres- range of 0.3 to 0.4 in current multivariate models ence of specific bacteria, to the severity of peri- of periodontitis that incorporate microbial factors. odontitis indicate that a substantial part of the These findings indicate that less than 20% of the 46 Periodontal Medicine variability in periodontal disease expression can be genes) because of a deficiency or excess of chromo- explained by the levels of specific microbes. It has somal material. Chromosomal abnormalities occur been shown that specific elements of host suscepti- in approximately I per 160 live births.15 The bility, such as an individual’s systemic disease state majority of these abnormalities are sporadic, and immune response, are important factors in dis- involving an extra chromosome due to nondis- ease expre~sion.~.~ junction of meiosis during egg or sperm formation. A minority of abnormalities result from chro- Genetics and Clinical Presentation mosomal rearrangements (ie, translocation) ,which of Periodontal Disease may be inherited or sporadic. Down syndrome (trisomy 21), which is caused by the presence of an It has long been observed that unusual forms of extra chromosome 21, is a classic example of a periodontitis, such as disease affecting young indi- chromosome abnormality. l5 viduals (early onset periodontitis), “run in families.” The evidence for a genetic influence on early- Mendelian Disorders onset periodontitis has been well reviewed in Mendelian disorders are caused by a mutation in a recent year~.~>~J’Since it was believed that adult single gene and, therefore, are also referred to as periodontitis was totally determined by bacterial single-gene (or major gene effect) disorders. The plaque, less effort was devoted to exploring a inheritance patterns of Mendelian disorders may genetic influence. In addition, the genetic influ- be described in terms of the classic patterns of how ence in an adult-onset chronic disease is difficult to certain traits, such as autosomal dominant or study since so many factors change during the autosomal recessive disorders, are transmitted course of the disease and it is more difficult to through successive generations. An autosomal study families with adult-onset disorders than dominant disorder is caused by a mutation of a those with diseases affecting children. gene located on one of the autosomes (chromo- Early studies reported significant differences in somes I to 22). Individuals usually have two alle- gingivitis among different ethnic group^.^ Howev- les (copies) of each autosomal gene. With autoso- er, the finding of familial aggregation or ethnic dif- mal dominant disorders, individuals may have one ferences in a disease does not prove a genetic com- “normal” copy of a gene and one “abnormal” copy ponent because a common familial environment or of the same gene. In dominant disorders, if one of the variable environments of different ethnic the two copies of the gene is abnormal that is suf- groups may bring about these findings.” However, ficient to cause disease. There is a 50% chance in recent years, new studies demonstrated substan- that each offspring of an affected individual will tial genetic influences on adult periodontitis. In receive the dominant gene from an affected par- particular, studies in twins indicate that a signifi- ent. Offspring who receive a normal copy of the cant part of the variance in clinical and radio- gene (and also have a normal copy from the other graphic measures of adult periodontitis may be parent) will not develop the disease or pass it on to explained by genetic factors. 12-14 The combination their offspring. l5 of two observations-( 1) the recognition that There are several general features of autosomal much of the clinical expression of periodontitis dominant disorders that may disguise the inheri- was not explainable solely by the bacterial parame- tance pattern, such as delayed age of onset, ters, and (2) studies in twins-led to renewed pleiotropism, and variable expression (Table interest in finding specific genetic factors that 4-1).15 Genetic disorders are not necessarily clini- influence the severity and therapeutic responses of cally evident at birth, and delayed age of onset is the most common form of periodontitis. found in the majority of common adult diseases. Pleiotropism refers to the multiple effects of a sin- Types of Genetic Disorders gle gene. Several common disease associations may be explained by pleiotropism, such as the increased Genetic diseases can be divided into three major incidence of both insulin-dependent diabetes mel- categories: chromosomal disorders, Mendelian dis- litus (IDDM) and autoimmune thyroid disease in orders, and non-Mendelian disorders. the same patient and family, suggesting a common immunogenetic basis for both disorders. Variable Congenital Chromosomal Disorders expression refers to the differences in the severity Congenital chromosomal disorders are caused by and/or extent of disease manifestation among an abnormal dose of normal genes (not abnormal affected individuals. l5 Role of Genetics in Assessment, Risk, and Management 47

With autosomal recessive disorders, two alleles Table 4-1. Autosomal Dominant Disorders of an abnormal gene are necessary for disease expression. Mected individuals are homozygous Common Autosomal Dominant Disorders for the disease gene (homozygotes). Individuals Familial hypercholesterolemia that have a single dose of the normal gene and a Familial combined hyperlipidemia single dose of the abnormal gene (heterozygotes) Features that may disguise this inheritance pattern are considered carriers. Although autosomal reces- Delayed age of onset sive disorders can occur at any time during an indi- Adult polycystic kidney disease: cysts are not vidual’s life, they more frequently occur during evident until the second or third decade of life infancy or childhood. l5 Pleiotropism A mutation at a single gene locus can produce Marfan syndrome: a single abnormal gene can a gene product that predisposes an individual to a produce changes in the great vessels, eyes, heart, disease. A single dose of a mutant allele (heterozy- and skeleton: probably through an alteration in a gote) is often associated with disease susceptibility structural protein common to these tissues whereas a double dose of a mutant allele (homozy- vdriable Expression gote) is associated with direct development of a Mitral valve prolapse: in a single family, affected more severe form of the disease.15 members may have significant rhythm distur- Some single-gene disorders occur with bances or mitral insufficiency whereas other fami- enough frequency to make a significant contribu- ly members have only an audible click on physical tion to a common disease or a subgroup of a com- examination with no other symptoms mon disease. For example, the heterozygous state for familial hypercholesterolemia occurs with a frequency of approximately I per 500 in the population. Gene carriers have a high probability of COMMON DISEASES GENERALLY developing atherosclerosis. In addition, this gene INVOLVE BOTH GENETIC AND is found in the heterozygous state in 5 to 10% of ENVlRON M ENTAL FACTORS men age 60 years or younger who experience myocardial infarcts. l5 From a population genetics point of view, a common disease is defined as an arbitrary frequency of Non-Mendelian Disorders approximately I affected individual per 1,000 in Most common adult-onset diseases have a genetic the p0pu1ation.l~King and associates defined the component that cannot be explained by either a genetic basis of a common disease as “the presence chromosomal abnormality or a major gene effect. of a genetically susceptible individual, an individ- In particular, the genetic influence of non- ual who may or may not develop the disease, Mendelian disorders does not fit the typical inher- depending on the interaction of factors such as itance patterns within families. For example, in other genes, diet, activity, environmental expo- cardiovascular disease, there is an unusual major sures, or even some degree of random biologic vari- gene disorder called hypercholesterolemia. Indi- ation such as occurs in the immune system and viduals with this Mendelian disorder will have may be operative during de~eloprnent.’~’~ severe cardiovascular disease at a very early age. There is no absolute distinction between com- Most cardiovascular diseases, however, do not mon and single-gene diseases because a single-gene involve hypercholesterolemia but seem to be mutation may not cause disease until the carrier of familial and to have genetic influences. These the gene is exposed to a specific environmental non-Mendelian disorders are undoubtedly multi- agent. For example, an individual with the P-glob- factorial; they are caused by a combination of ulin gene polymorphism that leads to sickle cell genetic and environmental factors. The genetics of anemia will have different clinical disease experi- these disorders is complicated by several factors: ences at sea level and at high altitudes, where the (1) a similar clinical condition may be the result of oxygen is more limited. The actions of several different disorders and different genetics (genetic genes are involved in most common diseases, and heterogeneity); (2) the clinical condition may be sometimes a few genes can be identified as playing polygenic-many additive genes, each of which a major role in susceptibility. Individuals with dif- produces a small effect; and (3) the clinical condi- ferent genetic backgrounds have different suscepti- tion may not be evident unless two different bilities; therefore, the etiologies of common dis- genetic factors are present (multilocus). eases are usually genetically heterogeneous, that is, 4 8 Periodontal Medicine different genetic mechanisms lead to the same clin- isoelectric focusing, or other methods of separa- ical endpoint. In addition, not everyone who is tion. There are frequently subtle differences in genetically susceptible will develop the disease. enzyme activities between products of different These points suggest that some individuals may alleles of the polymorphic genetic factor. These dif- have increased susceptibility whereas others will ferences may result in subtle differences in genetic have reduced susceptibility. susceptibility to a disease. The majority of common diseases fall between Studies have shown that stable immune phe- having a purely genetic cause and a purely envi- notypic characteristics, including cytokine produc- ronmental cause; they are the result of an interaction, antibody titer, and monocyte hnction, may tion between genetic and environmental factors. In result from specific genetic polymorphisms. For addition, some mechanisms of genetic susceptibil- example, studies have focused on the role of genet- ity involve the actions of genes that control envi- ics in an individual’s susceptibility to disease by ronmental response, such as the histocompatibility showing that individuals with an unusual genetic (human leukocyte antigen [HLA]) complex on variant in the chemokine receptor CCR5 demon- chromosome 6. The involved HLA genetic pattern strate a striking resistance to human immunodefi- identifies individuals who will have a specific ciency virus (HIV) infe~tion.~ immunologic response when exposed to various environmental agents. Influence of Genetic Susceptibility on The clinical manifestation of the gene(s) that an Different Characteristics of a Disease individual possesses is called “the phenotype.” Com- plex phenotypes, such as cardiovascular disease, The underlying genetic characteristics of a patient’s cluster in certain families but they do not exhibit immune system (a patient’s “resistance”) deter- simple Mendelian inheritance patterns and may mine, in part, how a patient will react to bacterial have many genetic and environmental causes. By challenges. Individuals are not equally susceptible this definition, most chronic, common disorders are to many common diseases, mainly due to differ- considered to be complex. The complexity origi- ences in their genetic constitutions. Genetic varia- nates from the fact that multiple genetic and envi- tion is important for classifying diseases, diagnos- ronmental factors may interact with each other in ing and managing patients with common disor- unpredictable ways; the association between the ders, defining the etiology of common diseases, phenotype and any single factor by itself may not be and evaluating family members of patients. The perceptible. With nonlinear interactions (including genetic basis of common diseases, including coro- genotype by environment interactions), clinical nary artery disease, obstructive lung disease, and expression may not be accurately predicted from periodontitis, has several similar factors. These fac- understanding the individual effects of each of the tors include clinical appearance in midlife, a fami- component factors considered alone, no matter how ly component, and onset of the underlying patho- well the separate components are understood. l6 genesis, which may begin as early as ad01escence.l~ Almost all common disorders have a familial com- Common Genetic Variations ponent, which suggests that the distribution of (Po Iy m o rp h i sm s) these diseases is not random, and certain individuals are at high risk.15 Gene polymorphisms are a mechanism by which There are different types of genetic suscepti- individuals may have variations within the biolog- bility-susceptibility to a disease, differences in ically normal range. In a population, a genetic the natural history of a disease, and different ther- polymorphism is present when variant forms of a apeutic responses. Susceptibility to the disease gene at a given locus exist with a frequency of more itself is the most direct type and may be consid- than I to 2%. One of the more well-studied exam- ered the most important type because it puts an ples of gene polymorphisms relates to enzymes individual and some family members at increased involved in normal metabolism. Estimates indicate risk of developing the disease. The advantages of that approximately 30% of all enzyme gene loci are assessing this type of susceptibility include being polymorphic, and approximately 7% of the popu- able to identify individuals at risk before disease lation is heterozygous at each enzyme 10cus.l~Poly- onset and the potential benefits of preclinical morphisms in enzyme genes produce alternative intervention. Susceptibility is usually a complex active forms of an enzyme that are shown to differ issue with common diseases. The actions of sever- from the standard enzyme, using electrophoresis, al genes are usually involved with common dis- Role of Genetics in Assessment, Risk, and Management 49 eases but few genes can be identified as playing a receptor that results in reduced phagocytic capaci- major role in the disease. Different genetic back- ties, which provide a mechanism for heritable sus- grounds create different susceptibilities, encourag- ceptibility to microbial infections. Genetic variants ing the opportunity for different etiologies to lead in Fc-gamma receptors have been associated with to the same clinical expression of a disease (ie, dif- both early-onset periodontitis2' and recurrent ferent species of bacteria can cause pneumonia or adult periodontitis.21 periodontal disease). Individuals may have susceptibility to differences in the natural history of a disease; they may ROLE OF GENETICS IN be more likely to follow a particular clinical course PERIODONTAL DISEASE for a disease. After initiation of the disease process, the genetic make-up of the affected individual can Periodontal diseases have many of the characteris- influence the course of the disease in terms of tics of complex diseases, such as the temporal severity and complications. Clinicians with the nature of the disease, difficulty in measuring and ability to identify these susceptibilities can, in turn, classifying disease phenotypes, and complex inter- identify individuals at risk for specific complica- actions between the host and microbial, environ- tions and apply specific interventions or different mental, and genetic factors, which make genetic therapies. A single genetic factor that significantly studies difficult. changes the clinical course of a disease may have Several immune response traits have been asso- great practical importance for the clinical manage- ciated with clinical forms of periodontitis, and the ment of the disease. underlying genetic determinants are known for Individuals may also exhibit susceptibility to some of these factors. It will be important to identi- different therapeutic responses, which is common- fy the genetic factors that imply significant clinical ly found to exist as a genetic subtype of the disease. risk. A gene can be considered as possibly having a In addition, individuals may exhibit genetic sus- causative or modifying role in periodontitis if the ceptibility to complications of a specific therapy or physiologic processes determined by the gene have variations in their response to therapy. Reductions been associated with disease presence or ~everity.~ in poor therapeutic responses or unwanted drug As previously mentioned, some mechanisms of complications could be achieved by an improved genetic susceptibility involve the actions of genes ability to recognize this type of susceptibility. that control environmental response, such as the HLA complex on chromosome 6. The chromo- Host Immune Response some 6 HLA region contains several genes to Microbial Infection involved in the immune response, and the TNF-a gene maps to this region. It has been shown that There are many genetic loci that have been associ- genetic polymorphisms in the 5' region of the ated with the immune response of the host to TNF-a gene are involved in the response to an microbial infection. Certainly, the most well-stud- infectious challenge; these polymorphisms may be ied genetic factor is the major histocompatibility important in some forms of periodontiti~.~ complex (MHC) on chromosome 6, which As previously discussed, the initiation of peri- defines the HLA system that is involved in many odontitis requires the accumulation of specific bac- interactions between the cells of immune teria. However, studies of the quantity and types of response. The MHC genetics have been associated bacteria have not fully explained the differences in with increased susceptibility to various microbial disease severity seen among adults. After disease infections, including tuberculosis, HIV, and cer- initiation, there is a correlation between some tain parasitic diseases. Recently, a polymorphism markers of periodontitis and the host immunoin- in the gene that produces a specific receptor flammatory response; yet, none of these markers (chemokine receptor CCR5) on the surface of could be used to predict in advance an individual's monocytes has been shown to produce strong susceptibility to disease. In addition, there has not resistance to HIV- 1 infection, even with frequent been a reliable mechanism for determining the exposure to the virus.18J9 course of the disease to identify patients who Both CD32 and CD16 are receptors on require more aggressive therapy. immunoinflammatory cells for the Fc fragment of Why are there clinical differences in the preva- immunoglobulin G (Fc-gamma). Variants of genes lence and severity of adult periodontitis? The that code for the Fc-gamma receptor produce a answer is that there is a strong genetic component 5 0 Periodontal Medicine to the disease. A patient’s resistance to periodontal 0.05 and 0.5 mm. The mean loss of attachment in disease is influenced by genetics, and this has been individuals with no progression of disease was I determined from a variety of sources: studies of mm at age 35 years, with an annual rate of destruc- twins, laboratory studies of antibodies, natural his- tion between 0.05 and 0.09. Most in the study tory studies, and cytokine genetics studies. ’’ group were caries free; therefore, essentially all the For many years, clinical and laboratory studies missing teeth were the result of periodontal dis- found substantial variability in the severity of peri- ease. Based on modern views of susceptibility, the odonitits, even with high plaque challenges. Loe results of this study show that there may be indi- and colleagues conducted a study on the natural viduals who are less susceptible to disease. history of periodontal disease in man over a 15- year period.22 The study group consisted of Sri Studies of Twins Lankan men (age range 14 to 31 years) who did not follow any conventional oral hygiene measures. The most convincing demonstration of a genetic They exhibited large amounts of plaque, calculus, influence on adult periodontitis came from studies and stain on their teeth, and almost all the gingival of twins. Comparison of concordance rates of dis- units were inflamed. Among this group, three sub- ease (ie, if both twins in a pair are affected, the con- populations were identified on the basis of inter- cordance rate is 100%) in monozygotic or dizygotic proximal loss of attachment and tooth mortality twins is the classic method for determining whether rates: (I) individuals with rapid progression of familial patterns of disease are the result of common periodontal disease (approximately SYo), (2) those genetic or common environmental factors. Mono- with moderate progression of periodontal disease zygotic twins are genetically identical whereas dizy- (about SlYo), and (3) individuals with no progres- gotic twins are no more genetically alike than sib- sion of periodontal disease beyond gingivitis lings. When the concordance rate is higher in (approximately 11Yo) (Figure 4-1). The group monozygotic twins compared with dizygotic twins, exhibiting rapid progression had a mean loss of especially same-sex dizygotic twins, a significant attachment of approximately 9 mm at age 35 years, part of the familial agreement is caused by genetic which increased to approximately 13 mm at age 45 factors. When the concordance rate is equal, the years, with an annual rate of destruction of 0.1 to familial agreement is mainly determined by envi- 1.0 mm. In individuals exhibiting moderate pro- ronmental factors. With monozygotic twins, it is gression, the mean loss of attachment was approx- sometimes difficult to separate heredity from envi- imately 4 mm at age 35 years and 7 mm at age 45 ronment as these twins tend to select similar envi- years, with an annual rate of destruction between ronments, probably because of their genetic iden- tity. Examples of diseases in which the concordance rate is higher in monozygotic twins compared with dizygotic twins include coronary heart disease, diabetes, and peptic ulcer disease. The concordance rate in monozygotic twins is rarely I OO%, suggesting an environmental or random component to these disorders, in addition to a genetic component. When 100% concordance is observed in monozygotic twins, genetic factors are of great importance in the specific environment in which the twins were studied.15 Michalowicz and colleagues conducted a study to examine the relative contribution of environmental and host genetic factors to the clinical fac- Figure 4-1. Sri Lanka: tooth loss. (Data from Loe H, Anerud tors of periodontal disease in adult twins.12 The A, Boysen H, Morrison E. Natural history of periodontal dis- study group included 77 monozygous twins (63 ease in man. Rapid, moderate, and no loss of attachment in pairs were reared together and 14 pairs were reared Sri Lankan laborers 14 to 46 years of age. The curves show the apart) and 33 dizygous twins. Probing depth, clin- number of teeth lost in each of the three groups that were based on the rate of disease progression. The numbers in boxes ical attachment loss, gingivitis, and plaque were (8%, 81%, 11%) show the percentage of the study population assessed from the Ramfjord index teeth, and boot- in that specific disease-progression group. J Clin Periodontol strap sampling was used to estimate and provide 19 86; 13 :431 -4 5 .) confidence limits of between-pair and within-pair Role of Genetics in Assessment, Risk, and Management 5 1 variances, heritability, and intraclass correlations. A may be considered a candidate for a significant significant genetic component was identified for modifying role in periodontitis if the physiologic plaque, gingivitis, probing depth, and attachment processes determined by the gene have been associ- loss based on ratios of within-pair variances or her- ated with the presence or severity of disease. It itability estimates. Heritability estimates showed should be emphasized that genetic variations that that between 38 and 82% of the population vari- dramatically alter major protective mechanisms are ance for the clinical factors of disease studied can unlikely to be involved in common chronic dis- be attributed to genetic factors.12Another study by eases such as periodontitis. Patients with such Michalowicz and colleagues estimated the genetic major defects are likely to suffer serious childhood variance for alveolar bone height in adult twins.13 problems and complications from various infec- Panoramic radiographs were obtained from 62 tious diseases. The most likely candidates for a pairs of reared-together monozygous twins, 25 genetic influence in adult periodontitis are, there- pairs of same-sex, reared-together dizygous twins, fore, genetic variants that produce a subtle change and 33 pairs of reared-apart monozygous twins. in the magnitude of biologic processes. Mesial and distal bone heights were determined as The most prominent candidates for a genetic a proportion of tooth length. By averaging these influence on adult periodontitis include factors that proportions from all measurable teeth, a full- produce variations in the relative ability of antibod- mouth bone score was determined for each twin. ies and PMNs to kill bacteria and factors that change Calculations of the between-pair and within-pair the relative magnitude of inflammatory processes. variances were made for each twin group. Results Genetic variations in the quantity of antibody showed that the population variances (between- and in the magnitude of PMN binding of antibody pair and within-pair) of the monozygous and dizy- (Fc-gamma receptors) have been described and gous twins were similar, validating a basic assump- have been associated with early-onset periodontitis. tion of the twin model. In addition, intraclass cor- One study associated genetic factors involved in Fc- relations and heritability estimates were calculated gamma receptors with recurrence of adult peri- for the reared-together monozygous (0.70) and odontitis in Japanese patients.2' Studies in U.S. dizygous twins (0.52), as well as the reared-apart adults have not supported these observation^.^^ monozygous twins (0.55). The results of this study The strongest biochemical associations with indicate that there is significant genetic variance the severity of periodontitis have been reported for for proportional alveolar bone height in the popula- prostaglandin E2 (PGE2), IL-1 and TNF-a, and tion. l3 In addition, comparisons of reared-together the enzymes that destroy collagen (matrix-metallo- and reared-apart adult monozygous twins showed proteinases). Genetic variations in these compo- that early family environment had no substantial nents should be reasonable candidates for influ- influence on probing depth and attachment loss ences on adult periodontitis. There are currently measures in adults.23 no data to indicate that variations in the genes for Although there was strong evidence for some PGE2 or for matrix-metalloproteinases influence genetic influence on the severity of adult peri- the severity of periodontitis. Variations in the odontitis, there was not, until the past few years, TNF-a genes were tested for association with clear evidence of a specific genetic factor that may severity of periodontitis and showed no association explain genetic susceptibility to periodontitis. with disease.' At present, data indicate that IL-I Increased understanding of the biology of peri- gene variations are involved in the clinical severity odontal disease and new understandings of genetic of periodontitis in adults. factors that influence responses to bacterial challenges guided the search for candidates that may Role of IL- I in Adult Periodontitis explain the genetic influences on periodontitis. Chemicals in the tissues that provide communica- Candidate Genes in Adult Periodontitis tions between cells are generally referred to as cytokines. One cytokine, IL-I , plays a critical sig- Recent reviews have discussed some of the key can- naling role in many different systems in the body didate genes that may be of value, given current and has been strongly implicated in the progres- knowledge, in the search for genetic influences on sion and severity of adult periodontitis. periodontiti~.~The key is to identify genetic factors The cytokines IL-la, IL-lp, and TNF-a are that are strong enough to significantly influence important mediators of inflammatory responses the clinical outcomes of disease. In general, a gene and appear to play a central role in the pathogene- 5 2 Periodontal Medicine sis of many chronic inflammatory disease^.^^>^^ It is A study by di Giovine and colleagues showed now well documented that their biologic activities that peripheral blood monocytes from individuals in vivo are sufficient to produce local inflamma- with at least one copy of allele 2 at IL-IB (+3953) tion and destruction of connective tissue and produced up to four times more IL-I in response bone.27The cytokine IL-I is one of the first chem- to the same bacterial challenge than those who ical mediators activated following any external were genotype negative.39 Individuals inherit one stimulus, such as a bacterial challenge. As an early copy of the IL-I gene from each parent. Individu- response factor, it activates other nonspecific and als who had two copies (homozygous) of the most protective mechanisms, including recruitment of common IL-IB (+3953) polymorphism (allele 1) PMNs and activation of blood clotting. It also acti- produced a certain amount of IL-Ip (5.2 ng/mL) vates specific protective mechanisms and is when stimulated by the bacterial component LPS. involved in wound healing and bone and connec- Individuals who were homozygous for the poly- tive tissue metabolism. morphism associated with periodontitis (allele 2) Higher production of these cytokines has also produced approximately four times more IL- I p been associated with response to infection, where than normal (I9.9 ng/mL) (Figure 4-2). And indi- local induction of IL-I and TNF facilitates the viduals with one copy of allele I and one copy of elimination of the microbial invasion. However, allele 2 of the IL-IB (+3953)polymorphism (het- classic studies also report that in some infectious erozygous) , produced approximately twice as conditions very high levels of monocytic cytokines much IL-Ip (12.4 ng/mL).39 are produced and initiate a cascade of concomitant Patients with the composite IL-I genotype events, such as tissue catabolism, vascular reactivi- have higher levels of IL-I in the gingiva than those ty, and hypercoagulation, with damaging effects on observed in genotype-negative patients. Recent the host.28>29 studies have determined the levels of IL-Ia and Elevated tissue and gingival fluid levels of IL- IL-Ip in gingival biopsies and the levels of IL-Ip Ip in particular have been repeatedly associated in gingival crevicular fluid (GCF).40 The IL-I with the severity of periodontiti~.~'-~~The rela- genotype positives had higher levels of IL-Ip in tionship between IL-I and periodontitis has been GCF, with the greatest differences between geno- extensively reviewed by Offenbacher. Although type-positive and genotype-negative patients in the inflammatory process automatically increases sites of minimal probing depth (Figure 4-3). Tissue the local tissue levels of IL-I, stable differences levels of IL- I flwere also higher and levels of IL- I a between people in cytokine production rates have were marginally higher in genotype-positive been rep~rted.~~>~~ patients. These findings were dramatic and indicate that IL-I genotype-positive patients will have Geneticvariations in the IL- I Genotype higher levels of IL-I in periodontal tissues when and Increased Levels of IL-l there is a bacterial challenge. Related observations were made in a pilot study by Jotwani and col- Three IL-I genes (IL-IA, IL-IB, and IL-IRN) clus- leagues who examined the response of periodontal- ter on chromosome 2q 13. Interleukin-IA and IL- 1B ly healthy patients to plaque accumulation. This encode the proinflammatory proteins IL- I a and study found that IL- I genotype-positive patients, IL-Ip, and IL-IRN encodes IL-lra, a related pro- but not the genotype-negative patients, had a sig- tein that functions as a receptor agonist. Several nificant increase in GCF IL-lp after 3 days with- genetic polymorphisms have been identified in the out oral h~giene.~' genes of the IL-I cluster. In recent studies, severe adult periodontal disease in nonsmokers38was cor- Genetic Variations in IL- I Genotype and related with a composite genotype in the IL-I gene Increased Severity of Adult Periodontitis cluster that includes at least one copy of allele 2 of the IL-IA-889 polymorphism and at least one copy The first report of an association between the IL-I of allele 2 of the +3953 polymorphism of the IL-IB genotype and severity of adult periodontitis was gene. The IL-IA (-889) locus is in > 99% linkage published in 1997.l Since that time, other studies disequilibrium (eg. the two are inherited together) that confirm these findings have been reported. with a polymorphism at the IL-IA (+4845) locus In the first report the study population includ- which is currently used in the laboratory in place of ed only adults with no known history of early-onset IL-IA (-889) in the composite genotype test for disease and most likely included patients with both severity of adult periodontitis. adult periodontitis and refractory periodontitis. The Role of Genetic:s in Assessment, Risk, and Management 53 association between severe periodontitis and the genetic polymorphism in the IL- 1 genes was present only when smokers were excluded, which confirmed the importance of smoking as a risk factor for periodontitis. This was the first study that identified a genetic polymorphism that corresponds with a phenotypic immune response variable (IL-1 production) in adult periodontitis patients.' The IL- 1 genotype identified in this study appears to be a marker of a strong biologic change that results in severe periodontitis, without regard to the amount of bacterial challenge. This does not mean that bacteria are not important in the disease process-quite Figure 4-2. Amount of IL-1 produced by patients who are the contrary. The first findings indicate that the sig- homozygous (2.2) or heterozygous (1.20 for the allele for nificant association between the IL-1 genotype and adult periodontitis . (Data from diGiovine FS, Cork MJ, severity of periodontitis did not require any adjust- Crane A, et al. Novel genetic association of an IL-lp gene ments-for the amount of bacterial plaque. The com- variation a + 3953 with IL-lp protein production and psori- bination of having either the specific genotype or asis [abstract]. Cytokine 1995;7:606.) smoking accounted for the majority (86Vo) of severe cases of periodontitis. The IL-1 genotype was a very strong predictor of severe periodontitis in nonsmok- type will have the same relationship to disease in all ers age 40 to 60 years (odds ratio 18.90) (Figure populations, the IL-1 genotype may be found less 4-4). Among similar-aged individuals with mild frequently in some populations than in Caucasians. periodontitis, 84% were genotype negative. ' It is also possible that other genetic factors may play It is noteworthy that the association between a role in other ethnic groups. At present, it has been the genetic polymorphism in IL- 1 genes with severe reported that IL-1 genotype positivity is found in periodontitis was only evident when smokers are approximately 30% of Caucasians' and Hispan- excluded. These data support the importance of ic~.~~It has been reported that genotype positivity is other environmental factors, such as smoking, as a much less common in the Chinese p~pulation.~~ risk factor for periodontitis."Jo3 The association of Studies are in progress to determine the prevalence severe periodontitis with smoking and the IL-1 of the IL-1 genotype in other populations. genotype suggests that both factors play an important role in the pathogenesis and clinical course of adult periodontitis. Other studies have confirmed these early observations. McDevitt and colleagues found similar associations between the IL-1 genotype and adult periodontitis (Figure 4-5) .42 McGuire and Nunn have reported an increased susceptibility to tooth loss after periodontal therapy in IL-1 genotype-positive patients.43 Recently, Gore and colleagues (1998) reported a significant association between the IL-1 f3 polymorphism and severity of disease.44 In this study, the composite genotype (IL-1A plus IL-1B) did not offer advantages over just the IL-1B markers. Such differences among the studies are not surprising as genetic studies usually have small numbers of subjects. The above studies were performed primarily in Figure 4-3. IL-1 is higher in the periodontal tissues of Caucasians. One obvious question is, what is the PST@positives. (Data from Engebretsson SE Lamster IB, et role of the IL-1 genotype in other ethnic groups? In al. The influence of interleukin-1 (IL-1) gene polymor- most of the populations that have been tested, this phisms on expression of IL-lp, and tumor necrosis factor genotype occurs in approximately 30% of individ- alpha (TNFa) in periodontal tissue and gingival crevicular uals.' Although it is expected that the IL-1 geno- fluid. J Per io do n to1 19 9 9 ;70 :5 6 7-73. 54 Periodontal Medicine

Figure 4-4. The periodontitis genotype defines a different disease susceptibility in adults. Age 35-60; odds ratio: 18.9; p < .001. The cumulative frequency distribution of non-smokers with 2 30% mean bone loss (severe) at different ages. The bars represent the cumulative percentage of subjects who had severe disease by the indicated age. Genotype positive (N=63).Reprinted with permission from J Clin Periodontol 1997;24:72-7.

The association between the IL-1 genotype and genotype-negative patients who are heavy smokers disease severity was unclear when heavy smokers will be susceptible to more severe periodontitis. This were included in the data analysis. What does this will certainly confuse the data analysis of research mean? It is well documented that smoking, by itself, studies unless this factor is taken into account in the is a strong risk factor for more severe periodontitis. analysis. One study that involves periodontal treat- It is therefore reasonable to expect that some IL-I ment shows a synergistic risk when a patient is both a smoker and is IL-1 genotype positive.43At present, it seems reasonable to expect that, as with risk factors for cardiovascular disease, multiple factors such as IL-I genotype and smoking convey increased risk of more severe disease. It is likely that larger studies will help to define the magnitude of interactions between smoking and the IL-I genotype as well as other risk factors.

Genetic Variations in IL- I Genotype and Response to Treatment

It seems reasonable to assume that if the IL-I genotype is associated with more severe disease, the genotype may also influence response to therapy. New data from McGuire and Nunn validate that as~umption.~~Over several years, McGuire and Nunn conducted studies to determine the effectiveness of clinical parameters in developing an Figure 4-5. Most nonsmoker patients with severe bone loss were PST@ positive. (Data from McDevitt M, Wang H-Y, accurate progn~sis.~’>~~In their first study, the Knobelman C, et al. IL-1 genetic association with perio- authors evaluated I 00 treated periodontal patients donitits in clinical practice. J Periodontol 1999. [in press]) under maintenance care for 5 years to determine Role of Genetics in Assessment, Risk, and Management 5 5 the relationship between assigned prognoses and type-positive patients, conventional periodontal the clinical criteria commonly used in developing a therapy and good maintenance care allowed the suc- progn~sis.~’Using multiple logistic regression cessful retention of most teeth. models, it was shown that improvement or wors- Studies so far have shown evidence that IL-I ening in prognoses was strongly associated with polymorphism analysis can provide valuable insight initial tooth malposition, probing depth, furcation into an individual patient’s likely response to vari- involvement, and smoking, when adjusted for ini- ous interventions. However, additional studies are tial prognosis. It was found that initial mobility necessary to provide greater insight into the rela- decreased the probability of improvement in prog- tionships between genetic factors and periodontal nosis whereas good oral hygiene increased the and restorative therapy. This genetic marker is not probability of improvement in prognosis; however, diagnostic; it is a prognostic test that is used to neither of these factors was shown to be significant identify individuals who have a much higher sus- in worsening the prognosis. On the other hand, ceptibility to adverse reactions to plaque.49 smoking doubled the probability of worsening of The finding of the association between the IL-1 prognosis at 5 years and decreased the probability polymorphism and an increase in IL- I f~production of improvement by 60%. According to the and more severe periodontal disease is consistent authors, the results of this study suggest that some with the current model of how genetic factors influ- clinical factors used in the assignment of prognoses ence common chronic diseases. If this model is are clearly associated with changes in a patient’s applied to periodontitis, it would involve a disease- clinical condition over time. initiating factor, which would most certainly be a In their second study, McGuire and Nunn eval- specific bacterium (ie, I! gingivulis, Bucteroides uated tooth loss in 100 treated periodontal patients forxythus, and A. uctinomycetemeomituns), and modi- under maintenance care to determine the effective- fiers of disease mechanisms that explain the clinical ness of commonly taught clinical parameters used in severity, including certain systemic diseases, smok- assigning an accurate prognosis for tooth survival.48 ing, psychosocial stress, and the IL-I genotype.‘ Using a Cox proportional hazards regression model, it was found that initial furcation involvement, Clinical Application probing depth, percent bone loss, mobility, and smoking were associated with an increased risk of Despite the general overall improvement in peri- tooth loss. Data from the study showed a relation- odontal health, periodontitis is still the number one ship between the assigned prognosis and tooth loss. The worst survival rate occurred in teeth with the worst prognosis but the commonly taught clinical parameters used in the traditional way for assigning prognosis do not adequately explain this relationship. In addition, the initial prognosis did not adequately predict survival of the tooth or explain the condition of the tooth. The results of this study indicate that when assigning prognosis, some clinical parameters should be weighted more heavily than other clinical parameters. The latest study by McGuire and Nunn (Figure 4-6) determined that the significant predictors of tooth loss in periodontal patients who were monitored for 14 years after active therapy were heavy smoking (increased risk for tooth loss of 2.88; meaning that heavy smokers had a 288% increased risk of losing teeth after therapy as compared to Figure 4-6. IL-1 genotype and heavy smoking were the pri- non-smokers or light smokers) and the IL-I geno- mary predictors of tooth loss after periodontal therapy. *An increased risk of 2 indicates that the patient is two times type (increased risk for tooth loss of 2.66).43 If more likely to lose teeth than patients without that risk fac- patients were both heavy smokers and IL-I geno- tor. (Data from McGuire MK, Nunn ME. Prognosis versus type positive they were 7.7 times more likely to lose actual outcome. IV. The effectiveness of clinical parameters teeth after periodontal therapy than all other and PST genotype in accurately predicting prognosis and patients. It should be noted that even in IL-I geno- tooth survival. J Periodontol 1999;70:49-56. 5 6 Periodontal Medicine cause of tooth loss in adults. In the United States Although scientific evidence and clinical experi- alone, over 50 million people have the disease. The ence have improved the accuracy and power of tra- cost to society in both human and economic terms ditional methods, the ability to predict the prog- is great. The indirect expenses of replacing teeth lost nosis and outcome for individual patients and due to periodontitis are much higher than the individual sites has been limited. direct periodontal expenditures. Patients, insurance To best appreciate how genetic information payers, and clinicians are seeking accurate treat- fits into the current concepts of disease, it is impor- ment and better preventive approaches. The genet- tant to describe the scientific and clinical model of ic aspects of the disease have been understood and periodontitis etiology and pathogenesis that is cur- accepted with increased enthusiasm because of the rently accepted by the vast majority of clinicians. tremendous strides made in molecular biology. Importantly, the new genetic features of the disease These new insights are beginning to find their way do not replace existing elements of the paradigm into practical translation and use by clinicians. and, in fact, provide clarification for many of its This section will briefly describe how to inte- uncertainties. grate information on the genetic basis of periodontitis into the overall framework of the patient’s Paradig m for Mic ro biol og ic diagnosis and treatment plan. Certain characteris- Periodontal Disease tics of genetic information make it different from almost any other kind of patient specific data the The main conceptual framework for the etiology dental professional deals with. These include scien- of periodontitis is based on the belief that peri- tific, ethical, inheritance, and practical considera- odontitis is an infection caused by plaque (Figure tions unique to information about heredity. How- 4-7). The assumptions of the model are: ever, although different, genetic information may be viewed as (just) another type of medical infor- 1. Periodontitis begins as gingivitis. mation about patients and their relatives. 2. In a large portion of the adult population (35%), gingivitis converts to periodontitis. Use of Genetic Information in Clinical 3. Approximately 10% of affected individuals Practice will develop severe forms of the disease. If left untreated, periodontitis may progress to The literature in the past 5 years has had increasing become more severe. amounts of space devoted to presentations of data 4. Plaque must be present for disease progression postulating an important role for genetics in the but the presence or the identification of spe- pathogenesis of adult periodontitis. Although much cific bacteria is not predictive of periodontitis of this information has been well accepted, its trans- severity on an individual-site basis. lation into clinically usehl practice has been very 5. Intrinsic factors (genetics) and extrinsic factors slow, primarily because there have been no com- (such as oral hygiene) account for the clinical mercially available methods that could be used by variability of disease manifestation. dentists wanting to know if their patient had a spe- 6. Adult periodontitis is a common, multifactor- cific periodontitis-implicated genotype. id, chronic disease. Most professional organizations have developed comprehensive guidelines for diagnosis, risk Since there are important differences in the assessment, and prevention of periodontitis combination of factors causing disease, it follows through measures aimed at reducing the risks of that the treatment for different groups of patients disease initiation or disease progression. Dentists, with periodontitis should not be the same. Other- dental hygienists, and their patients would like to wise, there is the possibility that some patients will have as much usehl information as possible in get too much treatment while some others do not order to guide decision making for periodontal get what they need. If 10% of patients with peri- treatment planning. Faced with the challenge of odontitis will develop severe disease, then the other ascertaining all relevant risk factors and then trying 90% will have only mild to moderate disease. How to put the information together with patient pref- can patients be identified as to their risk for hture erences, the clinician manages, organizes, and syn- severity of their disease? Are there tests or any other thesizes all the data to produce the best possible information that will help the clinician improve the treatment plan. The goal is to personalize the plan accuracy of the predictions about the patient’s hture and make it as accurate and predictive as possible. status? These are critical questions that interest all Role of Genetics in Assessment, Risk, and Management 57

Pathogenic bacteria present J. J. Smoker Nonsmoker

Genotype positive Genotype negative J. J. J. Increased risk for Increased risk for Lower risk for severe disease severe disease severe disease J. J. J. Smoking cessation More aggressive therapy Less aggressive therapy More frequent recall/ - surgery Less frequent recall/ maintenance - antimicrobials maintenance More frequent recall/ maintenance

Figure 4-7. Clinical utility of genetic testing. parties involved. Patients want the best treatment, Available techniques, tests, diagnostic proce- clinicians want to provide efficient therapy, and dures, and guides to treatment have either been insurance payers want to focus resources. Genetic weakly applicable on a patient-by-patient basis, or, susceptibility to the resident periodontal flora is one they have been impractical in terms of cost-effec- of the factors that determine the actual clinical pre- tiveness, and time management. sentation of disease. Assessment of other risk factors, The main barrier to widespread use of current such as smoking and systemic health, are always technology is its poor record in predicting the included in the development of a comprehensive patient’s fbture periodontal status. Clinical and bio- treatment plan but practical methods available to logic evaluations can tell the clinician about the cur- the clinician to determine the types of bacteria at rent status of the patient’s periodontium but these an individual periodontal site are limited. signs, symptoms, and clinical judgments have relatively weak prognostic value. By focusing attention CI inical Perspective on both the etiology and modifiers of periodontitis, rather than on “furing” the results of disease, practi- The practical use of genetic information offers the tioners can anticipate, manage, and prevent disease potential to change periodontitis treatment. Genet- much more effectively. For example, smoking, dia- ic predisposition to the onset of periodontitis means betes, family history, and other factors known to that some patients can be identified even before dis- increase the risk and susceptibility to periodontitis ease begins. This improves the chances of successfd are important to consider because they can influ- prevention. Genetic heterogeneity associated with ence the patient’s response to therapy. Patients with disease also extends to treatment responsiveness. more risk usually need more care. Optimum treat- Distinguishing patients who are of good responders ment implies managing the multiplicity of issues, from those who are poor responders will allow more etiologies, preferences, and physical, emotional, precise chemotherapeutic interventions because and inherited risk and susceptibility factors. drug targets will be more precise. For example, there may be different response patterns to a specific anti- Ethical Considerations inflammatory drug, depending on the nature of the individual patient’s cell receptors compared with The sensitivity of genetic information underscores those of another patient. Pharmaceutical companies the importance of understanding the often dis- are devoting vast resources to this endeavor that has cussed and highly debated issues dealing with been referred to as pharmacogenomics. genetic information. For most dental personnel, 5 8 Periodontal Medicine genetic information is distinguished from other During genetic counseling, the risks for a disease patient information because it is potentially pre- and the potential options for dealing with the risks dictive, permanent, and associated with blood rel- are discussed with the individual and often with atives. Many of the most important issues are sum- family members at risk. With diseases that are marized in Table 4-2. treatable, such as periodontitis, it has been shown that early intervention improves the outcome. For Genetic Counseling many common disorders, the process of family- based screening can be of value. After the initial There are two factors involved in disease risk: genetic risks are determined, these risks can be numerical risk and the burden or severity of the more clearly defined by performing additional disease. Well-defined mathematical rules for pre- studies in patients and family members who are at dicting risk are not available for many multifactor- risk.15 Family linkage and association data are ial (non-Mendelian) disorders. In this instance, being generated for many of the genetic markers clinicians rely on empiric observations, epidemio- associated with periodontitis. These data will assist logic data, and a variety of studies about recurrence the counselor in describing the level of risk to the risks. From nongenetic studies, approximate pre- patient and family members. dictions and generalization can be inferred and For common diseases, the physician and dentist direct application to the individual is limited. On will have responsibility for counseling patients about the other hand, genetic prognosis is concerned the implications of genetic susceptibility. Genetic with the prognosis for the affected individual and counselors may also be involved in this process, outlining disease risks for their different relatives. especially in the setting of large medical institutions.

TABLE 4-2. Summary of Genetic Information Issues for the Clinician* Representative Issues Discussion No distinctions between 1. For all diseases, whether or not there are reasonable treatments or preventive genetic information and options, presymptomatic, predictive genetic testing can introduce sensitive other forms of medical/ medidgenetic information. The feature of this category of information that dental information makes it sensitive is that it is subject to misinterpretation by patients, providers, insurers, and employers. In essence, this type of medical information is no different from other types of confidential medical facts about an individual, for example, whether or not a patient is HIV positive or negative. 2. In cases such as presymptomatic testing, the clinician must realize that the actual information about a patient’s genetic make-up will, itself, impact the livedmental health of otherwise healthy people. 3. Genetic information is not limited to the individual tested; the information is about the individual’s germline/family and thus may have consequences beyond treatment planning decisions for the tested patient. Clinical utility 1. There is a general consensus that genetic testing should not be withheld until enough data have been compiled to know exactly what a genetic test result means for all individuals in the general population, ie, it is not necessary to know the exact relationship between genotype and phenotype for the target marker(s). Effective treatments (therapeutics and even gene therapies) may be developed before all the complexities of interactions among genedgene sequences and genetic and environmental variables are known. 2. Genetic testing should be introduced when there is sufficient anahtical vaZidig (in essence, the test reliably determines the presence of the target marker(s) in the laboratory); there is sufficient clinical utility (there is a clinical benefit for patients, which also is a prerequisite for reimbursement); and patient safeguards (to ensure only informed, voluntary testing) are adhered to.

*Adapted from: M. Malinowsky, 1999. Role of Genetics in Assessment, Risk, and Management 59

Periodontal Disease-Specific Issues level of validity, as well as addressing ethical and Comments considerations. 1. Genetic tests for common diseases are not usu- Comment: Before deciding to use genetic ally considered to be classic “diagnostic tests,” testing as part of patient assessment and treat- and they do not eliminate the need for an ment planning, the clinician must ensure that accurate diagnosis and treatment plan. the test itself embodies certain attributes dis- Comment: Risk assessment, including the cussed in previous sections and summarized in use of genetic susceptibility testing, is an addi- Table 4-3. All five characteristics and consider- tional step, but not a substitute for a full diag- ations must be checked before the test is used. nostic evaluation. 2. Common diseases are multifactorial, and Genetic Testing in Dentistry because of this, genetic test results provide one Genetic testing for the IL-I genotypes in dentistry piece of information needed to form a diagno- was begun in 1997 with the introduction of the sis, prognosis, and treatment plan. PST test (PST@, Interleukin Genetics, Inc., San Comment: Most often, the diagnosis of a Antonio, TX). Its primary use is to provide addi- common disease is based on the identification tional information about a patient’s susceptibility of signs and symptoms associated with well- to adult periodontitis. Since it measures the established criteria. Signs of periodontitis absence or presence of specific markers of the include plaque, changes in gingival color, ini- patient’s inflammatory response to plaque, one of tial attachment loss, probing depth, bleeding the key components of the pathogenesis of peri- on probing, and suppuration. Negative genet- odontitis, its clinical utility is very high. Control of ic susceptibility test results by themselves do inflammation is a key component of many of the not rule out future occurrence of disease or treatment goals in esthetic, restorative, and recon- disease activity because one of the other con- structive dentistry. The currently available genetic tributing factors may contribute to the susceptibility test meets the five characteristics and observed pathology. Similarly, positive test conditions listed in Table 4-3. results do not mean that disease is inevitable. The primary use for information about a 3. Another important facet of genetic test results patient’s risk for disease initiation or progression is specific to periodontitis has to do with the the modification and individualization of therapeu- implications to people biologically related to tic interventions. Both the nature and the timing of the tested individual. therapy may be altered as a result of knowing a Comment: Depending on the nature of the patient’s risk for fbture disease. What the benefits of genetic association, offspring, siblings, parents, knowing a patient’s risks for disease, including their and others may carry genes that could put these genetic susceptibility to periodontitis, are and who people at increased disease risk. In the case of should be tested are two common questions often adult periodontitis, this information may be asked by practitioners and patients. The section helpful in establishing treatment recommenda- below discusses some essential factors about risk tions and preventive approaches. The decision assessment. Knowing about these factors will pro- to be tested for periodontitis susceptibility vide a context for determining how the genetic sus- should be made by the individual patient. ceptibility risk factor fits in the overall approach to 4. Essential scientific characteristics of genetic treating and preventing periodontal disease and its susceptibility tests must meet the highest relevance to restorative dentistry.

TABLE 4-3. Required Characteristics for Genetic SusceptibilityTests Associated with Common Diseases 1. The genotype must be associated with disease occurrence and, if possible, the mechanism known to be an integral part of the pathogenesis of the disease. 2. Analytical sensitivity and specificity must be determined, ie, how accurate the laboratory test and methods are in their ability to detect the genetic marker, if it is truly present. 3. Appropriate clinical validity must be ascertained: eg, odds ratio, for disease with and without the genetic marker. 4. The benefits and risks from test results must be known. 5. Treaunent initiation or change as a result of the information derived from the test must be available. 60 Periodontal Medicine

Risk Factor Determination controllable risks as possible. This may be accomplished through better home care, more The term “risk” is generally used to imply the frequent dental visits, smoking cessation, probability that an unfavorable or unwanted out- pocket reduction, or any other recommended come may occur in the future. Many studies have therapy. For patients who are found to be been conducted to identify the factors that increase genetically negative, the information can still an individual’s risk for developing periodontal dis- be used to motivate them to control other risk ea~e.~’>~lThe findings from these studies have factors (such as smoking) and increase their identified the following as risk factors for peri- chances of staying healthy. odontitis: smoking, diabetes mellitus, advancing 4. New periodontal patients as part of an initial age, poor oral hygiene status, microbial deposits, examination and objective measure of their inheritance, bleeding on probing, specific patho- risk for disease progression and patients who genic bacteria in the subgingival flora, and previ- have a familial history of periodontitis or who ous disease experience and severity. Some risks are have relatives who are genotype positive. Some strongly linked to disease causation (ie, pathogenic patients may be tested after initial therapy, bacteria in the subgingival flora), others may be especially if they are not responding well. background factors that enhance susceptibility (ie, 5. Biologic family members of genotype-positive advancing age), and some may suggest increased patients or patients with severe periodontal risk for future disease (ie, bleeding on probing). disease for prevention or early intervention. Patient decisions about treatment must be based 6. Putients with udvunced periodontal diseuse to on accurate information, including individual provide information that, when combined preferences, estimates of the patient’s prognosis, with other risk factors, can be used to optimize expected side effects and benefits, and efficiency of therapy and determine who needs aggressive the proposed treatment alternative^.^^ Although treatment and/or maintenance to minimize the data regarding risk factors are very good, the further disease progression and tooth loss. degree of patient variability and treatment respon- 7. Putients who ure cundiddtesfor complex restorutive siveness demonstrates the need for more research. procedures to enhance the success and maintain- ability of the case by considering the overall risk Patient Selection and Potential Benefit(s) profile of the patient in the treatment, mainte- of Genetic Susceptibility Testing nance, and follow-up plan. Marginal inflammation and bleeding are risk hctors associated with The list below describes some potential types of gingival recession. Patients who are “inflamma- patients and the benefits that may be derived from tion prone’’ due to their genetically variable the decision to determine the patient’s genotype. response to plaque can use this information to motivate them to improve their oral hygiene. 1. Putients with early signs of periodontal diseuse. 8. Adult orthodontic patients as part of an initial Testing can be done to better determine the screening for periodontal health status and risk appropriate level of therapy and maintenance assessment. If a patient is seen to be at risk for and to potentially minimize further disease developing severe periodontal disease on the progression and tooth loss. basis of genetic test results and/or other risk 2. Period0n tul muin tenunce patients. Individuals factors or already has periodontal disease, he or with continuing signs of disease will potential- she may benefit from more frequent periodon- ly benefit from understanding their risk for tal maintenance during orthodontic treatment. hture disease. This information should be combined with other risk factors (eg, smoking and diabetes) to determine who might benefit CONCLUSION from more or less aggressive treatment. The information may also help to determine the With the discovery of a specific genetic hctor that level of periodontal and inflammatory risk places individuals at a greater risk for the develop- prior to restorative or implant therapy. ment of periodontitis or more severe forms of the 3. Putients who ure resistunt to uccepting treutment disease, clinicians can tailor treatment for individual recommenddtions. If a patient is found to be patients, resulting in more effective therapy. In addi- genetically positive, the information may tion, by identifylng genotype-positive patients before motivate him or her to reduce as many of the disease initiation, clinicians may be able to prevent Role of Genetics in Assessment, Risk, and Management 6 1 the development of periodontitis in some patients 10. Hart TC. Genetic risk factors for early-onset peri- with the use of standard preventive measures. odontitis. J Periodontol 1996;67:355-66. There is little doubt that on the basis of risk 11. Alaluusua S, Asikainen S, Lai C. Intrafamilial and susceptibility factors, the practice of periodon- transmission of Actinobacillus actinomycetem- tics, will require a change of approach for dentistry comitans. J Periodontol 199 1;62:207-10. and for the patients and public it serves. Risk and 12. Michalowicz BS, Aeppli D, Virag JG, et al. Peri- predisposition assessment will be used more often odontal findings in adult twins. J Periodontol as first priority decision-making guides in diagnos- 199 1;62 (5)293-9. tic and therapeutic algorithms. Because clinicians 13. Michalowicz BS, Aeppli DC Kuba RK, et al. A can now identi+ and monitor periodontal risk con- twin study of genetic variation in proportional siderably earlier than before, there is an opportuni- radiographic alveolar bone height. J Dent Res ty for maximizing benefit/cost ratios. Early detec- 1991;70( 1 1): 143 1-5. tion enhances appropriate treatment planning, 14. Corey LA, Nance WE, Hofstede Schenkein HA. whether it is prophylactic, medical, or surgical. Self-reported periodontal disease in a Virginia twin population. J Periodontol 1993;64:1205-8. Acknowledgement 15. King RA, Rotter JI, Motulsky AG. The approach to genetic bases of common diseases. In: King The excellent drafting and editorial assistance of RA, Rotter JI, Motulsky AG, editors. The Kathy Barnes and Elaine Robertson were very much genetic basis of common diseases. New York: appreciated in the preparation of this chapter. Oxford University Press Inc.; 1992. 16. National Institutes of Health. Genetic architecture of complex phenotypes. Released on the Inter- REFERENCES net, June 8, 1998. 17. Newman M. Genetic, environmental, and behav- 1. Kornman KS, Crane A, Wang H-Y, et al. The inter- ioral influences on periodontal infections. Com- leukin-1 genotype as a severity factor in adult pend Contin Educ Dent 1998;19(1):25-31. periodontal disease. J Clin Periodontol 1997; 18. Dean M, Carrington M, Winkler C, et al. Genetic 24: 72-7. restriction of HIV- 1 infection and progression 2. Roberts FA, Hockett RD Jr, Bucy W, Michalek to AIDS by a deletion allele of the CKR5 struc- SM. Quantitative assessment of inflammatory tural gene. Hemophilia Growth and Develop- cytokine gene expression in chronic adult perio- ment Study, Multicenter AIDS Cohort Study, dontitis. Oral Microbiol Immunol 1997;12(6): Multicenter Hemophilia Cohort Study, San 336-44. Francisco City Cohort, ALIVE Study. Science 3. Haffajee AD, Socransky SS. Microbial etiological 1996;273(5283):1856-62. agents of destructive periodontal diseases. Peri- 19. Huang Y, Paxton WA, Wolinsky SM, et al. The role odontology 2000 1994;5:78-1 l l. of a mutant CCR5 allele in HIV-1 transmission 4. Tanner AC, Kent R, Maiden MFJ, Taubman MA. and disease progression. Nat Med 1996;2(11): Clinical, microbiological and immunological 1240-3. profile of health, gingivitis and putative active 20. Wilson ME, Bronson PM, Hamilton RG. periodontal subjects. J Periodontal Res 1996;31 : Immunoglobulin G2 antibodies promote neu- 195-204. trophil killing of Actinobacillus actinomycetemco- 5. Zambon JJ. Periodontal diseases: microbial factors. mitans. Infect Immun 1995;63(3):1070-5. Ann Periodontol 1996;1:879-925. 21. Kobayashi T, Westerdaal NA, Miyazak A, et al. 6. Kornman KS, di Giovine FS. Genetic variations in Relevance of immunoglobulin G Fc receptor cytokine expression: a risk factor for severity of polymorphism to recurrence of adult periodon- adult periodontitis. Ann Periodontol 1998;3(1): titis in Japanese patients. Infect Immun 1997; 327-38. 65 (9):3 5 56-60. 7. Hart TC, Kornman KS. Genetic factors in the 22. Loe H, Anerud A, Boysen H, Morrison E. Natural pathogenesis of periodontitis. Periodontology history of periodontal disease in man. Rapid, 2000 1997;14:202-15. moderate and no loss of attachment in Sri 8. Offenbacher S. Periodontal diseases: pathogenesis. Lankan laborers 14 to 46 years of age. J Clin Ann Periodontol 1996;1:821-78. Periodontol 1986;13( 5):43 1-45. 9. Hassell TM, Harris EL. Genetic influences in caries 23. Michalowicz BS. Genetic and heritable risk factors and periodontal diseases. Crit Rev Oral Biol in periodontal disease. J Periodontol 1994;65(5 Med 1995;6(4):319-42. Suppl):479-8 8. 62 Periodontal Medicine

24. Socransky SS, Haffajee AD, Cugini MA, et al. 38. Newman MG, Korman KS, Holtzman S. Associa- Microbial complexes in subgingival plaque. J tion of clinical risk factors with treatment out- Periodontol 1998;25:346-53. comes. J Periodontol 1994;65:489-97. 25. di Giovine FS, Duff GW. Interleukin-1-the first 39. di Giovine FS, Cork MJ, Crane A, et al. Novel interleukin. Immunol Today 1990;1 : 13-20. genetic association of an IL-lp gene variation a 26. Beutler B, Cerarni A. The biology of cachectinl +3953 with IL-lp protein production and pso- TNF-a primary mediator of the host response. riasis [abstract]. Cytokine 1995;7:606. Ann Rev Immunol 1989;7:625-55. 40. Engebretsson SE Larnster IB, Herrera-Abreu M, et 27. Probert L, Plows D, Kontogeorgos G, Kollias G. al. The influence of interleukin-lp gene poly- The type-i interleukin-1 receptor acts in series morphism on expression of IL-lp, and tumor with tumor-necrosis-factor (TNF) to induce necrosis factor alpha in periodontal tissue and arthritis in TNF-transgenic mice. Eur J Imrnunol gingival crevicular fluid. J Periodontol 1999;70: 1995;25:1794-7. 567-73 28. Jacob CO. Tumor-necrosis-factor-alpha in autoim- 41. Jotwani R, Avila R, Kim BO, Cutler CW. The munity-pretty girl or old witch. Immunol effects of an antiseptic mouthrinse on subclinical Today 1992;13:122-5. gingivitis in IL- 1 genotype-positive and -negative 29. Vassalli E The pathophysiology of tumor necrosis humans [abstract]. J Dent Res 1998; 77(B):921. factors. Ann Rev Immunol 1992;10:4 11-52. 42. McDevitt M, Wang H-Y, Knobelman C, et al. IL- 30. Lee HJ, Kang IK, Chung Cc Choi SM. The sub- 1 genetic association with periodontitis in clini- gingival microflora and gingival crevicular fluid cal practice. J Periodontol 1999. [In Press] cytokines in refractory periodontitis. J Clin 43. McGuire MK, Nunn ME. Prognosis versus actual Periodontol 1995;22:885-90. outcome. W. The effectiveness of clinical para- 31. Liu C-M, Hou L-T, Wong M-Y, Rossomando EF. meters and PST genotype in accurately predict- Relationships between clinical parameters, ing prognosis and tooth survival. J Periodontol interleukin-1 B and histopathologic findings of 1999;70:49-56. gingival tissue in periodontitis patients. Cytokine 44. Gore EA, Sanders JJ, Pandey Jc et al. Interleukin- 1996;8:161-7. 1B +3953 allele 2. Association with disease sta- 32. Preiss DS, Meyle J. Interleukin-1 beta concentra- tus in adult periodontitis. J Clin Periodontol tion of gingival crevicular fluid. J Periodontol 1998;25:78 1-5. 1994;65:423-8. 45. Caffesse RG, R de La Rosa M, G de La Rosa M. 33. Stashenko Fujiyoshi Obernesser MS, et al. PST genotypes in a periodontally healthy popula- Levels of interleukin-lb in tissue from sites of tion treated for mucogingival surgery [abstract]. active periodontal disease. J Clin Periodontol J Dent Res 1998;77(B):872.. 199 1;18:548-54. 46. Wu Y, Wang H-Y, di Giovine FS, Armitage GC. 34. Yavuzyilmaz E, Yamalik N, Bulut S, et al. The gin- Low prevalence of IL-1A and IL-1B polymor- gival crevicular fluid interleukin- 1 beta and phisms in a Chinese population [abstract]. J tumour necrosis factor-alpha levels in patients Dent Res 1998;77(B):738. with rapidly progressive periodontitis. Aust 47. McGuire MK, Nunn ME. Prognosis versus actual Dent J 1995;40:46-9. outcome. 11. The effectiveness of clinical para- 35. Cavanaugh PF Jr., Meredith ME Buchanon W, et al. meters in developing an accurate prognosis. J Coordinate production of PGEz and IL-1 p in the Periodontol 1996;67(7):658-65. gingival fluid of adults with periodontitis: its rela- 48. McGuire MK, Nunn ME. Prognosis versus actual tionship to alveolar bone loss and disruption by outcome. 111. The effectiveness of clinical para- twice daily treatment with ketorolac trometham- meters in accurately predicting tooth survival. J ine oral rinse. J Periodontal Res 1998;33(2): Periodontol 1996;67(7):666-74. 75-82. 49. Newman MG. Genetic risk for severe periodontal 36. Pociot F, Molvig J, Wogensen L, et al. ATaq' poly- disease. Compend Contin Educ Dent 1997; morphism in the human interleukin-1 beta (IL- 18(9):881-4. lp) gene correlates with secretion in vitro. Eur J 50. Genco RJ. Assessment of risk of periodontal dis- Clin Invest 1992;22:396-402. ease. Compend Contin Educ Dent 1994;18 37. Cox A, Duff GW. Cytokines as genetic modifjring (Suppl):S678-83. factors in immune and inflammatory diseases. J 51. Page RC, Beck JD. Risk assessment for periodontal Pediatr Endocrinol Metab 1996;9:129-32. diseases. Int Dent J 1997;47:61-87. CHAPTER5

CARDIOVASCULARDISEASES AND ORALINFECTIONS

Robert J. Genco, DDS, PhD, Steven Offenbacher, DDS, James Beck, PhD, Terry Rees, DDS, MSD

The relationship between oral infections and car- agement requires a thorough medical history and diovascular disease is well known, particularly with physical examination, evaluation of vital signs, and respect to orally derived bacteremias as a source of medical consultation, when indicated.&12In most organisms that infect damaged heart valves causing instances, guidelines for periodontal management bacterial endocarditis. Recently, evidence has of patients with cardiovascular diseases are well emerged relating periodontal infections to coro- established. One area, however, remains strongly nary artery disease and stroke. controversial, with many experts voicing markedly This chapter will discuss how oral infections different opinions; that is dental management of are related to bacterial endocarditis, coronary individuals with valvar heart disease. 13-17 artery disease, and stroke. Etiologic associations, Infective endocarditis (IE) is a microbial infec- case-control studies, mechanisms, and intervention of a native or prosthetic cardiac valve or sur- tion studies, where appropriate, as well as manage- rounding cardiac tissue. It may be caused by a vari- ment of periodontal patients at risk for infective ety of microorganisms, including bacteria, fungi, endocarditis and arteriosclerosis will be presented. rickettsiae, or chlamydia. The clinical course of IE The main goal of this chapter, therefore, is to pro- may be classified as acute (duration of less than vide a basis of knowledge relating oral infections, 6 weeks) or subacute (duration of more than especially periodontal disease, to cardiovascular 6 weeks). The two most common microorganisms diseases, with clinical management guidelines out- associated with community-acquired IE are Strep- lined, where appropriate. tococcus viriddns and Stuphylococcus uureus, either of which may, on occasion, be normal commensals in the oral cavity.18 The biologic load of these organ- THE PERIODONTAL PATIENT AT RISK isms may be markedly increased in the presence of FOR INFECTIVE ENDOCARDITIS oral infection such as chronic periodontitis. 14~19,20 Other causative microorganisms for IE include Cardiovascular diseases affect over 43 million indi- enterococci, which are occasionally found in the viduals in the United States, with a marked oral cavity, or gram-negative HACEK micro- increase among the geriatric population. lp3 Since organisms (Huemophilus species, Actinobucillus this population group is increasing in number and uctinomycetemcomituns, Curdiobucterium hominis, since more elderly individuals are dentate than in Eikenelh, and Kingelh), some of which, especially the past, there is also an increased incidence of A. uctinomycetemcomituns and Eikenelh corrodens, periodontal disease in this patient group. This, are putative periodontal pathogens. Other perio- coupled with recent evidence linking severe, gener- dontal pathogens which have been occasionally alized periodontitis with coronary artery disease, associated with IE include Cupnocytophugu and suggests that the periodontist must be prepared to Luctobucillus species. Nosocomial IE is most com- provide safe yet effective therapy to patients with monly caused by antibiotic-resistant S. uureus various types of heart condition^.^>^ Patient man- infection. 5,21-23 64 Periodontal Medicine

The increased use of heroin or other intra- ence of the disease. Today, however, earlier diagno- venously injected illicit drugs has hrther expanded sis has resulted in diminished occurrence of these the spectrum of causative organisms to include Cun- signs. Patients with subacute IE are also at risk for didu ulbicuns and other common skin-related emboli and abnormalities in the hnction of many microorganisms such as S. u~re~~.~~-~~Additionally, organs, including the spleen and kidney. Cerebral an increasing number of patients receive intravenous emboli may induce stroke or seizures, altered levels shunts or fistulas during hospitalization or have of consciousness, or other neurologic manifesta- them permanently placed; either of these may serve tions. Cardiac changes are consistent with underly- as a source for systemic sepsis caused by a variety of ing valvar or congenital heart defects and may lead microorganisms. For example, sepsis may be a spe- to congestive heart fail~re.~~>~~ cial problem for individuals receiving renal Diagnosis of endocarditis is based on the pres- hemodialysis or for those with diabetes mellitus that ence of classic symptoms: a persistent bacteremia use indwelling devices for administration of insulin. or fungemia and the presence of a heart murmur A growing number of patients suffer from acquired associated with valvar dysfunction. Transthoracic immunodeficiency syndrome or other immunosup- and transesophageal echocardiography are very pressant disorders, and many individuals are pre- accurate in the identification of anatomic heart scribed drugs that induce immun~suppression.~~changes associated with endocarditis. Differential Most IE occurs in individuals with no known valvar diagnosis may include acute rheumatic fever and lesions although the majority of patients in this altered heart function associated with dysfunction group usually have predisposing factors such as of organs other than the heart.23 coronary artery disease, alcoholism, intravenous Infective endocarditis has a high morbidity drug abuse, or long-term hernodialy~is.~~ and mortality, and therefore prevention is highly Individuals with cardiac valve prostheses are desirable. Preventive regimens include measures to especially susceptible to IE although those with reduce the potential for significant bacteremia native valvar damage and even those with undam- from the oral cavity, the skin, the upper respirato- aged heart valves may develop endocarditis. Infec- ry tract, and the gastrointestinal or urinary tive endocarditis may occur spontaneously or as a tract. 14-16,27 The following section will discuss den- result of focal sites of infection. Blood-borne path- tal management of individuals at risk for IE, par- ogenic microorganisms may lodge directly on heart ticularly bacterial endocarditis (BE) related to oral valves or on the endocardium near anatomic car- infection and/or therapeutic manipulation of diac defects. mouth tissues. 14-16,23,27 The incidence of IE has remained constant for several years although the epidemiology has changed. In the past, the most common cause of VALVAR HEART DISEASE IE in young individuals was rheumatic fever (RF). In contrast, RF and IE are now more common Valvar heart disease is a significant cause of cardiac among older individuals, especially those over 60 morbidity in individuals of all ages despite a sig- years of age with chronic heart disease or mitral nificant decline in the incidence of rheumatic dis- valve prolapse due to calcifications of one or more ease in the developed countries. The patient with of the valves or associated ~~ssu~s.~~,~~,~~,~~valvar disease may be especially susceptible to IE. Acute IE may result from bacteremias associat- The most common valvar anomalies include mitral ed with virulent strains of microorganisms. Signs regurgitation, often associated with mitral valve and symptoms may include abrupt onset of fever, prolapse; aortic stenosis resulting from congenital cutaneous and oral petechiae, and focal dermal deformity of the aortic or bicuspid valve; or senile gangrene. These features may be accompanied by valvar calcification. Aortic regurgitation may be intravascular coagulation, which markedly increas- associated with dilatation of the aorta as well as a es the risk for emboli and metastatic infection of defective aortic valve. Thus, valvar heart disease any body organ.23 may result from diverse pathologic process- Subacute IE may begin insidiously and persist es. 8,22,28,29 Valvar calcification may be associated for months. Affected individuals complain of fever, with congenitally acquired heart defects, mitral night sweats, myalgias, arthralgias, malaise, anorex- valve regurgitation due to mitral valve prolapse, ia, and easy fatigability.' In the past, clubbing of the aortic or bicuspid valve stenosis, or senility. These last digits of the fingers or the presence of Osler's calcifications of the valvar leaflets or their associat- nodes on the hands were frequent signs of the pres- ed chordae tendineue cordis or papillary muscles Cardiovascular Diseases and Oral Infections 6 5 can lead to turbidity and back-flow of blood, plac- TABLE 5- I. Cardiac Conditions Requiring ing the patient at risk for heart failure and/or IE. Prophylaxis for Dental Treatment Valvar disease tends to be progressive over time because degenerative changes may be superim- High Risk posed on an initial abn~rmality.~~.~~ Prosthetic cardiac valves, including bioprosthetic Several conditions are commonly associated and homograft valves with valvar stenosis or regurgitation. Rheumatic Previous infective endocarditis fever results from streptococcal sepsis, and it occa- Complex congenital cardiac malformations sionally induces an autoimmune phenomenon, in Systemic pulmonary shunts (surgically constructed) which antibodies against the streptococcal antigen Moderate Risk cross-react with valvar tissue. The initial lesion of Rheumatic heart disease, Kawasaki disease, connec- rheumatic heart disease is edema of valvar tissues. tive tissue disorders and, other conditions associated However, progressive fibrosis, calcification, and with valvar dysfunction, even after valvar surgery scarring may subsequently lead to valvar stenosis or Hypertrophic cardiomyopathy incompetence.22 Previous episodes of endocarditis - Mitral valve prolapse with valvar regurgitation may also predispose the affected individual to fur- - Most other congenital cardiac malformations, ther valvar damage and a recurrence of Despite IE. except as listed below in Table 5-2 increased use of antibiotics, RF continues to be the most common cause of mitral valve stenosis world- Modified from Dajani AS, Taubert KA, Wilson W, et al. Pre- wide but its importance is diminishing in the vention of bacterial endocarditis. Recommendations by the developed countries due, in part, to early diagnosis American Heart Association. Circulation 1997;96:358-66. and treatment.22 The incidence of valvar disease has increased in the geriatric population due to RF, valvar calci- Mitral valve prolapse (floppy valve syndrome) is fications with regurgitation, mitral valve prolapse, characterized by idiopathic loss of the fibrous and or valvar sten~sis.~~>~'As discussed earlier, an elastic tissue of the mitral valve leaflets or the chordae increasing number of elderly individuals are den- tendineae cordis. It is found in several heritable con- tate yet experience a general reduction in immune nective tissue disorders, especially Down syndrome, reSponse.2223253 Elders-Danlos syndrome, and Marfan syndrome.35It Heart transplantation or ischemic heart disease is also common in the general population, especially may induce degenerative calcification, rupture, or in young women, the elderly (especially men), and scarring of perivalvar tissue, any one of which may those affected by psychiatric conditions such as panic be associated with valvar regurgitation and an disorder, severe depression, or anorexia ner- increased risk for IE.31 Degenerative calcification is vosa.22,25,3740Therefore, any such history suggests a a common cause of aortic stenosis in the elderly or possible need for medical consultation and requires a in individuals with chronic renal dysfunction while calcification of the mitral annulus in the elderly (especially women) can also induce mitral regurgita- Table 5-2. Cardiac Conditions not Requiring tion or sten~sis.~~>~l-~~Other causes of valvar steno- Endocarditis Prophylaxis sis include radiation therapy, the use of serotonin agonists such as methysergide, or previous use of Isolated secundum atrial septal defect fenfluramine and phentermine in combination.22 Surgical repair of secundum atrial septal defects, Kawasaki disease is an acute febrile disease com- ventricular septal defects, or patent ductus arteriosus plex of unknown etiology. It features conjunctival after 6 months and without residua congestion, dryness of lips, skin, and the oral cavity, Previous coronary artery bypass graft cervical lymphadenopathy, and cardiovascular Mitral valve prolapse without valvar regurgitation changes, including coronary thromboarteritis, mitral Physiologic, functional, or innocent heart murmurs valve insufficiency, and myocardial i~chemia.~~>~~Previous rheumatic fever, Kawasaki disease or con- Congenital heart anomalies may induce car- nective tissue disorders without valvar dysfunction diac blood turbulence and permanent valvar dam- Cardiac pacemakers and implanted defibrillators age even after surgical repair. Therefore, patients Modified from Dajani AS, Taubert KA, Wilson W, et al. with certain congenital defects should be consid- Prevention of bacterial endocarditis. ered at lifetime risk for IE although the risk may be Recommendations by the American Heart Association. low (Tables 5-1 and 5-2). 14, 22 Circulation 1997; 96: 3 5 8-66. 66 Periodontal Medicine thorough understanding of the patient's condition tous disease and least successful in rheumatic heart and its possible rarnifi~ations.~~>~~ disease or end~carditis.~~>~~ Systemic lupus erythematosus (SLE) may Native valves may be surgically treated with place affected individuals at risk for valvar disease commissurotomy or PercutaneOus balloon valvulo- and subsequent IE. Lupus erythematosus may plasty. These therapies are often only palliative, and affect virtually any body organ. Recent evidence mitral valve prosthetic replacement may ultimately suggests that the cardiovascular system is frequent- be necessary, especially if the valves are heavily ly involved. Mitral valve insufficiency may occur scarred or calcified to such a degree that severe valve because SLE occasionally induces nonbacterial regurgitation is present. Prosthetic replacement, vegetations or thickening of the valves, sometimes however, has a higher mortality and morbidity.22 leading to regurgitation; however, IE is relatively Valvar prostheses may be either mechanical or rare. Liebman Sacks verrucae associated with SLE biologic, with each type presenting certain advan- may induce mitral valve prolapse if the valve tages and disadvantages. Currently, more than 40 leaflets or the chordae tendineae cordis are affect- types of mechanical valve prostheses are available ed. The antiphospholipid syndrome occasionally (Figure 5-1). They are often indicated for young or associated with SLE or other collagen-vascular dis- middle-aged individuals because they are generally orders may lead to myxomatous mitral valve tissue quite durable. The greatest structural risk is fracture changes and prolapse, with regurgitation in of the strut that holds the ball or disk in place. This, approximately one-third of patients with myxoma- however, rarely occurs. The disadvantage of the tous disease.23 Patients with SLE often receive mechanical prosthesis is that it predisposes the recip- immunosuppressant drugs on a long-term basis ient patient to thromboembolism, necessitating the which may increase susceptibility to IE.' 1,22,29 long-term use of anticoagulant medications.22 Echocardiographic examination will usually Bioprosthetic valves may be xenographic (usu- detect the presence of SLE-induced heart ally porcine) or allographic (Figure 5-2). On occa- lesion^.^^>^^ Medical consultation is indicated in sion, an autographic valve is transplanted from one patients with SLE to determine any need for pro- site to another following placement of a prosthesis phylactic antibiotic coverage during periodontal in the donor site. Bioprostheses are more likely to therapy. Patients with SLE that have not been deteriorate over time but durability increases in medically evaluated for cardiac changes should patients over age 60 years and continues to receive only emergency dental therapy with pro- improve with the increasing age of the recipient. phylactic antibiotic coverage until medical clear- Xenographs offer the advantage of a lower risk for ance is obtained.''>29 thromboembolism, and long-term anticoagulant Mitral regurgitation may be managed by sur- therapy is usually not necessary.22 gical correction or by prosthetic replacement of the Failure of mechanical valves is rare but can involved valves. Whenever possible, repair of have catastrophic effects (Figure 5-3). In contrast, native valves is the treatment of choice. It is most failure of bioprosthetic valves is an expected conse- likely to be successful in the presence of myxoma- quence, and young recipients of these devices

Figure 5-1. Diagram of a mechanical valvar prosthesis. Cardiovascular Diseases and Oral Infections 67

Figure 5-2. Porcine bioprosthesis: A, Closed. B, Open should anticipate future prophylactic replacement. or focal oral infections, with or without manipula- Fortunately, the degenerative process is slow and tion of oral ti~~~e~.~~J5~~5~~~~~~It is generally not may take many years to manifest significant hemo- possible to predict which patient will develop IE or dynamic symptoms.22 which particular procedure will be responsible. 14,45 Recently, Lamas demonstrated an absence of bacteremias among patients receiving oral mucosal DE NTAL CONS I DE RAT10 N S biopsies except when periodontal tissues were included in the specimen.43 The patient with valvar heart disease faces the risk Transient bacteremias may be induced by of congestive heart failure, hemodynamically sig- some surgical or nonsurgical periodontal treatment nificant arrhythmias, and IE. Although dentists procedures. However, these bacteremias rarely per- may provide dental care for patients with any of sist longer than 15 minutes and the majority dissi- these disorders, most often they are called upon to pate within 3 to 5 minute^.'^''^,^^ The risk of IE manage patients at risk of IE.35 Dental procedures derived from transient bacteremias associated with that involve manipulation of soft tissue and result manipulation of dental tissues must be weighed in bleeding can produce transient bacteremias. For against the cost and risk of complications associat- example, 43% of patients with periodontitis expe- ed with administration of systemic antibiotics. Use rienced transient bacteremia following routine periodontal probing4' Administration of local intraligamental analgesia may be more likely to induce odontogenic bacteremia than tooth extrac- ti~n.~~However, available evidence clearly indicates that transient odontogenic bacteremias may be associated with routine body functions such as chewing food and brushing teeth and many authorities have challenged the benefits of prophylactic antibiotic coverage for dental treatment procedures. 14-17,25 Not all bacteremias are significant in that they may be extremely transient (2 to 3 minutes) and may not involve microorganisms likely to lodge in damaged heart tissue.43 The incidence and severity of odontogenic bacteremias 68 Periodontal Medicine of prophylactic antibiotics may well induce a higher procedures is required, it may be prudent to morbidity and mortality rate than do transient observe an interval of 9 to14 days between proce- bacteremias, and several authorities have recom- dures to minimize the risk of the emergence of mended more conservative use of antibiotic pro- resistant strains of organisms. '',54-57 In the event phylaxis during dental treatment .7>14, '5~17,43 unanticipated bleeding occurs during low-risk In 1997, the American Heart Association dental procedures, the administration of antibi- (AHA) updated its recommendations for dental otics within 2 hours may be effective in prevent- management of patients at risk for IE induced by ing IE. There is no prophylactic benefit, however, odontogenic bacteremias.l4 These guidelines are if antibiotics are administered more than 4 hours applicable for prevention of endocarditis induced after the incident.14 by oral S. viriddns (alpha hemolytic Streptococcus). The AHA recommendations for specific pro- Dental procedures likely to induce significant bac- phylactic antibiotic regimens for dental procedures teremia are listed in Table 5-3, and procedures at are widely published and will not be repeated in this low risk of bacteremias are identified in Table 54. text. For most adults, oral administration of 2 g of There is some evidence that oral irrigation or amoxicillin I hour before the dental procedure is use of air-abrasive polishing devices may induce recommended. Clindamycin (600 mg I hour before bacteremia when used inappropriately or in the dental procedure), cephalexin/cefadroxil or patients with poor periodontal health, and these azithromycin/clarithromycin are recommended as devices are not recommended. '',4649 Rinsing with alternatives in patients that are allergic to penicillin. antimicrobial agents containing chlorhexidine glu- Intramuscular or intravascular antibiotic regimens conate or povidone iodine prior to manipulation are prescribed for patients that cannot take oral of dental tissues may reduce the overall bacterial medications. The recommendations are considered bioload. This may be especially important in high- adequate for patients that are at high risk from IE, risk patients and in those with poor oral hygiene. including those with cardiac valve prostheses.l4 There is, however, no conclusive evidence to con- Individuals that take penicillin for secondary firm that prerinsing reduces the risk of oral bac- prevention of rheumatic fever or for other purpos- teremias or IE.50-53Frequent home use of antisep- es may harbor oral microorganisms that are rela- tic rinses is not recommended due to the potential tively resistant to penicillin, amoxicillin, or ampi- for developing resistant microorganisms. l4 cillin. In such cases, the dentist should select clin- Certain cardiac conditions are more often damycin or another of the alternative regimens for associated with endocarditis than are others (see endocarditis prophylaxis. Cephalosporins should Tables 5-1 and 5-2). In patients at risk, antibiot- not be used due to the potential for microbial ic prophylaxis is recommended for a22 dental pro- cross-resistance between cephalosporin and peni- cedures likely to induce significant bleeding of cillin derivatives. hard or soft oral tissues to include surgical or nonsurgical periodontal therapy. If a series of dental TABLE 5-4. Dental Procedures with Low Bacteremia Risk TABLE 5-3. Dental Procedures Creating Restorative procedures with or without retraction Bacteremia Risk cord Dental extractions Local anesthetic injections Implant placement and tooth reimplantation Placement of rubber dams Surgical and nonsurgical periodontal procedures Suture removal Endodontic instrumentation beyond the root apex Placement or adjustment of orthodontic or removable or endodontic surgery prosthodontic appliances Initial placement of orthodontic bands Oral impressions Intraligamentary injection Fluoride treatments Prophylaxis when bleeding is expected Oral radiographs Subgingival placement of antibiotic fibers or strips Shedding of primary teeth

Modified from Dajani AS, Taubert KA, Wilson W, et al. Modified from Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. Recommendations by the American Heart Association. Circulation 1997; 96: 3 58-66. Circulation 1997; 96: 3 5 8-66. Cardiovascular Diseases and Oral Infections 69

Professional judgment may have to be used for patients that do not fit established guidelines set forth by the AHA. Tetracyclines are not recommended for prophylactic cardiovascular antibiotic coverage.l4 It has been suggested, however, that patients with periodontal diseases associated with tetracycline-sensitive organisms may be best treated by administration of tetracyclines for 2 to 3 weeks prior to periodontal treatment followed by a I -week delay and then performance of periodontal therapy using AHA-recommended prophylactic regimen^.^' When possible, multiple dental procedures should be performed on the day of prophylactic antibiotic coverage and further treatment delayed for 9 to 14 days before the same antibiotic is used. Medical consultation should be obtained as indicated for patients that require multiple, prolonged, or unusual regimens of prophylactic antibiotic coverage. The relationship between IE and periodontal treatment procedures incorporating local delivery of antibiotics or antimicrobials into gingival pockets is not known at present although the AHA recommends systemic prophylaxis when antibiotic fibers or strips are inserted, presumably because of the potential for traumatic injury and bleeding during these procedures. l4 Antibiotic prophylaxis minimizes the risk of infective endocarditis but does not preclude its occurrence, and the clinician must remain alert for persistent fever or other symptoms associated with the condition. '',59-61

PROSTHETIC VALVE ENDOCARDITIS

Individuals with prosthetic heart valves have high morbidity and mortality in the event IE occurs. Therefore, these individuals may require especially diligent dental care before and after open heart surgery. Potential oral foci of infection should be eliminated before the surgery.' 'J~,~~Questionable Figure 5-4. A 47-year-old Caucasian female with a history of teeth should not be retained, and the patient's rheumatic heart disease. The patient is scheduled for valve replacement open heart surgery in 1 month. A, Facial view. motivation and ability to maintain effective oral B, Mandibular anterior lingual view. C, Panoramic radiograph. hygiene procedures should be assessed (Figure 5-4). Prior to cardiac surgery, dental procedures associated with a high risk of significant bac- must be sustained, if possible, for the patient's life- teremia should be accompanied by appropriate time (Figures 5-6 and 5-7). For obvious reasons, prophylactic antibiotic support. When possible, antibiotic prophylaxis is indicated for all high-risk dental extractions should be accomplished at least dental treatment procedures. Some periodontal 2 weeks prior to the heart surgery to allow ade- treatment procedures may be contraindicated. For quate wound healing (Figure 5-5). example, surgical procedures that create an open Following placement of a prosthetic heart valve, wound surface (gingivectomy free gingival grafts) close medical-dental cooperation is essential. Peri- should probably be avoided due to the prolonged odontal therapy is usually not appropriate within 6 wound healing time. These procedures also may be months of valve placement, and periodontal health contraindicated in patients receiving concomitant 70 Periodontal Medicine

Figure 5-5. Same patient as Figure 5-4 one day before heart surgery. A, Maxillary anterior palatal view. Dental and periodontal infections have been eliminated. B, Mandibular anterior lingual view. anticoagulant therapy to minimize the potential for misleading information regarding the patient's state postoperative hem~rrhage.~' of coagulability. To standardize PT measurements, the World Health Organization developed an international reference thromboplastin, using human ANTICOAGULATED PATIENTS brain thromboplastin as the universal standard for comparison purposes. Each laboratory performing Patients with prosthetic valves, thromboembolic prothrombin tests must now compare their pro- phenomena, or other blood flow disturbances often thrombin against the standard. This results in a cor- receive anticoagulant medication immediately fol- rected normal prothrombin time for all medical lowing heart surgery or for their lifetime. laboratories.15,34,36 Under most circumstances, the Coumarin is usually used for outpatient anticoagu- INR for patients with a normal PT is approximate- lation. It exerts its effect through the competitive ly I .O. Patients requiring anticoagulant therapy are inhibition of vitamin K, with subsequent depletion usually maintained at an INR ranging from 1.2 to of coagulation factors dependent on that substance 4.5. So far as is known today, patients within this for their synthesis (11, VII, IX, and X). Coumarin range can receive all types of periodontal therapy, has a delayed onset and a prolonged effect. Its effec- provided local hemostatic measures are taken. tiveness is monitored via the corrected prothrom- These include atraumatic surgery, adequate wound bin time known as the international normalized closure using sutures, application of postsurgical ratio (INR). In the past, prothrombin times (PT) pressure, and the use of topical clotting agents such varied between laboratories, potentially leading to as thrombin, foamed gelatin, oxidized regenerated cellulose, or synthetic collagen. Oral rinses containing tranexamic acid have markedly reduced the risk of excessive hemorrhage without alteration of the INR level. 15,34,62 Tetracyclines are contraindicated in patients on anticoagulant drugs since they interfere with prothrombin formation.54 When contemplating procedures likely to cause bleeding, it is appropriate to communicate with the patient's phy~ician.'~On occasion, pharmacologic manipulation becomes necessary for the anticoagulated patient. If the patient can tolerate a wait of several hours or more, vitamin K administration will reverse the effect of coumarin. More urgent situations may require blood transfusion or infusion of Figure 5-6. Same patient as Figure 5-4 6 months after fresh-frozen plasma or packed platelets. '>' 5,23 successful placement of valvar prosthesis. A, Anterior view. Aspirin is often used as an antithrombotic agent B, Maxillary anterior palatal view. because of its inhibition of platelet aggregation. Cardiovascular Diseases and Oral Infections 7 1

Most cardiologists prescribe very small daily dosages remains one of the primary causes of death in the (80 to 325 mg). At these dose levels, the medication United States, Europe, and much of A~ia.‘~>‘~ will not significantly alter bleeding time. 15,62 On The process, supported by a considerable body occasion, however, patients on higher aspirin levels of evidence, is that atherosclerosis is an inflamma- are at a slight risk for prolonged postoperative hem- tory disease.“ This concept, also termed the Ross orrhage following periodontal therapy. For these response-to-inj ury hypothesis of atherosclerosis, individuals, the medication should be discontinued proposes that the initial lesion results from injury for 4 to 7 days prior to the scheduled procedure to the endothelium and leads to a chronic inflam- with the concurrence of the cardi~logist.~>”~ matory process in the artery. This results in the migration of monocytes through the endothelium Summary into the underlying tissue and the proliferation of smooth muscle cells. Activation of the monocytes The patient with valvar heart disease is frequently (macrophages) in the blood vessel leads to the encountered in dental practice. Safe and effective release of hydrolytic enzymes, cytokines, management of such patients requires close med- chemokines, and growth factors, which induces fur- ical and dental cooperation. Periodontal health ther damage, leading to focal necrosis. Accumula- and absence of oral foci of infection are essential, tion of lipids is a key feature of this process, and in and on some occasions, prophylactic antiobiotic later stages, the atheromatous plaque can be covered coverage is required for dental treatment proce- with a fibrous cap over the focal necrotic area. At dures. The dental practitioner must remain knowl- some point, the fibrous cap may become eroded and edgeable regarding current concepts in the man- rupture, which leads to thrombus formation and agement of such patients. occlusion of the artery, resulting in an infarction. The initial event in the development of an atheroma appears to be endothelial injury that ORAL INFECTIONS AS A RISK results in the activation of the endothelial cells. This FACTOR FORATHEROSCLEROSIS, results in the upregulation of surface adhesin mole- CORONARY ARTERY DISEASE,AND cules and chemokines, both of which result in ISCHEMIC STROKE monocyte recruitment from the bloodstream (Fig- ure 5-8). The monocytes then pass through the The role of infections in atherosclerosis has been endothelium into the blood vessel and become discussed for many years. Recently, evidence has macrophages. The macrophages in the atheroma are accumulated that certain common oral infections activated and produce growth factors, which induce play a significant in role in atherosclerosis. Athero- smooth muscle proliferation as well as production of sclerosis lesions can occur in large- and medium- cytokines and other mediators that further activate sized elastic and muscular arteries. They can lead to the endothelium. Macrophages also accumulate ischemic lesions of the brain, heart, or extremities lipids, especially low-density lipoproteins (LDL) in and can result in thrombosis and infarction of the oxidized or modified form. Modified LDL can affected vessels, leading to death. Cardiovascular be a major cause of injury of both the endothelium disease, mostly associated with atherosclerosis, and the underlying smooth muscle. When the LDL

Figure 5-7. The patient from Figure 5-4 has maintained oral health for 7 years after heart surgery. 72 Periodontal Medicine

sibly protect against atheroma formation. Dia- Endothelial injury betes, through hyperglycemia and glycation of LDL and other proteins, as well as the dyslipi- I demia associated with diabetes, cigarette smoking, Endothelial activation through toxic factors in smoke, and hypertension and hyperhomocystinemia are also factors that can lead to endothelial injury and the subsequent cas- f I Adhesion LDL Cytokines Chemokines molecule cade of events leading to atherosclerotic lesions. oxidation A \ expression Other stages in the formation of atherosclerotic plaque are depicted in Figure 5-9. A fatty streak can become a fibrous plaque, which becomes com- 2\I recruitment plex with a lipid core, calcification, and deposition U / of extracellular matrix protein. Activated T cells Macrophage accumulation F may stimulate metalloproteinase production by macrophages, which remodel the fibrotic plaque. I Eventually, a uniformly dense fibrous cap can cover Growth factors the atheroma resulting from deposition and remodeling of the extracellular matrix in the I plaque. Through remodeling of the extracellular Smooth muscle proliferation matrix, the fibrous cap may become thin and rupture, leading to activation of the clotting system with thrombosis. is thought that thrombosis and Figure 5-8. Illustration of mechanisms of atherosclerosis It resulting from endothelial injury. subsequent occlusion of the artery may be responsible for as many as one-half of the cases of acute myocardial infar~tion.~~ particles are trapped in the artery, they can undergo Figure 5-1 0 depicts the intersecting protease progressive oxidation and be internalized by cascade that connects the blood clotting system macrophages, with formation of lipid peroxidases with extracellular matrix deposition and degrada- and accumulation of cholesterol esters. This results tion. The extracellular matrix is produced by in the production of foam cells. Modified LDL is smooth muscle cells and endothelium and remod- chemotactic for other monocytes and can induce eled through degradation with endopeptidases, the the production of factors from macrophages that matrix metalloproteinases. From Figure 5-1 0 it expand the inflammatory response. can be seen that plasminogen is converted to plas- Antioxidants can increase the resistance of min in the presence of tissue plasmin activator LDL to oxidation, and this may explain why (TPA). Plasmin then activates the latent matrix antioxidants, such as vitamin E, can reduce the size metalloproteinases, which results in matrix degra- of fatty streaks and atherosclerotic lesions and pos- dation. Tissue inhibitors of matrix metalloproteinases (TIMPs) can inhibit matrix degradation whereas alpha-1-antitrypsin can inhibit plasmin- mediated degradation of the extracellular matrix. Fatty streak Plasmin can also result in the production of fibrin from fibrinogen, which then undergoes fibrinoly- J. is likely that inflammatory mediators, such as Endothelial activation sis. It cytokines and proteases produced by macrophages, f and other cells in the atheromatous plaque, as well Complex plaque as bacterial proteases, contribute to extracellular Fibrous plaque > with lipid core and calcification matrix remodeling of fibrofatty atheromatous plaques through activation at various stages in the protease cascade depicted in Figure 5-10. Plaque rupture J J. Role of Infections in Endothelial Injury Thrombosis There is accumulating evidence of an association Figure 5-9. Stages in the formation of atherosclerotic plaque. between some common infections of man and ath- Cardiovascular Diseases and Oral Infections 73

Figure 5-10. Proteases in the atheromatous plaque. TPA = tissue plasmin activator; MMP = matrix metalloproteinases;TIMPs = tissue inhibitors of matrix metalloproteinases; alAT = a1 antitrypsin. erosclerosis. One possible mechanism is through smoking. Mattila.. and ..colleagues7' studied 100 endothelial injury by infectious agents, triggering, patients with angiographic measurements of the in part, the inflammatory response seen in athero- degree of coronary artery occlusion and previous sclerosis. The role of infections has been recently MI. They used the dental pantomography index, reviewed by Danesh and colleagues,68and there is which assessed periapical lesions, vertical bony mounting evidence that infection with Cblamydiu defects, and furcations lesions in bone, and found pneumoniue, Helicobucterpylori, periodontal bacte- that dental infections were associated with coro- ria, and cytomegalovirus are associated with heart nary atheromatosis (p = .003). These results were disease (Table 5-5). statistically significant after adjusting for age, serum lipids, body mass index, social class, and Studies Relating Oral Infections hypertension. Arbes and colleagues studied the to Coronary Artery Disease association between the extent of periodontal attachment loss and self-reported history of heart Several studies relate oral infections, including attack from the National Health and Nutrition periodontal disease, to coronary artery disease. In Examination Survey (NHANES) I11 data.72They Table 5-6, case-control and cross-sectional studies found that when the percent of periodontal sites of the association between periodontal disease as per person with attachment loss of 2 3 mm were well as other oral conditions and coronary artery categorized as 0%, > 0 to 33%, > 33 to 67%, and disease are presented. In the study by Mattila and > 67%, the adjusted odds ratio with each higher colleague^,^^ 102 controls were compared with I 00 category of attachment loss as relative to the 0% patients that had a myocardial infarction (MI). category was 1.4 (0.8 to 2.5), 2.3 (1.2 to 4.4), and They measured oral status, using the total dental 3.8 (1.5 to 9.7), respectively. Adjustments were index (TDI), which is a measure of caries, peri- made for age, sex, race, socioeconomic status, odontitis, periapical lesions, and pericoronitis, and smoking, diabetes, high blood pressure, body mass the pantomographic index, which is a measure of periapical lesions, vertical bony defects, and hrca- tion lesions. They found that dental health was TABLE 5-5. Infections and Atherosclerosis worse in MI patients than in controls, after adjust- Injury ment for age, social class, smoking, serum lipids, and diabetes. In a large cross-sectional study of Cbhmydia pneumoniae 1,384 men, 45 to 64 years of age, Paunio and col- Helicobacter pylori league~~~found that a history of missing teeth was Periodontal bacteria (Porpbyromonas gingivalis, related to ischemic heart disease, after adjusting for Bacteroides forsytbus, and Campylobacter rectus) age, hypertension, geographic area, education, and Cytomegalovirus 74 Periodontal Medicine index, and serum cholesterol. This study supports remain unresolved by this study. Mattila and col- findings from previous cross-sectional studies of an leagues7* conducted a 7-year follow-up study of 214 association between periodontal disease and coro- subjects (182 men, 32 females) that had fatal and nary artery disease (CAD). These cross-sectional nonfatal CAD and measured the TDI as the oral and case-control studies support the hypothesis condition. They found that the TDI was a statisti- that oral infections, including periodontal disease, cally significant predictor of coronary artery disease are associated with CAD. after adjustment for smoking, diabetes, hyperten- Perhaps more convincing evidence for the asso- sion, socioeconomic status, previous MI, body mass ciation of periodontal disease and CAD comes from index, and serum lipids. a series of longitudinal and prospective studies, In 1996, Beck and colleagues75 published a which are tabulated in Table 5-7. One of the first study of 1,147 males enrolled in a normative aging longitudinal studies to address the association study. Fatal and nonfatal coronary heart disease between periodontal disease and coronary artery dis- and stroke were assessed over 18 years. Baseline ease was published by DeStefano and colleagues in radiographic measurements of alveolar crestal 1993.73They looked at 9,760 individuals in the heights were made, and the mean alveolar bone NHANES I, who were evaluated between 1971 and loss was dichotomized into high or low. Those 1974. These individuals were assessed at baseline for individuals with high levels of mean whole mouth periodontal disease using the Russell periodontal alveolar bone loss at baseline had a greater relative index, and for decayed and missing teeth, and these risk of total coronary heart disease (1.5; 95% CI individuals were followed up for 14 years for devel- 1.04 to 2.14) than those with low bone loss at opment of CAD. Subjects with periodontitis at baseline. These results remained statistically signif- baseline had a 25% increased risk of having CAD in icant, after adjusting for age, body mass index, sys- the follow-up period. In males under 50 years of tolic blood pressure, and cholesterol. High and low age, the relative risk was I .72 after adjusting for age, alveolar bone loss at baseline was also found to be blood pressure, and diabetes. Unfortunately, base- associated with fatal coronary heart disease, that is, line data on smoking was available for only about those with high levels of alveolar bone loss had a one-quarter of the subjects, hence these data are greater chance of developing fatal heart disease only partially adjusted for smoking. Therefore, with a relative risk of 1.9 (95% CI 1.10 to 3.43), lifestyle issues, such as smoking and oral hygiene, after adjusting for age, smoking, systolic blood

TABLE 5-6. Summary of Case-Control and Cross-sectional Studies of the Association between Periodontal Disease and Other Oral Conditions and Coronary Artery Disease Study Design/ Systemic Study Subjects Outcome Oral Condition Findings Mattila et al, 100 myocardial MI Total dental index Dental health worse in MI patients, 198969 infarction (MI); score and a after adjustments for age, social 102 controls “pantomographic” class, smoking, serum lipids, index of periapical and diabetes lesions, vertical bony defects, and furcation lesions Paunio et al, 1,384 men, 45 to History of Missing teeth Number of missing teeth 199370 64 years of age angina or statistically associated (p = .0374) previous MI with ischemic heart disease, along with age, hypertension, geographic area, education, and smoking Mattila et al, 100 angiography Degree of Dental Dental infections associated with 199371 patients coronary pantomographic coronary atheromatosis (p = .003), artery index after adjusting for age, serum lipids, occlusion, body mass index, socio economic previous MI status class, and hypertension Cardiovascular Diseases and Oral Infections 7 5

TABLE 5-7. Summary of Longitudinal Studies of the Association between Periodontal Disease and Other Oral Conditions and Coronary Artery Disease Study Design/ Systemic Study Subjects Outcome Oral Condition Findings DeStefano 9,760 in the Coronary Russell periodontal Subjects with periodontitis had 25% et al, National Health artery index, number increased risk of CAD. In males under 199373 and Nutrition d'isease of decayed and 50 years of age, the relative risk was Examination (CAD) missing teeth 1.72. Results were adjusted for age, Survey I blood pressure, diabetes, and partially adjusted for smoking Mattila et al, 214 subjects Fatal and Total dental The total dental index was a statistically 199574 (182 males, non fatal index significant predictor of CAD. Adjust- 32 females) at CAD ments made for smoking, diabetes, 7-year follow-up hypertension, socioeconomic status, previous MI, body mass index (BMI), and serum lipids Beck et al, 1,147 males Coronary Radiographic Dichotomized mean whole mouth bone 199675 heart disease interproximal loss hi-lo at baseline associated with (CHD) alveolar crestal total CHD with relative risk of 1.5 and stroke heights (1.04,2.14), after adjusting for age, BMI, systolic blood pressure, and cholesterol. Hi-lo alveolar bone loss at baseline associated with fatal CHD with relative risk of 1.9 (1.10, 3.43), after adjusting for age, smoking, systolic blood pressure, and diabetes. Cumulative incidence of CHD increased with greater levels of age- adjusted alveolar bone loss at baseline Joshipura 44,119 male health Coronary Self-reported Those who reported periodontal disease et al, professionals artery periodontal and less than 10 teeth at baseline had 199676 followed up over disease disease and a relative risk of CAD of 1.67. Adjust- 6 years self-reported ment was made for smoking, physical number of activity, hypertension, cholesterol, teeth family history of CAD, dietary and alcohol intake Genco et al, 1,372 Native Electrocardio- Alveolar bone Baseline periodontal disease showed that 199777 Americans followed graphic level and tooth for those s 60 years of age, periodontal up for 10 years; evidence of loss disease was a predictor for subsequent population has a cardiovascular CVD, with a relative risk of 2.68 low level of smoking disease (CVD) (1.30, 5.5) after adjusting for diabetes, age, gender, cholesterol, BMI, smoking, and hypertension pressure, and diabetes. From these studies assessing also found that the cumulative incidence of coro- total coronary heart disease and fatal heart disease, nary heart disease increases with greater levels of it appears that the analyses were adjusted for many age-adjusted alveolar bone at baseline, suggesting a of the important risk factors that are relevant to dose response, that is, the more periodontal disease both periodontal disease and heart disease. It is of at baseline, the greater is the cumulative incidence considerable interest that Beck and colleagues75 of coronary heart disease over time. 76 Periodontal Medicine

Joshipura and colleagues76studied 44,I 19 male confirmed in all the studies reported to date. In con- health professionals for a period of 6 years. Seven- clusion, there is considerable cross-sectional, case- hundred and fifty cases of CAD, including fatal and control, and longitudinal/epidemiologic evidence of nonfatal MI, were documented. Periodontal status an association between periodontal infection and and number of teeth were self-reported. It was CAD. Other oral infections also may contribute, found that among those men that reported peri- but the evidence suggests that caries, per se, is not odontal disease and fewer than 10 teeth at baseline, related to CAD. Good evidence is not yet available there was an increased risk of cardiovascular disease to determine if there is an association of periapical as compared with men that had 25 or more teeth at lesions, pericoronal lesions, or other oral infections baseline (I.67 relative risk). In those that reported with heart disease. Also, little evidence is available no previous periodontal disease, no relationship to for women, Hispanic, Black, or Asian populations coronary heart disease was found (1.11 relative with respect to the relationship between periodontal risk). This study mainly shows an association infections and heart disease. between tooth loss (in those that reported periodontal disease) and coronary heart disease. It is Studies Relating Oral Infections to Stroke likely that the reported tooth loss was associated with periodontal disease. Self-reported periodontal There are several studies which provide suggestive disease is fraught with inaccuracies and misclassifi- evidence for an association between atherosclerosis- cations; however, the authors point out that when related ischemic stroke and oral infections (Table combined with assessment of tooth loss, which may 5-8). One of the first studies to report this associa- be more accurately self-reported, this study does tion was conducted by Syrjanen and colleague^.^^ point to a possible association between heart disease In a case-control study, they compared 40 patients and periodontal disease. The relative risk of 1.67 with ischemic cerebral infarction with 40 randomly remained after adjustment for smoking, physical selected community-based controls that were activity, hypertension, cholesterol, family history of matched for age and gender. The systemic outcome CAD, and dietary and alcohol intake. was ischemic cerebral infarction, and oral condi- Genco and colleagues77reported a longitudi- tions were assessed by the TDI. These investigators nal study of 1,372 Native Americans, who were found a statistically significant poorer level of oral assessed for periodontal disease at baseline, and fol- health in patients with ischemic cerebral infarction lowed up for I O years for electrocardiographic evi- as compared to controls. However, this is a small dence of cardiovascular disease, using the Pooling case-control study that did not control for other criteria. Periodontal status was measured by alveo- co-risk or confounding factors, such as smoking, lar bone levels. It was found that baseline peri- hypertriglyceridemia, hypertension, and febrile odontal disease for those under age 60 years was a infections, which were also found to be at statisti- predictor of subsequent cardiovascular disease, cally significantly higher prevalence in the patient with a relative risk of 2.68 (95% CI 1.30 to 5.50). group. Therefore, the extent to which these other These results were significant, after adjusting for confounding variables were related to the associa- diabetes, age, gender, cholesterol, body mass index, tion between dental health and ischemic cerebral smoking, and hypertension. It should be noted infarction is not clear. However, this study suggests that in this population, the level of smoking is very that infections, per se, are related to ischemic cere- low, and, in fact, smoking per se was not a risk fac- bral infarction, and it is not unreasonable that oral tor for either cardiovascular disease or periodontal infections would also contribute. disease. Hence, this study was carried out in a pop- Grau and colleagues79 also presented a case- ulation which minimized or eliminated smoking as control study of 66 cases and 66 controls. The a co-risk factor, which may confound the relation- patients suffered from acute cerebral ischemia evi- ship between periodontal disease and heart disease denced by computed tomography (CT) or magnet- in other studies. ic resonance imaging (MRI), or from transient cere- All these data support the association of bral ischemia. These investigators also used the increased CAD, especially in men under age 60 to TDI, with orthopantomography as part of the 65 years. The relationship, however, is weaker for index. They found that poor dental status with a men over age 60 to 65 years in most of these stud- TDI of > 6 was associated with cerebral ischemia ies. The reason for the weak association in older (2.51,95% CI 1.20 to 5.20). Grau and colleagues79 individuals is not yet clear but the stronger relation- also analyzed the components of the TDI and ship in men under the age of 60 to 65 years remains found that there was no association with the dental Cardiovascular Diseases and Oral Infections 77

TABLE 5-8. Summary of Studies of the Association between Periodontal Disease and Other Oral Conditions and Stroke Study Design/ Systemic Study Subjects Outcome Oral Condition Findings Syrjanen Case-control; 40 Ischemic Total dental index (TDI) A statistically significantly poorer et al, patients with cerebral (caries, periodontitis, level of oral health was found 198978 ischemic cerebral infarction periapical lesions, and among patients as compared infarction, and pericoronitis included) with controls. However, 40 randomly smoking, hypertriglyceridemia, selected community hypertension, and febrile controls matched infections also greater for age and gender in patients than in controls Grau et al, Case-control; Acute cerebral TDI with Poor dental health (TDI >6) 199779 66 cases, ischemia orthopantomography was associated with cerebral 66 controls evidenced by ischemia with an odds ratio of CT or MRI; 2.51 (1.20, 5.2) after adjusting or transient for current smoking, diabetes, cerebral socioeconomic status, and ischemia pre-existing vascular disease Beck et al. Longitudinal 40 stroke cases, Mean alveolar bone High alveolar bone loss was 199675 follow-up of including 29 height, hi-lo predictive of subsequent 1,147 men with coronary dichotomous stroke with a relative risk of heart disease 2.8 (1.45, 5.48) after adjusting for age, smoking, diabetes, diastolic blood pressure, family history, and education Wu et al, Longitudinal, Cerebrovascular Subjects classified as Periodontitis was associated with 199980 NHANES I; disease, suffering from nonhemorrhagic stroke with a 9,962 adults nonhemorrhagic periodontitis, relative risk of 2.1 1 (1.30, 3.42). followed up and hemorrhagic gingivitis, no Increased risk for nonhemor- for 18 years stroke, and periodontal disease, rhagic stroke seen in men, transient cerebral and edentulous women, African Americans ischemia based on Russell and Caucasian Americans. The index population-attributable risk for nonhemorrhagic stroke was 19% based on baseline periodontal disease. caries component. These results were obtained after 2.8 (95% CI 1.45 to 5.48). These results were adjusting for current smoking, diabetes, socioeco- obtained after adjusting for age, smoking, diabetes, nomic status, and pre-existing vascular disease. diastolic blood pressure, family history, and educa- Beck and colleagues75provided the first longi- tional level. tudinal data relating stroke to oral infections. They The largest study relating stroke to periodon- followed up 1,147 men over 18 years of age and tal disease comes from Wu and colleagues.80They identified 40 stroke cases, including 29 that also studied the NHANES I database on 9,962 adults had coronary heart disease. Periodontal status was followed up for 18 years. The systemic outcome measured using the mean alveolar bone height, and was cerebrovascular disease, including nonhemor- dichotomized into high and low groups. They rhagic and hemorrhagic strokes and transient cere- found that high mean alveolar bone loss was pre- bral ischemia. Subjects were classified as suffering dictive of subsequent stroke with a relative risk of from periodontitis, gingivitis, or as exhibiting a 78 Periodontal Medicine healthy periodontium on the basis of the Russell atheroma formation. The first comes from studies periodontal index. They found that periodontitis finding Porpbyromonus gingivulis in carotid and at baseline was associated with nonhemorrhagic coronary atheromas.81>82The second comes from (ischemic) stroke, with a relative risk of 2.1 (95% the findings of Deshpande and colleagues83showing CI I .3 to 3.4). Of considerable importance was the in vitro that I? gingivulis can invade and may prolif- finding that in this same population, there was no erate in the endothelial cells. The third line of evi- association of periodontitis with hemorrhagic stroke. dence comes from studies by Herzberg and Meyer8* Hence the association of periodontal disease with showing that I? gingivulis is able to induce aggrega- ischemic stroke, which is largely due to atheroscle- tion of platelets, which is thought to be associated rotic lesions, and not with hemorrhagic stroke, with thrombus formation. Other possible mecha- which is associated with bleeding vessels, provides nisms include protease production by I? gingivulis hrther evidence for the role of infections in athero- and other periodontal pathogens, which may con- sclerotic processes. The increased risk for nonhem- tribute to remodeling of the extracellular matrix in orrhagic stroke was seen in men, women, African atheromatous plaques. Evidence for any of these Americans, and Caucasians. Baseline periodontal mechanisms is, at this point, in vitro or preliminary. disease accounted for 19% of the population-attrib- However, it is not unreasonable to expect that utable risk for nonhemorrhagic stroke in this study, organisms that infect atheromatous plaques may suggesting that periodontal disease is of significant contribute to their formation or to the thrombotic public health importance in relation to stroke. This events associated with myocardial infarction. study is of interest because there was an internal control, that is, there was no relationship between Indirect or Host-Mediated Effects periodontal disease in the same population and Triggered by Infection hemorrhagic stroke, which is not associated with atherosclerosis but rather with bleeding. One possible mechanism that has garnered con- In general, the relationship of oral infections, siderable support is that periodontitis induces an especially periodontal disease, to fatal and nonfatal inflammatory response that is manifested, in part, CAD as well as to nonhemorrhagic stroke, much by the production of acute-phase proteins, such of which is ischemic atherosclerotic stroke, strong- as C-reactive protein and fibrinogen, by the liver. ly points to a relationship between periodontal C-reactive protein and fibrinogen are indepen- infection and atherosclerosis and related sequelae dent risk factors for coronary artery disease, such as coronary artery and cerebral artery disease. hence if they are induced, in part at least, by periodontal infection, this may help explain the link between periodontal disease and heart disease. A MECHANISMS BY WHICH recent study by Wu and colleagues85 using the INFECTIONS MAY CONTRIBUTE NHANES I11 database, found that C-reactive TO ATHEROSCLEROSIS protein and plasma fibrinogen were related to poor periodontal health, which provides support Several possible mechanisms may operate indepen- for this hypothesis. dently or in concert to explain the association Another indirect effect of periodontal infec- between infections in general and periodontal tion that may explain the association between peri- infections specifically and atherosclerosis, myocar- odontal disease and heart disease is that periodon- dial infarction, and stroke. For purposes of discus- tal organisms contain proteins which cross-react sion, we will consider four main mechanisms: (I) with the heart. In fact, the heat-shock protein-60, direct effects of infectious agents in atheroma for- which is produced by Bucteroidesforytbus and I? mation; (2) indirect or host-mediated effects trig- gingivulis, has about 60% homology with the gered by infection; (3)common genetic predispo- mammalian heat-shock protein. It is known that sition for periodontal disease and atherosclerosis; antibodies to the heat-shock protein are found in and (4)common risk factors, such as lifestyle. patients with periodontal disease. It is conceivable then that these antibodies to heat-shock proteins Direct Effects of Infectious Agents of periodontal bacteria are cross-reactive with the in Atheroma Formation heat-shock protein that is exposed in an injured endothelium or atheromatous plaque. This could There are three lines of evidence suggesting that set in motion autoimmune phenomena and con- periodontal bacteria may have direct effects on tribute to atheroma formation. Cardiovascular Diseases and Oral Infections 79

Common Genetic Predisposition for Management of Periodontal Disease in Periodontal Disease and Athe roscle rosis Patients at High Risk for Atherosclerosis

There may be common genetic mechanisms which Since there is mounting evidence relating peri- provide the link between periodontal disease and odontal infections to atherosclerosis, it is reason- cardiovascular disease. Beck and colleagues75have able that patients with periodontal disease that are provided a model proposing that there is a geneti- at risk for atherosclerotic disease should be man- cally determined hyperinflammatory macrophage aged in the following manner: phenotype in periodontal disease, which contributes to the susceptibility for atherosclerosis. 1. Patients at high risk for atherosclerotic disease should be subjected to a complete periodontal Common Risk Factors Affecting Both examination. Periodontal Disease and Heart Disease 2. Patients that have periodontal disease should have a thorough medical history evaluating DeStefano and colleagues73found that periodon- systemic conditions, medications, and risk fac- tal disease and poor oral hygiene are stronger tors for atherosclerosis and related conditions indicators of risk of total mortality and of coro- such as heart disease and stroke. nary heart disease. They suggest that oral hygiene 3. Treatment of patients with periodontal disease may be an indicator or a surrogate for lifestyle and pre-existing atherosclerotic disease, such affecting personal hygiene and health care and as stroke, nonfatal myocardial infarction, and might explain the relationship between peri- atherosclerosis in general, should be coordinat- odontal disease and heart disease. Multiple stud- ed among health professionals to ensure that ies showing the relationship between periodontal patients are adequately managed taking into disease and heart disease, after adjusting for account medical as well as dental considera- many factors associated with lifestyle, such as tions and complications. smoking and weight, suggest that the relation- 4. Aggressive prevention of periodontal disease ship is not simply explained by lifestyle (see should be undertaken in patients at high risk Tables 5-6, 5-7, and 5-8). Also, the finding that for atherosclerotic disease. If periodontal dis- the graded exposure of periodontal disease leads ease exists in these high-risk patients, compre- to an increased cumulative index of coronary hensive treatment should be instituted to erad- heart disease argues against lifestyle as a simple icate, as much as possible, the periodontal explanation for this a~sociation.~~ infection and prevent its recurrence. The association between periodontal disease 5. Patients should be made completely aware of and cardiovascular disease or stroke could be due the possible relationship between heart disease, to residual confounders or incomplete control of stroke, and periodontal disease, without undu- confounders. As with most studies that adjust for ly alarming them, so that they may participate possible confounders, the adjustments may not be in the modification of risk factors for both complete, so associations of this magnitude may artherosclerosis and periodontal disease, such be due to residual confounders. Perhaps new stud- as smoking. ies with more detailed adjustments for confounders will clarify this issue. In fact, there are two studies in progress, supported by the Nation- REFERENCES al Institutes of Health (NIH), which may help resolve this issue. 1. Redding S, Montgomery M. Dentistry in systemic Further research will be needed to determine disease: In: Diagnostic and therapeutic approach which, and to what extent, factors act singly or in to patient management. Portland: JBK Publish- concert to contribute to the formation of athero- ing, Inc; 1990. E 169-213. matous plaques. It is important to know the mech- 2. Rose LF, Kaye D. Cardiovascular disorders. In: anisms, however, since they add evidence to sup- Internal medicine for dentistry. 2nd ed. Mosby port the association between periodontal infection Publishing CO;1990. p. 505-14. and atherosclerosis. In addition, knowing the 3. University of Washington. Medically compromised mechanisms may well lead to simple, cost-effective patient with cardiovascular disorders: a self- interventions that would moderate, in part, the instructional series in rehabilitation dentistry. contribution of infection to atherosclerosis. Seattle, WA; Module IV, Unit A.; 1986. 8 0 Periodontal Medicine

4. Mealey BL. Influence of periodontal infections on odontal infection and non-oral disease [guest systemic health. Periodontol 2000 1999. [In editorial]. J Dent Res 1998;77:1764-5. press] 21. Atkinson BA, Abu-Al-Jaibat A, LeBlanc DJ. 5. Mulligan R. Preventive care for the geriatric dental Antibiotic resistance among enterococci isolated patient. Cal Dent Assoc J 1984;12:21-32. from clinical specimens between 1953 and 6. Aragon SB, Buckley SB, Tilson HB. Oral surgery 1954. Antimicrobial Agents Chemother 1997; management of the geriatric patient. Spec Care 41:1598-600. Dent 1984;4:124-9. 22. Griffin BE Valvular heart disease. In: Dale DC, 7. Little JW, Falace, DA. Therapeutic considerations Federman DD, editors. Scientific American in special patients. Dent Clin North Am 1984; Medicine. New York, Ny: Scientific American 28:45 5-69. Inc.; 1998. 8. Little JW, Falace DA. Dental management of the 23. Karchmer AW. Infective endocarditis. In: Dale DC, medically compromised patient. 3rd ed. St. Louis: Federman DD, editors. Scientific American Mosby Publishing Co.; 1988. p. 83-195. Medicine. New York, Ny: Scientific American, 9. Matsuura H. Systemic complications and their Inc.; 1999. management during dental treatment. Int Dent 24. Sanabria TJ, Alpert JS, Goldberg R, et al. Increas- J 1989;39:113-21. ing frequency of staphylococcal infective endo- 10. McCarthy FM, Pallasch TJ, Gates, R. Document- carditis. Experience at a university hospital, ing safe treatment of the medical-risk patient. 1981 through 1988. Arch Intern Med 1990; J Am Dent Assoc 1989;119:383-9. 15 0: 130 5-9. 11. Mulligan R. Pretreatment for the cardiovascularly 25. Cowper TR. Pharmacologic management of the compromised geriatric dental patient. Spec Care patient with disorders of the cardiovascular sys- Dent 1985;5:116-23. tem. Infective endocarditis. Dent Clin North 12. Thornton JB, Wright JT. Special and medically Am 1996;40:611-47. compromised patients in dentistry. St. Louis: 26. Kupferwasser HD, Muller AM, Morh-Kahaly S, et Mosby Year-Book Publishers; 1989. p. 149-68. al. Clinical and morphological characteristics in 13. Cash J, Raab RW, Coke JM. Understanding your Streptococcus bovis endocarditis: a comparison patient with cardiac disease. J Colorado Dent with other causative microorganisms in 177 Assoc 1990;68:16-9. cases. Heart 1998;80:276-80. 14. Dajani AS, Taubert KA, Wilson W, et al. Preven- 27. Rees TD. Dental management of the medically tion of bacterial endocarditis. Recommenda- compromised patient. In: McDonald RE, Hurt tions by the American Heart Association. JAMA WC, Gilmore HW, Middleton, RA, editors. 1997;277: 1794-80 1. Circulation 1997;96: Current therapy in dentistry. 7th ed. St. Louis: 358-66. C.V. Mosby Co.; 1980. p. 1-30. 15. Mealey BL. Periodontal implications: medically 28. McKinsey DS, Ratts TE, Bisno AL. Underlying compromised patients. Ann Periodontol 1996; cardiac lesions in adults with infective endo- 1:25 6-32 1. carditis. Am J Med 1987;82:681-8. 16. Rees TD. Adjunctive therapy. Discussion section 29. Zysset MK, Montgomery MT, Redding SW, Dell’ X. In: Nevins M, Becker W, Kornman K, edi- Italia LJ. Systemic lupus erythematosus: a con- tors. Proceedings of the world workshop in clin- sideration for antimicrobial prophylaxis. Oral ical periodontics. Chicago, IL: The American Surg Oral Med Oral Pathol Oral Radiol Endod Academy of Periodontology; 1989. 1987;64:30-4. 17. Strom BL, Abrutyn E, Berlin JA, et al. Dental and 30. Friedlander AH, Yoshikaua TT. Pathogenesis, man- cardiac risk factors for infective endocarditis. A agement, and prevention of infective endocardi- population-based, case-control study. Ann tis in the elderly dental patient. Oral Surg Oral Intern Med 1998; 129:761-9. Med Oral Pathol Oral Radiol Endod 1990; 18. Younessi OJ, Walker DM, Ellis Dwyer DF. Fatal 69: 177-8 1. Stapbylococcus aureus infective endocarditis: den- 3 1. Friedlander AH. Risk assessment of the older dental implications. Oral Surg Oral Med Oral tal patient: a review of the pathophysiology of Pathol Oral Radiol Endod 1998;85:168-72. the cardiovascular system. Spec Care Dent 1987; 19. Burne RA. Concise review. Oral streptococci, prod- 7:41-2. ucts of their environment. J Dent Res 1998; 32. Bayer AS, Lam K, Ginzton L, et al. Stapbylococcus 77:445-52. aureus bacteremia. Arch Intern Med 1987;147: 20. Slots J. Causal or casual relationship between peri- 4 5 7-62. Cardiovascular Diseases and Oral Infections 8 1

33. Devereux RB, Kramer-Fox R, Kligfield E Mitral 49. Romans AR, App GR Bacteremia, a result from valve prolapse: causes, clinical manifestations, oral irrigation in subjects with gingivitis. J Peri- and management. Ann Intern Med 1989;lll: odontol 1971;42:757-60. 305-17. 50. Barco CT. Prevention of infective endocarditis: a 34. Rees TD. Periodontal considerations in patients review of the medical and dental literature. J with bone marrow or solid organ transplants. Periodontol 1991;62:5 10-23. 1999. In: Periodontal Medicine etc. 51. Bender IB, Naidorf IJ, Garvey GJ. Bacterial endo- 35. Rees, TD, Rose LF. Periodontal management of carditis: a consideration for physician and den- patients with cardiovascular diseases [position tist. J Am Dent Assoc 1984;109:415-20. paper, American Academy of Periodontology]. J 52. MacFarlane TW, Ferguson MM, Mulgrew CJ. Periodontol 1996;67:627-35. Post-extraction bacteremia: role of antiseptics 36. Taylor MH, Peterson DS. Kawasaki’s disease. J Am and antibiotics. Br Dent J 1984;156:179-81. Dent Assoc 1982;104:44-7. 53. Tzukert AA, Leviner E, Sela M. Prevention of infec- 37. Barnett ML, Friedman D, Kastner, T. The preva- tive endocarditis: not by antibiotics alone. Oral lence of mitral valve prolapse in patients with Surg Oral Med Oral Pathol Oral Radiol Endod Down’s syndrome: implications for dental man- 1986;62:385-8. agement. Oral Surg Oral Med Oral Pathol 54. Fay JT, O’Neal RB. Dental responsibility for the 1988;66:445-7. medically compromised patient IV. J Oral Med 38. Clemens JD, Ransohoff DF. A quantitative assess- 1984;39:218-25. ment of pre-dental antibiotic prophylaxis for 55. Kilmartin C, Munroe C. The dental management patients with mitral-valve prolapse. J Chron Dis of the cardiac patient requiring antibiotic pro- 1984;37:531-41. phylaxis. J Can Dent Assoc 1986;52:77-82. 39. Friedlander AH, Gorelick DA. Panic disorder: its 56. Kilmartin C, Munroe CO. Cardiovascular diseases association with mitral valve prolapse and and the dental patient. J Can Dent Assoc 1986; appropriate dental management. Oral Surg Oral 52513-8. Med Oral Pathol Oral Radiol Endod 1987; 57. Leviner E, Tzukert AA, Berioliol R, et al. Develop- 63: 309- 12. ment of resistant oral viridans streptococci after 40. Meyers DG, Starke H, Pearson PH, Wilken MK. administration of prophylactic antibiotics: time Mitral valve prolapse in anorexia nervosa. Ann management in the dental treatment of patients Intern Med 1986;105:384-6. susceptible to infective endocarditis. Oral Surg 41. Daly C, Mitchell D, Grossberg D, et al. Bacter- Oral Med Oral Pathol Oral Radiol Endod aemia caused by periodontal probing. Aust 19 87;64: 4 17-20. Dent J 1997;42:77-80. 58. Slots J, Rosling BG, Genco RJ. Suppression of 42. Roberts GJ, Simmons NB, Longhurst E Odonto- penicillin-resistant oral Actinobacillus actino- genic bacteraemia and intraligamental analgesia. mycetemcomitans with tetracycline: considerations Br Dent J 1992;173:195. in endocarditis prophylaxis. J Periodontol 1983; 43. Lamas W. A study of transient bacteremia follow- 54:193-6. ing an intraoral soft tissue biopsy [thesis]. Dallas, 59. American Dental Association. Patients with cardio- TX Baylor College of Dentistry-TAMUS; vascular disease. Oral Health Care Guidelines 1998. 1989; September:1-13. 44. Francis JL. Significance of bacteremias of dental 60. Baltch AL, Pressman HL, Schaffer C, et al. Bac- origin. J Am Dent Assoc 1986;112:306-8. teremia in patients undergoing oral procedures. 45. Pallasch TJ. Antibiotic prophylaxis: theory and Arch Intern Med 1988;148:1084-8. reality. Calif. Dent Assoc J 1989;17:27-39. 61. Steinberg BJ, Brown S. Dental treatment of the 46. Berger SA, Weitzman S, Edberg SC, Coreg JI. Bac- health compromised. Medical and psychological teremia after the use of an oral irrigating device. considerations. Alpha Omegan 1986;79:34-41. Ann Intern Med 1974;80:510-1. 62. Glasser S. The problems of patients with cardiovas- 47. Felix JE, Rosen S, App GR Detection of bac- cular disease undergoing dental treatment. J Am teremia after the use of an oral irrigation device Dent Assoc 1977;94:1158-62. on subjects with periodontitis. J Periodontol 63. Mulligan R, Weitzel KG. Pretreaunent manage- 1971;42:785-7. ment of the patient receiving anticoagulant 48. Hunter KM, Holborow DW, Kardos TB, et al. drugs J Am Dent Assoc 1988;117:479-83. Bacteremia and tissue damage resulting from air 64. Breslow JL. Cardiovascular disease burden increases, polishing. Br Dent J 1989;167:275-7. NIH hnding decreases. Nat Med 1997;3:600-1. 82 Periodontal Medicine

65. Braunwald E. Shattuck Lecture-cardiovascular oral health and coronary heart disease. J Dent medicine at the turn of the millennium: tri- Res 1996;75:1631-6. umphs, concerns, and opportunities. N Engl J 77. Genco RJ, Chadda S, Grossi S, et al. Periodontal Med 1997;337:1360-9. disease is a predictor of cardiovascular disease in 66. Ross R Atherosclerosis-an inflammatory disease. a Native American population [abstract]. J Dent N Engl J Med 1999;340:115-26. Res 1997;76(Special Issue):3158. 67. Falk E, Shah PK, Fuster V. Pathogenesis of plaque 78. Syrjanen J, Peltola J, Valtonen V, et al. Dental disruption. In: Fuster V, Ross R, Topol EJ, edi- infections in association with cerebral infarction tors. Atherosclerosis and coronary artery disease. in young and middle-aged men. J Intern Med Vol 2. Philadelphia: Lippincott-Raven; 1996. 1989;255:179-84. p. 492-510. 79. Grau AJ, Buggle F, Ziegler C, et al. Association 68. Danesh J, Collins R, Peto R. Chronic infections between acute cerebrovascular ischemia and and coronary heart disease: is there a link? Lancet chronic and recurrent infection. Stroke 1997; 1997;350:430-6. 28: 1724-9. 69. Mattila K, Nieminen M, Valtonen V, et al. Associ- 80. Wu T, Trevisan M, Genco RJ, et al. Periodontal ation between dental health and acute myocar- disease and risk of cerebrovascular disease: the dial infarction. BMJ 1989;298:779-82. first National Health and Nutrition Examina- 70. Paunio K, Impivaara 0, Tiekso J, Maki J. Missing tion Survey and its follow-up study. JAMA teeth and ischaemic heart disease in men aged 1999. [In press] 45-64 years. Eur Heart J 1993;14Suppl:54-6. 81. Haraszthy VI, Zambon JJ, Trevisan M, et al. Iden- 71. Mattila KJ, Valle M, Nieminen MS, et al. Dental tification of pathogens in atheromatous plaques infections and coronary atherosclerosis. Athero- [abstract]. J Dent Res 1998;77(Special Issue): sclerosis 1993;103:205-11. 273. 72. Arbes S, Slade GD, Beck JD. Association between 82. Chiu B, Viira E, Evans RT, Genco RJ. Detection of extent of periodontal attachment loss and self- an odontopathogen: Porphyromonas gingivalis in reported history of heart attack: an analysis of atherosclerotic plaques: an immunohistochemical NHANES I11 data. J Dent Res 1999. [In press] and in situ hybridization study. Appl Immuno- 73. DeStefano F, Anda RF, Kahn HS, et al. Dental dis- histochem Molec Morphol 1999. [In press] ease and risk of coronary heart disease. BMJ 83. Deshpande RG, Kahn MB, Genco CA. Invasion of 1993;306:688-91. aortic and heart endothelial cells by Porphyromonas 74. Mattila KJ, Valtonen W, Nieminen M, Huttunen gingivalis. Infect Immun 19 9 8;66: 5 337-43. JK. Dental infection and the risk of new coro- 84. Herzberg MC, Meyer MW. Effects of oral flora on nary events: prospective study of patients with platelets: possible consequences in cardiovascu- documented coronary artery disease. Clin Infect lar disease. J Periodontol 1996;67:1138-42. Dis 1995;20:588-92. 85. Wu T, Trevisan M, Genco RJ, et al. An examination 75. Beck J, Garcia J, Heiss G, et al. Periodontal disease of the relation between periodontal health status and cardiovascular disease. J Periodontol 1996; and cardiovascular risk factors: serum total and 67: 1123-37. HDL cholesterol, C-reactive protein, and plasma 76. Joshipura KJ, Rimm EB, Douglas CW, et al. Poor fibrinogen. Am J Epidemiol 1999. [In press] CHAPTER6

RELATIONSHIPSBETWEEN PERIODONTAL AND RESPIRATORY DISEASES

Frank A. Scannapieco, DMD, PhD

Respiratory diseases are responsible for a significant underlying viral pneumonia. Up until the early part number of deaths and considerable suffering in of this century, bacterial pneumonia was a com- humans. These diseases are widely prevalent. For mon, severe, and often fatal infe~tion.~With the example, lower respiratory infections were the third advent of the widespread use of antibiotics, many of commonest cause of mortality worldwide in 1990 these infections became treatable. However, the (causing 4.3 million deaths), and chronic obstructive continuing emergence of antibiotic-resistant bacte- pulmonary disease (COPD) was the sixth leading ria (eg, penicillin-resistant pneumococci) suggests cause of mortality (2.2 million deaths);' it was the that the number of cases of bacterial pneumonia fourth leading cause of death in the United States in caused by resistant organisms will increase in the 1996,2 claiming 100,000 lives while pneumonia years to come.' Thus, knowledge of the pathogene- and influenza together caused almost 84,000 deaths. sis of and the risk factors for bacterial pneumonia is Accumulating evidence suggests that oral dis- critical to the development of strategies for the orders, particularly periodontal disease, may influ- treatment and prevention of these infections. ence the course of respiratory infection. This chap- Pneumonia can be classified as community ter will describe the major respiratory diseases acquired or hospital acquired (nosocomial) . These caused or influenced by bacteria, the epidemiolog- types of pneumonia differ with respect to their ic evidence that supports a role for oral bacteria in causative agents (Table 6-1). Community- the process of respiratory infection, and possible acquired bacterial pneumonia is usually associated mechanisms that may explain the role of oral bac- with Streptococcus pneumoniue and Huemopbilus teria in the process of respiratory infection. influenzue, with other species such as Mycophsmu pneumoniue, CbhmydA pneumoniue, Legionellu pneumopbih, and a variety of anaerobic species also RESPIRATORY DISEASES in~olved.~>~The spectrum of organisms responsible for nosocomial pneumonia is quite different, with Bacterial Pneumonia gram-negative bacilli (including enterics such as Escbericbiu co li, Klebsielh p neu mo n iue, Serrutiu Pneumonia is a group of related diseases caused by spp., and Enterobucter spp. as well as Pseudomonus a wide variety of infectious agents, including bacte- ueruginosu) and Stupbylococcus uureus being the ria, mycoplasma, fungi, parasites, and viruses, most pre~alent.~J-''The spectrum of organisms resulting in infection of the pulmonary parenchy- prevalent in nursing homes is even broader, with ma (Figure 6-1). Pneumonia can be a life-threaten- pathogens common to both community- and ing infection, especially in the elderly and immuno- hospital-acquired pneumonias in~olved.~ compromised and it is a significant cause Infections are of particular concern in the of morbidity and mortality in patients of all ages. hospital environment. Greater than 5% of all hos- Bacterial pneumonia, a common form of the dis- pitalized patients develop an infection following ease, can arise de novo or as a superinfection of an their admission to the hospital, and pneumonia 84 Periodontal Medicine typically accounts for 10 to 20% of these.1°-13 condition is characterized by chronic obstruction Hospital-acquired pneumonia often prolongs hos- to airflow, with excess production of sputum pital stay, increases patient care costs, and causes resulting from chronic bronchitis (CB) and/or significant morbidity and mortality. l4 There are emphysema. l7 Chronic bronchitis is the result of more than 300,000 nosocomial respiratory infec- irritation to the bronchial airway, which causes an tions each year,ll leading to about 20,000 expansion of the proportion of mucus-secreting deaths,13 and such infection adds 7 to 9 days to cells within the airway epithelium (Figure 6-2). the average length of stay in the h0spita1.l~The These cells secrete excessive tracheobronchial annual direct cost of diagnosing and treating mucus sufficient to cause cough with expectora- nosocomial pneumonia may exceed $2 billion. l5 tion for at least 3 months of the year over two con- While also contributing to a significant number of secutive years." Emphysema is defined as the dis- deaths by acting as a complicating or secondary tention of the air spaces distal to the terminal factor, pneumonia is of special significance in the bronchiole with destruction of the alveolar septa. elderly population, accounting for the majority of Chronic bronchitis is quite prevalent, with 20 admissions to hospitals from nursing h~mes.~J' to 30% of all adults over 45 years reporting a history of asthma or chronic br0n~hitis.l~Chronic bron- Chronic Obstructive Pulmonary Disease chitis is more prevalent in men than in woman, with about 20% of all adult males displaying some Another severe respiratory disease affecting a sig- evidence of it.17 The prevalence of the disease in nificant segment of the population is COPD. This women is on the rise since more women are smok-

Figure 6-1. Histopathology of bronchopneumonia. A, Low power of a bronchiole showing the presence of an inflammatory exudate in its lumen. A patchy inflammatory cell infiltrate is observed in the subephithelial region. (Hematoxylin-eosin stain, original magnification x 20) B, Higher power view illus- trates the simple columnar ciliated epithelium that lines the bronchiole. The lamina propria and lumen of the bronchiole contain numerous inflammatory cells. (Hematoxylin-eosin stain, original magnification x 400) C, High power view of pulmonary alveoli shows early red hepatization characterized by capillary congestion in the septae. In addition, an extensive neutrophilic exudation in the alveoli is also observed. (Hema- toxylin-eosin stain, original magnification x 400) Relationships between Periodontal and Respiratory Diseases 8 5

TABLE 6-1. Etiology of Bacterial Pneumonia Community-Acquired Pneumonia Nosocomial Pneumonia Streptococcus pneumoniae Gram-negative bacilli (including enterics such as Escherichia coli, Haemophilus injuenzae Klebsiella pneumoniae, Serratia spp, Enterobacter spp, Pseudomonas Mycoplasma pneumoniae aeruginosa) Chlamydia pneumoniae Staphylococcus aureus Legionella pneumophila Staphylococcus aureus Candida albicans Anaerobic species

ing than ever before. The incidence of emphysema Pathogenesis and Risk Factors is less well known since the main tool for noninva- for Lung Infection sive diagnosis (computed tomographic [CT] scan- The lung is composed of numerous units formed by ning) cannot be applied to population studies. It is the progressive branching of the airways. The airway interesting that it is rare to find lungs completely of each terminal respiratory unit (bronchiole, alveo- free of emphysema post mortem. However, the vast lar duct, alveolar sac, and alveoli) is lined by epithe- majority of individuals, while showing well-defined lial cells in close proximity on their basal aspect to histologic evidence of emphysema, will not have the capillaries, which permits the efficient exchange clinical symptoms of the disease. of gases. In normal healthy individuals, the lower The major risk factor for COPD is a history of airways are normally sterile, in spite of the fact that prolonged cigarette smoking, with chronic exposure the secretions of the upper airways are heavily cont- to toxic atmospheric pollutants (eg, second-hand aminated with microorganisms seeded from the oral smoke) also being a contributory factor. Genetic and nasal surface^.^^>^^ Sterility of the lower airway is conditions, such as the presence of a defective maintained by intact cough reflexes, the action of alp ha 1-anti t r ypsin gene, variant alpha 1-ant ichy- the tracheobronchial secretions, mucociliary trans- motrypsin, alpha2-macroglobulin,vitamin D-binding protein, and blood group antigen genes, may also predispose subjects to this disease.20 One of the major complications of COPD is the occurrence of “exacerbations,” or episodes in which there are objective signs that the disease has worsened such as increased sputum production showing a change in color and/or consistency, cough, dyspnea, chest tightness, and fatigue. The factors responsible for the initiation of exacerbation are not completely known although they are thought to be provoked, in part, by bacterial infection.21)22 The organisms most closely associated with exacerbations are nontypeable H. influenzue, S. pneumoniue, and Moruxellu cuturrhulis. It should be pointed out that the frequency of exacerbations in COPD patients varies from individual to individual. The frequency of exacerbations is not related to the severity of lung disease. Although viral infections, fluid overload, and allergy have been Figure 6-2. Histopathology of panacinar emphysema. Low suggested to enhance the risk for exacerbation, no power view shows distended alveoli, destruction of the alve- studies have yet proven the role of these factors in olar walls, and fibrosis. (Hematoxylin-eosin stain, original the disease process.’’ magnification x 20) 8 6 Periodontal Medicine port of inhaled microorganisms and particulate All these patient groups tend to have a greater inci- material from the lower respiratory tract to the dence of bacterial pneumonia than the population oropharynx, and immune and nonimmune defense as a whole.34 factors (cell-mediated immunity, humoral immuni- Generally accepted risk factors that predispose ty, and polymorphonuclear leukocytes).5,25 Other to nosocomial pneumonia include the presence of defense factors contained within the secretions that underlying diseases such as chronic lung disease, coat the pulmonary epithelium include surfactant, congestive heart failure, or diabetes mellitus, age other proteins such as fibronectin, complement, and > 70 years; mechanical ventilation or intubation, a immunoglobulins. The lung also contains a rich sys- history of smoking, previous antibiotic treatment, tem of phagocytic cells, which remove microorgan- immunosuppression, a long preoperative stay, isms and particulate debris. and/or prolonged surgical procedures. 10-12,28 Other Microorganisms can contaminate the lower air- commonly accepted risk factors in mechanically ways by four possible routes: aspiration of oropha- ventilated patients include placement of intracranial ryngeal inhalation of infectious aerosols, pressure monitors, anti-stress ulcer therapy, hospi- spread of infection from contiguous sites,27 and talization in the fall or winter seasons, and changes hematogenous spread from extrapulmonary sites of of ventilatory circuits every 24 hours.12>28In nursing infection (eg, translocation from the gastrointesti- home residents, risk factors for pneumonia include nal tract).27 Aspiration of the oropharyngeal con- difficulty with oropharyngeal secretions, deteriorat- tents is the commonest route of infection. While ing health status, and occurrence of unusual events claims have been made supporting the stomach as a (conhsion, agitation, falls, or wandering) .35 primary source of nosocomial respiratory It is possible that oral disorders such as perio- pathogens,28especially in patients treated with H2- dontal disease may also predispose subjects to blockers and other antiulcer medications, it is more nosocomial pneumonia. For example, hospitalized likely that most pathogens first colonize the sur- patients, especially those admitted to an intensive faces of the oral cavity or pharyngeal mucosa before care unit, are likely to pay less attention to person- a~piration.~~These pathogens can colonize from an al hygiene than less ill patients. One important exogenous source or can emerge following over- dimension of this personal neglect may be dimin- growth of the normal oral flora after antibiotic ished attention to oral hygiene. A lapse in oral treatment. Common respiratory pathogens such as hygiene may optimize conditions that contribute S. pneumoniue, Streptococcus pyogenes, M. pneumo- to the initiation of pneumonia. niu, and H. injuenzue can colonize the oropharynx and be aspirated into the lower airways. As will be discussed below, other species thought to comprise DENTAL CONSIDERATIONS the normal oral flora, including Actinobucillus uctinomycetemcomituns, and anaerobes such as Popby- Oral Bacteria as Etiologic Agents romonus gingivulis and Fusobucterium spp., can also of Respiratory Infection be aspirated into the lower airways to cause pneu- It is possible that the teeth can serve as a reservoir monia. Indeed, studies using careful sampling and for respiratory infection. Indeed, the notion that strict anaerobic culture conditions have found that the oral cavity may influence the bacterial flora of a considerable proportion of community-acquired the lower bronchi is not new. For example, Potter and nosocomial pneumonia may involve anaerobic and colleagues noted in 1968 that infected teeth agent^.^^>^' Pneumonia can be the result of a mixed were present in 25% of 80 patients with potential infection, with anaerobes combining with faculta- respiratory pathogens in the bronchi, as against tive agents such as oral viridans streptococci or only 7.5% of 80 patients free of pathogens in the enteric rods.31>32 bronchi.36 Oral bacteria can be released from the Aspiration of oropharyngeal secretions is not dental plaque into the salivary secretions, which uncommon, even in healthy subjects. Studies have are then aspirated into the lower respiratory tract demonstrated that 50% of normal adults aspirate to cause pneumonia (Figure 6-3). It has long been oropharyngeal contents during sleep. However, known that severe anaerobic lung infections can aspiration occurs more frequently in individuals occur following aspiration of salivary secretions, with impaired consciousness, such as alcoholics, especially in patients with periodontal dis- drug abusers, and epileptics, and those with chron- ease.5,25,34,37Estimates have been made that 30 to ic swallowing disorders or mechanical interven- 40% of all cases of aspiration pneumonia, necro- tions such as nasogastric or endotracheal t~bes.~~>~~tizing pneumonia, or lung abscess involve anaero- Relationships between Periodontal and Respiratory Diseases 8 7 bic bacteria.38A variety of oral anaerobes and fac- respiratory pathogens. Dental plaque may therefore ultative species have been cultured from infected provide a reservoir for colonization of respiratory lung fluids, including I! gingivulis, Bucteroides pathogens that can be shed into saliva. Contamina- grucilus, Buctero ides o rulis, Bucte ro ides b uccue, tion of the distal portions of the respiratory tree by Eikenellu corrodens, Fusobucterium nucleutu m, saliva containing such organisms may result in pul- Fuso bucterium necropho ru m, A. uctinomycetem co mi- monary infections. It should also be pointed out tuns, Peptostreptococcus, Clostridium, and Actino- that respiratory pathogens that establish in dental myces.”*’ Most, if not all, of these organisms have plaque may be difficult to eradicate. It is well known been implicated as etiologic agents in the patho- that bacteria in biofilms are much more resistant to genesis of periodontal di~ease.~~>~~It is also possible antibiotics than planktonic ba~teria.‘~ that viridans streptococci, thought to be exclusive- Previous studies have documented that ly benign members of the oral flora, may partici- patients admitted to medical intensive care units pate in the initiation and/or progression of pneu- (ICU) have poorer oral hygiene than nonhospital- monia.32,43,50-52 ized patients and have a higher prevalence of respi- Oral bacteria may also have a role in the exac- ratory pathogen colonization on the teeth and oral erbations of COPD. For example, oral bacteria can mucosa than do age- and gender-matched outpa- be cultured from a significant proportion of the lung fluids obtained from transtracheal aspiration, a technique that avoids contamination with oropharyngeal secretions. Thus, anaerobic bacteria (presumably from the oral cavity) were cultured from 17% of transtracheal aspirates from patients with COPD.53The distal airway of COPD subjects frequently shows bacterial colonization by presumably nonpathogenic oral bacteria, including oral streptococci (Table 6-2) .24 Indeed, Streptococ- cus viriduns was found to be the cause of pneumonia in 4% of COPD patients.54 Laboratory studies suggest that oral anaerobes such as I! gingivulis can cause marked inflammation when instilled into the lungs of laboratory animals. 55 A relationship between the systemic humoral response to Prevotellu species (bacteria associated with periodontal disease) and ventilator- associated pneumonia in hospitalized patients has also been described. Thus, colonization of patients by Prevotellu species may be associated with an infectious process leading to ventilator-associated pneumonia and a systemic humoral re~ponse.~‘

Dental Plaque as a Reservoir of Respiratory Pathogens Figure 6-3. Oral bacteria, oral infection, and pneumonia. I11 persons probably do not pay close attention to Bacteria that colonize the supra- or subgingival dental plaque oral hygiene. Several studies have documented that are shed into the saliva. These pathogenic bacteria can be hospitalized individuals tend to have poorer oral either those associated with periodontal disease (I? gingiualis, hygiene than matched ambulatory, community- Fusobacterium nucleaturn) or respiratory pathogens (I? aerug- dwelling control^.^^-'^ Lack of attention to oral inosa, KLebsieLLa pneumonia). The saliva is aspirated into the hygiene results in an increase in the mass and com- lower respiratory tract (bronchus), where an infection can ensue. Cytokines from diseased periodontal tissues can enter plexity of dental plaque, which may foster bacterial the saliva from the gingival crevice fluid and also be aspirated interactions between indigenous plaque bacteria and to stimulate local inflammatory processes that contribute to acknowledged respiratory pathogens such as the initiation and/or progression of infection in the lung. I! ueruginosu and enteric ba~illi.‘~These interactions With permission from Scannapieco FA. Role of oral bacteria may result in colonization of the dental plaque by in respiratory infection. J Periodontol 1998;70:793-802. 8 8 Periodontal Medicine

TABLE 6-2. Bacterial Colonization of the Lower Airway Determined by Bronchoscopic Protected Specimen Brush Number of Percent Subjects Patients Colonized Flora Healthy 15 12 Viridans streptococci, group D streptococci, S. aureus Bronchogenic 33 39 Viridans streptococci, Neisseria, Stapbylococcus, H. influenme, carcinoma S. pneumoniae COPD 18 83 Viridans streptococci, Neisseria, Stapbylococcus, Co ynebacterium, Candida, Haemopbilus, S. pneumoniae, S. aureus Bronchiectasis 17 82 Viridans streptococci, group D streptococci, Stapbylococcus Long-term 32 38 Viridans streptococci, Co ynebacterium, M. catambalis, S. aureus tracheostomy

COPD= chronic obstructive pulmonary disease. With permission from Cabello H, Torres A, Celis R, et al. Bacterial colonization of distal airways in healthy subjects and chronic lung disease: a bronchoscopic study. Eur Resp J 1997;10: 1 137-44.

tients (Table 6-3) .59,65 In some cases, respiratory 3-month period assessed the colonization of dental pathogens comprise up to 100% of the cultivable plaque by respiratory pathogens.61The amount of aerobic flora. In general, heavily colonized patients dental plaque on the teeth of inpatients increased tend to be on antibiotic therapy. Respiratory over time, as did the proportion of respiratory pathogens are also more likely to colonize the oral pathogens in their dental plaque. A high concor- cavities of patients with teeth or dentures than dance was found between respiratory colonization edentulous patients not wearing dentures. This of dental plaque by pathogens and the presence of finding suggests that respiratory pathogen colo- the same pathogens in tracheal aspirate cultures and nization is favored by the presence of nonshedding between salivary and dental plaque cultures. Clini- surfaces and/or the conditioning of mucosal sur- cally, 2 I patients developed a nosocomial infection faces by dental plaque. in the ICU. Dental plaque colonization on days 0 More recently, a prospective study of 57 con- and 5 was significantly associated with the occur- secutive patients admitted to medical ICU during a rence of nosocomial pneumonia and bacteremia. In

TABLE 6-3. Comparison of Patient Characteristics between the Preventive Dentistry Clinic (PDC) and the Medical lCUs at BGH andVAMC PDC BGH VRMC Mean age (years) 62.4 63.6 63.8 Gender (male/total numer patients studied) 23/25 12/19 32/34 Mean APACHE I1 score* Not done 14.8 17.1 Oral hygiene (mean plaque score)? 1.4 1.7 1.9 % positive oral cultures+ 16 (4/25) 58 (11/19)§ 65 (22/34)§

BGH = Buffalo General Hospital; VAMC = Veterans Administration Medical Center; ICU = intensive care unit; APACHE = Acute Physiology, Age, Chronic Health Evaluation; PDC = Preventive Dental Clinic *APACHE I1 score was used to semiquantitate the physiologic status of each patient at the time of admission to the medical ICU.65aThis system evaluates a variety of parameters, including physiologic information (temperature, mean arterial pressure, heart rate, respiratory rate, oxygenation, arterial pH, serum levels of Nay K, and creatinine, hematocrit, white blood count), the patient's age, chronic health status, and cardiovascular, renal, respiratory, and immune status. The higher the score, the more severely ill is the patient. +Plaquescore performed as described by Silness and L0e.65a '% of patients having colonization of buccal mucosa and/or dental plaque with a target respiratory pathogen (enteric rod, I? aeruginosa, S. aureus). §The differences observed were found to be significantly different from PDC patients by contingency table analy~is.~~,~~~ Relationships between Periodontal and Respiratory Diseases 8 9 six cases of nosocomial infection, the pathogen was outpatients (Figure 6-4). Colonized long-term care first isolated from the dental plaque. facility subjects tended to be colonized to a much Taken together, these results strongly suggest greater degree than did those dental clinic outpa- that patients admitted to medical ICUs have a sig- tient subjects (42.88 k 53.4 versus 0.02 k 0.04). nificant risk for oral colonization by respiratory In summary, these results suggest that nursing pathogens. Thus, the oral cavity may serve as home subjects (who are at greater risk for lower res- important nidus of infection for respiratory disease piratory infection) have a greater tendency for their in high-risk subjects, such as hospitalized or dental plaque to be colonized by respiratory COPD patients. pathogens. This finding is substantiated by the It has been suggested that high-risk patients in report of Mojon and colleagues," who found that nursing home settings are also at risk for lower res- poor oral hygiene may be a major risk factor for piratory tract infection. The possibility therefore respiratory tract infection in elderly institutional- exists that, like the hospital intensive care environ- ized individuals. ment, poor oral health may predispose nursing home residents to oral colonization by respiratory Oral Status and Chronic pathogen^.^'>^' Recently, the prevalence and distrib- Obstructive Pulmonary Disease ution patterns of suspected respiratory pathogens in the dental plaque of older individuals living in a To evaluate the relationship between COPD and long-term care facility were studied.62 Findings oral health status, a study was performed and data from this group were compared with those from a from the National Health and Nutrition Examina- similar number of age-, race-, and gender-matched tion Survey I (HANES I) was analy~ed.~~Of community-dwelling subjects. Briefly, no differ- 23,808 individuals, 386 reported a suspected res- ences were noted in the prevalence of colonization piratory condition that was further assessed by a by respiratory pathogens between the long-term physician. These subjects were categorized as hav- care facility subjects and dental outpatient subjects; ing a confirmed chronic respiratory disease (chronic 25% (7 of 28) of long-term care facility subjects bronchitis or emphysema), acute respiratory dis- were colonized with respiratory pathogens versus ease (influenza, pneumonia, acute bronchitis), or 27% (8 of 30) of dental clinic outpatients. Howev- not to have a respiratory disease. er, when only those subjects that were positively Significant differences were noted between colonized were considered (with the respiratory subjects having no disease and those having a pathogen comprising 2 0. I Yo of the total cultivable chronic respiratory disease confirmed by a physi- flora), there was a statistically significant difference cian. Individuals with a confirmed chronic respira- between the prevalence of subjects that were colo- tory disease had a significantly greater oral hygiene nized in each group (14% [4 of 281 of the long- index (OHI) than had subjects without a respirato- term care facility subjects versus 0% [0 of 301 of the ry disease. Logistic regression analysis was per- dental clinic outpatients). Nursing home subjects formed to simultaneously control for multiple vari- harbored more dental plaque than did the dental ables including gender, age, race, OHI, and smok-

Figure 6-4. Comparison of dental plaque status of community-dwelling and nursing home residents. A, Facial aspect of mandibular anterior teeth of a typical community-dwelling elder. B, Facial aspect of mandibular anterior teeth of a typical nursing home resident elder (Courtesy of Dr. Stephanie Russell, New York University School of Dentistry). 9 0 Periodontal Medicine ing status. The final model included OH1 and the periodontal and oral hygiene status of the sub- smoking status alone. The results of this analysis jects te~ted.~~-~~For example, a direct relationship suggest that for patients having the highest OH1 has been found between the ability of saliva to values, the odds ratio for chronic respiratory disease degrade fibronectin and oral hygiene Sub- was 4.5. These data are supported by the recent jects practicing meticulous oral hygiene (dental study of Hayes and colleague^,^^ who found that hygiene students) have very low levels of salivary periodontal disease, measured as alveolar bone loss fibronectin degrading enzymes. In contrast, saliva from periapical radiographs, was an independent samples collected from laboratory workers having risk factor for COPD in adult males enrolled in the less than ideal oral hygiene had higher amounts of Veterans Administration Normative Aging study. enzyme activity, and saliva collected on awakening in the latter group had even higher levels. The Potential Mechanisms of Action source of these enzymes has been attributed to bac- of Oral Bacteria in the Pathogenesis teria75>76,78-80or polymorphonuclear leukocytes, of Respiratory Infection which enter the saliva from the gingival ~ulcus.~~It is conceivable that in subjects with periodontal dis- Several mechanisms can be envisioned to help ease that harbor dental plaque with elevated levels of explain how oral bacteria can participate in the bacteria such as I? gingivulis and spirochetes (bacte- pathogenesis of respiratory infection: ( 1) oral ria known to be prolific producers of proteases), pathogens (such as I? gingivulis, A. uctinomycetemco- protease activity may alter the mucosal epithelium mituns) may be aspirated into the lung to cause in such a way as to increase the adhesion and colo- infection; (2) periodontal disease-associated nization by respiratory pathogens (Figure 6-5A). enzymes in saliva may modifi- mucosal surfaces to Such bacteria may also produce other enzymes such promote adhesion and colonization by respiratory as mannosidase, hcosidase, hexosaminidase, and pathogens; (3) periodontal disease-associated sialidase, known to be elevated in the saliva of such enzymes may destroy salivary pellicles on patho- patient^.^^.^^ Exposure of the epithelium and glyco- genic bacteria; and (4) cytokines originating from proteins to such enzymes may increase the adhesion periodontal tissues may alter respiratory epitheli- of gram-negative bacteria to the mucosal surface by um to promote infection by respiratory pathogens. exposing the “buried adhesin receptors on the mucosal epitheli~m,~~which may foster increased Periodontal DiseaseAssociated Enzymes adhesion and colonization by respiratory pathogens. in Saliva Modifying Mucosal Surfaces Previous studies have shown that respiratory Destruction of Protective Salivary Pellicles pathogens such as I? ueruginosu may adhere better to by Oral Bacteria oral epithelial cells obtained from patients colonized Recent evidence suggests that the respiratory by respiratory pathogens than to cells harvested pathogen H. influenzae binds to mucins contained from noncolonized patient^.^'>^^ Trypsin treatment within the mucosal ~ecretions.~~-~~This binding of epithelial cells from noncolonized patients in may involve sialic acid re~idues.~~>~~In the context of vitro resulted in increased adhesion by respiratory COPD, it is possible that subjects with poor oral pathogens. These data suggest that a mucosal alter- hygiene may have elevated levels of hydrolytic ation promoted enhanced bacterial adhesion by enzymes (eg, sialidase) in their saliva. These enzymes these bacteria, perhaps the loss of fibronectin from may process mucins to reduce their ability to bind the epithelial cell surface.73 Buccal epithelial cells to and clear pathogens such as H. inJuenzae (Figure from critically ill patients, all colonized by I? uerugi- 6-5B). Conversely, the enzymes may process the nosu, interacted with greater numbers of bacterial respiratory epithelium to modulate the adhesion of cells in vitro and possessed lesser amounts of surface such pathogens to the mucosal surface (Figure fibronectin as determined by immunofluorescence. 6-5C). Indeed, several studies have suggested that The removal of fibronectin (by exposure to proteas- certain oral bacteria can break down a variety of sali- es) may unmask mucosal surface receptors for respi- vary component^.^^.^^ Thus, poor oral hygiene ratory pathogen adhesins. Other investigators have results in increased dental plaque load and salivary also pointed out an inverse relationship between the hydrolytic enzyme levels. These enzymes may then amount of mucosal epithelial cell fibronectin and destroy the protective domains of the host secretory gram-negative bacilli binding to these cells.74 components (eg, mucins), thus diminishing non- Saliva contains many hydrolytic enzymes, and specific host defense against respiratory pathogens the amount of enzyme activity in saliva is related to in high-risk subjects. Relationships between Periodontal and Respiratory Diseases 9 1

Cytokines That May Alter Respiratory in the expression of such adhesion molecules may Epithelium alter the interaction of the bacterial pathogens with Periodontal disease (periodontitis) is a localized the mucosal surface.94 chronic inflammatory disease caused by bacterial One mechanism proposed for the gross airway infection of the periodontal tissues by bacteria in epithelial damage observed in COPD involves dental plaque, resulting in the destruction of the release of proinflammatory cytokines (ie, IL-8) from supporting bone and connective tissues. In the respiratory epithelium, resulting in the recruit- untreated periodontal disease, oral pathogens con- ment and infiltration of neutrophils and the subse- tinuously stimulate the cells of the periodontium quent release of proteolytic enzymes and toxic oxy- (epithelial cells, endothelial cells, fibroblasts, gen radicals from the ne~trophils.~~~~'.The mecha- macrophages, white cells) to release a wide variety nism of release of cytokines from the respiratory of cytokines and other biologically active mole- epithelium may be the result of the binding of res- cule~.~~,92 Cytokines produced by epithelial and piratory pathogens (eg, H. influenme) or their prod- connective tissue cells in response to these bacteria ucts to the respiratory epithelial cells, followed by including interleukin (1L)-1a, IL-1 p, IL-6, stimulation of the respiratory epithelial cells to pro- IL-8, and TNF-cx.~~Oral bacteria can also stimulate duce a variety of cytokines. This mechanism has the peripheral mononuclear cells to release cytokines been demonstrated for medical pathogens such as S. (IL-la and TNF-a). In fact, oral streptococci (for pneumoniue and H. influenzue, which are also example, Streptococcus sunguis), which are abun- known to attach to mucosal receptors and to stimu- dant in dental plaque, stimulate the release of high late cytokine production by the underlying cells.97It levels of these cytokines from such cells.93Epithe- is also conceivable that the oral bacteria in secretions lial cells are also known to alter the expression of come in contact with the respiratory epithelial sur- the adhesion molecules on the surface of various faces and may adhere to the mucosal surface. Oral cells in response to cytokine stimulation. Variation bacteria are routinely cultivated, for example, from

Figure 6-5. A, Dental pathogens such as I? gingivalis produce enzymes (such as proteases) that alter mucosal surface adhesion receptors for respiratory pathogens such as H. influenzae, which adhere, colonize, and can subsequently be aspirated into the lung to cause infection. B, Oral bacteria such as I? gingivalis produce enzymes that degrade the salivary molecules that normally form a pellicle on the pathogens, which prevents the pathogens from adhering to mucosal surfaces. C, Oral bacteria produce enzymes that degrade the salivary pellicle on the mucosal surface, thereby exposing adhesion receptors for respiratory pathogens. 0, Cytokines from the saliva, from inflamed periodontal tissues, upregulate the expression of adhesion receptors on the mucosal surfaces to promote respiratory pathogen colonization. With permission from Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1998;70:793-802. 92 Periodontal Medicine tonsillar epitheli~m.~~These bound oral bacteria of a longitudinal study of medical and dental con- may stimulate cytokine production by mucosal ditions in nursing home residents, observed an epithelium. It is also possible that cytokines origi- association between the development of aspiration nating from the oral tissues (for example, from the pneumonia and dental status.''* Among 26 den- gingival crevicular fluid^^^-'^'), which exit the gingi- tate nursing home residents followed up for I year, val sulcus to be mixed with whole saliva, may cont- 5 (19.8%) developed pneumonia compared with 2 aminate the distal respiratory epithelium to stimu- (7.6%) of 26 edentulous nursing home residents. late the respiratory epithelial cells. These stimulated Because of the key role that oropharyngeal respiratory cells may then release other cytokines bacterial colonization plays in the pathogenesis of that recruit inflammatory cells (eg, neutrophils) to bacterial pneumonia, several methods have been the site. These inflammatory cells may release proposed to reduce or eliminate colonization in hydrolytic enzymes and other modifying molecules, susceptible patients, such as those on mechanical resulting in damaged epithelium that may be more ventilation. We hypothesize that improved oral susceptible to colonization by respiratory pathogens. hygiene in the hospital setting may decrease the Oral bacteria may influence the expression and occurrence of oropharyngeal colonization by respi- effects of cytokines in more novel ways. Darveau and ratory pathogens and thus decrease the risk of colleaguedo2have shown that IL-8 is secreted by gin- nosocomial pneumonia. Current oral hygiene gival epithelial cells in response to components of the measures recommended by nursing educators are normal oral flora. In contrast, I;' gingivulis strongly probably inadequate to prevent dental plaque for- inhibits IL-8 accumulation from the gingival mation. '05 One method, called selective digestive epithelial cells. Inhibition was shown to be associ- decontamination (SDD), uses antibiotics topically ated with a decrease in mRNA for IL-8. Antago- applied to the surfaces of the gastrointestinal tract nism of IL-8 accumulation did not occur in KB (including the oral cavity) to reduce the carriage of cells, an epithelial cell line that does not support pathogenic bacteria and thus to prevent respirato- high levels of intracellular invasion by I;' gingivulis. ry infection. '06-'08 For example, the use of lozenges Furthermore, a noninvasive mutant of I? gingivulis containing polymyxin B, tobramycin, and ampho- was unable to antagonize IL-8 accumulation. They tericin B have been shown to diminish oral colo- concluded that invasion-dependent destruction of nization by gram-negative ba~illi.''~The study by the gingival IL-8 chemokine gradient at sites of Pugin and colleagues' '' has particular relevance I;' gingivulis colonization may impair mucosal because it focused on the elimination of oropha- defense. It is not yet known if I;' gingivulis would ryngeal colonization by pathogens and the subse- have a similar effect on the respiratory epithelium. quent development of pneumonia. These investi- Such an effect might result in perturbation of local gators used topical oropharyngeal antibiotics (ver- cytokine networks and thus promote a destructive sus topical placebo) in mechanically ventilated inflammatory lesion within the lung. patients. Oropharyngeal colonization by aerobic gram-negative bacilli and S. uureus and also pneu- Prevention of Oral Colonization by monia rates were significantly reduced in the treat- Potential Respiratory Pathogens ed population versus the placebo group (16% versus 78%; p c .OOOl). These findings suggest that Few studies have evaluated the role of poor oral focusing specifically on factors promoting oropha- hygiene and/or periodontal disease in the develop- ryngeal bacterial colonization may be useful in ment of pneumonia in high-risk patients (for developing other strategies to prevent colonization example, those that are mechanically ventilated). and thereby prevent bacterial pneumonia in sus- Several reports have documented a strong associa- ceptible populations. However, while diminishing tion between periodontal disease and an increased the colonization rate of pathogenic bacteria in the frequency of oral infections in nursing home resi- hospital setting, SDD does not appear to have an dent~.~~'''~However, there are no studies that have effect on the mortality rate"' and seems to foster identified an association between poor oral the selection of antibiotic-resistant bacteria and hygiene and the increased incidence of pneumonia cross-infection.' 12,' l3 These findings have raised in such subjects. A possible link between poor oral doubts about the widespread use of SDD. Other hygiene and the increased incidence of pneumonia approaches to reduce colonization of these in nursing home residents has been suggested but pathogens certainly deserve more study. no supporting evidence was provided.65 Recently, Maintenance of good oral hygiene may, by Terpenning and colleagues, in a preliminary report itself, reduce oropharyngeal colonization by respi- Relationships between Periodontal and Respiratory Diseases 9 3 ratory pathogens. Methods of maintaining good staff education, hand washing, and the proper use oral hygiene in mechanically ventilated patients, if of gloves and gowns, all have a positive impact on as effective as SDD in reducing pneumonia occur- reducing nosocomial pneumonia. Additional rence, may be much less expensive than SDD reg- attention paid to oral hygiene may even further imens, may lessen the risk of emergence of antibi- reduce the risk of nosocomial pneumonia. Unfor- otic resistance among bacteria indigenous to the tunately, little information is available concerning intensive care unit, and may lessen antibiotic use. the effect of improved oral hygiene on infection The overall effect may be a reduction in the cost of rates in the hospital or nursing home setting. It intensive care. Similarly, if providing and main- would, therefore, seem reasonable to perform taining good oral hygiene in nursing home resi- appropriate studies to evaluate the effect of dents is effective in reducing pneumonia rates, sig- improved oral hygiene on respiratory pathogen nificant benefits to this high-risk population colonization in high-risk subjects. would include reduced morbidity and mortality related to pneumonia occurrence, reduced medical care costs because hospital admissions will be REFERENCES reduced, and an enhanced sense of well being.58 1. Harvard School of Public Health B, Massachusetts, Although antiseptics with demonstrable abili- US. Mortality by cause for eight regions of the ty to disinfect the oral environment are avail- world: global burden of disease study. Lancet able, ‘14~’15 little research has been done concerning 1997;349:1269-76. the efficacy of these agents to inhibit oral respira- 2. Petty TL, Weinmann GG. Building a national strat- tory pathogen colonization in institutionalized egy for the prevention and management of and patients. Chlorhexidine appears to be a reasonable research in chronic obstructive pulmonary dis- choice for this as it has been shown to reduce ease. JAMA 1997;277:246-53. plaque and salivary levels of bacteria by up to 3. Garibaldi RA, Brodine S, Matsumiya S. Infections 85%.‘16 Interestingly, chlorhexidine gluconate has among patients in nursing homes: policies, been shown to reduce transfer of group strepto- B prevalence and problems. N Engl J Med 1981; cocci from mother to infant during parturition. l7 ’ 305~731-5. An analogous method used in the mouth may 4. Bentley DW. Bacterial pneumonia in the elderly: inhibit oral colonization by respiratory pathogens, clinical features, diagnosis, etiology, and treat- with minimal risk. Chlorhexidine has had wide- ment. Gerontologist 1984;30:297-307. spread use in dentistry to inhibit dental plaque for- 5. Donowitz GR, Mandell GL. Acute pneumonia. In: mation, ‘14 gingivitis,’ l8 and oral mucosal ulcera- Mandell GL, Douglas RG, Bennett JE, editors. tion~.’’~This agent also appears to inhibit the pro- Principles and practice of infectious diseases. duction of proteases by subgingival bacteria. 120 By New York: Churchill Liningstone; 1990. inhibiting protease activity, chlorhexidine may 6. Levy SB. The challenge of antibiotic resistance. Sci diminish the potential of these enzymes to process Arn 1998;278:46-53. oral surfaces to expose “cryptitopes” that may act as 7.0stergaard L, Andersen PL. Etiology of community- receptors for bacterial ad he sin^.^^ acquired pneumonia. Evaluation by transtra- An interesting report by DeRiso and col- cheal aspiration, blood culture, or serology. Chest leagues12’ suggests that a 0.12% chlorhexidine glu- 1993;104:1400-7. conate oral rinse reduced the overall nosocomial 8. Rosenthal S, Tager IB. Prevalence of grarn-negative infection rate by 65% in 353 patients admitted to rods in the normal pharyngeal flora. Ann Intern a cardiovascular ICU, and the incidence of total Med 1975;83:355-7. respiratory tract infections by 69%. These investi- 9. Bartlett JG, O’Keefe Tally FE et al. Bacteriology gators also noted a 43% reduction in the use of of hospital-acquired pneumonia. Arch Intern nonprophylactic antibiotics in chlorhexidine-treat- Med 1986;146:868-71. ed patients. Finally, overall mortality was reduced 10. Cunha BA. Hospital-acquired pneumonias, clinical to I. 16% in the chlorhexidine-treated group versus diagnosis and treatment. Hosp Phys 1986;22: 5.56% in the placebo group. 12-7. A variety of recommendations have been made 11. Toews GB. Nosocomial pneumonia. Am J Med Sci to reduce the incidence of nosocomial pneumo- 1986;29 1:355-67. nia. l2 Fastidious infection control remains the cor- 12. Craven DE, Steger KE, Barber Tw. Preventing noso- nerstone of prevention. Surveillance of potential comial pneumonia: state of the art and perspec- pathogens, identification of high-risk patients, tives for the 1990s. Am J Med 1991;91:44S-53S. 94 Periodontal Medicine

13. Wenzel RI?. Epidemiology of hospital-acquired piratory infections. New York: Churchill Liv- infection. In: Balows A, Hausler WJ, Herrmann ingstone; 1986. p. 269-92. U, et al, editors. Manual of clinical microbiol- 27. Fiddian-Green R, Baker S. Nosocomial pneumonia ogy. Washington, D.C.: American Society for in the critical ill: product of aspiration or Microbiology; 1991. p. 147-50. translocation? Crit Care Med 1991;19:793-9. 14. Boyce JM, Potter-Bynoe G, Dziobek L, Solomon 28. Sinclair DG, Evans Tw. Nosocomial pneumonia SL. Nosocomial pneumonia in Medicare in the intensive care unit. Br J Hosp Med 1994; patients. Hospital costs and reimbursement pat- 51:177-80. terns under the prospective payment system. 29. Bonten MJM, Gaillard CA, Tie1 FW, et al. The Arch Intern Med 1991;151:1109-14. stomach is not a source for colonization of the 15. Wenzel RI?. Hospital-acquired pneumonia: upper respiratory tract and pneumonia in ICU overview of the current state of the art preven- patients. Chest 1994; 105:878-84. tion and control. Eur J Clin Microbiol Infect 30. Bartlett JG, Finegold SM. Anaerobic infections of Dis 1989;8:56-60. the lung and pleural space. Am Rev Respir Dis 16. McDonald AM, Dietsche L, Litsche M, et al. A ret- 1974;1 1056-77. rospective study of nosocomial pneumonia at a 31. Bartlett JG. Anaerobic bacterial infections of the long-term care facility. Arn J Infect Cont 1992; lung. Chest 1987;9 1: 90 1-9. 20:234-8. 32. Shinzato T, Saito A. A mechanism of pathogenicity 17. Ingram RH. Chronic bronchitis, emphysema, and of “Streptococcus milleri group” in pulmonary airways obstruction. In: Isselbacher KJ, Braun- infection: synergy with an anaerobe. J Med wald E, Wilson JD, et al, editors. Harrison’s Microbiol 1994;40:118-23. Principles of internal medicine. New York: 33. Elpern EH, Scott MG, Petro L, Ries MH. Pul- McGraw-Hill; 1994. p. 1197-206. monary aspiration in mechanically ventilated 18. Society AT. Standards for the diagnosis and care of patients with tracheostomies. Chest 1994;105: patients with chronic obstructive pulmonary 563-6. disease. Arn J Respir Crit Care Med 1995;152: 34. Finegold SM. Aspiration pneumonia. Rev Infect S77- 121. Dis 1991;13:S737-42. 19. Renwick DS, Connolly MJ. Prevalence and treat- 35. Harkness GA, Bentley DW, Roghman KJ. Risk fac- ment of chronic airways obstruction in adults tors for nosocomial pneumonia in the elderly. over the age of 45. Thorax 1996;51:164-8. Am J Med 1990;89:457-63. 20. Sandford AJ, Weir TD, Pare PD. Genetic risk fac- 36. Potter RT, Rotman F, Fernandez F, et al. The bac- tors for chronic obstructive pulmonary disease. teriology of the lower respiratory tract. Bron- Eur Resp J 1997;10:1380-91. choscopic study of 100 clinical cases. Am Rev 21. Murphy TF, Sethi S. Bacterial infection in chronic Respir Dis 1968;97:1051-61. obstructive pulmonary disease. Am Rev Respir 37. Schreiner A. Anaerobic pulmonary infections. Dis 1992;146:1067-83. Scand J Infect Dis 1979;19 Suppl:77-9. 22. Fagon JY, Chastre J. Severe exacerbations of 38. Brook I, Frazier EH. Aerobic and anaerobic micro- COPD patients: the role of pulmonary infec- biology of empyema. A retrospective review in tions. Semin Respir Infect 1996;ll: 109-18. two military hospitals. Chest 1993;103: 1502-7. 23. Laurenzi GA, Potter RT, Hass EH. Bacteriologic 39. Goldstein EJ, Kirby BD, Finegold SM. Isolation of flora of the lower respiratory tract. N Engl J EikeneZZa corrodens from pulmonary infections. Med 1961;265: 1273-8. Arn Rev Respir Dis 1979;119:55-8. 24. Cabello H, Torres A, Celis R, et al. Bacterial colo- 40. Suwanagool S, Rothkopf MM, Smith SM, et al. nization of distal airways in healthy subjects and Pathogenicity of EikeneZZa corrodens in humans. chronic lung disease: a bronchoscopic study. Eur Arch Intern Med 1983;143:2265-68. Respir J 1997;10:1137-44. 41. Joshi N, O’Bryan T, Appelbaum PC. Pleuropul- 25. Levison ME. Pneumonia, including necrotizing monary infections caused by EikeneZZa corrodens. pulmonary infections (lung abscess). In: Issel- Rev Infect Dis 1991;13:1207-12. bacher KJ, Braunwald E, Wilson JD, et al, edi- 42. Zijlstra EE, Swart GR, Godfroy FJM, Degener JE. tors. Harrison’s Principles of internal medicine. Pericarditis, pneumonia and brain abscess due New York: McGraw-Hill; 1994. p. 1184-9 1. to a combined Actinomyces-ActinobaciZZus actino- 26. Megran DW, Chow AW. Bacterial aspiration and mycetemcomitans infection. J Infect 1992;25: anaerobic pleuropulmonary infections. In: 83-7. Sande MA, Hudson LD, Root RK, editors. Res- 43. Mahomed AG, Feldman C, Smith C, et al. Does Relationships between Periodontal and Respiratory Diseases 9 5

primary Streptococcus virihns pneumonia exist? 58. Karuza J, Miller WA, Lieberman D, et al. Oral sta- S Afr Med J 1992;82:432-4. tus and resident well-being in a skilled nursing 44. Lorenz KA, Weiss PJ. Capnocytophageal pneumo- facility population. Gerontologist 1992;32: nia in a healthy man. West J Med 1994;160: 104-12. 79-80. 59. Scannapieco FA, Stewart EM, Mylotte JM. Colo- 45. Morris JF, Sewell DL. Necrotizing pneumonia nization of dental plaque by respiratory caused by mixed infection with Actinobacillus pathogens in medical intensive care patients. actinomycetemcomitans and Actinomyces israelii: Crit Care Med 1992;20:740-5. Case report and review. Clin Infect Dis 60. Kiyak HA, Grayston MN, Crinean CL. Oral 1994;18:450-2. health problems and needs of nursing home res- 46. Yuan A, Luh KT, Yang PC. Actinobacillus actino- idents. Comm Dent Oral Epidemiol 1993;21: mycetemcomitans pneumonia with possible sep- 49-52. tic embolization [letter]. Chest 1994;105646. 61. Fourrier F, Duvivier B, Boutigny H, et al. Colo- 47. Chen AC, Liu CC, Yao WJ, et al. Actinobacillus nization of dental plaque: a source of nosocomi- actinomycetemcomitans pneumonia with chest a1 infections in intensive care unit patients. Crit wall and subphrenic abscess. Scand J Infect Dis Care Med 1998;26:301-8. 1995;27:289-90. 62. Russell SL, Boylan RJ, Kaslick R, et al. Respiratory 48. Moore WEC, Moore LW. The bacteria of perio- pathogen colonization of the dental plaque of dontal disease. Periodontol 2000 1994;5: institutionalized elders. Spec Care Dent 1999; 66-77. 19~1-7. 49. Slots J, Rams TE. Microbiology of periodontal dis- 63. Komiyama K, Tynan JJ, Habbick BF, et al. ease. In: Slots J, Taubman MA, editors. Con- Pseudomonas aeruginosa in the oral cavity and temporary oral microbiology and immunology. sputum of patients with cystic fibrosis. Oral St. Louis, MO: Mosby-Year Book Inc.; 1992. Surg Oral Med Oral Pathol 1985;59:5904. p. 425-43. 64. Costerton JW, Lewandowski 2, Caldwell DE, et al. 50. Appelbaum PC, Cameron EW, Hutton WS, et al. Microbial biofilms. Ann Rev Microbiol 1995; The bacteriology of chronic destructive pneu- 49:711-45. monia. S Afr Med J 1978;53:541-2. 65. Scannapieco FA, Mylotte JM. Relationships 5 1. Pratter MR, Irwin RS. Viridans streptococcal pul- between periodontal disease and bacterial pneu- monary parenchymal infections. JAMA 1980; monia. J Periodontol 1996;67:11 14-22. 243:25 15-7. 65a. Silness J, Loe H. Periodontal disease in pregnancy. 52. Marrie TJ. Bacteremic community-acquired pneu- 11. Correlation between oral hygiene and perio- monia due to viridans group streptococci. Clin dontal condition. Acta Odontol Scand 1964; Invest Med 1993;16:38-44. 24:747-59. 53. Haas H, Morris JF, Samson S, et al. Bacterial flora 65b.Knaus WA, Draper EA, Wagner Dc Zimmerman of the respiratory tract in chronic bronchitis: JE. APACHE 11: a severity of disease classifica- comparison of transtracheal, fiberbronchoscop- tion system. Crit Care Med 1985;13:818-29. ic, and oropharyngeal sampling methods. Am 66. Limeback H. The relationship between oral health Rev Respir Dis 1977;1 16:4 1-7. and systemic infections among elderly residents 54. Torres A, Dorca J, Zalacain R, et al. Community- of chronic care facilities: a review. Gerodontolo- acquired pneumonia in chronic obstructive pul- gist 1988;7:13 1-7. monary disease: a Spanish multicenter study. 67. Limeback H. Implications of oral infections on sys- Arn J Respir Crit Care Med 1996;154:1456-61. temic diseases in the institutionalized elderly 55. Nelson S, Laughon BE, Summer WR, et al. Char- with a special focus on pneumonia. Ann Perio- acterization of the pulmonary inflammatory dontol 1998;3:262-75. response to an anaerobic bacterial challenge. 68. Mojon Budtz-Jmgensen E, Michel Jc Limeback Arn Rev Respir Dis 1986;133:212-7. H. Oral health and history of respiratory tract 56. Grollier G, Dore Robert R, et al. Antibody infection in frail institutionalised elders. response to Prevotelh spp. in patients with ven- Gerodontologist 1997;14:9-16. tilator-associated pneumonia. Clin Diag Lab 69. Scannapieco FA, Papandonatos GD, Dunford RG. Immunol 1996;3:61-5. Associations between oral conditions and respi- 57. Bagramian RA, Heller W. Dental health assess- ratory disease in a national sample survey popu- ment of a population of nursing home residents. lation. Ann Periodontol 1998;3:251-6. J Gerontol 1977;32:168-74. 70. Hayes C, Sparrow D, Cohen M, et al. Periodontal 9 6 Periodontal Medicine

disease and pulmonary function: the VA longi- 85. Reddy MS, Murphy TF, Faden HS, Bernstein JM. tudinal study. Ann Periodontol 1998; 257-6 1. Middle ear mucin glycoprotein: purification 71. Johanson WG, Pierce AK, Sanford AK, Thomas JI? and interaction with nontypable Haemophilus Nosocomial respiratory infections with gram- influenzde and Moraxelh catambalis. Otolaryn- negative bacilli: the significance of colonization go1 Head Neck Surg 1997; 116: 175-80. of the respiratory tract. Ann Intern Med 1972; 86. Davies J, Carlstedt I, Nilsson AK, et al. Binding of 77:70 1-6. Haemophilus influenzde to purified mucins from 72. Johanson WG, Higuchi JH, Chaudhuri TR, the human respiratory tract. Infect Immun Woods DE. Bacterial adherence to epithelial 1995;63:2485-92. cells in bacillary colonization of the respiratory 87. Barsum W, Wilson R, Read RC, et al. Interaction tract. Am Rev Respir Dis 1980;121:55-63. of fimbriated and nonfimbriated strains of 73. Woods DE, Straus DC, Johanson WG, Bass JA. unencapsulated Haemophilus influenzde with Role of fibronectin in the prevention of adher- human respiratory tract mucus in vitro. Eur ence of Pseudomonas aeruginosa to buccal cells. J Respir J 1995;8:709-14. Infect Dis 1981;143:784-90. 88. Fakih MG, Murphy TF, Pattoli MA, Berenson CS. 74. Abraham SN, Beachey EH, Simpson WA. Adher- Specific binding of Haemophilus influenzae to ence of Streptococcus pyogenes, Escherichia coli minor gangliosides of human respiratory epithe- and Pseudomonas aeruginosa to fibronectin-coat- lial cells. Infect Immun 1997;65:1695-700. ed and uncoated epithelial cells. Infect Immun 89. van der Hoeven JS, van den Kieboom CW, Camp 1983;41:1261-8. PJM. Utilization of mucin by oral Streptococcus 75. Nakamura M, Slots J. Salivary enzymes. Origin species. Antonie van Leeuwenhoek 1990;57: and relationship to periodontal disease. J Perio- 165-72. dontal Res 1983;18:559-69. 90. Scannapieco FA. Saliva-bacterium interactions in 76. Zambon JJ, Nakamura M, Slots J. Effect of perio- oral microbial ecology. Crit Rev Oral Biol Med dontal therapy on salivary enzyme activity. J 1994;5:203-48. Periodontal Res 1985;20:652-9. 91. Reddi K, Wilson M, Nair S, et al. Comparison of 77. Gibbons RJ, Etherden I. Fibronectin-degrading the pro-inflammatory cytokine-stimulating enzymes in saliva and their relation to oral activity of the surface-associated proteins of cleanliness. J Periodontal Res 1986;21:386-95. periodontopathic bacteria. J Periodontal Res 78. Loesche WJ, Syed SA, Stoll J. Trypsin-like activity 1996;31:120-30. in subgingival plaque. A diagnostic marker for 92. Wilson M, Reddi K, Henderson B. Cytokine- spirochetes and periodontal disease. J Periodon- inducing components of periodontopathogenic to1 1987;58:266-73. bacteria. J Periodontal Res 1996; 3 1:393-407. 79. Wikstrom M, Linde A. Ability of oral bacteria to 93. Kjeldsen M, Holmstrup Lindemann RA, degrade fibronectin. Infect Immun 1986;51 : Bendtzen K. Bacterial-stimulated cytokine pro- 707-1 1. duction of peripheral mononuclear cells from 80. Frandsen EG, Reinholdt J, Kilian M. Enzymatic patients of various periodontitis categories. J and antigenic characterization of immunoglob- Periodontol 1995;66:139-44. ulin A1 proteases from Bacteroides and Capnocy- 94. Svanborg C, Hedlund M, Connell H, et al. Bacte- tophaga spp. Infect Immun 1987;55:631-8. rial adherence and mucosal cytokine responses. 81. Cimasoni G, Ishikawa I, Jacccard F. Enzyme activ- Receptors and transmembrane signaling. Ann ity in the gingival crevice. In: Lehner T, editor. N Y Acad Sci 1996;797:177-90. Borderland between caries and periodontal dis- 95. Khair OA, Davies RJ, Devalia JL. Bacterial- ease. London: Academic Press; 1977. p. 13-41. induced release of inflammatory mediators by 82. Quinn MO, Miller VE, Dal Nogare AR. Increased bronchial epithelial cells. Eur Respir J 1996;9: salivary exoglycosidase activity during critical 1913-22. illness. Am J Respir Crit Care Med 1994;150: 96. Durum SK, Oppenheim J. Proinflammatory 179-83. cytokines and immunity. In: Paul WE, editor. 83. Weinmeister KD, Dal Nogare AR Buccal cell car- Fundamental immunology. New York, NY bohydrates are altered during critical illness. Am Raven Press Ltd.; 1993. J Respir Crit Care Med 1994;150: 13 1-4. 97. Hikansson A, Carlstedt I, Davies J, et al. Aspects 84. Gibbons RJ, Hay DI, Childs WC, Davis G. Role of on the interactions of Streptococcus pneumoniae cryptic receptors (cryptitopes) in bacterial adhe- and Haemophilus influenzde with human respi- sion to oral surfaces. Arch Oral Biol 1990;35: ratory tract mucosa. Arn J Respir Crit Care Med 107s-114s. 1996;154:s 187-9 1. Relationships between Periodontal and Respiratory Diseases 9 7

98. Brook I, Yocum Foote PAJ. Changes in the core trolled trial in intensive care units of selective tonsillar bacteriology of recurrent tonsillitis: decontamination of the digestive tract with 1977-1993. Clin Infect Dis 1995;21:171-6. nonabsorbable antibiotics. N Engl J Med 99. Rossomando EF, White L. A novel method for the 1992;326:594-9. detection of TNF-alpha in gingival crevicular 112. Johanson WG, Seidenfeld JJ, de 10s Santos R, et al. fluid. J Periodontol 1993;64:445-9. Prevention of nosocomial pneumonia using 100. Tatakis DN. Interleukin- 1 and bone metabolism: topical and parenteral antimicrobial agents. Am a review. J Periodontol 1993;64:416-3 1. Rev Respir Dis 1988;137:265-72. 101. Birkedal-Hansen H. Role of cytokines and inflam- 113. Hurley JC. Prophylaxis with enteral antibiotics in matory mediators in tissue destruction. J Perio- ventilated patients: selective decontamination or dontal Res 1993;28:500-10. selective cross-infection? Antimicrob Agents 102. Darveau W, Belton CM, Reife RA, Lamont RJ. Chemother 1995;39:941-7. Local chemokine paralysis, a novel pathogenic 114. Tonelli PM, Hume WR, Kenney EB. Chlorhexi- mechanism for Porpbyromonas gingivalis. Infect dine: a review of the literature. J West SOCPerio- Immun 1998;66:1660-5. dontol 1983;31:5-30. 103. Viglid M. Oral hygiene and periodontal condi- 115. Exner M, Gregori G, Pau Hw,Vogel F. In vivo tions among 20 1 dentate institutionalized elder- studies on the microbicidal activity of antisep- ly. Gerodontologist. 1988;4:140-5. tics on the flora of the oropharyngeal cavity. J 104. Terpenning M, Bretz W, Lopatin D, et al. Bacteri- Hosp Infect 1985;6 Suppl:185-8. al colonization of saliva and plaque in the elder- 116. Balbuena L, Stambaugh U, Rarnirez SG, Yeager C. ly. Clin Infect Dis 1993;16 Suppl:3 14-6. Effects of topical oral antiseptic rinses on bacter- 105. Luckman J, Sorensen KC. Medical-surgical nurs- ial counts of saliva in healthy human subjects. ing. Philadelphia, PA: W.B. Saunders Co.; Otolaryngol Head Neck Surg 1998;118:625-9. 1987. 117. Nilsson G, Larsson L, Christensen K, et al. 106. Kerver AJH, Rommes JH, Mevissen-Verhage EA_E, Chlorhexidine for prevention of neonatal colo- et al. Prevention of colonization and infection in nization with group B streptococci. V. Chlor- critically ill patients: a prospective randomized hexidine concentrations in blood following study. Crit Care Med 1988;16:1087-93. vaginal washing during delivery. Eur J Obstet 107. Nord CE, Heindahl A. Impact of orally adminis- Gynec Reprod Biol 1989;31 :22 1-6. tered antimicrobial agents on human oropha- 118. Lang NE Brecx MC. Chlorhexidine gluconate- ryngeal and colonic microflora. J Antimicrob an agent for chemical plaque control and pre- Ther 1986; 18 Suppl C: 159-64. vention of gingival inflammation. J Periodontal 108. Stoutenbeek Cc Hendrik HISF, Miranda DR, et Res 1986;21 Suppl 16:74-89. al. The effect of oropharyngeal decontamination 119. Ferretti GA, Ash RC, Brown AT, et al. Control of using topical nonabsorbable antibiotics on the oral mucositis and candidiasis in marrow trans- incidence of nosocomial respiratory tract infec- plantation: a prospective double blind trial of tions in multiple trauma patients. J Trauma chlorhexidine. Bone Marrow Transplant 1988;3: 1987;27:357-64. 483-94. 109. Spijkervet FKL, Saene HKFV, Saene JJMV, et al. 120. Radford JR, Homer KA, Naylor MN, Beighton Effect of selective elimination of the oral flora D. Inhibition of human subgingival plaque pro- on mucositis in irradiated head and neck cancer tease activity by chlorhexidine. Arch Oral Biol patients. J Surg Oncol 199 1;46:167-73. 1992;37:245-8. 110. Pugin J, Auckenthaler R, Lew Dc Suter PM. 121. DeRiso AJN, Ladowski JS, Dillon TA, et al. Oropharyngeal decontamination decreases inci- Chlorhexidine gluconate 0.12% oral rinse dence of ventilator-associated pneumonia. A reduces the incidence of total nosocomial respi- randomized, placebo-controlled, double-blind ratory infection and nonprophylactic systemic clinical trial. JAMA 1991;265:2704-10. antibiotic use in patients undergoing heart 111. Gastinne H, Wolff M, Delatour F, et al. A con- surgery. Chest 1996;109:1556-61. CHAPTER7

TOBACCOUSE AND 1NTERVENTION

Robert E. Mecklenburg, DDS, MPH Sara G. Grossi, DDS, MS

The good news is that three-quarters of the adult healing are exceedingly more prevalent in smokers population in the United States do not use tobac- compared with nonsmokers. Periodontal disease co. Smoking decreased in the general population has been added to the ever-increasing list of health from 42% in 1965 to 25% by 1995.l Among consequences (oral and systemic) of tobacco smok- adults aged 18 to 24 years, tobacco use was approx- ing."12 Chronic exposure to many substances in imately half as high in 1991 (23%) as in 1965 tobacco and tobacco byproducts significantly (46%).2Among high school seniors, the prevalence affects the prevalence and progression of periodon- of daily smoking decreased from 29% in 1976 to tal disea~es.~'~J~J~So profound is the negative 17% in 1992.3Public awareness of the risks associ- effect of cigarette smoking on the periodontium ated with tobacco use is increasing, and some pub- that exposure to second-hand smoke accounts for lic policy ground has been gained, such as the 30% of periodontal disease in nonsmokers.14 In enactment of several community, state, and federal addition, tobacco use complicates periodontal clean-air laws. therapy and substantially reduces the possibility of The bad news is that trends in tobacco use favorable treatment outcome^.^^-^^ Integrating reversed during the 1990~.~Large, protracted tobacco intervention services within clinical prac- tobacco industry advertising and promotion cam- tice is a prudent clinical step and professional paigns influenced the susceptible adolescent popu- obligation. From a broader perspective, providing lation. Youth use of tobacco increased year by year such services is a civic duty. All scientifically sound after 1991 to 43% of U.S. high school students clinical intervention services available to the health using cigarettes, smokeless tobacco, or cigars in professional should be applied to help dental 1997, which is a 32% increase. By 1997, this trend patients overcome this life-endangering behavior. led to a new increase in tobacco use among adults aged 18 to 24 years.3a Some cigarette smokers switched to or started using smokeless/spit tobacco COST OF USING TOBACCO and/or cigars, and some never-smokers began using smokeless/spit tobacco and/or cigars only. A Most adults and adolescents are aware that tobac- common mistaken belief is that a reduced risk is co use jeopardizes their health but may not realize equivalent to a negligible risk.3b>3cAlso, few youths how great the risk is compared with other behav- appreciate the addictive properties of nicotine iors that are considered risky.' Cigarette smoking is inherent in the use of any tobacco product, non the most important preventable cause of morbidi- adults perceive the extent of their tobacco-related ty and mortality in the United States. It is respon- health risks.3 sible for more than 400,000 deaths each year Cigarette smoking is the single most impor- (1998 estimate, 430,700).18 Indeed, nearly one of tant and modifiable factor responsible for cases of every five American deaths can be attributed to lung cancer, hypertension, and cardiovascular dis- cigarette smoking. Each year, more than 140,000 eases in the western world. Malignant and prema- women die as a result of smoking-related diseases. lignant oral lesions alike have been associated with Among women, cardiovascular disease is the most cigarette ~moking.~>~Generally speaking, soft tis- common cause of smoking-related death. l9 Lung sue conditions, dental caries, and delayed wound cancer, the second most common cause, has been 1 O O Periodontal Medicine rising rapidly since the early 1960s and, in 1989, smokers. Since smokers with slight or moderate exceeded breast cancer as the most common form periodontitis were either excluded from this analy- of cancer death among women.20The lung cancer sis or included as controls, this figure may represent mortality rate among men has stabilized but an underestimation of the real magnitude of the remains the leading cause of cancer in all male age association. Current smokers were also 3.3 times groups ages 15 and 01der.~l-~~ more likely to attend a periodontal practice office Tobacco use produces massive economic costs compared with nonsmoker^.^^ The effect of smok- to society. The direct annual cost of treating smoking on periodontal tissues is cumulative and dose ing related illness is greater than the gross sales of dependent (Figures 7-2 and 7-3). Evidence for this tobacco product^.^^>^^ When the indirect costs of biologic gradient is demonstrated in the Erie smoking during pregnancy, lost workdays, lost out- County Study, where 80% of individuals smoking put from early death or retirement and the external at least 20 pack-years exhibited moderate to severe costs, such as fires caused by smoking, are added to periodontal disease, measured by either clinical medical costs, the burden to the U.S. economy in attachment loss (see Figure 7-2)8 or alveolar bone 1998 approaches $130 billion per year, more than loss (see Figure 7-3) .9 Clinically, smoking-associated two and a half times the gross sales of tobacco prod- periodontal disease presents with thick inflamed uct~.~~’~~Intangible costs add to the burden, such as marginal gingiva and generalized recession. The tobacco-related suffering, disability, and worsening buccal marginal gingiva of both upper and lower in the quality of life. Cigar and pipe smoking and anterior teeth often present with the characteristic the use of smokeless/spit tobacco significantly ele- stain of smoker melanosis (Figure 74).The degree vate health risks and are not safe alternatives to cig- of alveolar bone destruction far exceeds the peri- arette ~moking.~“.~~.~~Their relatively low propor- odontal destruction evident clinically (Figures 7-5 tion of use and recent increase in popularity do not and 7-6). If these figures do not speak for them- provide as solid an evidence base for adverse eco- selves, 30% of the incidence of periodontal disease nomic consequences as does the overwhelming evi- in nonsmokers is accounted for by exposure to dence attributed to cigarette smoking. environmental (household) second-hand smoke.l4 On a global perspective tobacco use is responsi- Thus, cigarette smoking is the single, modifiable ble for about 4 million deaths each year. That figure environmental factor responsible for the excess represents more deaths than are caused by HIV, prevalence of periodontal disease in the population. tuberculosis, maternal mortality, motor vehicle acci- Cases of periodontal disease attributed solely to dents, suicides, and homicides combined. By 2030, smoking are by far greater than the ones owed to the World Health Organization projects that tobacco other important factors such as diabetes mellit~s.~ will be the leading cause of death and disability, Accordingly, cigarette smoking has been demon- killing more than 10 million people annually. 28a,28b strated to fit all of the nine “Bradford Hill criteria” These statistics are even more alarming when one for causation and, as such, is proposed as a causal considers that all smoking-related deaths are essen- factor in severe periodontal disease.32 tially preventable. The decline in cigarette smoking in the United States over the last 25 years has not been Mechanisms of Tobacco Toxicity equal across all populations. The number of adults to the Periodontium currently remains high, and adult prevalence has changed little from 1993 to 1997.l Increased trends There is an established biologic rationale for the in tobacco use by youths in the United States por- negative effect of cigarette smoking on periodontal tends a worsening state of tobacco-related diseases. tissues. First and foremost, smoking has an immunosuppressive effect on the host, adversely Cost to the Periodontium: Risk Factors affecting host-parasite interactions. Peripheral blood polymorphonuclear leukocyte motility, chemotaxis, Cigarette smoking accounts for approximately half and phagocytosis are significantly im~aired,~~-~~ the cases of periodontitis diagnosed in young adults thus, compromising this very important first line of (< 35 years ).29 A meta-analysis from six cross-sec- defense against subgingival bacteria. In addition, tional and case-control studies reported an odds smokers have decreased antibody production, espe- ratio of 2.82 (95% CI 2.36 to 3.39) for “severe” cially IgG2P7 the subclass most important in the periodontal disease (Figure 7-1) .30 Smokers are, opsonization of periodontal bacteria, and decreased therefore, almost three times more likely to show immunoregulatory T-cell subset ratios.38 The net severe periodontal disease compared with non- result is that periodontal organisms in current ciga- Tobacco Use and Intervention 1 O 1

Bergstrom, 1989 h - -rI Haber and Kent, 1992 :30 - E Locker, 1992 E - - 20 - z Haber et al, 1993 I 1 I ?- Y 8 10 Stoltenberg et al, 1993 - n Grossi et al, 1994 w 0 Overall w I1 12.0 23.0 14.0 >4.0 Mean attachment loss (mm) 357911 Figure -2. Dose-dependent effect of cigarette smoking and Odds ratio severity of attachment loss. For every 10 pack-years incre- Figure 7-1. Meta-analysis of smoking as a risk factor for ment, there is 1 mm increase in mean attachment loss. periodontal diseases. Bars indicate the 95% confidence lim- Adapted from Grossi et al. J Periodontol 1994;65:260-7. its for the depicted odds ratios. Adapted from Papapanou, PN. Periodontal Idiseases: epidemiology. Ann Periodontol 1996;l:l-36. oral cavity. Periodontal intervention studies consistently demonstrate that smokers do not heal as well rette smokers escape specific and nonspecific as nonsmokers after periodontal therapy. The clin- immune clearance mechanisms allowing them to ical outcomes of periodontal therapy, that is reduc- establish as subgingival inhabitants. Alteration in tion in pocket depth and gain in probing attach- the physical subgingival environment, such as ment level, are significantly reduced in current decreased oxygen tension, would allow the over- smokers compared with former and nonsmokers growth of an essentially anaerobic In addi- (Figure 7-7) 15~17,48,49The reduced clinical response ton, cigarette smoking also increases bacterial adhe- to mechanical therapy seen in current smokers is sion to epithelial cells.41 Indeed, current smokers are paralleled by a persistence of subgingival B. significantly more likely to be infected with Buc- forsytbus and I? gingivulis compared with nonsmok- teroides forsytbw and Porpbyromonus gingivulis com- ers or former smokers (Figure 7-8).16 This reduced pared with nonsmoker^.^^ clinical response is directly related to active smok- Several studies have demonstrated the absorp- ing. Former smokers, on the other hand, respond tion of nicotine in periodontal tissues. Nicotine has to periodontal therapy in a manner similar to been detected on root surfaces in smokers with peri- never-smokers. l6 Although no studies have specifi- odontal disease.43Cotinine, the major metabolite of cally addressed the effect of smoking cessation on nicotine, is found in the serum, saliva, and gingival periodontal therapy, indirect data from interven- crevicular fluid of smokers.44Fibroblasts exposed to tion studies that have included former smokers nicotine have shown reduced ~roliferation$~migra- indicate that smoking cessation restores the host’s tion, and attachment to root surfaces.46In addition, fibroblasts have been shown to nonspecifically bind 30 and internalize which could, in turn, -r result in an alteration of the cell metabolism, including collagen synthesis and protein secretion. In summary, cigarette smoking appears to trigger a cycle of impaired immune response, anaerobic subgingival infection, and connective tissue cytotoxicity, leading to greater severity of periodontal disease and impaired wound healing.

Tobacco Use and Response < 2.0 2.0-2.9 3.0-3.9 24 to Periodontal Therapy Mean alveolar bone loss (mm) Figure 7-3. Severity of alveolar bone loss is directly propor- Nonsurgical Therapy tional to the overall lifetime exposure to tobacco smoke, Scientific evidence shows that smoking impairs measured as pack-years. Adapted from Grossi et al. J Perio- wound healing throughout the body, including the dontol 1995;66:23-9. 102 Periodontal Medicine

smoker~.~~In a 15-year prospective study of mandibular implant prostheses, current smoking was more closely associated with marginal bone loss around implants than was poor oral hygiene.56 In summary, current smoking is by far the most significant factor responsible for impaired periodontal wound healing and poor clinical outcome following flap and -regenerative surgery and implant fail~re.5~>5~,5~-5~

Figure 7-4. Female heavy smoker (more than 20 pack- Supportive Periodontal Therapy years). Attached gingiva is thick, chronically inflamed, and and Need for Re-treatment fibrotic. Smoker melanosis is evident as well. Two independent studies on the long-term effects of supportive periodontal therapy (SPT) consistently agreed that smokers have a less favorable response to healing capacity to levels comparable with those SPT compared with nonsmokers. 17,50 This reduced who never smoked. response is dose dependent in that heavy smokers, that is, > 20 cigarettes per day, respond less favorably Surgical, Regenerative, and Implant Therapy than light smokers (< 19 cigarettedday) to long- Current cigarette smoking impairs wound healing term SPT. l7 Both studies report the encouraging following surgical periodontal therapy to a greater finding that former smokers respond to STP in a extent than following nonsurgical therapy. Smok- manner similar to those that never smoked. A sim- ers that underwent periodontal surgery with either ilar benefit of smoking cessation has been reported modified Widman flap or mucoperiosteal flap had for dental implant survival.58 Ninety percent of significantly less reduction in pocket depth and patients diagnosed with refractory periodontitis are gain in probing attachment levels compared with current smoker^.^' Thus, not only does smoking nonsmoker^.^' Cigarette smoking has also been result in reduced response to all modalities of peri- associated with a reduced healing response after odontal treatment and less favorable outcome, sus- guided tissue-regeneration therapy in the deep ceptibility to recurrence and need for re-treatment intrabony defe~ts~l>~~and with an 80% failure rate are increased as well. in the treatment of furcation defects.53 Current smoking also decreases the percentage of root cov- Cost to Patient and Provider toTreat erage that takes place after tissue grafting.54Eighty Tobacco-Related Periodontal Conditions percent of current smokers undergoing intraoral bone grafting and simultaneous implant placement When one considers the simple fact that severe peri- showed impaired wound healing, defined as loss of odontal disease will result in more clinic visits, longer bone or implant, compared with only 10% of non- clinic appointments, and more complex treatment procedures than will less severe forms of disease, the

Figure 7-6. Radiographic evaluation of same patient as in Fig- ure 7-5. Generalized severe alveolar bone loss is evident, Figure 7-5. Male heavy smoker (more than 20 pack-years) involving 50% of the root length or more. Furcation involve- with severe periodontal disease. Gingival tissue is thick, ment (class 111) in all molars is evident. Degree of alveolar bone fibrotic, and with receded margins. destruction in this patient exceeds the clinical involvement. Tobacco Use and Intervention 103 increased cost of treating smoking-related periodontal disease to both patient and provider becomes evident. If one then considers that 80% of moderate to severe periodontal disease is associated with heavy smoking, the figures are rather staggering. If the costs of periodontal treatment are calculated, smoking is second only to number of remaining teeth and age. Following the same trend seen for disease severity and response to periodontal therapy smoking, measured as number of cigarettes per day, has a significant effect both on the treatment cost per patient and per individual tooth.59 Thus, in addition to causing and exacerbating oral diseases and condi- Figure 7-7. Clinical response to mechanical periodontal tions, tobacco use adversely affects oral health care. therapy in smokers and nonsmokers at 3 months after ther- Occasionally, patients that exhibit tobacco-related apy, in deep sites (pocket depth 2 5 mm). Current smokers diseases may require special planning, premedica- had significantly less (p < .OOl) reduction in pocket depth and gain in clinical attachment (p < .OS) in deep pockets tion, consultation, or unanticipated medical care compared with former and nonsmokers. The clinical during their oral health care. Conversely tobacco response to mechanical therapy in former smokers was com- intervention services for the prevention and treat- parable with that in nonsmokers, suggesting the benefit of ment of oral diseases also benefit the general health smoking cessation in response to periodontal therapy. PD = and well-being of the patient and reduce collateral pocket depth; CAL = clinical attachment loss. risks to clinical practice and society.60 postsynaptic neurons. Intraneuronal changes occur UN DERLY I NG DISEASE that alter gene expression. With repeated exposure, central nervous system (CNS) stimulation by nico- Understanding of the nature of nicotine depen- tine gradually wanes, and more nicotine becomes dency is essential to applying substantive, efficient necessary to ward off withdrawal symptoms. Brain means to treat this debilitating condition. Provid- metabolism initially increases and then stabilizes in ing periodontal therapy or several other clinical the presence of nicotine. Thus, continued periodic services to tobacco users without treating their dosing with nicotine becomes a necessity for indi- tobacco dependency is analogous to painting a viduals to function normally as they would had rusty surface-a major underlying cause and/or major contributor to the problem is not addressed, thus predisposing to recurrence. Nicotine dependency is a progressive, chronic, relapsing disease; it is a brain disease imbedded in a social context. That is, nicotine governs tobacco- using behavior, but many psychologic and social cues reinforce the process. Nicotine is considered as addictive as other commonly used substances of abuse; however, more tobacco experimenters become dependent and, once dependent, have greater difficulty while quitting and lower success rates.'l This is partly because of the low cost and easy availability of tobacco and partly because use is socially acceptable in some environments.62 At the molecular-cellular level, nicotine is a Figure 7-8. Percent of patients that became negative for tertiary amine that is highly psychoactive. In the A. actinomycetemcomitans, B. forsythus, and I? gingivalis at 3 brain, chronic exposure to nicotine stimulates months following mechanical periodontal therapy. Half as many smokers continued to become negative for any of these release of dopamine and other neurotransmitter periodontal organisms after treatment compared with non- monoamines into the CNS neuronal cleft and smokers, suggesting that the reduced clinical response to other sites. In the presence of repeated exposure, periodontal treatment seen in smokers is due to persistence nicotinic acetylcholine receptors proliferate on the of periodontal infection of these patients. 104 Periodontal Medicine they never been exposed. A pack-a-day smoker, is likely to have been caused or exacerbated by drawing ten puffs, self-administers about 200 the substance. “hits” each day. This frequently repeated behavior A nicotine-dependent individual uses the drug becomes part of the dependency. for avoidance of withdrawal symptoms as much as The presence of low levels of nicotine in the or more than for perceived benefits such as calm- body over time produces many other effects. For ing, stimulation, or suppression of hunger. A major example, in the cardiovascular system, nicotine component of the “pleasure” of smoking or chew- increases circulating catecholamines, modulates ing is relief from the building withdrawal symp- heart A-V node conduction, contracts collateral toms produced by nicotine depletion. arteries, promotes platelet aggregation, increases low density lipoproteins, decreases high density With permission from Henningfield JE, Cohen C, lipoproteins, and promotes formation of athero- Pickworth WB. Psychopharmacology of nicotine. In: sclerotic plaques. In the respiratory tract, it Orleans CT, Slade J, editors. Nicotine addiction: prin- decreases cilia motility, increases airway resistance, ciples and management. New York, Ny: Oxford Uni- and decreases lung tissue elasticity. versity Press; 1993. Physical dependency on nicotine is recognized by a cluster of specific patterns of behavior. DMS-IV Criteria for Nicotine Withdrawal Dependent individuals typically construct their A. Daily use of nicotine for at least several weeks. daily activities around the self-administration of nicotine. B. Abrupt cessation of nicotine use, or reduction in The American Psychiatric Association diag- the amount of nicotine used, followed within 24 nostic criteria for substance dependency, which hours by four (or more) of the following signs: includes nicotine addiction are given below: 1. dysphoric or depressed mood 2. insomnia DMS-IV Diagnostic Criteria for Substance 3. irritability, frustration or, anger Dependence 4. anxiety A maladaptive pattern of substance use, leading to 5. difficulty concentrating clinically significant impairment or distress, as man- 6. restlessness ifested by three or more of the following, occurring 7. decreased heart rate at any time in the same 12-month period: 8. increased appetite or weight gain Tolerance, as defined by C. The symptoms in criterion B cause clinically a need for markedly increased amounts of the significant distress or impairment in social, substance to achieve the desired effect, or occupational, or other important areas of hnc- markedly diminished effect with continued use tioning. of the same amount of the substance. D. The symptoms are not due to a general medical condition and are not better accounted for Withdrawal, as manifested by by another mental disorder. the characteristic withdrawal syndrome for the substance; With permission from Hughes JR. Nicotine withdraw- the substance is taken to relieve or avoid with- al, dependence, and abuse. In: Widiger TA, Frances AJ, drawal symptoms; or Pincus HA, editors. DMS-IV sourcebook. Washington, the substance is often taken in larger amounts or D.C.: American Psychiatric Association; 1994. p. 109- over longer periods than was intended. 63 ILJ.U. There is persistent desire or unsuccessfd effort to cut down substance use A great deal of time is spent in activities neces- EPIDEMIOLOGY OFTOBACCO USE sary to abstain from the substance, use the substance, or recover from its effects. Physical dependency upon nicotine is not, of Important social, occupational, or recreational course, a factor when an individual is first exposed. activities are given up or reduced because of sub- Initially, a very small level of exposure can produce stance use. The substance use is continued symptoms of nicotine intoxication such as dizzi- despite knowledge of having a persistent or ness, nausea, and conhsion. Establishing patterns recurrent physical or psychological problem that of tobacco use occur gradually over months to years Tobacco Use and Intervention 10 5 and occur for a variety of psychologic and social education, 29% among high school graduates, and reasons.'"'' Desire for tobacco products in adoles- less than 2% for individuals that had at least 4 years cents is cultivated by tobacco industry advertising of college education.72As defined by the Social Secu- and promotions. A wide variety of communication rity Administration, 22% of individuals above the channels are used. Also, the tobacco industry poverty level smoked and 28% of those below the actively attempts to circumvent and abolish barriers poverty level. In addition to poverty, other sociode- to youth access, recognizing that adolescents, mographic hctors associated with higher prevalence although comprising less than 10% of the market, of smoking are being a blue collar worker, separat- are vital to the industry's long-term profitability. ed or divorced, and in active military service.72 Nearly 90% of users begin as children and The prevalence of cigarette smoking is highest adolescents, long before they become old enough among American Indians and Alaska Natives (39%), to legally purchase tobacco products. It is estimat- intermediate in African Americans (26%)and Euro- ed that of the more than 5,000 young people each pean Americans (25%), and lowest in Hispanics day that try smoking for the first time, more than (20%) and Asian Americans and Pacific Islanders 3,000 become regular smokers, many for decades (18%).74Smokeless tobacco use is also highest and some for life.67 Few adolescents smoke daily. among American Indians and Alaska Natives of both However, long before a daily pattern is established, genders, followed by European Americans (12%), nicotine dependency has begun. An individual that Hispanics (5%), and African Americans (2%).Cul- has smoked as few as 100 cigarettes is at high risk tural and socioeconomic factors may influence ini- of becoming a long-term, dependent smoker. tiation, but genetic factors may contribute to some Smokeless tobacco users quickly develop high races being more susceptible than others once nicotine tolerance and dependency due to the exposed to ni~otine.~~>~'Within any race, genetic steady transfer of nicotine across the oral mucosa factors in some individuals predispose them to and throughout the body. nicotine dependency when exposed.77 With continued exposure, the effects of nico- No single factor determines patterns of tobac- tine on the central nervous system gradually co use among racial/ethnic minority groups. These increase, building up to a physical dependency that patterns are the result of complex interactions of dominates the pattern of use.68 Once dependency multiple factors, such as socioeconomic status, cul- is established, the desire for nicotine becomes the tural characteristics, acculturation, stress, biologic principal reason that individuals continue to use elements, targeted advertising, price of tobacco tobacco products. Indeed, nicotine is one of the products, and varying capacities of communities to most addictive substances known, and the vast mount effective tobacco control initiative^.^^ majority of people that quit smoking relapse with- Certain effects of nicotine, such as its ability to in day^.'^,^' Thus, each year, only 2 to 3% of suppress appetite, may selectively increase the risk smokers become nonsmokers without help.7' of nicotine dependency in women. Evidence indi- About 70% of adults that smoke would like to cates that people with depression are especially vul- stop, and about 34% attempt to quit each year.72 nerable to nicotine dependency, and since the More women than men would like to stop, but prevalence of depression is twice as high in women women have greater difficulty in doing so. Adoles- as in men, this relationship may be particularly cent patterns are similar, with 50 to 74% of 12- to important for women.79 18-year-olds wanting to stop and 40 to 49% per- It is alarming that by 1997, tobacco use in cent making an attempt to quit. One survey high school students was 43%. This exceedingly showed that among adolescents that smoked at high smoking prevalence in adolescents suggests a some time within the past month but are not smok- commensurate rise in the number of adults that ing daily, over 30% found they could not will want to quit, as well as an increase in the incidence of tobacco-related morbidity and mortality.

NICOTINE DEPENDENCY RISK FACTORS WHO QUITS?

Smoking prevalence has consistently been in inverse In recent years, tobacco use among men has relation to education and income. In 1993, the declined more rapidly than among women so that prevalence of current smoking among adults was rates are similar (27 versus 24%), and differences 37% for persons that had completed 9 to I I years of may become smaller in the fbture. Men are some- 106 Periodontal Medicine what less interested than women in quitting (67 are cost effective. Long-term tobacco users develop versus 73%), but a greater number of men than chronic conditions that often become time-con- women have quit (5 1 versus 47%).72 suming patient management problems. Smokers Surveys of gender differences in the ratios of are ill more often than are nonsmokers, which fre- cigarette smoking cessation suggest that men have quently leads to problems with appointments, an easier time of it (49 versus 40%). When the medical considerations, and emergencies during ratios are adjusted for the use of other tobacco treatment. Many patients are prematurely lost to products (cigars, pipes, smokeless tobacco), how- practice when tobacco-related disabilities severely ever, the ratios are quite similar (42 versus 40%). restrict their mobility and resources. More men than women merely switch from ciga- Many professional organizations have devel- rettes to other forms of tobacco to sustain their oped support systems that help clinicians integrate nicotine dependency rather than truly quit. Long- cessation services into their practices. For example, term abstinence rates for those that quit show vir- several dental organizations have adopted tobacco- tually no difference by gender.80Thus, men and related clinical policies. The American Dental Asso- women may have different reasons for initiation, ciation (ADA) now has published and distributed a continuing to use, wanting to quit, quitting, and guide to therapeutics titled “Tobacco counseling staying abstinent, but the net behavior outcome is for the control and prevention of oral disease,” not very significant. Nevertheless, helping patients established a service code (01320) and included during the quitting process requires an apprecia- tobacco use status and interest in quitting questions tion of gender differences; physiologic factors, such in the ADA Health History Form. Educational as differential sensitivity and tolerance to nicotine, guidelines have been developed for educational more intense withdrawal symptoms by women, institutions. Such infrastructure developments help timing of quit attempts in relation to the menstru- ease the integration of clinical tobacco intervention al cycle; and behavioral and psychologic factors, services into practice.85 such as women’s fear of weight gain, greater need for social support, and their lower confidence in their ability to quit.8’ TREATING NICOTINE DEPENDENCY

Nicotine dependency is not merely a “risk factor” DENTAL PROFESSION’S ROLE for other disease, but it is a disease requiring treat- IN TREATING NICOTINE ADDICTION ment in its own right.86There are numerous methods for helping nicotine-dependent patients. In recent years, dentists have been acquiring clini- Unfortunately, most are not supported by scientific cal tobacco intervention skills. A quarter of den- evidence, even though some seem attractive or are tists (24%) routinely identify their patients’ status popular. Until recently, empirical approaches, pri- of tobacco-use and accordingly advise them to marily combinations of methods, have been used. quit.82More than half the dentists that do not pro- Any method will yield its success stories. When vide such services state that they desire training studied, using scientifically sound methods, and that would enable them to do ~o.~~>~*Thereasons critically analyzed, success rates for most methods for providing clinical tobacco intervention services do not compare favorably with not using the are compelling. method. Often individual successes can be Of course, helping patients quit and stay absti- explained by other factors. nent is an ethical obligation. Overwhelming evi- Systematic studies of smoking cessation began dence indicates that tobacco is harmful to oral in earnest during the early 1980~~~Randomized health and that smoking status is an important fac- controlled trials demonstrated that physicians, tor in the prognoses of several dental therapies, using minimum clinical intervention methods, including periodontal therapy, oral surgery, implant could be effective in increasing patient cessation dentistry, and cosmetic dentistry. Second, clinical rate^.^^-^^ Dentists and other clinicians subsequent- tobacco intervention services have a moral basis as ly were also shown to be as effe~tive.~~~~~Currently, well. It is a regular act of citizenship to attempt to there is overwhelming evidence that medical and preserve life and prevent injury and death. Smoking dental practices are an essential part of helping the kills half the regular users, and half of these will die public avoid and discontinue tobacco use.97 prematurely, losing, on average, two decades of Within the scientific community, “success” is life.28bThird, clinical tobacco intervention services considered long-term abstinence, with “long-term” Tobacco Use and Intervention 107 defined as being tobacco-free for 6 months or Ask, Advise, Assist, and Arrange (Table 7-1).101>102 longer. Studies that do not include follow-up for at First proposed by Marc Manley and Thomas Glynn least 5 months are generally not seriously consid- of the National Cancer Institute, the steps have ered when assessing effectiveness. “Abstinence” is remained the core of successfd clinical programs, defined as being tobacco free, not nicotine free. even when other names are applied. The basic steps Food and Drug Administration (FDA)-approved are as follows: nicotine replacement products are routinely used to help individuals quit using tobacco. Some prod- Ask ucts are available without prescription. In 1981, a 2-mg nicotine gum was approved Identify the tobacco use status of every patient. by the FDA to supplement behavioral interven- “DOyou use tobacco?”This information should be tions. During the 1990s, a variety of nicotine considered a vital ~ign.’~~J~*Inquiry can be inte- replacement products and one non-nicotine tablet grated within existing patient questionnaire sys- were approved. Other pharmaceutical agents are tems. It is essential that each patient record show under investigation. Research on nicotine addic- the current tobacco use status so that all clinic staff tion and CNS hnction promises to provide more are aware of it. lo5As nicotine dependency is chron- effective treatments in the hture. There is no “sil- ic and relapsing, it is important to ask this question ver bullet” method or pharmaceutical agent. at every encounter. Of course, since most patients Although a selected combination of clinical meth- do not use tobacco, the answer under most cir- ods combined with an FDA-approved pharmaceu- cumstances is a brief “no.” Tobacco users must be tical agent can significantly increase cessation rates, asked about the duration and intensity of their use, none sustain long-term abstinence for as many as past experience with quitting, and especially about half the number of the individuals that make a ces- their desire to stop. “How interested are you in sation attempt.97a quitting now?” Since 1996, Clinical Practice Guideline Num- ber 18: Smoking Cessation of the Agency for Advise Health Care Policy and Research (AHCPR) has become the international gold standard for clinical This step focuses on building the patient’s motiva- tobacco intervention services.98This guideline and tion to be tobacco free. Although brief and simple, its subsequent revisions (one scheduled for early building motivation is one of three basic clinical 2000) can help focus valuable clinician time on intervention services. Commend never-users and services that are evidence based and return the former users on the wisdom of their behavior. This highest success rates for the time invested. The fol- is an especially important message to children and lowing statements and recommendations are based adolescents to help prevent and postpone initiation on or taken from the guideline, except where sup- and to former users, who are vulnerable to relapse. plemental references are shown. Although the long-duration, intensive treat- 1. Advise all tobacco users in clear language that ments are more effective than the brief treatments, you think they should quit. Patients place such interventions can be reserved for smoking ces- great weight on such advice by clinicians. sation specialists and other specialists in the management of patients who experience multiple relaps- es, have multiple drug dependencies, are mentally TABLE 7- I. Basic Steps of Successful challenged, or have severe psychiatric disorders. Smoking Cessation Program Guidelines are available for such clinician~.~~J~~ However, most patients can be approached by and “4 AY benefit from brief, practical interventions by even Ask Identifjr the tobacco use status of every the busiest clinician of any health discipline. patient Advise Increase the tobacco user’s interest in quitting RECOMMENDED MINIMUM CLINICAL Assist Help those who are ready with their INTERVENTION METHODS problem solving skills and with p harmacotherapy A practical routine should be integrated into every Arrange Arrange follow-up support throughout clinical practice. Basic steps are known as the “4As,” the quitting process 10 8 Periodontal Medicine

2. Associate use with existing patient health con- The clinician acts as a caring, skilled facilitator ditions. When possible, show the patient his because, of course, the primary responsibility or her own tobacco-related conditions. remains with the individual that must quit. Three Patients also should understand other health specific components are essential: establishing a risks and tobacco risks to planned health ser- plan for (I) preparing to quit, (2) coping with psy- vices and prognoses, but not only that. chologic and social cues during the quitting 3. Ask each patient for his or her own reasons for process, and (3) managing the physical challenges wanting to quit. Most will have a reason, per- of nicotine withdrawal. haps several. Expressing those reasons helps strengthen them, even though many have little Preparing to Quit to do with health. The patient’s reasons provide Ask the patient to choose a quit date. The date ide- clues to which the clinician can add motivating ally should be within 2 weeks, but not so soon that ideas and perspectives that help dispel unwar- there is no time for mental preparation. Give the ranted hesitancy. The clinician should be as patient a reminder of the date, perhaps on a pre- upbeat as possible. Emphasize the benefits of scription form, that can be posted at home. quitting in terms that are specific to each Suggest that the patient inform family, friends, patient’s interests, circumstances, and culture. and co-workers and solicit their support. One’s spouse can be an especially important ally. The Many patients will not be interested in quit- patient should arrange to have others that use ting at the moment, but the “Advice” step tobacco not use it in their presence during the strengthens the decision-making process that indi- quitting process. viduals must progress through to initiate a behav- The final use of tobacco should be during the ior change. The discussion clarifies in the patient’s day before the selected quit date. Advise the patient mind the opinion of a respected individual. It to remove all tobacco products and the materials introduces to contented users ideas that will begin that they use from home, car, work place, and any to offset their reasons for continuing. Discussion other readily accessible site. helps individuals that are generally interested in Advise that other forms of tobacco also con- quitting to begin thinking more seriously about tain nicotine and their use will work against the what they are doing to themselves and about their goal of quitting for good. prospects for living tobacco free. Discussion identifies highly motivated patients, that is, those that Coping with Psychologic and Social Cues previously attempted to quit or have an intention Ask the patient what is most likely to lead to a to quit in the foreseeable fbture. A clinician’s relapse and how he or she would plan to manage advice to quit can trigger the decision to act. that. Encourage the patient to solve the problem. The patient’s desire for clinical therapy to be Then offer specific suggestions and answer patient successful and enduring can influence his or her concerns. desire to quit. Other personal benefits become Advise that even a single puff is dangerous and bonus advantages in this situation. The ever-pre- often leads to relapse. sent goal of doing everything possible to save each Caution that alcohol and other drug use patient’s life may remain a silent imperative in the impairs judgment and can lead to relapse. clinician’s mind. Stress and weight gain are two common con- Patients that are not interested in quitting at cerns. The quit date selected should be at a time of the moment should be offered assistance in the least possible stress; however, the management of future, “When (not if) you are ready, I’ll be glad to stress should be discussed, and the patient should help.” In addition, patients should be given moti- be advised that the transition period is often vational literature that is appropriate to their inter- accompanied by a period of anxiety, restlessness, ests, circumstances, and, if possible, culture. insomnia, and reduced ability to concentrate while the brain adjusts to the absence of nicotine. Help Assist the patient with stress management strategies that are alternatives to using tobacco. While “Ask” and “Advise” are routine steps for all Although dieting should be postponed dur- patients, the “Assist” step is used with a subset of ing the first few weeks, alternatives to adding patients that are ready to quit. This step focuses on calories and approaches to burning calories helping patients cope with the quitting process. should be addressed. Advise the patient that Tobacco Use and Intervention 109 weight gain is a minor risk compared with con- ance problems, and little clinician time and tinuing to use tobacco. Tell the patient to tackle effort are required to train patients in their one problem at a time; first be confident that they effective use. A patch is applied to a different have quit using tobacco for good before working skin area each day to minimize irritation. on weight gain. The use of nicotine gum may Three brands of patch are available in three delay weight gain. strengths, according to patch size, and are used If the patient has previously attempted to quit either for 16 or 24 hours each (Table 7-2). and relapsed, address how to deal with that specif- The largest patch is used for the initial 4 weeks ic situation. Determine if the precipitating event and the next smaller sizes for two 2-week, was due to nicotine withdrawal, psychologic,or a stepped withdrawal periods. The midsize social situation. patch should be used initially by patients that Provide literature on the quitting process. This are light smokers (less than 10 cigarettes daily) saves clinician time and can be referred to as often or are of small stature (weight less than 100 as wanted. The AHCPR’s booklet “You can quit,” pounds). One patch is used for 16 hours only available in eight languages, the National Cancer and patches are used for 6 weeks, after which Institute’s “Clearing the air,” and other organiza- use is discontinued entirely. If the particular tion pamphlets provide reinforcement to motiva- patch is not effective for a patient, another tion and offer suggestions for preparing to quit and brand may help. managing the effects of quitting, such as nicotine withdrawal and weight gain. Such booklets describe coping strategies not commonly shown in the flyers TABLE 7-2. Recommended Agents to aimed at motivating various segments of the public. Manage Nicot i ne Withdrawal As with other substances of abuse, individuals that successfully quit must appreciate that perma- Nicotine Replacement Agents nent CNS neuron changes have occurred. They Patch must be alert to the possibility that even a single Habitrol@(Novartis) exposure can rapidly lead to complete relapse, even Nicotine years after quitting. 21 mg Certain psychologic states, such as acute stress, 14 mg depression, or encountering a previously learned 7 mg social cue, can trigger a relapse. Prostep@(LederZe Labs) 22 mg/24 h Managing the Physical Dynamics 11 mg/24 h of Nicotine Withdrawal Nicotrol@(McNeiZ Consumer) 1. Prescribe or recommend an FDA-approved 15 mg/l6 h nicotine replacement for use, beginning on the Nicoderm@CQ@ (SmitbKZine Beecbam Consumer) quit date. The intent is to reduce the intensity - Step I 21 mg/24 h and duration of nicotine withdrawal symp- - Step I1 14 mg/24 h toms while the patient is learning to cope with - Step I11 7 mg/24 h the psychologic challenges and social cues that Gum had become part of the addiction. It extends Nico re t t e@(Sm itbKZine Beecbam Consumer) the use of the one drug that drives tobacco use 2 mg or 4 mg behavior, but places its administration under Nasal spray supervision and in amounts that do not pro- Nicotrol@NS (McNeiZ Consumer) duce the “hits” or peaks of nicotine in the Nicotine brain. Also, the patient learns how to live 0.5 mg without possessing tobacco products and Inhaler going through the rituals of using tobacco- Nicotrol@Inhaler (McNeiZ Consumer) associated paraphernalia. 2 mg Nicotine transdermal patches approximate- 4 mg ly double long-term abstinence compared with Non-nicotine agents abstinence using behavioral intervention Bupropion HCL alone.”‘ Patches are often the preferred route Zyban@(Gho WeZhome) for clinical use because there are few compli- 150 mg 1 1 O Periodontal Medicine

The 4-mg nicotine gum (nicotine polacri- evidence of nicotine dependency and a clear lex) is usually preferred when a skin disease or desire to quit using tobacco. adhesive allergy rules out use of a patch, when Many individuals that are not successfd in a patient has not been successful with using a becoming nicotine fiee are able to become patch, as a supplement to a patch, or when tobacco free by using a nicotine replacement for gum is preferred by the patient for any rea- several months or indefinitely. l3>ll4 Although SO~.~O~One piece should be used every I to 2 continued use of a nicotine replacement beyond hours for 6 weeks, then every 2 to 4 hours for a 10- to 12-week period is not recommended, it 3 weeks, and 4 to 8 hours for 3 weeks. Patients is infinitely better than returning to tobacco use. must be instructed to chew each piece until a Nicotine is harmfd, but not as much as many peppery taste is noticeable, and then to park other tobacco constituents. Of the at least 2,550 the gum as nicotine absorption occurs. The known compounds in tobacco and over 4,000 "chew and park" routine is followed for about compounds in tobacco smoke, primary tobacco 30 minutes per piece. The patient must be biohazards include at least 43 carcinogens, such instructed to stop using acidic liquids such as as the nicotine nitrosamines, and alpha-emitting coffee, soft drinks, and fruit juices, at least 15 radionuclides, such as Polonium 2 10. Tobacco minutes before using the gum since the nico- smoke contains carbon monoxide, thiocyanate, tine is not absorbed in an acidic environment. herbicide, fungicide, and pesticide residues, Light smokers may use a 2-mg gum. Long- tars, and many other substances that promote term quit rates are about 40 to 60% higher in disease and impair body functions. Tobacco is using nicotine gum than in using behavioral a highly polluting nicotine delivery system. intervention alone. 2. Bupropion HCl (Zyban) is a nicotine replace- The nicotine nasal spray is an option that ment alternative. Bupropion is used in tobac- simulates the rapid delivery effect of cigarette co use cessation treatment as a centrally acting ~moking.'~~J~~The recommended dosage is non-nicotine agent. The long-term abstinence one spray into each nostril 8 to 16 times daily. rate through its use is equivalent to that Long-term quit rates reported are from 18 to through using a nicotine patch. l5 Patients 27%. The nicotine oral inhaler is another that are strongly dependent upon nicotine option. 'OJ Its ritual and sensory aspects may use bupropion in combination with a resemble smoking. The recommended dosage nicotine replacement. is up to 16 cartridges per day. Long-term quit The patient's medical history, current rates are reported to range from 13 to 28%. medical status, and patterns of behavior must Use of any of the products are recommended be carefully evaluated before recommending for an 8- to 10-week period.l12 bupropion. It interacts with many drugs, Contraindications for all nicotine replace- including alcohol, antipsychotic agents, hepatic ments are similar. They are not recommended enzyme inducers and inhibitors, levodopa, and for patients in an immediate postmyocardial monoamine (MAO) inhibitors. This is of con- infarction period, those that have severe arrhy- cern because many of these potentiate the risk thmias, or those that have a severe or worsening of seizures. The use of bupropion is con- angina pectoris. Specific contraindications traindicated in patients being treated with include skin disorders for patches, asthma or Wellbutrin (which is also bupropion HCl), chronic nasal disorders for nasal spray and antipsycho tics, antide pressan ts, theop hylline, inhalation systems, and temporomandibular or systemic steroids and in patients that joint disorders or dentures for nicotine gum. abruptly discontinue use of a benzodiazepine Because of the serious risks of smoking to or another agent that lowers seizure threshold. both mother and fetus, pregnant smokers Bupropion is contraindicated in patients with should be offered intensive counseling. Nico- anorexia nervosa or bulimia, bipolar disorders, tine replacement should be used during preg- CNS tumor, a history of head trauma or drug nancy only if the increased likelihood of smok- abuse, hepatic or renal impairment, recent his- ing cessation, with its potential benefits, out- tory of myocardial infarct, unstable heart dis- weigh the risk of nicotine replacement and ease, psychosis, or seizure disorders. l6 potential concomitant smoking. The use of bupropion differs from nicotine Nicotine replacement should be consid- replacement in that bupropion treatment should ered for adolescents, only when there is clear begin 7 to 10 days before the patient-selected Tobacco Use and Intervention 11 1

quit date, whereas the pharmaceutical nicotine acupuncture. There is no evidence supporting substitution should begin on the quit date. the use of herbal products and foods for tobac- A recent review of randomized clinical tri- co intervention. als and of meta-analyses of smoking interven- It is recommended that those few practical tion studies concludes that pharmacotherapy (brief) methods that are supported by substan- for smoking cessation should be made avail- tial scientific evidence be mastered and routine- able to all smokers.l17 All currently available ly used. They can become the basis for develop- therapies appear equally efficacious, approxi- ing one’s art and practice, as the science of clin- mately doubling the quit rate compared with ical tobacco intervention services evolves. Clin- placebo. In addition, combined therapies are ical interventions against an addictive behavior more successful in obtaining long-term suc- must be considered incremental. Indeed, most cess. Thus, combining patch with gum or patients relapse, but this should not be a deter- patch with bupropion may increase the quit rent. Other adverse health conditions also have rate compared with any single treatment. l7 recurrences. As with other chronic diseases and 3. Consult package inserts, the Pbysiciun? Desk conditions, cures for smoking cessation are Reference, the ADA Cuide to Accepted Dentul unusual, but the absence of a high success rate Therapeutics, and comparable resources for from single intervention attempts are never a dosage and management information on spe- reason to withhold treatment, especially when cific FDA-approved pharmaceutical agents for continued tobacco use is clearly a high risk to tobacco use cessation. a multitude of diseases and life itself. 4. Other pharmaceutical agents have been studied. There is little scientific evidence for the Arrange use of clonidine, either as a primary or as an adjunctive pharmacologic treatment for tobac- Establish a schedule for follow-up contacts, either co use cessation. There is no scientific evidence in person or by telephone. Although some increase demonstrating the effectiveness of any antide- in patient quit rates can be anticipated from a sin- pressant other than bupropion. The use of gle encounter, long-term abstinence is dramatically anxiolytics, benzodiazepines, lobeline, silver improved, three to four-fold, when there is timely acetate, cotinine, beta blockers, glucose, sodi- follow-up. um bicarbonate, and stimulants have not been Schedule a first contact by clinic staff for a day shown to be effective. The use of mecamy- or two before the patient-selected quit date. This lamine, buspirone, phenylpropanolamine, and serves as a quit date reminder, as an expression of various other drugs, independently and in support and encouragement, and as an opportuni- combination with approved agents, are under ty to solicit questions and concerns related to investigation but not recommended for use preparations. outside the research protocols. The recommended post-quit-date follow-up Other behavioral intervention methods and contact schedule is four to seven contacts over a 3- nonpharmacologic agents have been assessed. month period. The first follow-up contact should Of the self-help methods, hotline/helpline be within 2 weeks of the quit date, preferably with- support is effective, but providing video and in the first week. The second, third, and fourth audiotapes, lists of community programs, and contacts should be near the end of the first, second, pamphlets and booklets is not. Group coun- and third months. Studies suggest that fewer than seling is beneficial for selected individuals but four and more than seven contacts yield lower is no more effective than the basic clinical results than this follow-up interval and frequency. interventions described above. Evidence does During each follow-up contact, the clinician not support methods based on motivation, should applaud success. If a lapse occurred, the weighddiednutrition counseling, exercise/fit- patient should be asked for a recommitment to ness, contingency contracting, relaxation/ total abstinence. Remind the patient that a lapse breathing, or nicotine fading. Aversive smok- can be used as a learning experience, and review ing increases cessation rates and may be used, the circumstances that caused it. Ask the patient with caution, with smokers that desire such how he or she could better manage that situation treatment or have been unsuccessful using next time. Suggest alternative behaviors. other interventions. There is insufficient evi- Even if the patient remains abstinent, identifi- dence to assess the effectiveness of hypnosis or problems encountered and anticipate challenges in 112 Periodontal Medicine the immediate fbture. Review the benefits, includ- mended to other individuals. Although it is not ing potential health benefits, to be derived from necessary to assess psychiatric comorbidity prior to cessation. Discuss specific problems such as weight initiating an intervention, such an assessment may gain, negative mood/depression, prolonged nico- be helpful in that it allows the clinician to prepare tine withdrawal, and lack of support for cessation for an increased likelihood of relapse or for exacer- from others. Discussion helps the patient to clarify bation of the comorbid condition as a result of and cope with such problems. nicotine withdrawal. Individuals that experience All treatment strategies apply to individuals depressive and anxiety symptoms are at higher risk that are of any age, gender, or ethnic origin, gener- for smoking initiation. l9 Individuals experiencing ally healthy or ill, or inpatient or outpatient. All psychiatric disorders are at high risk of initiation treatment strategies apply to adolescents who want and may smoke as a form of se1f-treatment.l2’ to quit using tobacco. Clinicians should be firm Individuals with a history of clinical depression are but nonjudgmental and should personalize the more likely to experience a recurrence during the encounter to the individual situation. quitting process.12’ One primary finding has been that all types of clinicians are about equally effective, that is, regardless of discipline. Providing a brief interven- TREATMENT ENVIRONMENT tion can yield about a 50% increase in patient quit rates compared with not helping. It is significant Providing clinical intervention services requires a that interventions by multiple providers reinforce team approach. Clinic personnel, the office envi- and nearly quadruple patient quit rates. Success ronment, and the management system need a few may be partially due to previous efforts by col- simple adjustments for services to be provided effi- leagues; lack of immediate success with a patient ciently, effectively, and pleasantly. First, one indi- actually serves as an important preparation for a vidual, usually not the primary-care provider, needs subsequent clinician contact that becomes persua- to be responsible for the service operation. All sive. Thus, each clinician is part of a broad, not members of the clinic team need to understand the necessarily known-by-name, professional tobacco objectives and methods employed. The “ASK” step intervention network. is usually managed by the receptiodreceiving staff; As little as 3 minutes’ cessation helps produce as well as the recording of the patient’s tobacco use a significant increase in long-term abstinence from status. This is verified when other vital signs are tobacco. However, even less than 3 minutes’ cessa- taken and initial work-up begun. Diagnosis and tion yields a measurable benefit over self-help treatment planning must include the “Advice” step. methods. If 3 or more minutes are not available, ‘fASsist” is often begun by the primary clinician or even the briefest help should be employed, given other provider. Other staff may provide more the ever increasing life-threatening risk when the detailed help for the patient that commits to a quit individual continues to use tobacco and the impor- date and ensure that the “Arrange” step is done so tance of reinforcement by multiple providers, to that follow-up will occur. achieve a commitment to quitting and long-term Clinic staff that use tobacco present a special abstinence. More intense interventions, that is consideration. Patients should not be able to deter- more time-per-patient contact, increase long-term mine that staff do so, for mixed messages are sent abstinence rates. about the clinic being a responsible health unit. In general, actual cessation rates vary widely by Offers to help patients quit may lack credibility if demographic factors, such as income and educa- smelly hands, hair, or clothes are detected. Every tional level. The practical clinical intervention effort must be made to encourage tobacco-using methods recommended above compare the relative staff to quit. Intense help may be needed. Employ- increase in long-term abstinence compared to ee unions, personnel offices, and facility directors withholding clinician intervention and are not may need to be involved. absolute values. Also, any quit attempt is useful as The clinic’s physical environment should con- preparation for long-term abstinence. It is estimat- vey a positive tobacco-free message. A “Thank you ed that unsuccessful cigarette smokers, on average, for not Smoking” sign establishes the authority of make three to four attempts before achieving long- the office in a manner that invites cooperation. term abstinence.’ l8 The absence of ash trays and presence of posters Tobacco users with psychiatric comorbidity and a display of motivational literature enhances should be offered the same treatments recom- the message. Magazines available for patients Tobacco Use and Intervention 113 should not carry tobacco advertizing. The back stream of unique opportunities to counter the covers are especially important since they may be influence of the tobacco industry by helping pre- seen by several patients at once. vent nicotine addiction among youths and increas- Patient records should have an identifjbg ing the determination of adult tobacco users who mark so that all clinic staff can easily recognize the are trying to break free. tobacco use status of each patient. Records of Studies supported by the National Cancer patients who are tobacco-free also need an identiG- Institute during the 1980s and statewide demon- ing mark so that patients whose tobacco use status stration projects in the 1990s demonstrated that has not been determined will be easily recognized. tobacco use among adults can decline at twice the Basic information required is patient status and rate of secular trends when media, community, interest in quitting. More complete information business, policy, and professional tobacco educa- includes details about duration, intensity, and type tion and public health promotion efforts are made of tobacco used, the level of patient dependency on concurrently. Messages via these channels reinforce nicotine, factors that would enhance or hinder a each other, helping the public conclude that avoid- quit attempt, and the history of previous quit ing tobacco use is in their own best interests and attempts. Such information, when completed by those of their loved ones and communities. patients saves clinic staff time. The record should During the 1990s, concurrent with media cov- include progress notes on cessation attempts. Also, erage of the struggle between public health and the the recall system should be able to trigger a contact tobacco industry, the FDA approved several phar- with patients who are making a quit attempt. The macologic agents to aid smoking cessation. Adver- contacts should be scheduled for a day or two tising and promotion by pharmaceutical compa- before the quit date, during the first few days post nies contributed to public awareness that smoking quit date, and at least once a month through the cessation is possible and desirable and that certain quitting period. drugs could help. Nicotine replacement products The clinic system should trigger an inquiry were determined to be sufficiently safe, delivering about all patients of any age. Of course, prenatal vis- substantially lower peak doses than self-adminis- its focus on the importance of both mother and tered tobacco products. Two brands of nicotine fetus being tobacco free until term. The caregivers of patch and two strengths of nicotine gum were infants and children less than age 5 years need the “4 approved for over-the-counter sales. As.” Ask about tobacco use in the home and other The public is better informed about risks in tobacco smoke exposure. Advise that steps be taken tobacco use, including nicotine dependency, than to protect the infants and children from exposure. ever before. There is a willingness, indeed an In addition to discussion with caregivers, children expectation, that health professionals are informed aged 5 to I1 years should be asked directly, com- and interested in helping patients quit. National mended for not using tobacco, and be given other Center for Health Statistics surveys consistently reinforcing messages to help counter the allure show that each year about 70% of smokers want to already being transmitted by the tobacco industry quit and about a third make a quit attempt. Yet, and to prevent initiation. Adolescents need to be only slightly over 60% of U.S. physicians report encouraged to quit as well as given proved messages that they identifi- patient smoking status, and to avoid tobacco and exposure to tobacco smoke. slightly over a fifth report counseling their patients Beyond individual patient contact, clinicians that are smokers. It is even less encouraging when have unlimited opportunity to prevent adolescent it is noted that most counseling is selective, pri- interest in tobacco, prevent initiation, prevent marily restricted to patients already exhibiting clin- nicotine addiction, and promote cessation. Health ical symptoms of smoking-related diseases. Few professionals are respected opinion leaders in pro- smoking patients that do not exhibit a smoking- fessional affairs, religious and other community related disease are counseled. 122 organizations, hobby and other personal interests, Primary barriers to counseling have been a and with patients that are involved in the develop- belief that intervention is not effective, not know- ment of public policy, worksite policies, adminis- ing which methods are effective, lack of compensa- trative affairs, and public education. Educated tion for the service, and perceived time available to views about tobacco, born of one’s experience with provide help. The AHCPR Clinicul Prdctice Guide- patients and organized initiatives, carry weight. It line responds to such concerns. Many methods are is from such discussions that community norms examined, and those most effective are recom- evolve. Each health professional has a continuing mended. Recommendations are targeted at clini- 114 Periodontal Medicine cians that have little time, specialists, researchers, sary to make cessation services a routine practice. educators, administrators, and health policy mak- The experience of a few successful cases provides ers. Studies show that the health-care system must satisfaction and ensures commitment to bringing support tobacco cessation services. Managed-care hope of successful cessation to people whose tobac- programs are taking note that tobacco cessation has co use places them at high risk of developing major been found to be more cost effective than any other life-threatening illnesses. preventive medical service. 123 Standards for facility Clinicians also have expanding opportunities accreditation are being upgraded to include clinical to help patients in a collective manner. Profession- tobacco intervention services. Having the Clinicul al opinion and guidance are important to the pub- Pructice Guideline as an evidence-based model, sev- lic’s development of self-directed health behaviors. eral health professions are integrating tobacco top- ics appropriately into educational curricula and continuing education programs. As the 1990s draw AREAS OF FUTURE RESEARCH to a close, the health professions are developing the necessary infrastructure. Tobacco-related research questions abound. Major conferences, government agencies, and public advocacy organizations frequently update informa- SUMMARY AND CONCLUSION tion on tobacco and behavior, tobacco as a risk factor, tobacco dependency, tobacco and adolescents, The late 1980s and 1990s have brought an over- tobacco cessation, tobacco economics, and tobacco whelming body of evidence to substantiate intervention policy research agenda. On the one unequivocally that tobacco use has a profound hand, fruits of such areas of research benefit indi- negative effect on periodontal disease severity, viduals engaged in the tobacco-related aspects of prevalence, incidence, and progression. Tobacco oral health care, research, education, program use has also a profound negative effect on the management, and policy making. On the other, health and well being of users, society, and clinical experts in oral health affairs provide insights into practice. The public is increasingly aware of this related general health and human behavior fact. Tobacco use is preventable. Most nicotine research questions, professional education system dependent individuals want to quit and can quit, content, health-care policies and practices, and when guided by proper support. monitoring and assessment systems. Advances in the art and science of addiction Some areas of research need leadership by oral medicine, and especially nicotine addiction medi- health investigators. Their focus is on how each of cine, are being increasingly published in the pro- the many forms of tobacco and tobacco use prac- fessional literature and presented in scientific tices impact on oral health and oral health care. forums. Some convergence is occurring in the Research is needed on the public response to the understanding and treatment of all substances of dental profession as a resource for tobacco cessa- abuse, binding stronger relations between the tion assistance and how the profession regards its behavioral and bench sciences. In recent years, sev- ability to help the public through its clinical and eral pharmacologic agents for smoking cessation extraclinical endeavors. More research is needed on have been approved by the FDA. Additional phar- how to provide effective intervention when avail- macologic agents and refined behavioral interven- able smoking cessation therapies are ineffective; tion methods should be expected. the impact of tobacco use on the oral and cranio- Adoption of scientifically sound clinical facial development of the growing fetus, infants, tobacco cessation services is a professional obliga- children, adolescents; and the direct and con- tion, a moral imperative, and a practical matter. tributing influence of tobacco on oral diseases and Three to five minutes of cessation assistance inte- conditions and on prognoses, recovery, and recur- grated into other clinical services is a life-saving rence. Tobacco-related oral health research is need- service that benefits patients, community, and ed within subpopulations, on the basis of race/ practice. Periodontal health and prognoses for ethnicity, gender, age, lifestyle, codependencies, periodontal therapy substantially improve when and environmental factors. patients quit smoking. Assessment of the expanding scientific base for The AHCPR’s Clinicul Pructice Guideline tobacco intervention services is a professional Number 18: Smoking Cessution provides the infor- imperative for researchers, educators, and clini- mation needed to develop the art and skill neces- cians. Such monitoring ensures that professional Tobacco Use and Intervention 115 education and practice are evidence-based, that 10. Mandel I. Smoke signals: an alert for oral disease. health service resources expended are in the best J Am Dent Assoc 1994;125:872-8. interests of both patient and public, and that the 11. Genco RJ. Risk factors for periodontal diseases. J dental profession is a viable member of a broad Periodontol 1996;67:1041-9. community of professional, public, and private sec- 12. Bergstrom J. Cigarette smoking as risk factor in tors committed to creating a tobacco-free society. chronic periodontal disease. Dent Oral Epi- demiol 1989;17:245-7. 13. Machtei EE, Dunford R, Hausmann E, et al. Lon- REFERENCES gitudinal study of prognostic factors in established periodontitis patients. J Clin Periodontol 1. U.S. Department of Health and Human Services. 1997;24(2):102-9. Cigarette smoking among adults-United States, 14. Ho AW, Grossi SG, Genco RJ. Assessment of pas- 1995. MMWR 1997;46:1217-20. sive smoking and risk for periodontal disease 2. T .S. Department of Health and Human Services. [abstract]. J Dent Res 1999;78:542. Surveillance for selected tobacco-use behaviors 15. Kinane DF, Rafiar M. The effects of smoking on -United States, 1900-1 994. MMWR 1994;43 mechanical and antimicrobial periodontal ther- (SS-3):34. apy. J Periodontol 1997;68:467-72. 3. T .S. Department of Health and Human Services. 16. Grossi SG, Zambon J, Machtei EE, et al. Effects of Tobacco use among high school students- smoking and smoking cessation on healing after United States, 1997. MMWR 1998;47:229-33. mechanical periodontal therapy. J Am Dent 3a. Wechester H, Riggot NA, Gledhill-Hoyt J, Lee H. Assoc 1997;128:599-607. Increasing levels of cigarette use among college 17. Kaldahl WB, Johnson GK, Patil KD, Kalkwarf KL. Levels of cigarette consumption and response to students: a cause for national concern. JAMA 1998;280:1673-8. periodontal therapy. J Periodontol 1996;67: 675-8 1. 3b. Gall EA, Garvey AJ, Garcia RI. Alveolar bone loss 18. U.S. Department of Health and Human Services. and tooth loss in male cigar and pipe smokers. J Reducing the health consequences of smoking: Arn Dental Assoc 1999;130:57-64. 25 years of progress: a report of the Surgeon 3c.Iribarren C, Tekawa IS, Sidney S, Friedman GD. General. U.S. Department of Health and Effects of cigar smoking on the risk of cardio- Human Services, Public Health Service, Centers vascular disease, chronic obstructive pulmonary for Disease Control, Center for Chronic Disease disease, and cancer in men. NEJM 1999;340: Prevention and Health Promotion, Office on 1773-80. Smoking and Health, DHHS Publication No. 3d.Ayaian JZ, Cleary PD. Perceived risks of heart dis- (CDC) 89-841 1;1989. p. 204-17. ease and cancer among cigarette smokers. JAMA 19. McGinnis JM, Foege WH. Actual causes of death in 1999;28 1: 1019-21. the United States. JAMA 1993;270:2207-12. 4. Research, Science and Therapy Committee. Tobac- 20. U.S. Department of Health and Human Services. co use and the periodontal patient. J Periodon- Mortality trends for selected smoking-related to1 1996;67:51-6. cancers and breast cancer-United States 1950- 5. Mecklenburg RE, Greenspan D, Manley Mw, et al. 1990. MMWR 1993;42:857,863-6. Tobacco effects in the mouth. Bethesda, MD: 21. U.S. Department of Health and Human Services. NIH publication No. 93-3330;1991.p 5-13. Cigarette smoking-attributable mortality and 6. Burgan SW. The role of tobacco use in periodontal years of potential life lost-United States, 1990. diseases: a literature review. Gen Dent 1997;45: MMWR 1993;42:645-9. 449-60. 22. Wingo PA, Tong T, Bolden S. Cancer statistics, 7. Haber J, Wattles J, Crowley M, et al. Evidence for 1995. Cancer 199 5;45 :8-30. cigarette smoking as a major risk factor for 23. Landis SH, Murray T, Bolden S, Wingo PA. Can- periodontitis. J Periodontol 1993;64:16-23. cer statistics, 1998. Cancer 1998;48:6-29. 8. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of 24. U.S. Department of Agriculture. Tobacco outlook risk for periodontal disease. I. Risk indicators for and situation report. April 1996;TBS-234: attachment loss. J Periodontol 1994;65:260-7. tables 1,33,34. 9. Grossi SG, Genco RJ, Machtei EE, et al. Assess- 25. U.S. Department of Health and Human Services. ment of risk for periodontal disease. 11. Risk Medical-care expenditures attributed to ciga- indicators for alveolar bone loss. J Periodontol rette smoking-United States, 1993. MMWR 1995;66:23-9. 1994;43:469-72. 1 16 Periodontal Medicine

26. Summers LH. The economic case for comprehen- ship between oxygen tension and subgingival sive tobacco legislation. Department of the bacterial flora in untreated human periodontal Treasury remarks at the George Washington pockets. Infect Immun 1983;42:659-67. School of Health; March 25, 1998. Table 1. 40. Mettraux G, Gusberti F, Graf H. Oxygen tension 27. National Cancer Institute. Cigars: health effects (p02) in untreated human periodontal pockets. and trends. Smoking and tobacco control, J Periodontol 1984;55:516-21. monograph 9. National Cancer Institute; 1998. 41. Venditto MA. Therapeutic considerations: lower NIH Publication No. 98-1302. respiratory tract infections in smokers. J Am 28. National Cancer Institute. Smokeless tobacco or Osteopath Assoc 1992;92:897-900. health: an international perspective. Smoking and 42. Zambon JJ, Grossi SG, Machtei EE, et al. Cigarette tobacco control, monograph 2. National Cancer smoking and subgingival infection. J Periodon- Institute; 1992. NIH Publication No. 93-3461. to1 1996;67:1050-5. 28a. Hurt RD. Treat tobacco dependence and “bend 43. Cuff MJ, McQuade MJ, Scheidt MJ, et al. The pres- to treat.” Bull World Health Org 1999;77:367. ence of nicotine on root surfaces of periodontally 28b. Peto R, Lopez AD, Boreham J, Thun M, Health C diseased teeth in smokers. J Periodontol 1989; Jr. Mortality from tobacco in developed coun- 60(10):564-9. tries: indirect estimations from national vital 44. McGuire JR, McQuade MJ, Rossman JA, et al. statistics. Lancet 1992;339:1268-78. Cotinine in saliva and gingival crevicular fluid of 29. Linden GJ, Mullally BH. Cigarette smoking and smokers with periodontal disease. J Periodontol periodontal destruction in young adults. J Perio- 1989;60(4):176-81. dontol 1994;65:718-23. 45. Silverstein I? Smoking and wound healing. Am J 30. Papapanou PN. Periodontal diseases: epidemiology. Med 1992;93(lA):22~-24s. Ann Periodontol 1996;1 : 1-36. 46. Raulin LA, McPherson JC 111, McQuade MJ, 31. Haber J, Kent U. Cigarette smoking in a peri- Hanson BS. The effect of nicotine on the odontal practice. J Periodontol 1992;63:100-6. attachment of human fibroblasts to glass and 32. Gelskey SC. Cigarette smoking and periodontitis: human root surfaces in vitro. J Periodontol methodology to assess the strength of evidence 19 88; 59 (5): 3 18-25. in support of a casual association. Comm Dent 47. Hanes PJ, Schuster GS, Lubas S. Binding, uptake Oral Epidemiol 1999;27:16-24. and release of nicotine by human gingival 33. Kenney EB, Kraal JH, Saxe SR, Jones J. The effect fibroblasts. J Periodontol 199 1;62(2):142-7. of cigarette smoke on human oral polymorpho- 48. Preber H, Begstrom J. The effect of non-surgical nuclear leukocytes. J Periodontal Res 1977;12: treatment on periodontal pockets in smokers 223-34. and nonsmokers. J Clin Periodontol 1986; 34. Noble R, Penny B. Comparison of leukocyte count 13 (4) :3 19-23. and function in smoking and nonsmoking 49. Grossi SG, Skrepcinski FB, DeCaro T, et al. young men. Infect Immun 1975;12:550-5. Response to periodontal therapy in diabetics 35. Corberand J, Laharraghe Nguyen F, et al. In vitro and smokers. J Periodontol 1996;67:1094-102. effect of tobacco smoke components on the hnc- 50. Ah MK, Johnson GK, Kaldahl WB, et al. The effect tion of normal human polymorphonuclearleuko- of smoking on the response to periodontal ther- cytes. Infect Imrnun. 1980;30:649-55. apy. J Clin Periodontol 1994;21(2):91-7. 36. MacFarlane GD, Herzberg MC, Wolff LF, Hardie 51. Tonetti MS, Pini-Prato G, Cortellini I? Effect of NA. Refractory periodontitis associated with cigarette smoking on periodontal healing fol- abnormal polymorphonuclear leukocyte phago- lowing GTR in infrabony defects: a preliminary cytosis and cigarette smoking. J Periodontol retrospective study. J Clin Periodontol 1995; 1992;63:908-13. 22(3):229-34. 37. Tew JG, Zhang J-B, Quinn S, et al. Antibody of 52. Rosen PS, Marks MH, Reynolds MA. Influence of the IgGz subclass, Actinobacillus actinomy- smoking on long-term clinical results of intra- cetemeomitans and early-onset periodontitis. J bony defects treated with regenerative therapy. Periodontol 1996;67(Suppl):317-22. J Periodontol 1996;67:1159-63. 38. Costabel U, Bross KJ, Reuter C, et al. Alterations in 53. Rosenberg ES, Cutler SA. The effect of cigarette immunoregulatory T-cell subsets in cigarette smoking on the long-term success of guided tis- smokers: a phenotypic analysis of brochoalveolar sue regeneration: a preliminary study. Ann R and blood lymphocytes. Chest 1986;90:3944. Austral Col1 Dent Surg 1994;12(4):89-93. 39. Loeshe WJ, Gusberti F, Mettraux G, et al. Relation- 54. Miller PD Jr. Root coverage with the free gingival Tobacco Use and Intervention 117

graft: factors associated with incomplete cover- 66. U.S. Department of Health and Human Services. age. J Periodontol 1987;58(10):674-81. Preventing tobacco use among young people: a 55. Jones JK, Triplett RG. The relationship of cigarete report of the Surgeon General. Washington, smoking to impaired intraoral wound healing: a D.C.: U.S. Department of Health and Human review of evidence and implications for patient Services, Public Health Service, Centers for Dis- care. J Oral Maxillofac Surg 1992;50(3):237-40. ease Control and Prevention, Center for Chronic 56. Lindquist LW, Carlsson GE, Jemt T. A prospective Disease Prevention and Health Promotion, Ofice 15-year follow-up study of mandibular fixed on Smoking and Health; 1994. p. 125-46. prosthesis supported by osseointegrated implants. 67. Pierce JC Fiore MC, Novotny TE, et al. Trends in Clin Oral Implant Res 1996;7:329-36. cigarette smoking in the United States. JAMA 57. Bain CA, Moy PK. The association between the 1989;26 1:6 1-5. failure of dental implants and cigarette smoking. 68. U.S. Department of Health and Human Services. Int J Oral Maxillofac Implants 1993;8:609-615. The health consequences of smoking: nicotine 58. Bain CA. Smoking and implant failure-benefits addiction: a report of the Surgeon General. of a smoking cessation protocol. J Oral Maxillo- Rockville, MD: U.S. Department of Health and fac Implants 1996;11:756-759. Human Services, Public Health Service, Centers 59. Sintonen H, Tuominen R. Exploring the determi- for Disease Control, Center for Health Promo- nants of periodontal treatment costs: a special tion and Education, Office on Smoking and focus on cigarette smoking. SOCSci Med 1989; Health; 1988. 29:835-44. 69. Henningfield JE, Cohen C, Slade JD. Is nicotine 60. U.S. Department of Health and Human Services. more addictive than cocaine? Br J Addict 1991; The health benefits of smoking cessation: a 86:5 65-9. report of the Surgeon General. Rockville, 70. Hughes JR, Gulliver SB, Fenwick JW. Smoking MD:U.S. Department of Health and Human cessation among self-quitters. Health Psycho1 Services, Centers for Disease Control and Pre- 1992;11:33 1-4. vention, Center for Chronic Disease Prevention 71. Fiore MC. Trends in cigarette smoking in the Unit- and Health Education, Office on Smoking and ed States: the epidemiology of tobacco use. Med Health; 1990. DHHS Publication No. (CDC) Clin North Am 1992;76:289-303. 90-8416, vii-viii. 72. U.S. Department of Health and Human Services. 61. Henningfield JE, Cohen C, Pickworth WB. Psy- Cigarette smoking among adults: United States, chopharmacology of nicotine. In: Orleans CT, 1993. MMWR 1994;43:925-30. Slade J, editors Nicotine addiction: principles 73. U.S. Department of Health and Human Services. and management. New York, Ny: Oxford Uni- Preventing tobacco use among young people: a versity Press; 1993. report of the Surgeon General. Washington, 62. Hughes JR Smoking as a drug dependence, a reply D.C.: U.S. Department of Health and Human to Robinson and Pritchard. Psychopharmacology Services, Centers for Disease Control and Pre- 1993;113:282-3. vention, Center for Chronic Disease Prevention 63. Hughes JR Nicotine withdrawal, dependence, and and Health Promotion, Office on Smoking and abuse. In Widiger TA, Frances AJ, Pincus HA, Health; 1994. et al, editors. DMS-IV sourcebook. Washing- 74. Giovino GA, Henningfield JE, Tomar SL, et al. ton, D.C.: American Psychiatric Association; Epidemiology of tobacco use and dependence. 1994. p. 109-16. Epidemiol Rev 1995;17:48-65. 64. U.S. Department of Health and Human Services. 75. Caraballo RS, Giovino GA, PechacekTF, et al. Racial Preventing tobacco use among young people: a and ethnic differences in serum cotinine levels of report of the Surgeon General. Washington, cigarette smokers. JAMA 1998;280:135-9. D.C.: U.S. Department of Health and Human 76. Perez-Stable EJ, Herrera B, Jacob P 111, Benowitz Services, Public Health Service, Centers for Dis- NL. Nicotine metabolism and intake in black ease Control and Prevention, Center for Chron- and white smokers. JAMA 1998;280:152-6. ic Disease Prevention and Health Promotion, 77. Spitz MR, Shi H, Yang F, et al. Case-control study Office on Smoking and Health; 1994. of D2 dopamine receptor gene and smoking sta- 65. Institute of Medicine. Lynch BS, Bonnie RJ, edi- tus in lung cancer patients. J Natl Cancer Inst tors. Growing up tobacco free: preventing nico- 1998;90:358-63. tine addiction in children and youths. Washing- 78. U.S. Department of Health and Human Services. ton, D.C.: National Academy Press; 1994. Tobacco use among U.S. racial/ethnic minority 1 18 Periodontal Medicine

groups-African Americans, American Indians program. Ann Intern Med 1989; 110:640-7. and Alaska Natives, Asian Americans and Pacif- 91. Wilson DMC, Taylor DW, Gilbert JR, et al. A ran- ic Islanders, and Hispanics: a report of the Sur- domized trial of a family physician intervention geon General. Atlanta, GA: U.S. Department of for smoking cessation. JAMA 1988;260:15704. Health and Human Services, Centers for Dis- 92. Kottke TE, Brekkle MI, Solberg LI, Hughes JR. A ease Control and Prevention, National Center randomized trial to increase smoking interven- for Chronic Disease Prevention and Health Pro- tion by physicians: doctors helping smokers, motion, Office on Smoking and Health; 1998. round I. JAMA 1989;261:2101-6. 79. Fant RV, Everson D, Dayton G, et al. Nicotine 93. Cohen SJ, Stookey GK, Katz BE et al. Helping dependence in women. J Am Med Wom Assoc smokers quit: a randomized controlled trial with 1996;51:19-20,22-3. private practice dentists. J Am Dent Assoc 80. U.S. Department of Health and Human Services. 1989;11 8:41-5. The health benefits of smoking cessation: a 94. Hollis JF, Lichtenstein E, Vogt TM, et al. Nurse- report of the Surgeon General. Washington, assisted counseling for smokers in primary care. D.C.: U.S. Government Printing Office; 1990 Ann Intern Med 1993;118:521-5. DHHS Publication No. (CDC) 90-8416. 95. Dix SM, McGhan WF, Lauger G. Pharmacist 81. Gritz ER, Nielsen IR, Brooks LA. Smoking cessa- counseling and outcomes of smoking cessation. tion and gender: the influence of physiological, Am Pharm 1995;NS35:20-32. psychological, and behavioral factors. J Am Med 96. Wewers ME, Bowen JM, Stanislaw AE,Desimone Wom Assoc 1996;51:35-42. VB. A nurse-delivered smoking cessation inter- 82. Tomar SL, Husten CG, Manley MW. Do dentists vention among hospitalized postoperative and physicians advise tobacco users to quit? J patients-influence of a smoking-related diag- Am Dent Assoc 1996;127:259-65. nosis: a pilot study. Heart Lung 1994;23:15 1-6. 83. Dolan TA, McGorray SE Grinstead-Skigen CL, 97. National Cancer Institute. Tobacco and the clini- Mecklenburg RE. Tobacco control activities in cian: interventions for medical and dental prac- U.S. dental practices. J Am Dent Assoc 1997; titioners. U.S. Department of Health and 128:1669-79. Human Services, Public Health Service, Nation- 84. Hayes C, Kressin N, Garcia R, et al. Tobacco con- al Institutes of Health, 1994. NIH Publication trol practices: how do Massachusetts dentists No. 94-3693. compare with dentists nationwide? J Massachu- 97a. Cincirpini PM, McClure JB. Smoking cessation: setts Dent SOC1997;46:9-12,14. recent developments in behavioral and pharma- 85. Mecklenburg RE. Tobacco: addiction, oral health, cologic interventions. Table 2. Oncology 1998; and cessation. Quint Int 1998;29:250-2. 12:249-2 5 9. 86. Orleans CT. In: Orleans CT, Slade J, editors: Nico- 98. Fiore MC, Bailey WC, Cohen SJ, et al. Clinic prac- tine addiction: principles and management. tice guideline number 18: smoking cessation. New York, NY Oxford University Press; 1993. U.S. Department of Health and Human Ser- I? ix. vices, Public Health Service, Agency for Health 87. National Cancer Institute. Smoking, tobacco, and Care Policy and Research, Centers for Disease cancer program: 1985-1989 status report. Control and Prevention; 1996. AHCPR Publi- Bethesda, MD: U.S. Department of Health and cation No. 96-0692. Human Services, Public Health Service, Nation- 99. Fiore MC, Bailey WC, Cohen SJ, et al. Smoking al Institutes of Health, National Cancer Insti- cessation: information for specialists. U.S. tute; 1990. NIH Publication No. 90-3107. Department of Health and Human Services, 88. Ockene JK, Kristellar J, Goldberg R. Increasing the Public Health Service, Agency for Health Care efficacy of physician-delivered smoking inter- Policy and Research, Centers for Disease Con- ventions: a randomized clinical trial. J Gen trol and Prevention; 1996. AHCPR Publication Intern Med 199 1;6: 1-8. No. 96-0694. 89. Cohen SJ, Stookey GK, Katz BE et al. Encourag- 100.Hughes JR, Fiester S, Goldstein MG, et al. Practice ing primary care physicians to help smokers guidelines for the treatment of patients with quit: a randomized, controlled trial. Ann Intern nicotine dependence. Am J Psychiatry 1996; Med 1989;110:648-52. 153:S1-31. 90. Cummings SR, Coates TJ, Richard RJ, et al. Train- 101. Glynn TJ, Manley Mw. How to help your patients ing physicians in counseling about smoking ces- stop smoking: a National Cancer Institute man- sation: a randomized trial of the “Quit for Life” ual for physicians. U.S. Department of Health Tobacco Use and Intervention 119

and Human Services, Public Health Service, agement of patients using smoking cessation National Institutes of Health; 1989. NIH Pub- aids. Dent Clin North Am 1996;40:779-80 1. lication No. 90-3064. 113.Fagerstrom KO, Tejding R, Westin A, Lunell E. 102.Husten CG, Manley MW. How to help your Aiding reduction of smoking with nicotine patients stop smoking. Am Fam Phys 1990;42: replacement medications: hope for the recalci- 1017-26. trant smoker?Tobacco Cont 1997;6:311-6. 103.Fiore MC. The new vital sign. JAMA 1991;266: 114.Warner KE, Slade J, Sweanor DT. The emerging 3 1834. market for long-term nicotine maintenance. 104. Fiore MC, Jorenby DE, Schensky AE,et al. Smok- JAMA 1997;278:1087-92. ing status as the new vital sign: effect on assess- 115.Hurt RD, Sachs DPL, Glover ED, et al. A comment and intervention in patients who smoke. parison of sustained-release bupropion and Mayo Clin Proc 1995;70:209-13. placebo for smoking cessation. N Engl J Med 105.Cohen SJ, Christen AG, Katz BE et al. Counseling 1997;337:1 195-202. medical and dental patients about cigarette 116. Somerman M, Mecklenburg RE. Cessation of smoking: the impact of nicotine gum and chart tobacco use. In Ciancio SG, editors. ADA guide reminders. Am J Public Health 1987;77:313-6. to dental therapeutics. Chicago, IL: ADA Pub- 106.Fiore MC, Jorenby DE, Baker TB, Kenford SL. lishing Company; 1998. p. 505-16. Tobacco dependence and the nicotine patch: 117.Hughes JR, Goldstein MG, Hurt RD, Shiffman S. clinical guidelines for effective use. JAMA Recent advances in the pharmacotherapy of 1992;268:2687-94. smoking. JAMA 1999;28 1:72-6. 107. Henningfield JE. Nicotine medications for smoking 118.Prochaska J, DeClemente C, Norcross J. In search cessation. N Eng J Med 1995;333:1196-203. of how people change: applications to addiction 108. Hjalmarson A, Franzon M, Westin A, Wiklund 0. behaviors. Am Psycho1 1992;47:1102-14. Effect of nicotine nasal spray on smoking cessa- 119.Patton GC, Carlin JB, Coffey C, et al. Depression, tion. A randomized, placebo-controlled, double- anxiety, and smoking initiation: a prospective blind study. Arch Intern Med 1994;154: study over 3 years. Am J Public Health 1998;88: 25 67-72. 1518-22. 109.Benowitz NL, Zevin S, Jacob P 111. Sources ofvari- 120.Nisell M, Nomikos GG, Svenson TH. Nicotine ability in nicotine and cotinine levels with use of dependence, midbrain dopamine systems and nicotine nasal spray, transdermal nicotine, and psychiatric disorders. J Pharmacol 1995;76: cigarette smoking. Br J Clin Pharmacol 1997; 157-62. 43:259-67. 121.Glassman AH, Helzer JE, Covey LS, et al. Smok- 11O.Leischow SJ, Nilsson F, Franzon M, et al. Efficacy ing, smoking cessation, and major depression. of the nicotine inhaler as an adjunct to smoking JAMA 1990;264:1546-9. cessation. Am J Health Behav 1996;20:364- 122.Thorndyke AN, Rigotti NA, Stafford RS, Singer 71. DE. National patterns in the treatment of 111. Schneider NG, Olmstead R, Nilsson F, et al. Effi- smokers by physicians. JAMA 1998;279:604-8. cacy of a nicotine inhaler in smoking cessation: 123.Cromwell J, Bartosch WJ, Fiore MC, et al. Cost- a double-blind, placebo-controlled trial. Addic- effectiveness of the clinical recommendations in tion 1996;91:1293-306. the AHCPR guideline for smoking cessation. 112.Ostrowski DJ, DeNelsky GY. Pharmacologic man- JAMA 1997;278:1759-66. CHAPTER8

DIABETESMELLITUS

Brian Mealey DDS, MS

Diabetes mellitus is a disease of metabolic dysreg- called insulin-dependent diabetes, and type 2 dia- ulation, primarily of carbohydrate metabolism, betes, previously known as non-insulin-dependent characterized by hyperglycemia (elevated blood diabetes (Table 8-1). Because insulin injection is glucose) that results from defects in insulin secre- frequently used in the treatment of both forms of tion, impaired insulin action, or both. Alterations diabetes, the terms “insulin-dependent” and in lipid and protein metabolism are also seen. “non-insulin-dependent” were often confusing. Chronic elevation in blood glucose is associated The new classification is based on the underlying with long-term dysfunction and damage to numer- pathophysiology of the disease types, rather than ous organs, especially the eyes, kidneys, heart, on treatment approaches. nerves, and blood vessels. Gestational diabetes is another form of the dis- Approximately 16 million Americans (6 to 7% ease that occurs during pregnancy and generally of the population) have diabetes, but about half resolves after parturition. Other, less common forms these individuals are unaware that they have the of diabetes may be related to genetic defects in disease.’ More than 600,000 new cases are diag- insulin-secreting cells in the pancreas, genetic defects nosed each year, and the worldwide prevalence of in insulin action, pancreatic diseases or injuries, diabetes is projected to double between 1994 and drug- or chemical-induced changes in metabolism, 2010, to 240 milli~n.~>~The number of cases in other endocrine disorders, infections, and genetic the United States continues to rise due to increas- syndromes of which diabetes is one c~mponent.~ ing population and life expectancy, combined with an increased prevalence of obesity, which is strongly associated with the most common form of dia- TABLE 8- I. Classification of Diabetes betes. The total direct and indirect costs of diabetes Mellitus constitute almost 12% of all annual health care costs in the United States, exceeding $90 billion.* Type 1 diabetes (formerly, insulin-dependent diabetes) Given the high prevalence of this disease, it is like- Type 2 diabetes (formerly, non-insulin-dependent ly that every practicing dentist will encounter diabetes) patients with diabetes. In a dental practice with Gestational diabetes 2,000 patients and an average prevalence of 6 to Other types of diabetes 7%, approximately 120 to 140 patients would - Genetic defects in p cell function have diabetes. Again, only half these people would - Genetic defects in insulin action be aware of their diabetic condition. - Pancreatic diseases or injuries Pancreatitis, neoplasia, cystic fibrosis, trauma, pancreatectomy CLASSIFICATION AND - Infections PATHOPHYSIOLOGY OF DIABETES Cytomegalovirus, congenital rubella - Drug-induced or chemical-induced diabetes Over the past three decades, the diagnosis and clas- Glucocorticoids, thyroid hormone sification of diabetes has undergone numerous - Endocrinopathies changes. In 1997, the American Diabetes Associa- Acromegaly, pheochromocytoma, glucagonoma, tion provided the current clas~ification.~The two hyperthyroidism, Cushing’s syndrome most common forms are type I diabetes, formerly - Other genetic syndromes with associated diabetes 122 Periodontal Medicine

During digestion, most foods are broken down ry hormones serve to balance glycemia (Table into glucose, which then enters the circulatory sys- 8-2). While these hormones have a wide variety of tem and is subsequently used by tissue cells for functions, they all result in elevation of blood glu- energy and growth (Figure 8-1). Most cells, exclud- cose. If insulin function is normal, as in the non- ing those in the brain and central nervous system, diabetic patient, elevated blood glucose levels require the presence of insulin to allow glucose resulting from secretion of counter-regulatory hor- entry. Insulin binds to specific cellular receptors to mones are quickly normalized through compen- exert its effects. Insulin is produced by the (S cells of satory secretion of endogenous insulin. If, howev- the pancreas, and increased insulin secretion occurs er, insulin secretion is impaired, as in the diabetic in response to increased blood glucose concentra- patient, elevated blood glucose levels in response to tions. With the secretion of insulin from the pan- counter-regulatory hormone release will remain creas into the circulatory system and its subsequent elevated. For example, if an individual with type 1 binding to its cellular receptors, glucose is able to diabetes is placed under significant stress, epineph- exit the bloodstream and enter the tissues, resulting rine and cortisol are released. This causes an in its utilization by the cells and thus decreases increase in blood glucose levels. Since the patient is blood glucose concentrations. Decreased insulin unable to secrete insulin, hyperglycemia results. production or diminished insulin action will alter glucose metabolism and result in hyperglycemia. Type I Diabetes Conversely, increased insulin levels may cause hypoglycemia (low blood glucose). Type 1 diabetes is caused by cell-mediated autoim- The excess glucose that is not required by the mune destruction of the insulin-producing fi cells body for current activity is stored in the liver in the in the pancreas. This results in- absolute- insulin form of glycogen. In the fasting state, or when glu- deficiency; the individual no longer produces cose demand exceeds glucose available from recent insulin. The rate of (S-cell destruction is variable. food consumption, the liver breaks down glycogen Some individuals, especially children and adoles- and releases glucose into the bloodstream through cents, quickly develop signs and symptoms of type the process of glycogenolysis. The liver also pro- 1 diabetes following rapid destruction of (S cells. duces glucose through the process of gluconeogen- Others retain some insulin-producing capacity as esis-the production of glucose from noncarbohy- the (S cells are slowly destroyed. Numerous markers drate sources such as amino acids and fatty acids. are available for assessing risk and aiding diagnosis Insulin is the primary hormone that reduces of type 1 diabetes, including autoantibodies to pan- blood glucose levels. A group of counter-regulato- creatic islet cells, insulin, glutamic acid decarboxy- lase, and tyrosine phosphata~es.~One or more of these markers can be detected in 90% of type 1 diabetic patients at the time of initial diagnosis. Type 1 diabetes has multiple genetic predisposi- tions but is also strongly related to various environmental factors. Monozygous (identical) twins have a concordance rate for type 1 diabetes of approximately 30 to 50%. Thus, less than half the monozygous siblings of patients with type 1 diabetes will be diagnosed with the disease. This suggests that envi-

TABLE 8-2. Hormonal Control of Glycemia Figure 8-1. Insulin control of blood glucose. Hormonal control of blood glucose by insulin. Ingestion of food results Hormones that raise blood glucose in increased blood glucose levels. The pancreas is stimulated Glucagon to increase insulin secretion. Insulin then allows glucose to Catecholamines (epinephrine) enter cells, especially muscle. Insulin also stimulates storage Growth hormone of excess glucose by muscle and the liver in the form of Thyroid hormone glycogen. Insulin prevents the breakdown of stored glycogen Glucocorticoids (cortisol) into glucose by the liver. The net result is a decrease in blood Hormone that lowers blood glucose glucose levels. Glycogen stores are used during periods of Insulin fasting or increased tissue glucose demand. Diabetes Mellitus 123

TABLE 8-3. Characteristics of Type I and Type 2 Diabetes Type 1 Diabetes Type 2 Diabetes Age at onset Generally c30 years Generally in adulthood Most common body type Thin or normal stature Obese Race most commonly affected White African American, Hispanic, American Indian, (in the United States) Pacific Islanders Family history Common More common Rapidity of clinical onset Abrupt Slow Pathogenesis Autoimmune p cell Insulin resistance, impaired insulin secretion, destruction increased liver glucose production Endogenous insulin None Decreased, normal, or elevated production Susceptibility to ketoacidosis High Low Treatment may include Diet, exercise, insulin Diet, exercise, oral agents, insulin

ronmental influences are superimposed on the was once known as “juvenile” diabetes (Table 8-3). genetic components. Susceptibility to type I dia- However, it may be diagnosed at any age. Onset of betes is linked to the presence of certain genetically clinical symptoms is usually abrupt. Most people determined antigens found on the cell surface of with type I diabetes are of normal weight or are lymphocytes (human leukocyte antigens [HLA]). thin in stature. The lack of endogenous insulin These HLA associations are linked primarily to DQ production makes the type I individual dependent and DR genes. Some HLA loci, such as DR3 and on exogenous insulin injections for survival. DR4, are associated with increased risk for develop- People with type I diabetes are highly suscepti- ing type I diabetes while other loci may be protec- ble to ketoacidosis.2 In the absence of adequate tive. Alterations in these major histocompatibility insulin levels, glucose cannot be used by the tissue complex (MHC) antigens on cell surfaces may and remains in the bloodstream, leading to cellular explain why individuals become intolerant of self- starvation. Body fat stores are then broken down antigens, resulting in T-cell-mediated destruction of for energy through the process of lipolysis. The pancreatic p cells. The complex genetic susceptibili- glycerol portion of triglyceride is converted to glu- ty of type I diabetes is not clearly understood. cose, and free fatty acids are released. With pro- Onset of p-cell destruction in people with a longed insulin deficiency, lipolysis continues and genetic susceptibility to type I diabetes may be ini- fatty acids are converted to ketones. Increased tiated by an environmental event. Viral infections ketone levels in body fluids lead to excretion of have long been targeted as possible triggering ketones in the urine. Large amounts of water are events although evidence is not conclusive. Of par- excreted along with ketones, resulting in dehydra- ticular interest are coxsackie virus, cytomega- tion. Diabetic ketoacidosis results from accumula- lovirus, and rubella infections. A working model of tion of ketones in body fluids, increased loss of elec- type I diabetes suggests that an environmental trolytes in the urine, and alterations in the bicar- event may cause focal damage to pancreatic p cells.3 bonate buffer system (Table 84). If not treated The autoantigens that are then released from the properly, severe acidosis can lead to coma or death. damaged p cells are taken up by antigen-presenting Severe diabetic ketoacidosis usually occurs cells such as macrophages. The autoantigens are when the signs and symptoms of undiagnosed then processed and presented to host T helper cells, type I diabetes are not recognized or when the which respond via increased cytokine production. known diabetic patient’s glycemia is poorly con- These cytokines cause influx into the pancreatic trolled. For many individuals, a diagnosis of type islets of both nonspecific and antigen-specific I diabetes is not made until they are hospitalized mononuclear inflammatory cells. These cells release for treatment of acute ketoacidosis. In the patient cytokines that eventually result in the death of with previously diagnosed type I diabetes, keto- p cells and loss of insulin production. acidosis may be precipitated by systemic infection The onset of type I diabetes occurs most often or stress. Elevated levels of cortisol, epinephrine, before the age of 30 years; in fact, type I diabetes or glucagon as a result of stress promote increased 124 Periodontal Medicine

increased glucose production by the liver. The clin- TABLE 8-4. Signs, Symptoms, and ical effect of these disorders is the same as in type Laboratory Findings in Diabetic Ketoacidosis I diabetes, namely, hyperglycemia. Evidence Nausea and vomiting strongly suggests that the initial defect in the Abdominal pain pathogenesis of type 2 diabetes is insulin resis- Dehydration tance, which is eventually followed by impaired Dry mucous membranes insulin ~ecretion.~ Tachycardia Even though the pancreas still produces Hypotension insulin, the presence of insulin resistance prevents Abnormal skin turgor transport of glucose into tissue cells, causing Kussmaul’s respiration hyperglycemia. Relative to nondiabetic individu- Altered mental state als, pancreatic insulin secretion may also be Possible coma decreased, worsening hyperglycemia. Paradoxical- Hyperglycemia ly, in many type 2 diabetic patients, there is actu- Increased blood urea nitrogen (BUN) and serum ally an increase in insulin production. This is a creatinine direct result of insulin resistance and the subse- Decreased serum potassium and phosphorus quent decrease in glucose utilization. The pancreas Acidosis (arterial pH ~7.3) may respond to poor glucose utilization and hyperglycemia by a compensatory increase in insulin production, resulting in hyperinsulinemia. There hepatic glucose production and ketogenesis. may also be differences in pathophysiology within Ketoacidosis is often seen when the type I diabet- the type 2 diabetic population. The majority of ic person remains hyperglycemic for several days or people with type 2 diabetes are obese, and these longer due to inadequate amounts of exogenous individuals tend to exhibit significant insulin resis- insulin or excessive amounts of glucose intake. tance accompanied by hyperinsulinemia. Obesity Many people with type I diabetes suffer multiple itself can result in insulin resistance, even in the episodes of diabetic ketoacidosis as a result of poor absence of diabetes.8 Conversely, thin individuals daily glycemic control. with type 2 diabetes primarily suffer from impaired insulin secretion, with insulin resistance being less Type 2 Diabetes severe than in obese pe~ple.~ Type 2 diabetes has a stronger genetic compo- Type 2 diabetes is much more common than type nent than type I, with a concordance rate of up to I, constituting 90% of all diabetic cases. While 90% in identical twins.9 Unfortunately, while over type I diabetes is most common in Caucasian 250 genes have been tested for possible relation- Americans, the prevalence of type 2 is higher in ships with type 2 diabetes, none has shown consis- African Americans, Hispanics, American Indians, tent associations in multiple study populations. l0 and Pacific islander^.^ The highest prevalence and It is possible that no single genetic defect is respon- incidence of type 2 diabetes in the United States is sible for type 2 diabetes. Besides obesity, acquired found in the Pima Indian population of Arizona, risk factors for type 2 diabetes include advancing in which almost 50% of those between 30 and 65 age and a sedentary lifestyle. years of age have the disease. Type 2 diabetes com- Unlike the sudden onset of clinical symptoms monly leads not only to hyperglycemia but also to in type I diabetes, type 2 diabetes may remain hypertension, dyslipidemia (elevated triglycerides undiagnosed for years. Thus, it is estimated that and/or decreased high-density lipoprotein) , central about half of all patients with type 2 diabetes are obesity (abdominal), and atherosclerosis. This unaware of their condition. Because they still pro- group of disorders is often called “the insulin resis- duce endogenous insulin, people with type 2 dia- tance syndrome,” or “syndrome X.”5>6 betes are not generally dependent on exogenous The pathophysiology of type 2 diabetes is dif- insulin administration for survival. However, a ferent from that of type I. While the specific eti- large number of these individuals take insulin ologies are not known, autoimmune destruction of injections as a part of their treatment regimen. flcells does not occur. Type 2 diabetes is character- Type 2 diabetic patients are also resistant to ketosis ized by three major abnormalities: (I) peripheral since their pancreatic insulin production is usually resistance to insulin, particularly in muscle; (2) sufficient to suppress ketone formation. Under impaired pancreatic insulin secretion; and (3) conditions of extreme physiologic stress, type 2 Diabetes Mellitus 12 5 patients may develop ketoacidosis. With pro- vascular disease but may be risk factors in con- longed hyperglycemia, individuals with type 2 dia- junction with other components of syndrome X. betes may develop hyperosmolar nonketotic acidosis. Excretion of large amounts of glucose in the Gestational Diabetes urine is accompanied by significant water loss. Failure to replace lost fluids may lead to electrolyte Gestational diabetes usually develops during the imbalance and acidosis in the absence of ketones. third trimester of pregnancy but can occur earlier.

Another similar entity called hyperosmolar nonaci- About 4% of all LVDregnancies in the United States dotic diabetes is characterized by severe hyper- are complicated by gestational diabetes. l2 An glycemia (plasma glucose >600 mg/dL), hyperos- increased prevalence of gestational diabetes is seen molarity, and dehydration. This disorder is associ- in women who are overweight, older than 25 years ated with severe fluid depletion and renal impair- of age, have a family history of diabetes, and are ment, with a high mortality rate. members of ethnic groups with higher prevalence rates for type 2 diabetes (African American, His- Im pai red Glucose ToleranceA mpai red panic, American Indian). l3>l4The disorder appears Fasting Glucose to have a similar pathophysiology to IGT/IFG and type 2 diabetes, ie, it is strongly associated with Impaired glucose tolerance (IGT) and impaired insulin resistance. fasting glucose (IFG) imply a metabolic state Gestational diabetes significantly increases between normal glycemia and diabetes. Many peo- perinatal morbidity and mortality as well as ple with IGT have normal blood glucose levels increasing the rate of cesarean delivery. l5 Diagnosis most of the time, often manifesting hyperglycemia of gestational diabetes is important because proper only after challenge with a large glucose load.4 management significantly improves pregnancy Those with IFG have elevated fasting glucose lev- outcomes.'' About 6 weeks or more after parturi- els but may be normal in a fed state. Both IGT and tion, women with gestational diabetes are reclassi- IFG are not considered to be clinical entities in fied as having either diabetes, IGT, IFG, or nor- themselves. Rather, they are primarily risk factors moglycemia. Most patients who develop gestation- for future development of diabetes." In fact, they al diabetes return to normal after delivery. Others can be seen as intermediate stages in all types of will be diagnosed at some time postpartum with diabetes. Both IGT and IFG are strongly associat- IGT, IFG, type 1 or type 2 diabetes. It is estimated with insulin resistance and with syndrome X.' ed that 30 to 50% of women with a history of ges- Endogenous insulin production is normal and tational diabetes will develop type 2 diabetes with- remains so in the majority of IGT/IFG patients. in 10 years of the initial diagnosis. However, about 30 to 40% of patients with IGT/IFG will develop type 2 diabetes within 10 years after initial diagnosis. During the transition CLASSIC COMPLICATIONS to type 2 diabetes, several changes OCCU~.~Insulin OF DIABETES resistance increases and insulin secretion is impaired as p-cell hnction diminishes. Hepatic In addition to dysregulation in carbohydrate, lipid glucose production also increases. Eventually, the and protein metabolism, type I and type 2 dia- patient manifests overt clinical and laboratory betes are associated with a classic group of micro- signs of diabetes. vascular and macrovascular complications (Table Patients with IGT/IFG are not at increased 8-5). While the microvascular complications of risk for microvascular complications such as those retinopathy, nephropathy, and neuropathy are seen in diabetic individuals. However, they are at specifically associated with diabetes, macrovascular greater risk for cardiovascular disease than are peo- diseases occur in the nondiabetic population as ple with normal glucose tolerance. The reasons well. However, the risk of macrovascular disease is why IGT and IFG increase the risk of cardiovascu- greatly increased in diabetic patients. lar disease are not well understood. Both IGT and These complications are the major cause of the IFG are frequently associated with hypertension, high morbidity and mortality of diabetes. The dia- hypertriglyceridemia, and low levels of high-densi- betic patient has a dramatically increased risk for ty lipoproteins (HDL), all well-known risk factors visual impairment or blindness, kidney failure, for cardiovascular disease. Thus, IGT/IFG may not limb amputation, stroke, and myocardial infarc- be directly involved in the pathogenesis of cardio- tion. Sustained hyperglycemia plays a central role 126 Periodontal Medicine

ischemia, which may then lead to proliferation of TABLE 8-5. Classic Complications of abnormal blood vessels and fibrous tissue from the Diabetes Mellitus surface of the retina out into the vitreous, a process Retinopathy known as proliferative retinopathy. These new Blindness blood vessels are fragile and may bleed into the vit- Nephropathy reous. As that blood is reabsorbed from the vitre- Renal failure ous, scarring occurs. Over time, macular edema Neuropathy and proliferative retinopathy may lead to severe Sensory vision loss or blindne~s.~J~ Autonomic Renal failure is the leading cause of death in Macrovascular disease (accelerated atherosclerosis) the type 1 diabetic population. Approximately 35 Peripheral to 45% of type I patients develop nephropathy, Cardiovascular (coronary artery disease) compared with about 20% of type 2 individuals. Cerebrovascular (stroke) The mesangium, the membrane supporting the Altered wound healing capillary loops in the renal glomeruli, expands due to increased production of mesangial matrix proteins.18 As the mesangium expands, the surface in the onset and progression of diabetic complica- area for glomerular capillary filtration decreases, tions. The duration of diabetes is an important risk and the glomerular filtration rate (GFR) declines. factor as the prevalence of these complications The basement membrane in glomerular capillaries increases with longer duration of disease. Hyper- also thickens, further decreasing glomerular filtra- tension and dyslipidemia are also risk factors for tion. Clinically, the earliest sign of diabetic both microvascular and macrovascular complica- nephropathy is the excretion of small amounts of tions. There are also genetic influences affecting albumin in the urine (microalbuminuria) . With the propensity to develop these complications. progressive disease and reduction in glomerular fil- Vascular complications of diabetes result from tration capacity, macroalbuminuria may develop, microangiopathy and atherosclerosis.17-19 Changes with large amounts of protein excreted in the urine in the blood vessels include endothelial prolifera- (proteinuria). Increased renal blood pressure may tion and thickening of the basement membrane, also occur. The expanding mesangium, thickening thickening of the walls of larger vessels, and of capillary basement membranes, renal hyperten- increased lipid deposition and atheroma forma- sion, and declining GFR may then progress to tion. These changes occur throughout the body end-stage renal disease. Patients with end-stage and are primarily responsible for the majority of renal disease are treated with hemodialysis, peri- diabetic complications. toned dialysis, or kidney transplantation, each of Diabetic retinopathy consists of both prolifer- which has its own host of potential complications ative and nonproliferative changes in the retina. and adverse sequelae. Development of retinopathy increases as the dura- Diabetic neuropathy occurs in up to 50% of tion of diabetes increases and is more common in diabetic patients, its prevalence increasing with the type 1 diabetes.19After 15 years' duration of type 1 duration of diabetes.20Neuropathy may affect the diabetes, about 95% of individuals have some sensory, motor, and autonomic nerves. Peripheral degree of retinopathy, with about 50% having the sensorimotor neuropathy is the most common more advanced form of proliferative retinopathy. variety, frequently manifesting as numbness or tin- The earliest retinal changes are nonproliferative gling of the toes or feet. This may be accompanied and include dilation, occlusion, and increased per- by muscle weakness or cramping, alterations in meability of retinal blood vessels. The basement gait, and burning pain. As neuropathy worsens, the membrane of retinal capillaries thickens, and paresthesia or dysesthesia may disappear and be microaneurysms develop. Extravasation of blood replaced by hypoesthesia or even anesthesia. This from the capillaries results in soft and hard exudate reduction in sensory ability makes the affected formation on the retina. Microaneurysms tend to areas highly prone to injury since the patient is occur near the macula, the region of the retina unable to perceive painful stimuli. Diabetic foot responsible for visual acuity and central vision. ulcers resulting from repetitive injury to an insen- Macular edema may result from hemorrhages and sate foot are a major cause of hospitalization and deposit formation, leading to loss of central vision amputation. The patient is unable to perceive pain and acuity. Capillary occlusion causes retinal in the limb, leading to repeated trauma. When Diabetes Mellitus 127 combined with alterations in wound healing Hyperglycemia increases the oxidation of LDL, capacity and changes in the peripheral vasculature, and oxidized LDL is much more atherogenic than this otherwise relatively minor injury may lead to the native form. Thrombus formation is also great- gangrene and amputation of the affected area (Fig- ly enhanced in the diabetic patient. Increased fibrin ures 8-2). deposition along the vessel wall and increased Diabetic neuropathy may also affect the auto- platelet aggregation lead to formation of intravas- nomic nervous system. Cardiovascular autonomic cular microthrombi.22 These alterations can cause neuropathy can lead to dysrhythmias and alter- intermittent hypercoagulation. Increased formation ations in blood pressure. Genitourinary neuropathy of atheromas and microthrombi in the diabetic may cause incontinence due to hypotonia or atonia patient results in increased risk for thromboembol- of the bladder. Sensory and autonomic genitouri- ic events such as stroke and myocardial infarction. nary neuropathy often leads to impotence in dia- Peripheral thromboemboli place end-terminal betic men. Diabetic gastroparesis results from gas- organs at risk for poor oxygenation and exchange of trointestinal neuropathy and manifests as delayed metabolic waste products. Risk factors commonly gastric emptying, sensation of fullness, nausea and associated with atherosclerosis, coronary artery dis- vomiting. Diabetic diarrhea may present as noctur- ease, and stroke in the nondiabetic population- nal diarrhea or incontinence, alternating with peri- smoking, hypertension, obesity, and dyslipi- ods of constipation. The mechanisms involved in demia-also apply to diabetes patients. The pres- diabetic neuropathy are not completely under- ence of diabetes, however, warrants more aggressive stood. Sustained hyperglycemia is certainly management and alteration of these risk factors. involved and alterations in specific glucose-linked The underlying pathophysiology of diabetes biochemical processes may lead to progressive complications is complex and diverse. Hyper- structural and functional nerve changes.2.20 glycemia is, in large part, responsible for both the The most common cause of death in type 2 macrovascular and microvascular complications. diabetes is myocardial infarction, underlining the Hyperglycemia alters cell function and produces a importance of macrovascular complications in cascade of events leading to the structural changes these individuals. l7 Similarly, macrovascular com- seen in affected tissues. Current research has focused plications are very common in type I diabetes. on alterations in lipoprotein metabolism and on Atherosclerosis affects the cardiac, cerebral, and nonenzymatic glycosylation of proteins as possible peripheral vasculature. Atherosclerosis and coro- common links between these various complications. nary artery disease are not unique to the diabetic Because the physical and chemical properties population, but the risk and incidence of these of membranes are determined, in part, by the fatty changes are significantly increased in diabetes. Hyperglycemia plays an important role in macrovascular disease. Increased intimal thickness and atheroma formation are related to hyperglycemia-induced tissue alterations. Increased thickness of vessel walls leads to partial obstruction and reduced blood flow. Atheroma formation further narrows the vessels, diminishing the flow of blood. Decreased blood flow in peripheral vessels leads to alteration in tissue homeostasis and wound healing. In central vessels, reduction in blood flow places major organs such as the heart and brain at risk for altered function. l7 Poorly controlled or previously undiagnosed diabetic patients have major modifications in their lipoprotein metabolism.21,22 Triglyceride levels are often dramatically elevated while HDL levels are decreased. Low-density lipoprotein (LDL) levels may be normal, but there are often changes in LDL composition. In some cases, LDL levels are Figure 8-2. Gangrenous foot (dorsal view) in patient with long- also markedly elevated. Improved glycemic control standing diabetes mellitus. Foot was amputated due to extensive generally improves lipoprotein metabolism. tissue necrosis (Photograph courtesy of Dr. Kathyrn Cripps). 128 Periodontal Medicine acids within the phospholipid bilayer, alterations ment, these are converted to a more stable but still in lipid metabolism may have wide-ranging effects reversible glucose-protein adduct known as an on cellular function.21 Oxidization of LDL in the Amadori product. Normalization of glycemia at this hyperglycemic patient may increase oxidant stress, stage results in reversal of the Amadori product. inducing chemotaxis of monocytes/macrophages Thus, while these early glycosylation products in affected tissues such as vessel walls. Once resi- increase when blood glucose levels are elevated, a dent within the affected tissue site, oxidized LDL return to normal glycemia results in their reversal, may induce alterations in cellular adhesion as well and they do not accumulate in tissues. If hyper- as increased production of chemotactic factors, glycemia is sustained, the Amadori products become cytokines, and growth factors.23 This may then highly stable and form AGEs. Because AGEs are lead to increased vessel wall thickness and forma- irreversible, once formed, they remain attached to tion of atheromas and microthrombi in the large proteins for the lifetime of those proteins. Thus, vessels and alterations in endothelial cell function even if hyperglycemia is corrected, the level of AGES and vascular permeability in the microvasculature. in the affected tissues does not return to normal. Another common link between the complica- Formation of AGES varies among individuals; tions of diabetes is the glycosylation of proteins, AGEs form in everyone, not only in people with lipids, and nucleic a~ids.~~>~~In many diabetic diabetes. The accumulation of AGES also increases patients, the small blood vessels of the retina, with age and may be the basis for many age-relat- glomerulus, and endoneurial region and the walls of ed physiologic changes. However, AGE accumula- the large blood vessels accumulate deposits of carbo- tion is greatly increased in many diabetic hydrate-containing plasma proteins. In addition, patient^.'^>^^ There is significant heterogeneity in expansion of the extracellular matrix is seen in all AGE formation within the diabetic population. It these sites. Increased basement membrane thickness is thought that this heterogeneity may provide a is noted in the retina and around the nerves, the partial explanation for the variation in the inci- mesangial matrix is thickened in the glomerulus, dence of complications seen in diabetes. While and accumulation of collagen is seen in the diabet- hyperglycemia is distinctly linked to the onset and ic arteries. The cumulative effect is a progressive progression of diabetic complications, there are narrowing of the vessel lumen and decreased per- many poorly controlled diabetic individuals who fusion of affected organs. do not develop significant complications. Con- The carbohydrate-containing proteins which versely, some patients with well-controlled diabetes accumulate in patients with sustained hyper- still develop complications. It is postulated that the glycemia are known as advanced glycosylation end- differences between individuals in AGE accumula- products (AGEs).24-26 Formation of AGEs begins tion may explain some of this variance in compli- with the attachment of glucose to the amino groups cations within the diabetic population. on proteins to form an unstable Schiff base adduct Advanced glycosylation end-products form on (Figure 8-3). Through a slow chemical rearrange- collagen, a major component of the extracellular matrix. Once formed, AGEs cause increased collagen cross-linking, resulting in the formation of highly stable collagen macromolecules that are resistant to normal enzymatic degradation and tissue turno~er.~~-~'This causes the accumulation of protein at the affected site. In the blood vessel wall, AGE-modified collagen accumulates, thickening the vessel wall and narrowing the lumen. In addition, circulating LDL in the vessel lumen is immo- bilized in the presence of AGE-modified arterial ~ollagen.~'>~~:~~The amount of LDL that covalent- ly cross-links to collagen increases as levels of AGE increase. Therefore, hyperglycemia contributes to Figure 8-3. Advanced glycosylation end-product formation. formation of increasing levels of AGE-modified Glucose attaches to the amino-terminal end of proteins to collagen in the vessel wall. Circulating LDL form unstable Schiff-base adduct. Over a period of weeks, this product stabilizes to form a reversible Amadori product. With cross-1inked to this AGE-modified sustained hyperglycemia, the Amadori product rearranges to gen and contributes to atheroma formation in the form irreversible advanced glycosylation end-product. diabetic macrovasculature. Diabetes Mellitus 129

The formation of AGEs occurs in both the gia (excessive hunger). Patients may also suffer central and peripheral diabetic arteries and is from weakness, malaise, irritability, blurriness or thought to contribute greatly to macrovascular other changes in vision, nausea, and dry mouth. complications of diabetes. The modification of col- The type 1 patient who does not seek medical eval- lagen by AGEs also occurs in the basement mem- uation quickly may develop diabetic ketoacidosis. brane of small blood vessels. Again, AGE-modified The diagnosis of diabetes is established collagen accumulates and increases basement through recognition of its signs and symptoms and membrane thickness, altering normal homeostatic by laboratory evaluation. Urinalysis was once a pri- transport across the membrane. mary diagnostic tool, but is no longer used in this At the cellular level, AGEs have significant manner. Hyperglycemia may lead to excretion of effects. Accumulation of AGEs not only affects glucose in the urine. Urinary glucose can be detect- extracellular matrix components but can affect ed by use of a urine dip-stick test. However, many matrix-to-matrix interactions and cell-to-matrix diabetic patients do not excrete large amounts of interactions. A receptor for AGEs known as RAGE glucose, even at relatively high blood glucose levels. (receptor for AGE) has been identified on the sur- Conversely, finding glucose in the urine is not face of smooth muscle cells, endothelial cells, neu- diagnostic for diabetes as glucose may be excreted rons, and mono~ytes/macrophages.~~-~~Hyper- from the kidneys in nondiabetic conditions. glycemia results in increased RAGE expression and The primary methods used to diagnose dia- AGE-RAGE interaction. The effect on the betes mellitus and monitor blood glucose levels endothelial cells is an increase in vascular perme- have been the fasting blood glucose, a combination ability and thrombus f~rmation.~'The AGE- of fasting blood glucose plus a 2-hour test after RAGE interaction on smooth muscle cells results glucose loading @hour postprandial), and oral in cellular proliferation within the arterial wall. As glucose tolerance tests. In 1997, the American Dia- AGEs are chemotactic for monocytes, AGE-RAGE betes Association provided the most current labo- interaction induces increased cellular oxidant stress ratory diagnostic parameters for diabetes33 (Table and activates the transcription factor Nf-KB on 8-6). The new diagnostic guidelines allow use of a monocytes. This then alters the phenotype of the casual (nonfasting) plasma glucose for diagnosis monocyte/macrophage and results in increased and restrict routine use of the oral glucose toler- production of proinflammatory cytokines and ance test. These diagnostic tests clearly demon- growth factors such as interleukin- I (IL-I), tumor strate the individual's capacity to regulate plasma necrosis factor (TNF), platelet-derived growth fac- glucose levels. tor (PDGF), and insulin-like growth factor The fasting and casual plasma glucose tests (IGF).27>28>31>32All these cytokines and growth fac- and the oral glucose tolerance test allow determi- tors have been shown to contribute to the chronic nation of glycemia at the moment in time when inflammatory process in the formation of athero- the blood sample is drawn. They do not allow eval- matous lesions. Interestingly, oxidized LDL, ele- uation of glycemic control over a more extended vated in many diabetic patients, also activates NF- time period. The primary test used for this purpose KB, and may result in similar processes. Thus, is the glycosylated hemoglobin assay (also called alterations in lipid and protein metabolism the glycohemoglobin test). This test measures the induced by the sustained hyperglycemia character- amount of glucose bound to the hemoglobin mol- istic of diabetes may play a major role and provide ecule on red blood cells. Glucose binds irreversibly a common link between all the classic complica- to hemoglobin to form glycosylated hemoglobin tions of this disease. and will remain bound for the lifespan of the red blood cell, ranging from about 30 to 90 days. This process is an example of AGE formation. The CLINICAL PRESENTATION AND higher the blood glucose levels over time, the DIAGNOSIS OF DIABETES greater is the percentage of glycosylated hemoglobin. The glycosylated hemoglobin value is propor- The onset of type 1 diabetes is usually quite sud- tional to the blood glucose levels; thus, this test den while type 2 diabetes may be present for years gives a measure of the blood glucose status over the before the patient develops symptoms. The classic preceding 30 to 90 days. signs and symptoms of undiagnosed diabetes are Two different glycosylated hemoglobin tests polydipsia (excessive thirst), polyuria (excessive are available: the hemoglobin A1 (HbAl) test and urination), unexplained weight loss, and polypha- the hemoglobin Alc (HbAlc) test. Each has a dif- 130 Periodontal Medicine

Table 8-6. Laboratory Diagnostic Criteria for Diabetes Laboratoy Methods" 1. Symptoms of diabetes plus casual (nonfasting) plasma glucose 2 200 mg/dL. Casual glucose may be drawn at any time of day without regard to time since the last meal. Classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. 2. Fasting plasma glucose 2126 mg/dL. Fasting is defined as no caloric intake for at least 8 hours. 3. Two-hour postprandial glucose 2200 mg/dL during an oral glucose tolerance test. The test should be performed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water.? Categories offdsting phsma glucose (FPG) 1. FPG c 110 mg/dL = normal fasting glucose 2. FPG 2110 mg/dL and c126 mg/dL = Impaired fasting glucose (IFG) 3. FPG 2126 mg/dL = provisional diagnosis of diabetes (must be confirmed on subsequent day as described below) Categories of 2-hour postprandialglucose (2bPG) 1. 2hPG c140 mg/dL = normal glucose tolerance 2. 2hPG 2140 mg/dL and c200 mg/dL = impaired glucose tolerance (IGT) 3. 2hPG 2200 mg/dL = provisional diagnosis of diabetes (must be confirmed on subsequent day as described below)

*Whatever method is used, it must be confirmed on a subsequent day by using any one of the three methods. +Thethird method is not recommended for routine clinical use.

ferent range of normal values, with the normal a strip which is inserted in the glucometer (Figure HbAl being less than about 8% and the normal 8-5). A reading of capillary whole blood glucose is HbAlc less than 6 to 6.5%.34,35Because different given in I to 2 minutes. The person can then laboratories use different forms of the assay, glyco- adjust their medication, food consumption, or sylated hemoglobin values must be interpreted in activity level on the basis of the test results. the context of the range of normal values for the There are numerous glucometers on the mar- individual medical laboratory performing the ser- ket, each with slightly different user instructions. vice. The American Diabetes Association recom- The frequency with which the diabetic patient uses mends that diabetic patients try to achieve a target SBGM depends on the patient's individual treat- HbAlc of An HbAlc >8% suggests that ment regimen. In some cases, the blood glucose may alteration in patient management is needed to be checked once a day, or even less often. In other improve glycemic control. patients, especially those using insulin, the blood More recently, glycosylated albumin and fruc- glucose may be checked many times daily. In gener- tosamine tests have been developed as monitoring al, the more intensively a diabetes patient is man- tools although they are not used as commonly as aged, the more frequently he or she will use SBGM. the glycosylated hemoglobin assay. Fructosamine levels provide assessment of glycemic control over the past 4 to 6 weeks.37The normal range for fruc- ORAL DISEASES AND DIABETES tosamine is 2 to 2.80 mmol/L. While the above laboratory tests are available Oral complications of diabetes may include alter- for professional diagnosis of diabetes and determi- ations in salivary flow and constituents, increased nation of glycemic control, the advent of self- incidence of infection, burning mouth, altered blood glucose monitoring (SBGM) has allowed the wound healing, and increased prevalence and individual diabetic patient to rapidly assess his or severity of periodontal disease. Xerostomia and her own blood glucose levels almost instantaneous- parotid gland enlargement may occur in the dia- ly. Almost all diabetic patients using insulin and betic indi~idual.~~>~~These complications may be many on oral agents have a glucometer for SBGM. related to the degree of glycemic control.40 Dia- A small sterile lancet is used to create a puncture betes patients may complain of burning mouth on the finger. A drop of capillary blood is drawn syndrome associated with decreased salivary flow. from the puncture site (Figure 84)and placed on Dry mucosal surfaces are easily irritated and often Diabetes Mellitus 13 1

tions used to manage blood glucose levels, many TABLE 8-7. Oral Agents for Treatment of diabetic patients also take other drugs for treat- Diabetes ment of related complications or unrelated disor- Sulfonylureas ders. These drugs can have xerostomic effects. First generation Therefore, xerostomia may result not from the - Chlorpropamide diabetic condition itself but from medications - Tolazamide taken by the patient. Autonomic neuropathy may - Tolbutamide also cause disturbances in the regulation of saliva Second generation ~ecretion.~‘Salivary flow is controlled by sympa- - Glyburide thetic and parasympathetic pathways. Diabetic - Glipizide neuropathy may disturb these pathways, leading - Glimepiride to decreased salivation. Nonsulfonylurea insulin secretogogues In recent studies of type 2 diabetic subjects Repaglinide and nondiabetic controls, no significant differ- Biguanides ences in salivary flow rates were seen.46There were Metformin also no differences between groups in the organic Thiazolidinediones constituents of saliva. However, the effect of xeros- Troglitazone tomic medications on salivary flow rates was a-glucosidase inhibitors greater in diabetic individuals than in control Acarbose patients. No differences were seen in the prevalence of corona1 caries or root caries.47The salivary counts of acidogenic bacteria (Streptococcus mutuns provide a favorable substrate for the growth of fun- and lactobacilli) were similar between the diabetic gal organisms. The incidence of candidiasis may be increased in patients with diabetes41although not all studies support this relati~nship.~’ Dental caries rates may also be altered in diabetes. While some studies have shown an increased caries incidence in diabetes,43 others have demonstrated similar or lower rates than in nondiabetic individual^.^^>^^ An increased caries rate may be associated with decreased salivation or with increased glucose concentrations in the saliva and gingival crevicular fluid (GCF). Conversely, most diabetic patients restrict fermentable carbohydrate intake as part of their disease management diet. This less cariogenic diet may be associated with decreased caries rates. In addition to medica-

Figure 8-5. Test strip in glucometer with glucose reading. Figure 8-4. Obtaining drop of blood for glucometer test- Blood is placed on a specific area of the glucometer strip. ing. Finger lancet used to “prick finger and drop of blood After an appropriate period of time, blood glucose reading is “milked” from puncture site. given by the glucometer. 132 Periodontal Medicine and nondiabetic subjects. Likewise, carriage of sali- est in the younger age groups. For example, diabet- vary yeasts was similar between groups. ic subjects from 15 to 34 years of age had mean attachment loss and bone loss scores approximately Diabetes and Periodontal Disease twice as high as similar-aged nondiabetic subjects. In a multivariate risk analysis, it was determined The influence of diabetes on the periodontium has that diabetic subjects had a risk of periodontitis 2.8 been thoroughly studied. It is difficult to make to 3.4 times higher than nondiabetic subjects after definitive conclusions from many of these studies adjusting for the effects of confounding variables owing to the heterogeneity of study designs, differ- such as age, sex, and oral hygiene measures. ences in the populations studied, changes in the A recent meta-analysis of data from several classification of periodontal diseases and diabetes studies of type 2 diabetes and periodontal disease over the years, changes in the methods for diag- was performed.53These studies included a total of nosing diabetes and evaluating glycemic control, 3,524 adults over 18 years of age and clearly inadequacy of study controls, and differences in demonstrated a significant association between periodontal parameters or outcome variables mea- periodontitis and diabetes mellitus. Diabetes may sured. Some research with relatively small numbers influence not only the prevalence and severity of of subjects suggests that diabetes has little influ- periodontitis but also the progression of disease. ence on the prevalence and severity of periodontal Taylor and colleagues demonstrated that type 2 diseases. However, modern epidemiologic methods diabetes significantly increased the rate of alveolar used in large populations have clearly established bone loss progression over a 2-year period when that diabetes is a risk factor for periodontal disease. compared to nondiabetic subjects.56The risk for Diabetes is often associated with increased gin- progressive bone loss was 4.2 times greater in dia- gival inflammation in response to bacterial betic subjects, with the greatest increase in risk plaq~e.4&-~'This response may be related to the level occurring in patients under the age of 34 years. of glycemic control, with subjects with well-con- The relationship between metabolic control of trolled diabetes having a similar degree of gingivitis diabetes and periodontal disease is not clear.57Some as nondiabetic individuals and poorly controlled diabetic patients with poor glycemic control devel- diabetic subjects having significantly increased op extensive periodontal destruction while others do inflammati~n.~1,52 Increased gingival inflammation not. Conversely, many patients with well-controlled may be seen in diabetic subjects even though plaque diabetes have excellent periodontal health, but others levels are similar to nondiabetic controls. develop periodontitis. In this way, periodontal dis-

The IDrevalence of IDeriodontitis in diabetic ease is similar to the classic complications of dia- adolescents and young adults is significantly greater betes. Poor glycemic control is clearly associated than similar-aged nondiabetic indi~iduals.4~While with increased risk for complications, but not all some young &abetic people develop periodontitis, patients with poorly controlled diabetes develop especially those with poor metabolic control, peri- these complications. While there is no unequivocal odontal disease is much more common in adults. In dose-response relationship between glycemia and a thorough analysis of the literature, Papapanou periodontitis, many studies support the clinical demonstrated that the majority of studies show a observation that patients with poorly controlled dia- more severe periodontal condition in adult patients betes of long duration tend to develop more with diabetes than in nondiabetic adults.53 advanced periodontal destruction than diabetic In large populations, type 2 diabetes has been patients with good metabolic control. Over 2 to 3 shown to be a significant risk factor for periodonti- years, Seppala and colleagues demonstrated that tis. The Pima Indian population of Arizona, with subjects with poorly controlled diabetes had signifi- the highest prevalence of type 2 diabetes in the cantly greater longitudinal attachment loss and bone world, has been extensively st~died.~*>~~The preva- loss than did subjects with well controlled dia- lence of attachment loss and bone loss was greater bete~.~~Tervonen and Oliver showed that subjects among diabetic subjects than among nondiabetic with poor metabolic control over the preceding 2 to control subjects in all age groups. The differences in 5 years had a significantly greater prevalence of deep disease prevalence were most pronounced in the probing depths and advanced attachment loss than younger age groups. In addition, periodontal did subjects with good glycemic control.59Longitu- destruction was more severe in diabetic patients, dinally, Taylor and colleagues found that poor with greater mean bone loss and attachment loss. glycemic control was associated with significantly Again, the differences in disease severity were great- increased risk of progressive bone loss compared Diabetes Mellitus 133 with better metabolic control.56 Thus, metabolic tium. These are primarily related to changes in the control of diabetes may be an important variable in subgingival microbiota, GCF glucose levels, peri- the onset and progression of periodontal disease. odontal vasculature, host response, and collagen Patients with well-controlled diabetes may be simi- metaboli~m.~~While early studies showed possible lar to nondiabetic individuals. It is important to differences in subgingival bacterial colonization remember that periodontal disease prevalence and between diabetic and nondiabetic patients with severity varies greatly within the nondiabetic popu- periodontitis, more recent research has demon- lation. Presence of periodontal disease in a diabetic strated few differences. Periodontally diseased sites individual may therefore have more to do with other in diabetic patients harbor similar species as com- risk factors for periodontitis such as poor oral parable sites in nondiabetic individ~als.~~>~~>~*This hygiene and smoking than it does with the mere lack of significant differences between diabetic and presence of a diabetic state. nondiabetic individuals in the primary bacterial An important question for the dental practi- etiologic agents of periodontal disease suggests that tioner is, Will diabetic patients with periodontal the increased prevalence and severity of periodon- disease respond favorably to periodontal treatment titis in diabetes may be due to differences in host In a study of patients with predominantly well-con- response factors. trolled diabetes and moderate to advanced peri- Increased blood glucose levels in diabetes are odontal disease, Christgau and colleagues found reflected in increased levels of GCF glucose.6566In similar responses to nonsurgical scaling and root vitro studies show decreased chemotaxis of peri- planing when compared with nondiabetic subjects odontal ligament fibroblasts to PDGF when 4 months after treatment." Conversely, patients placed in a hyperglycemic environment compared with poorly controlled diabetes often have a less with normoglycemic condition^.^^ Thus, elevated favorable response to treatment than those with GCF glucose levels in diabetes may adversely affect well-controlled diabetes." Westfelt and colleagues periodontal wound healing events and the local performed a longitudinal assessment of diabetic host response to microbial challenge. subjects and nondiabetic controls with moderate to Changes affecting the renal, retinal, and per- advanced periodontitis.62 Patients received scaling ineural vasculature in diabetes also occur in the and root planing, modified Widman flap surgery periodontium. Increased thickness of gingival cap- and supportive periodontal therapy every 3 illary endothelial cell basement membranes and months. Five years after the study began, there was the walls of small blood vessels may be seen in dia- a similar percentage of sites gaining or losing betic individual^.^^-^' This thickening may impair attachment, and a similar percentage of sites with oxygen diffusion and nutrient provision across stable attachment levels when comparing diabetic basement membranes. Increased thickness of small and nondiabetic subject groups. Most of the dia- vessel walls results in narrowing of the lumen, betic patients in this study had well-controlled or altering normal periodontal tissue homeostasis. moderately well-controlled glycemia. The formation of AGEs occurs in the peri- Diabetic patients must be examined individual- odontium as it does in other tissue sites. Schmidt ly to assess their potential response to periodontal and colleagues have demonstrated a two fold therapy. The mere presence of diabetes does not con- increase in AGE accumulation in diabetic gingiva demn the person to a less fivorable periodontal out- compared with gingiva from nondiabetic subjects. come. A diabetic patient with good glycemic control Increased oxidant stress was also noted in diabetic can be expected to respond in a fishion similar to the tissues.71 Enhanced oxidant stress has been target- nondiabetic subject. The presence of poor glycemic ed as the underlying mechanism responsible for control may place the patient at risk of a less favor- the widespread vascular injury associated with dia- able response. In addition, other factors such as betes. The formation of AGEs stimulates arterial smoking or poor plaque control may adversely affect smooth muscle cell proliferation, increasing thick- the response to periodontal therapy in diabetic indi- ness of vessel walls. In the capillaries, enhanced viduals, just as they may in a nondiabetic person. cross-linking of AGE-modified collagen in the basement membrane inhibits the normal degrada- Mechanisms of Diabetic Influence on tion of these proteins, increasing the thickness of Periodo nt iu m the basement membrane. Elevated LDL levels, especially common in type 2 diabetes, may cause A number of possible mechanisms have been pro- changes in the gingival vasculature.21The AGE- posed by which diabetes may affect the periodon- modified arterial collagen in gingival blood vessel 134 Periodontal Medicine walls can bind circulating LDL, resulting in halts the migration of the monocytes, fixing them atheroma formation and further narrowing of the at the local site. The AGE-RAGE interaction then vessel lumen. All these events may play a role in induces a change in monocyte phenotype, upregu- altering the tissue response to periodontopathic lating the cell and significantly increasing proin- bacteria, resulting in increased severity and pro- flammatory cytokine production. This provides gression of periodontitis. another explanation for increased GCF production Altered host defenses have long been consid- of TNFa, PGE2 and IL-lfl noted in diabetic ered important in the pathogenesis of periodontitis patients with peri~dontitis.~~.~~ associated with diabetes. Defects in polymor- As previously discussed, there is a great deal of phonuclear leukocyte (PMN) adherence, chemo- heterogeneity in AGE formation within the diabet- taxis, and phagocytosis have been observed in some ic population. Thus, these AGE-associated changes individuals with diabetes. 57,72,73 Many of these may be present in some patients but absent in oth- PMN abnormalities can be corrected with ers. Those individuals at greatest risk for increased improved glycemic control. Defects affecting this AGE accumulation and its adverse effects are those first line of defense against subgingival microbial with poor glycemic control, who may accumulate agents may result in significantly increased tissue large deposits of AGES within target tissues. Simi- destruction. In many diabetic patients, PMN func- larly, the patient with poorly controlled diabetes is tion is normal. Oliver and colleagues have even sug- most likely to suffer more rapid and advanced peri- gested hyper-responsiveness or increased numbers odontal destruction. However, just as some individ- of PMNs within the gingival crevice of poorly con- uals with poorly controlled diabetes do not develop trolled diabetic patients as indicated by elevated lev- classic vascular complications of the disease, some els of the PMN-derived enzyme fl-glucuronida~e.~~such patients have little, if any, significant peri- The monocyte/macrophage cell line is critical odontal disease. The variability in AGE formation to cell-mediated host defense in periodontal dis- may provide some explanation for the variance in eases. Studies suggest that many diabetic patients risk of periodontal complications of diabetes. possess a hyper-responsive monocyte/macrophage Collagen is the primary constituent of gingival phenotype in which stimulation by bacterial anti- connective tissue and the organic matrix of alveo- gens such as lipopolysaccharide (LPS) results in lar bone. Changes in collagen metabolism con- dramatically increased proinflammatory cytokine tribute to alterations in wound healing and to peri- prod~ction.~~Salvi and colleagues have demon- odontal disease initiation and progression. Pro- strated significantly increased production of proin- teinases are enzymes involved in matrix degrada- flammatory cytokines by monocytes derived from tion. In the periodontium, these matrix metallo- patients with diabetes compared with nondiabetic proteinases (MMPs) include collagenases, gelati- subjects.76In response to LPS from the periodon- nases, and ela~tases.~~>~~There are at least 12 distal pathogen I;' gingivulis, diabetic monocytes pro- tinct members of the MMP family, and these duced 24 to 32 times the level ofTNFa compared enzymes are responsible for the breakdown of bone with nondiabetic monocytes. Also, there was a four and connective tissue during periodontal disease. fold increase LPS-stimulated monocyte production Matrix metalloproteinases are produced by all of of PGE2 and IL-lfl in diabetic subjects than in the major cell types in the periodontium when nondiabetic subjects.77 The gingival crevicular activated by various cytokines and growth factors, fluid levels of PGE2 and IL-1 fl were significantly including PMNs, fibroblasts, macrophages, higher in diabetic patients with periodontitis than endothelial cells, osteoblasts, and o~teoclasts.~~ in nondiabetic subjects with a similar degree of Increased collagen breakdown through stimu- periodontal destruction. lation of collagenase activity has been observed in It is likely that there is a genetic component to the periodontium of diabetic patients.80 Collage- the development of a hyper-responsive mono- nases primarily degrade more newly formed and, cyte/macrophage phenotype in some diabetic therefore, more soluble collagen macromolecules. patients. Not all individuals with diabetes have this Sustained hyperglycemia results in AGE modifica- phenotype. The formation of AGEs also plays an tion of existing collagen, with increased cross-link- important role in the upregulation of the mono- ing. The net effect of these alterations in collagen cyte/macrophage cell line. Accumulation of AGEs metabolism is a rapid degradation of recently syn- in the periodontium stimulates influx of mono- thesized collagen by host collagenase and a pre- cytes. Once in the tissue, AGEs interact with the dominance of older, highly cross-linked, AGE- receptor RAGE on monocyte cell surfaces. This modified collagen. Since collagen production and Diabetes Mellitus 135 degradation exist as a highly balanced homeostatic patients with severe periodontitis, those with mechanism, changes in collagen metabolism result severe periodontal disease had a significantly in altered wound healing in response to physical or greater prevalence of cardiovascular and kidney microbial wounding of the periodontium. Impair- complications during the I- to I I-year follow-up ed wound healing is a well-recognized complica- period than did patients with minimal periodontal tion of diabetes and may affect any tissue site, disease.88 This was true despite the fact that including the periodontium. HbAlc levels were similar in both groups, indicat- Reduction in host collagenase production can ing a similar level of long-term glycemic control. be achieved by tetracycline thera~y.~~,~',~~This is Thus, the classic complications of diabetes may be accomplished via mechanisms which are indepen- closely associated with periodontal disease in these dent of the antimicrobial properties of these individuals, lending further credence to the con- agents. Low-dose tetracyclines and chemically cept that periodontal disease may be the "sixth modified tetracyclines (CMTs), which have no complication of diabete~."~~ antimicrobial effect, have been shown to signifi- If periodontal infection adversely affects cantly decrease collagenase production and colla- glycemic control in diabetes, then the question gen degradati~n.~~~~~Although CMTs are not yet arises, Can periodontal treatment directed at elim- available for routine use, tetracyclines such as ination of pathogenic organisms and reduction of doxycycline, minocycline, and tetracycline HCl inflammation have a positive impact on glycemic have been used for many years. Low-dose doxycy- control? In case studies of patients with poorly cline is now available as we1P although its use in controlled diabetes and periodontitis, improve- diabetic patients has not yet been reported. Due to ment in metabolic control has been noted coinci- their anticollagenolytic effect, tetracyclines and dent with improvement in periodontal health fol- CMTs have potential benefits in inhibiting the lowing treatment. In 1960, Williams and Mahan onset and progression of periodontitis, arthritis, performed extractions and periodontal surgery in and osteoporosis, among other condition^.^^ In a combination with systemic antibiotic therapy on 9 disease such as diabetes, where collagenase produc- diabetic patients with severe periodontitis to elim- tion is significantly increased, these agents may inate periodontal infe~tion.~'The metabolic para- have even greater beneficial effects by normalizing meters, including daily insulin dose and periodic collagen metabolism and wound healing events. blood glucose readings, were crude by today's standard but were routinely used at the time. With improved periodontal health, 7 of the 9 patients EFFECTS OF PERIODONTAL had decreased daily insulin requirements, some by INFECTION ON GLYCEMIC over 50%. Miller and colleagues evaluated the CONTROL OF DIABETES effect of scaling and root planing combined with 14 days of systemic doxycycline on glycemia in 9 While diabetes significantly impacts the periodon- poorly controlled type I diabetic patients with tium, evidence also suggests the potential for peri- period~ntitis.~'At post-treatment examinations 4 odontal infection to adversely influence glycemic and 8 weeks after therapy, 5 of 9 patients had sig- control in diabetes. Taylor and colleagues exam- nificant improvement in bleeding on probing. ined subjects with type 2 diabetes to determine These same 5 subjects also had improvement in whether severe periodontitis increased the risk for metabolic control, indicated by significant reduc- poor glycemic control.87 The subjects, some of tions in HbAlc values. The 4 patients who had no whom had severe periodontitis and others who did improvement in bleeding on probing also had no not, all had relatively well-controlled glycemia at improvement in glycemic control. This noncon- baseline, as indicated by glycosylated hemoglobin trolled case study suggests that improved peri- (HbAl) levels of less than 9%. At re-examination odontal health may be accompanied by a parallel 2 years later, a greater proportion of subjects with improvement in metabolic control of diabetes, and severe periodontitis had poor glycemic control indicates the potential systemic benefits of peri- (HbAl >9%) than did subjects without severe odontal treatment in patients with poorly con- periodontitis. Severe periodontitis at baseline was trolled diabetes and periodontitis. associated with a six fold increased risk of poor In the first long-term placebo-controlled study glycemic control at follow-up. of its kind, Grossi and colleagues examined a large In a case-control study of diabetic adults hav- group of poorly controlled type 2 diabetic patients ing gingivitis or mild periodontitis compared with with severe periodontitis following non-surgical 136 Periodontal Medicine dkbridement combined with either systemic doxy- DIABETES AND DENTAL IMPLANT cycline (100 mg/day) or placebo for 14 days.92,93 THERAPY All patient groups had significant reductions in gingival bleeding and probing depths, with gains in There is little scientific evidence regarding the suc- clinical attachment. Doxycycline-treated patients cess or failure of dental implant therapy in diabet- had a greater reduction in prevalence of I;' gingivuis ic individuals. Diabetes is often considered a rela- at 3 and 6 months. The doxycycline-treated tive contraindication to implant placement, but in patients also demonstrated significant reductions in well-controlled diabetes there is no reason to avoid HbAlc at 3 months, which gradually reverted to implant therapy. Patients with poorly controlled baseline levels by 6 months. Placebo-treated sub- diabetes may not respond well to any surgical treat- jects had no significant change in HbAlc levels at ment, including implant placement, due to any time point. Consequently, the combination of impaired wound healing. In animal models, dia- subgingival dkbridement and systemic doxycycline betes has been associated with decreased bone-to- resulted in significant short-term improvement in implant contact and decreased bone density in the the parameters of metabolic control. peri-implant regi~n.~~.~~It is not known if this Conversely, subjects with well-controlled or occurs in humans. The effect of diabetes on long- moderately controlled diabetes and periodontitis term clinical implant stability is also unknown at who receive scaling and root planing without this time. adjunctive systemic antibiotic therapy may demonstrate no significant changes in glycemic control despite improvement in their periodontal MEDICAL MANAGEMENT OF parameter~.~'>~*The mechanisms by which adjunc- DIABETES tive antibiotics may induce positive changes in glycemic control when combined with thorough Treatment of diabetes aims to achieve blood glu- mechanical dkbridement are unknown at this cose levels as close to normal as possible and to pre- time. It is possible that improved glycemia is asso- vent diabetic complications. The American Dia- ciated with the more complete elimination of betes Association has standards of care to guide pathogenic organisms in antibiotic-treated patients. treatment, with a goal of achieving HbAlc levels Tetracyclines and CMTs are also known to sup- <7%.37This goal is difficult to attain for most dia- press glycosylation of proteins, AGE formation, betic patients, and the majority of these individu- and MMP activity.78 als have less than ideal metabolic ~ontrol.~~~J~~SP e- Acute bacterial and viral infections have been cific goals of therapy include maintaining normal shown to increase insulin resistance and aggravate growth and development, attaining normal body glycemic contr01.~~>~~This occurs in both diabetic weight, avoiding sustained hyperglycemia or symp- and nondiabetic individuals. Insulin resistance per- tomatic hypoglycemia, preventing diabetic sists for an extended period of time after clinical ketoacidosis and nonketotic acidosis, and immedi- recovery from infection, often for weeks or ately detecting and treating long-term diabetic months. In the type 2 diabetes patient, who complications. Treatment options for type 2 dia- already has significant insulin resistance, further betes may include diet, exercise, weight control, resistance induced by infection may considerably oral medications, and insulin injections. Generally, exacerbate poor glycemic control. In type I a combination of these therapeutic approaches is patients, prescribed doses of injected insulin may used. While treatment for type I diabetes also be insufficient to maintain good glycemic control involves diet, exercise, and weight control, insulin in the presence of infection-induced tissue resis- injection is essential to sustain life. tance. It is possible that chronic gram-negative Diet, exercise, and weight control are the periodontal infections may also result in increased mainstay of therapy. Proper diet allows intake of insulin resistance and poor glycemic control.97 carbohydrate, protein and fat in proportions com- Periodontal treatment designed to decrease the mensurate with the target weight and nutritional bacterial challenge and reduce inflammation might needs. Obesity is common in type 2 diabetes and restore insulin sensitivity over time, resulting in contributes substantially to insulin resistance. improved metabolic control. The improved Exercise and weight reduction significantly glycemic control seen in studies of combined improve tissue sensitivity to insulin and utilization mechanical and antibiotic periodontal therapy of glucose by target tissues. Even small reductions would support such a hypothesis. in body weight can have dramatic effects on Diabetes Mellitus 13 7 insulin sensitivity. Many patients with type 2 dia- the initial development of retinopathy, nephropa- betes take oral medications which either increase thy, and neuropathy in subjects who entered the pancreatic insulin production, decrease production study free of these complications. The study also of glucose by the liver, improve tissue sensitivity to determined the effect of intensive insulin therapy insulin, or alter absorption of carbohydrate from on the progression of these complications in the gut. All type 1 diabetic patients and many type patients who began the study with pre-existing 2 patients inject exogenous insulin to allow glucose early complications. utilization by the tissues. Self-blood glucose moni- The results of the DCCT provided strong evi- toring through use of a glucometer is recommend- dence that improved glycemic control, achieved ed for all type 1 and most type 2 diabetic individ- through intensified insulin regimens, inhibited the uals as it provides vital feedback to the patient onset and delayed the progression of diabetic com- regarding blood glucose levels and allows tailoring plications. lo1~lo2The risk of developing retinopathy and adjustment of individual treatment regimens was reduced by 76% in intensively treated patients on the basis of knowledge- of -glucose levels at dif- compared with those on conventional insulin regi- ferent times of the day. mens. The progression of existing retinopathy In the course of a typical day, blood glucose decreased by 54% in the intensively treated group. levels rise after meals, resulting in increased pan- Albuminuria, a sign of nephropathy, and clinical creatic insulin secretion (see Figure 8-1). Insulin neuropathy were reduced by 54% and 6O%, respec- allows glucose to be removed from the blood- tively. Thus, change from conventional insulin reg- stream for tissue utilization and storage; thus, imens, which rarely achieve normoglycemia, to blood glucose levels fall. A feedback mechanism intensive regimens resulted in improved glycemic then results in decreased insulin secretion until the control and dramatic reductions in the risk of next meal when the cycle is repeated (Figure 8-6). microvascular complications. Improvement in In healthy subjects, blood glucose fluctuations are glycemic control was also associated with a reduc- held within a relatively tight range throughout the tion in macrovascular complications. lo3 The day, rarely falling below 60 mg/dL or rising above potential reduction in morbidity and mortality 150 mg/dL. In diabetes mellitus, wide ranges in related to diabetic complications seen in the glycemic fluctuation are common even with treat- DCCT led the American Diabetes Association to ment. Deficiencies in plasma insulin levels result in issue a position statement declaring that a primary hyperglycemia while excess levels of insulin cause goal in treating type 1 diabetes is to attain blood hypoglycemia. The ideal treatment of the diabetic glucose control “at least equal to that achieved in individual would establish glycemic patterns simi- the intensively treated cohort” of the DCCT. lo4 lar to those of nondiabetic persons. Physicians have begun to intensify insulin regi- In 1985, a prospective, randomized, controlled, multicenter clinical trial known as the Dia- betes Control and Complications Trial (DCCT) was begun to determine the relationship between glycemic control and diabetic complications. loo This landmark study compared the effects of intensive insulin therapy directed at near normalization of glycemia with the effects of conventional insulin therapy on the initiation and progression of microvascular complications in type 1 diabetes. In the DCCT, 1,441 type 1 diabetic subjects were followed for 3 to 9 years after being randomly assigned to one of two groups. The first was a conventional insulin therapy group, who took 1 or 2 insulin injections each day. The second was an intensive insulin therapy group, who took 3 or 4 Figure 8-6. Glucose-insulin relationship. Rise in blood glu- daily injections or used an external subcutaneous cose following each meal or snack stimulates increased insulin secretion, which then allows glucose utilization and insulin infusion pump. The study was designed to storage. Blood glucose levels decrease until the next meal, determine whether intensive insulin therapy, used when the cycle is repeated. In healthy subjects, glycemic to maintain blood glucose values within the nor- fluctuations are held within a tight range between approxi- mal range over a long period of time, could prevent mately 60 and 150 mg/dL. 138 Periodontal Medicine mens in response to these results, and diabetic tissue sensitivity to insulin, thereby stimulating patients who know about the DCCT are motivat- glucose utilization in muscle. It also reduces blood ed to improve their glycemic control. lo5~lo6 glucose levels by suppressing gluconeogenesis in Several studies have substantiated the conclu- the liver. Like metformin, troglitazone generally sions of the DCCT for individuals with type 2 dia- does not cause hypoglycemia. betes as ~ell.~'~J'~In one study with a similar The a-glucosidase inhibitor acarbose works in design, the patient group that maintained near-nor- a manner different from other oral agents. Taken mal blood glucose values over a 6-year study period with meals, acarbose slows the digestion and had a 69% reduction in the risk of retinopathy uptake of carbohydrates from the gut, thus lower- compared with the group with poorly controlled ing postprandial peaks in blood glucose. Since diabetes.lo7 The risk of neuropathy and nephropa- acarbose is not absorbed, few systemic effects are thy decreased by 57% and 70%, respectively. The seen although gastrointestinal side effects are not risk of cardiac, cerebral, and peripheral macrovas- uncommon. Acarbose may be used by both type I cular complications was reduced by 54%. Thus, it and type 2 diabetic patients. While acarbose itself is likely that dental professionals will encounter does not cause hypoglycemia, when taken by a increasing numbers of type I and type 2 diabetic patient who also uses insulin or sulfonylureas, the patients using intensified treatment regimens. delay in glucose absorption from the gut into the bloodstream can lead to relative insulin excess and Oral Agents Used in Diabetes hypoglycemia.

A number of oral agents are used to treat type 2 Insulin Therapy diabete~~>~*J'~(Table 8-7). Sulfonylureas stimulate the flcells of the pancreas to increase insulin secre- Insulin is used by all patients with type I diabetes tion. First-generation sulfonylureas are used infre- and many patients with type 2 diabetes. Insulin is quently today. Second-generation agents (glipizide, administered by subcutaneous injection, usually glyburide, and glimepiride) are more potent, pro- with a syringe. Insulin pumps provide an insulin duce less significant side effects, and have fewer infusion through a subcutaneous catheter. The drug interactions than first-generation sulfony- amount of insulin taken each day and the exact reg- lureas. However, the major complication of sul- imen for insulin delivery vary with each patient. l1 fonylurea therapy is hypoglycemia, which may be Insulins vary in their onset, peak, and duration more frequent with second-generation agents. As of activity and are classified as rapid-, short-, inter- pancreatic insulin secretion increases in response to mediate-, or long-acting (Table 8-8). While sulfonylureas, food intake must be adequate to human insulin is currently the most used, beef and avoid low blood glucose levels. pork insulins are also still encountered. An ideal Repaglinide is a new antidiabetic agent, insulin profile obtained by insulin injection would which, like sulfonylureas, stimulates pancreatic closely mimic daily insulin fluctuations in nondia- insulin secretion."' It does so via a different mech- betic individuals (see Figure 8-6), a very difficult anism, and its pharmacodynamic properties are goal to achieve. Lispro and regular insulin are gen- unique. Unlike sulfonylureas which have a dura- erally taken close to meal time in an attempt to tion of action of 12 to 24 hours, repaglinide is match the peak absorption of glucose from the gut rapidly absorbed, reaching peak plasma levels in 30 into the bloodstream with the peak activity of the to 60 minutes. It is then rapidly metabolized into injected insulin. Ultralente insulin is taken to sim- inactive metabolites, with a plasma half-life of only ulate the basal metabolic rate of insulin secreted about I hour. The drug is taken with meals, and it from a normally functioning pancreas. Ultralente decreases postprandial blood glucose peaks, com- is often called "peakless" insulin due to its very mon in type 2 diabetes, to a significantly greater slow onset, minimal peak activity and long dura- degree than sulfonylureas. tion of action. Intermediate-acting insulins such as Metformin lowers blood glucose primarily by NPH and lente have a slower onset and peak activ- preventing glycogenolysis in the liver. It also ity than rapid- or short-acting insulins. Thus, increases tissue uptake and utilization of glucose, NPH or Lente insulin injected at 7:OO AM will usu- counteracting the insulin resistance characteristic ally reach its peak activity sometime around noon of type 2 diabetes. Unlike sulfonylureas, met- or shortly thereafter. formin rarely causes hypoglycemia. Troglitazone, a While many regimens exist, some convention- relatively new thiazolidinedione agent, increases al daily insulin injection regimens include (I) a Diabetes Mellitus 139

TABLE 8-8. Types of Insulin Insulin Type Insulin ClassiJication Onset of Activity Peak Activity Duration ofActivity Lispro Rapid-acting 15 min 30 to 90 min <5 h Regular Short-acting 30 to 60 min 2to3h 4to 12h NPH Intermediate-acting 2to4h 4to lOh 14 to 18 h Lente Intermediate-acting 3to4h 4to 12h 16 to 20 h Ultralente Long-acting 6to 1Oh 12 to 16 h 20 to 30 h single morning injection of intermediate-acting have less variability in absorption and activity than insulin; (2) a single morning injection of interme- either intermediate- or long-acting insulins. Insulin diate-acting insulin mixed with regular or lispro injection is timed so that peak plasma insulin levels insulin; (3) twice-daily injections of intermediate- coincide with peak postprandial glucose levels. acting insulin; or (4) twice-daily injections of Intensive regimens may also include intermediate- intermediate-acting insulin mixed with regular or or long-acting insulin to provide a basal metabolic lispro insulin (Figures 8-7, 8-8, 8-9). While the level of plasma insulin (Figure 8-1 0, 8-1 1). insulin injection regimen in Figure 8-9 appears to Insulin pumps use either regular or lispro closely mimic the normal pancreatic insulin secre- insulin only. A continuous basal metabolic infu- tion profile seen in Figure 8-6, even this regimen sion rate is programmed into the pump to mimic often results in relatively poor glycemic control normal pancrea;ic basal secretion. Then-the patient with wide fluctuations in blood glucose levels programs a bolus of insulin prior to each meal. The throughout the day. This was clear in the DCCT, pump is battery operated and delivers insulin from where glycemic control with all conventional regi- a storage syringe within the pump through tubing mens was poor compared with intensive regimens. into a subcutaneous catheter. The catheter and The variability in the activity of injected insulin infusion set are changed every 2 to 3 days. Since makes it very difficult to match peak plasma the results of the DCCT were published, the num- insulin levels with peak blood glucose levels fol- ber of patients using intensive insulin regimens has lowing ingestion of food. increased significantly.' l2 However, even the most Intensive insulin regimens such as those used in intensive insulin regimens used in highly motivat- the DCCT generally dictate injection of regular or ed patients are relatively poor substitutes for a nor- lispro insulin before each meal since these insulins mally functioning pancreas.

Figure 8-7. Conventional insulin injection regimen: one Figure 8-8. Conventional insulin injection regimen: one injection of NPH/Lente. Example of conventional insulin injection of NPH/Lente mixed with Regular/Lispro. Exam- regimen using single injection of intermediate-acting insulin ple of conventional insulin regimen using single injection of (NPH or Lente) each day. Arrow indicates time of injection. intermediate-acting insulin (NPH or Lente) mixed with The only meal that is covered by injected insulin is lunch. short-acting (Regular) or rapid-acting (Lispro) insulin. Glucose absorbed from breakfast, dinner, and evening snack Arrow indicates time of injection. Glucose absorption from remains in the bloodstream due to insufficient insulin levels, breakfast and lunch is covered by injected insulin but that resulting in hyp er gl ycemi a. from dinner and evening snack is not. 14 0 Periodontal Medicine

36% of severe hypoglycemic reactions occurred without warning symptoms for the patient. In another 5 I Yo of cases, warning symptoms occurred but were not recognized as such by the patient. This suggests the seriousness with which dental practitioners should manage hypoglycemia, especially in insulin-using diabetic patients.

DENTAL MANAGEMENT OF THE DIABETIC PATIENT Figure 8-9. Conventional insulin injection regimen: two injections of mixed Regular/Lispro and NPH/Lente. Exam- Patients who present to the dental office with intra- ple of conventional insulin regimen using both morning and oral findings suggestive of a previously undiagnosed evening injections of intermediate-acting insulin (NPH or diabetic condition should be questioned closely. Lente) mixed with short-acting (Regular) or rapid-acting Questions should be targeted toward eliciting a (Lispro) insulin. Arrows indicate time of injection. Theoret- ically, glucose absorption from all meals is covered. clear history of polydipsia, polyuria, polyphagia, or recent unexplained weight loss. Patients should also be asked about family history of diabetes. Hypoglycemia is the most common complica- The patient in Figure 8-12, a 50-year-old tion of insulin therapy. Hypoglycemia can and does Mexican-American male, presented with general- occur in patients using oral sulfonylurea agents; ized moderate adult periodontitis. Heavy accumu- however, its incidence is higher in those taking lations of plaque and calculus were noted. The insulin injections. While intensified treatment regi- patient was healthy, although obese, and was tak- mens decrease the risk of long-term diabetic com- ing no medications. Following scaling and root plications, they increase the risk of hypoglycemia. In planing, he failed to return for re-evaluation. Five the DCCT, the incidence of severe hypoglycemia years later, he presented again to the periodontist. was three times higher in the intensive insulin group This time, severe bone loss was noted in the incisor compared with the conventional therapy and molar regions (Figure 8-12B). Oral hygiene group.' l3>ll4 Severe hypoglycemia was defined as was poor, but the rapidity of bone loss was incon- hypoglycemia in which the neurologic impairment sistent with adult periodontitis. Upon questioning, was so severe that the patient required the assistance the patient stated that it was common for him to of another person. One-third of all severe hypo- urinate three to five times a night. The positive his- glycemic episodes in the DCCT led to seizures or loss of consciousness. Perhaps even more significant,

Figure 8-1 1. Intensive insulin regimen: three daily injections of Regular/Lispro plus one injection of NPH/Lente. Figure 8-10. Intensive insulin regimen: three daily injections Example of intensive insulin regimen using injections of of Regular/Lispro plus one injection of Ultralente. Example of Regular or Lispro insulin before breakfast, lunch, and din- intensive insulin regimen using injections of Regular or Lispro ner. A single injection of intermediate-acting (NPH or insulin before breakfast, lunch, and dinner. A single injection Lente) insulin is taken at bedtime to cover an evening snack of long-acting (Ultralente) insulin in the morning provides and the increased glucose production that normally occurs basal metabolic insulin levels during the day. before awakening in the morning. Diabetes Mellitus 14 1

Figure 8-12. A, Six-radiograph set of anterior teeth (minimal bone loss). Fifty-year-old patient prior to diagnosis of diabetes. Heavy local factors with mild to moderate adult periodontitis. B, Six-radiograph set of anterior teeth (severe bone loss). Five years after initial presentation, patient in Figure 8-12 has severe bone loss. Patient had undiagnosed type 2 diabetes. tory of polyuria led to appropriate laboratory eval- In known diabetic patients, it is important to uation and diagnosis of type 2 diabetes. establish the level of glycemic control early in the Rapid attachment loss and bone loss that are examination process. This can be done through inconsistent with local factors may indicate an physician referral or review of medical records. underlying systemic component to the patient’s Most patients who do SBGM record their glucose periodontal condition. When supported by a thor- readings for future review by their diabetes man- ough review of the medical history, clinical exami- agement team. Having the patient bring this log to nation and laboratory evaluation, a previously the dental office may provide the practitioner with undiagnosed diabetic state may be revealed. Other information regarding the patient’s overall periodontal manifestations of undiagnosed dia- glycemic control and normal blood glucose fluctu- betes include enlarged, hemorrhagic gingival tis- ations during the day. It is helpful to determine the sues and multiple periodontal abscesses (Figure patient’s most recent glycosylated hemoglobin val- 8-1 3). If the clinician suspects undiagnosed dia- ues, since this test provides a measure of glycemic betes, laboratory evaluation and physician referral control over the preceding 2 to 3 months (Table are indicated (see Table 8-6). 8-9). Comparison with past values provides infor- Previously diagnosed but poorly controlled mation on the stability of glycemic control over diabetic patients may present with oral manifesta- time. Addressing the issue of glycemic control at tions similar to the undiagnosed diabetic individ- the beginning of treatment often results in ual. The patient in Figures 8-13 and 8-14 had improved periodontal status, affording a more type 2 diabetes. Her glycemic control had wors- accurate assessment of actual treatment needs. ened considerably over the previous 12 months as Periodontal therapy, if needed, involves numerous indicated by a rise in HbAlc values from 7.7 to patient visits and regularly scheduled maintenance 13.9% in 1 year. She acknowledged poor compli- following active treatment. Thus, the dentist and ance with her oral antidiabetic medication regi- dental hygienist are in a perfect position to encour- men. In patients with suspected poorly controlled age patient compliance and control. diabetes, dental treatment should be limited ini- The patient with well-controlled diabetes with tially to provision of emergency care.34 Referral to no significant complications can generally be man- the patient’s physician should include a description aged in a fashion similar to the nondiabetic dental of intraoral findings and a brief outline of the patient, with the notable exception of the need to patient’s dental treatment needs. The dental prac- monitor for signs and symptoms of hypoglycemia titioner should request evaluation of the patient’s during treatment. Key considerations related to glycemic control and appropriate medical manage- dental treatment of the diabetic patient include ment prior to elective dental treatment. stress reduction, diet modification, inpatient versus 142 Periodontal Medicine

Local anesthetics used in conjunction with most dental procedures may contain varying concentrations of vasoconstrictors (eg, I /I 00,000 epinephrine). Use of these agents has minimal effect on blood glucose levels, probably due to their relatively slow absorption from the local site and the low concentrations and small volumes used. Profound anesthesia with such agents minimizes endogenous epinephrine release.34 Periodontal therapy often requires surgical procedures that may iesult in mild to moderate postoperative discomfort. Modification of the diabetic patient's diet may be needed as a result of Figure 8-13. Mandibular anterior teeth from lingual view. compromised chewing and swallowing that can Sixty-year-old African American female with poorly con- accompany extensive dental procedures.">' l5 trolled type 2 diabetes. Enlarged, hemorrhagic gingival tissue While many diabetic individuals are very knowl- at multiple sites. edgeable about diet and medication modifications, others are not. It may be necessary to consult the patient's diabetes management team prior to the outpatient care, antibiotic use, changes in medica- appointment for suggested liquid or semi-solid tion regimens, and appointment timing. l l5>ll' dietary alternatives. Stress reduction and adequate pain control are Most diabetic patients can be easily managed important in treating the diabetic patient. Epi- in the dental office on an outpatient basi~.~~~,~~' nephrine and cortisol secretion often increases in However, for those with very poor glycemic con- stressful situations. Both these hormones elevate trol, severe medical complications, and extensive blood glucose levels and interfere with glycemic treatment needs that will alter dietary and medica- control. Efforts to allay patient apprehension and tion regimens for extended periods of time, hospi- minimize discomfort are important and may talization may be considered. Diabetic patients include preoperative sedation and analgesia. '"J'' with severe head and neck infections should be treated in a controlled medical environment to avert possible life-threatening complications. Antibiotics are not necessary for routine dental treatment in most diabetic patients but may be considered in the presence of overt infection.34Antibi- otic coverage prior to surgical treatment should be considered in patients with poorly controlled diabetes. l l Since elective procedures are generally deferred until adequate glycemic control is achieved, this most often applies to emergency situations such as periodontal and periapical abscesses or other acute odontogenic infections. Adjunctive antibiotic therapy may also be considered in the management of periodontal disease. As previously discussed, the

TABLE 8-9. Laboratory Evaluation of Diabetes Control Glycated Hemoglobin Assay (HbAlc): 4 to 6% Normal <7% Good diabetes control 7 to 8% Moderate diabetes control Figure 8-14. Radiograph of mandibular >8% Action suggested to improve anterior teeth (severe incisor bone loss) diabetes control from patient in Figure 8-14. Diabetes Mellitus 143 use of systemic tetracycline antibiotics in conjunc- It may be impossible to plan dental appoint- tion with mechanical root dkbridement may have ments to avoid peak insulin activity. In these beneficial effects not only on the periodontium but instances, the dentist simply needs to be aware on glycemic control as well. that the patient is at risk for hypoglycemia, assess At one time, a general recommendation was the patient’s pretreatment blood glucose level made for diabetic patients to have their dental with their glucometer, and have a carbohydrate appointments in the morning. This recommenda- source readily available. Just as patients with asth- tion was also made for many other medically com- ma are encouraged to bring their inhaler to the promised patients. While morning appointments dental appointment, or patients with angina to may be preferable for some diabetic patients, oth- bring their nitroglycerine, dental practitioners ers may be better treated in the afternoon. should recommend that diabetic patients who do Appointment timing often depends on the partic- SBGM bring their glucometer to the dental office ular medication regimen used by each individual for each visit. Patients can check their blood glu- patient. When possible, it is best to plan dental cose levels at the beginning of the appointment. treatment either before or after periods of peak If glucose levels are at or near the lower end of insulin activity because hypoglycemic reactions are normal, the patient may consume some carbohy- more likely to occur when insulin levels are drates before starting treatment to avoid hypo- l6 Type 2 diabetic patients taking sulfony- glycemia during the appointment. For example, if lureas are at risk for hypoglycemia. In their case, it a long dental procedure is planned and the is prudent, when possible, to plan dental treatment patient’s pretreatment blood glucose is below 70 to avoid periods of peak drug activity. Metformin to 80mg/dL, having the patient drink 120 mL (4 and troglitazone rarely cause hypoglycemia. 02) of fruit juice may prevent hypoglycemia dur- If the patient takes insulin, the dentist should ing treatment. On the other hand, a markedly determine the exact type being used. Its onset of elevated pretreatment blood glucose (eg, greater activity and time of peak activity relative to the than 3OOmg/dL) may suggest postponement of planned dental therapy should be determined (see the procedure until metabolic control is assessed Table 8-8). The greatest risk of hypoglycemia is usu- and improved. ally during the time of peak insulin activity: 30 to In addition to determining pretreatment glu- 90 minutes after injection of lispro insulin; 2 to 4 cose levels, the dentist should determine the type hours after injection of regular insulin, or approxi- of insulin the patient takes, when it was last taken, mately 6 to 8 hours after injection of NPH or Lente and the amount taken. Next, it is important to insulin (see Figures 8-7 to 8-1 1). The primary fac- find out when the patient last ate, what they ate, tor to consider is the peak action of the insulin taken and how the last food consumption relates to the and the amount of glucose being absorbed from the normal intake at that time of day.34J15J16For gut following the last meal. A key question to con- example, if the patient took their usual dose of sider is, Will the amount and type of food eaten regular insulin in the morning before breakfast ‘match‘ the level of insulin activity?To determine the but then either failed to eat or ate a lighter break- answer, other questions must be asked. Did the fast than usual, the patient is at increased risk for patient follow his or her usual routine, eat the same hypoglycemia if the dental appointment is sched- amount and type of food, and take the same uled in the morning. Carbohydrate intake must be amount of insulin as always?Or did they skip a meal adequate to “match” plasma insulin levels or hypo- or reduce the amount of food eaten before their glycemia will result. If dental treatment requires dental appointment? These are important questions alteration in diet either before or after the to ask since any reduction in normal food con- appointment, the patient’s medication regimen sumption, if not accompanied by a reduction in may need to be changed. Patients who are on insulin dose, may place the patient at higher risk of NPO (nothing by mouth) orders before dental hypoglycemia during the dental treatment. For treatment may need to have their insulin regimen example, the patient who takes intermediate-acting altered. Sulfonylurea doses may also need adjust- insulin in the morning (see Figures 8-7 to 8-9) but ment. In these cases, physician consultation may then skips lunch before the afternoon dental be indicated. Physicians frequently recommend appointment faces a significant risk of hypo- reduction in the insulin dose that immediately glycemia. The NPH or Lente insulin will peak in the precedes lengthy or extensive procedures. Longer- early afternoon, and blood glucose levels may fall term adjustments are often made when diet mod- precipitously since the patient has not had any food. ifications will occur. 144 Periodontal Medicine

Management of Diabetic Emergencies these forms will generally elevate blood glucose within 10 to 20 minutes, with relief of symptoms. Medical emergencies related to diabetic complica- Changes in blood glucose can be confirmed by tions may occur in the dental office. For example, glucometer. If symptoms have not resolved in a macrovascular disease can lead to myocardial short period of time or the glucometer readings infarction or a cerebrovascular accident, and show persistent low blood glucose, another 15 g of nephropathy may cause renal failure. However, the carbohydrate should be given. If this does not ele- most common medical emergency in diabetic vate blood glucose, the parenteral route of treat- patients is hypoglycemia. As seen in the DCCT, ment should be considered. ‘16 hypoglycemia is a potentially grave complica- In these cases, or when the patient is sedated tion. l3>ll4 Frequent causes of hypoglycemia are ( 1) or unable to take food or drink by mouth, 25 to 30 injection of excess insulin; (2) delaying or skipping mL of 50% dextrose or I mg of glucagon can be meals or snacks while taking the usual dose of given intravenously. In the absence of intravenous insulin or oral sulfonylurea; (3) increasing exercise access, I mg of glucagon can be injected subcuta- without adjusting food intake or the dose of neously or intramuscularly at practically any loca- insulin or sulfonylurea; (4)consuming alcohol and tion of the body. Glucagon injection results in confusing signs of hypoglycemia with those of glycogenolysis in the liver, releasing glucose from alcohol intoxication; and, (5)stres~.~~Jl~Jl~ glycogen stores and rapidly increasing blood sugar Symptoms of hypoglycemia include confu- levels. The patient should recover within 5 to 15 sion, shakiness or tremors, agitation, sweating, and minutes following treatment. If not, a call for tachycardia (Table 8- 10). If unrecognized and emergency medical assistance is warranted. When untreated, hypoglycemia may lead to seizures, a patient experiences symptomatic hypoglycemia coma, and death. If a patient has symptoms of requiring emergency treatment in the dental office, hypoglycemia and brought a glucometer to the they should be monitored for approximately I hour dental appointment, they should immediately to ensure comdeteI recoverv.J Evaluation of the check the blood glucose level. Symptoms of hypo- blood glucose level by glucometer can confirm glycemia are likely to occur if the blood glucose normoglycemia. drops below 60 mg/dL but may occur in some In some cases, hyperglycemia may present patients at higher or lower threshold levels. with symptoms similar to hypoglycemia. If a glu- To treat hypoglycemia in a conscious patient, cometer is not available to accurately determine the dentist should give approximately 15 g of oral blood glucose levels and the patient has symptoms carbohydrate in a form that will be rapidly absorbed (Table 8-11). About 120 to 180 mL (4 to 6 oz) of fruit juice or soda is usually adequate TABLE 8- I I. Emergency Treatment of to relieve symptoms. Alternatively, 3 or 4 tea- Hypoglycemia spoons of table sugar or an appropriate amount of hard candy may be given. Tubes of cake icing are Establish blood glucose level with glucometer, if possible. easy to store and provide a rapid source of readily In awake patient, give 15 g of carbohydrate orally; in absorbed carbohydrate. Oral carbohydrate in the form of 120 to 180 mL (4 to 6 oz) fruit juice or sugared soda; 3 to 4 tsp table sugar; TABLE 8-10. Signs and Symptoms of hard candy; or Hy poglycemia cake frosting in tube. Confusion If patient unable to use oral route and IV is in place, Shakiness, tremors administer Agitation 25 to 30 mL 50% dextrose (D50) IV; or Anxiety 1 mg glucagon IV. Sweating If patient unable to use oral route and IV is not in Dizziness place, administer Tachycardia 1 mg glucagon subcutaneously or intrarnuscularly. Feeling of “impending doom” Monitor patient for 1 hour after recovery. Seizures Seek emergency medical assistance if patient does not Loss of consciousness respond. Diabetes Mellitus 14 5 suggestive of hypoglycemia, immediate carbohy- hypoglycemia. In what seems at first glance to be a drate intake or administration of glucose-elevating paradox, the risk for hypoglycemic emergencies medication is indicated. When in doubt, the increases as glycemic control improves and glyco- patient who is known to have diabetes and experi- sylated hemoglobin values decrease.l l3 Determin- ences shakiness, sweating, tachycardia, or agitation ing the patient's past glycosylated hemoglobin val- should be treated presumptively for hypoglycemia. ues prior to treatment not only provides an excel- If the symptoms turn out to have been caused by lent assessment of the patient's degree of metabol- hyperglycemia rather than hypoglycemia, the small ic control but may also suggest their relative risk amount of additional carbohydrate given will gen- for severe hypoglycemia. For example, the patient erally not have a significant negative effect. Con- with a recent HbAlc of 7.5% may pose a greater versely, if carbohydrate or medication to elevate risk of hypoglycemia than a patient with a recent blood glucose levels is withheld from a patient who HbAlc of 11%. is actually experiencing hypoglycemia, in the mis- With time, some diabetic patients lose their taken belief that the symptoms are being caused by ability to recognize impending hypoglycemia, a hyperglycemia, severe sequelae are possible. The phenomenon known as hypoglycemia unaware- best means of rapidly determining the true nature ness.' l8 Hypoglycemia unawareness may occur not of the emergency is measurement of capillary only in intensively treated patients but in those on blood glucose with a glucometer. conventional insulin regimens or oral agents as Hyperglycemic crisis is a far less common emer- well. While signs and symptoms of hypoglycemia gency in the dental office than is hypoglycemia. Pro- are common when blood glucose levels fall below longed hyperglycemia may result in diabetic 60 mg/dL, patients with hypoglycemia unaware- ketoacidosis in people with type I diabetes while in ness may feel completely normal at levels of 40 type 2 diabetes it may cause hyperosmolar nonke- mg/dL or lower. This places the patient at risk of totic acidosis or hyperosmolar nonacidotic dia- developing severe hypoglycemia and impairs their betes. l l' Onset of hyperglycemic emergencies occurs ability to take appropriate corrective measures. more slowly than does hypoglycemia, generally after Onset of emergencies in patients with hypo- protracted elevation of blood glucose. Hyper- glycemia unawareness may be immediate and glycemic emergencies require immediate medical without warning. Dental practitioners should evaluation and treatment. Basic life support proce- question their diabetic patients as to the frequency dures should be performed, including opening the of hypoglycemic episodes and the most common airway, administering oxygen, evaluating circula- symptoms experienced by them. tion, and monitoring vital signs. The emergency medical system should be activated and the patient transported to a hospital as soon as possible. THE DIABETIC PATIENT AND The classic signs and symptoms of hypo- THE ROADTO ORAL HEALTH glycemia may not be present immediately prior to a severe hypoglycemic reaction. The patient receiv- Ensuring oral health in patients with diabetes ing conscious sedation in conjunction with dental requires an expanded scope of medical and dental therapy may have even more difficulty recognizing knowledge. There is undoubtedly a close relation- the warning symptoms. Constant verbal and visu- ship between diabetes and periodontal disease, a al contact and assessment of the patient's subjective relationship requiring hrther study and explo- symptoms is necessary. The danger of hypo- ration. Diabetes increases the risk of periodontal glycemia may be reduced by periodic glucose mon- destruction, especially in patients whose glycemic itoring during longer dental appointments. control is poor. These same patients are most like- As part of the initial medical history, diabetic ly to report to the dental office with significant patients should be questioned about their past his- periodontal treatment needs. All diabetic patients tory of hypoglycemic episodes. In the DCCT, should have routine dental evaluation and preven- patients with a history of previous severe hypo- tive therapy. The practitioner who understands the glycemia had a 112% higher risk of having anoth- role of diabetes in the etiology of oral diseases, the er severe hypoglycemic reaction compared with potential for oral infections to influence glycemic those with no prior hi~tory.''~The strongest pre- control, the current medical therapeutic approach- dictor of severe hypoglycemia was the number of es to diabetes, and the implications of diabetes on previous hypoglycemic episodes. l4 The patient's dental care provides the patient with the best glycemic control may also relate to the risk for chances of successful treatment outcomes. 146 Periodontal Medicine

REFERENCES D, Shenvin RS, editors. Diabetes mellitus. 5th ed. Stamford, CT: Appleton & Lange; 1997. 1. National Diabetes Data Group: Diabetes in Amer- 18. Steffes Mw. Pathophysiology of renal complica- ica, 2 ed. Bethesda, MD: National Institutes of tions. In: Porte D, Shenvin RS, editors. Diabetes Health. NIH Publication No 95-1468; 1995. mellitus. 5th ed. Stamford, CT: Appleton & 2. De Sanctis RW, Dec GW. Cardiomyopathies. In: Lange; 1997. Dale DC, Federman DD, editors. Scientific 19. Klein R Retinopathy and other ocular complica- American Medicine. New York: Scientific tions in diabetes. In: Porte D, Shenvin RS, edi- American Inc.; 1995. tors. Diabetes mellitus. 5th ed. Stamford, CT: 3. Mandrup-Poulsen T. Recent advances-Diabetes. Appleton & Lange; 1997. Br Med J 1998;316:1221-5. 20. Greene DA, Feldman EL, Stevens MJ, et al. Dia- 4. Edelman SV. Type I1 diabetes mellitus. Adv Inter- betic neuropathy. In: Porte D, Shenvin RS, edi- nal Med 1998; 43:449-500. tors. Diabetes mellitus. 5th ed. Stamford, CT: 5. American Diabetes Association. Report of the Appleton & Lange; 1997. Expert Committee on the Diagnosis and Classi- 21. Iacopino AM. Diabetic periodontitis: possible fication of Diabetes Mellitus. Diabetes Care lipid-induced defect in tissue repair through 1997;20:1 183-97. alteration of macrophage phenotype and func- 6. Reaven GM. Role of insulin resistance in human tion. Oral Diseases 1995;1:214-29. disease. Diabetes 1988;37:1595-607. 22. Colwell JA, Jokl R Vascular thrombosis in diabetes. 7. Eriksson J, Franssila-KallunkiA, Ekstrand A, et al. In: Porte D, Shenvin RS, editors. Diabetes mel- Early metabolic defects in persons at increased litus. 5th ed. Stamford, CT: Appleton & Lange; risk for non-insulin-dependent diabetes melli- 1997. tus. N Engl J Med 1989; 321:337-43. 23. Brunzell JD, Chait A. Diabetic dyslipidemia: 8. Bogardus C, Lillioja S, Mott DM, et al. Relationship pathology and treatment. In: Porte D, Shenvin between degree of obesity and in vivo insulin RS, editors. Diabetes mellitus. 5th ed. Stamford, action in man. Am J Physiol 1985;248:E286-91. CT: Appleton & Lange; 1997. 9. Newman B, Selby JV, Slemenda C, et al. Concor- 24. Vlassara H. Recent progress on the biologic and dance for type 2 (non-insulin-dependent) dia- clinical significance of advanced glycosylation betes mellitus in male twins. Diabetologia end products. J Lab Clin Med 1994;124:19-30. 1987;30:763-8. 25. Brownlee M. Glycosylation and diabetic complica- 10. Ghosh S, Schork NJ. Genetic analysis of NIDDM. tions. Diabetes 1994;43:836-41. 26. Monnier VM, Glomb M, Elgawish A, Sell DR. Diabetes 1996;45:1-14. The mechanism of collagen cross-linking in dia- 11. Charles MA, Fontboune A, Thibult N, et al. Risk betes. A puzzle nearing resolution. Diabetes factors for NIDDM in white populations: Paris 1996:45(Suppl3):S67-72. Prospective Study. Diabetes 1991;40:796-9. 27. Schmidt AM, Hori 0, Brett J, et al. Cellular recep- 12. Engelgau MM, Herman WH, Smith PJ, et al. The tors for advanced glycosylation end products. epidemiology of diabetes and pregnancy in the Implications for induction of oxidant stress and cel- U.S., 1988. Diabetes Care 1995;18:1029-33. lular dyshnction in the pathogenesis of vascular 13. Dietrich ML, Dolnicek TF, Rayburn WR. Gesta- lesions. Atheroscler Thromb 1994; 14: 1521-8. tional diabetes screening in a private midwest- 28. Schmidt AM, Hori 0, Cao R, et al. RAGE. A novel ern American population. Am J Obstet Gynecol cellular receptor for advanced glycosylation end 1987;156: 1403-8. products. Diabetes 1996;45(Suppl 3):S77-80. 14. Marquette GC Klein VR, Niebyl JR. Efficacy of 29. Vlassara H, Bucala R Recent progress in advanced screening for gestational diabetes. Am J Perina- glycosylation and diabetic vascular disease: role to1 1985;2:7-14. of advanced glycosylation end product recep- 15. Magee MS, Walden CE, Benedetti TJ. Influence of tors. Diabetes 1996;45(Suppl 3):S65-6. diagnostic criteria on the incidence of gestation- 30. Esposito C, Gerlach H, Brett J, et al. Endothelial al diabetes and perinatal morbidity. JAMA receptor-mediated binding of glucose-modified 1993;269:609-15. albumin is associated with increased monolayer 16. Langer 0, Rodriguez DA, Xenakis EMJ, et al. permeability and modulation of cell surface Intensified versus conventional management of coagulant properties. J Exp Med 1992;170: gestational diabetes. Am J Obstet Gynecol 1387-407. 1994;170: 1036-47. 3 1. Kirstein M, Aston C, Hintz R, Vlassara H. Recep- 17. Steinberg D. Diabetes and atherosclerosis. In: Porte tor-specific induction of insulin-like growth fac- Diabetes Mellitus 147

tor I in human monocytes by advanced glycosy- control subjects. The role of the autonomic ner- lation end product-modified proteins. J Clin vous system. Oral Surg Oral Med Oral Pathol Invest 1992;90:43946. Oral Radiol Endod 1998;86:69-76. 32. Vlassara H, Brownlee M, Monogue K, et al. 47. Collin HL, Uusitupa M, Niskanen L, et al. Caries Cachetin/TNF and IL- 1 induced by glucose- in patients with non-insulin-dependent diabetes modified proteins: role in normal tissue remod- mellitus. Oral Surg Oral Med Oral Pathol Oral eling. Science 1988;240:1546-8. Radiol Endod 1998;85:680-5. 33. American Diabetes Association Expert Committee 48. Gusberti FA, Syed SA, Bacon G, et al. Puberty gin- on the Diagnosis and Classification of Diabetes givitis in insulin-dependent diabetic children. J Mellitus. Committee Report. Diabetes Care Periodontol 1983;54:714-20. 1997;20:1 183-97. 49. Cianciola LJ, Park BH, Bruck E, et al. Prevalence 34. Mealey BL. Impact of advances in diabetes care on of periodontal disease in insulin-dependent dia- dental treatment of the diabetic patient. Com- betes mellitus (juvenile diabetes). J Am Dent pend Contin Educ Dent 1998;19:41-58. Assoc 1982;104:653-60. 35. Tsuji I, Nakarnoto K, Hasegawa T, et al. Receiver 50. De Pommereau V, Dargent-Pare C, Robert JJ, operating characteristic analysis of fasting plasma Brion M. Periodontal status in insulin-depen- glucose, HbAlc, and fructosamine on diabetes dent diabetic adolescents. J Clin Periodontol screening. Diabetes Care 1991 ; 14: 1075-7. 1992;19:628-32. 36. American Diabetes Association. Standards of med- 51. Ervasti T, Knuuttila M, Pohjamo L, Haukipuro K. ical care for patients with diabetes mellitus. Dia- Relation between control of diabetes and gingi- betes Care 1998;2l (Suppl 1):S23-3 l. val bleeding. J Periodontol 198556:154-7. 37. American Diabetes Association. Self-monitoring of 52. Karjalainen KM, Knuuttila MLE. The onset of dia- blood glucose (consensus statement). Diabetes betes and poor metabolic control increases gin- Care 1993;16:60-5. gival bleeding in children and adolescents with 38. Thorstensson H, Flak H, Hugoson A, Olsson J. insulin-dependent diabetes mellitus. J Clin Peri- Some salivary factors in insulin-dependent dia- odontol 1996;23:1060-7. betics. Acta Odontol Scand 1989;47:175-83. 53. Papapanou PN. 1996 World Workshop in Clinical 39. Sreebny LM, Yu A, Green A, Valdini A. Xerostomia Periodontics. Periodontal diseases: epidemiolo- in diabetes mellitus. Diabetes Care 1992;15: gy. Ann Periodontol 1996;l:l-36. 900-4. 54. Emrich LJ, Shlossman M, Genco RJ. Periodontal 40. Harrison R, Bowden WH. Flow rate and organic disease in non-insulin-dependent diabetes mel- constituents of whole saliva in insulin-depen- litus. J Periodontol 1991;62:123-30. dent diabetic children and adolescents. Pediatr 55. Shlossman M, howler WC, Pettitt DJ, Genco RJ. Dent 1987;9:287-90. Type 2 diabetes mellitus and periodontal dis- 4 1. Fisher BM, Lamey PJ, Samaranayake Le et al. Car- ease. J Am Dent Assoc 1990;121:532-6. riage of Candidd species in the oral cavity in 56. Taylor GW, Burt BA, Becker ME et al. Non- diabetic patients: relationship to glycaemic con- insulin dependent diabetes mellitus and alveolar trol. J Oral Pathol 1987;16:282-4. bone loss progression over 2 years. J Periodontol 42. Phelan JA, Levin SM. A prevalence study of den- 1998;69:76-83. ture stomatitis in subjects with diabetes mellitus 57. Oliver RC, Tervonen T. Diabetes-a risk factor for or elevated plasma glucose levels. Oral Surg Oral periodontitis in adults? J Periodontol 1994;65: Med Oral Pathol 1986;62:303-5. 530-8. 43. Jones RB, McCallum RM, Kay EJ, et al. Oral 58. Seppala B, Seppala M, Ainamo J. A longitudinal health and oral health behavior in a population study on insulin-dependent diabetes mellitus of diabetic clinic attenders. Community Dent and periodontal disease. J Clin Periodontol Oral Epidemiol 1992;20:204-7. 1993;20:16 1-5. 44. Tenovuo J, Alanen Larjava H, et al. Oral health 59. Tervonen T, Oliver RC. Long-term control of dia- of patients with insulin dependent diabetes mel- betes mellitus and periodontitis. J Clin Perio- litus. Scand J Dent Res 1986;94:33846. dontol 1993;20:431-5. 45. Tavares M, DePaola Soparkar Joshipura K. 60. Christgau M, Palitzsch KD, Schmalz G, et al. Prevalence of root caries in a diabetic popula- Healing response to non-surgical periodontal tion. J Dent Res 1991;70:979-83. therapy in patients with diabetes mellitus: clini- 46. Meurman JH, Collin HL, Niskanen L, et al. Saliva cal, microbiological, and immunological results. in non-insulin-dependent diabetic patients and J Clin Periodontol 1998;25:112-24. 14 8 Periodontal Medicine

61. Tervonen T, Karjalainen K. Periodontal disease als with advanced periodontal disease and a related to diabetic status. A pilot study of the genetic predisposition to diabetes mellitus. J response to periodontal therapy in type 1 dia- Periodontol 198152: 167-73. betes. J Clin Periodontol 1997;24:505-10. 74. Oliver RC, Tervonen T, Flynn DG, Keenan KM. 62. Westfelt E, Rylander H, Blohme G, et al. The effect Enzyme activity in crevicular fluid in relation to of periodontal therapy in diabetics. Results after metabolic control of diabetes and other peri- 5 years. J Clin Periodontol 1996;23:92-100. odontal risk factors. J Periodontol 1993;64: 63. Zambon JJ, Reynolds H, Fisher JG, et al. Microbi- 358-62. ological and immunological studies of adult 75. Offenbacher S. 1996 World Workshop in Clinical periodontitis in patients with non-insulin Periodontics. Periodontal diseases: pathogenesis. dependent diabetes mellitus. J Periodontol Ann Periodontol 1996;15321-78. 1988;59:23-31. 76. Salvi GE, Collins JG, Yalda B, et al. Monocytic 64. Sastrowijoto SH, Hillemans van Steenbergen TJ, TNF-a secretion patterns in IDDM patients et al. Periodontal condition and microbiology of with periodontal diseases. J Clin Periodontol healthy and diseased periodontal pockets in type 1997;24:8-16. 1 diabetes mellitus patients. J Clin Periodontol 77. Salvi GE, Yalda B, Collins JG, et al. Inflammatory 1989;16:3 16-22 mediator response as a potential risk marker for 65. Kjellman 0. The presence of glucose in gingival periodontal diseases in insulin-dependent dia- exudate and resting saliva of subjects with betes mellitus patients. J Periodontol 1997;68: insulin-treated diabetes mellitus. Swed Dent J 127-35. 1970;63:11-9. 78. Ryan ME, Ramamurthy NS, Golub LM. Matrix 66. Ficara AJ, Levin ME Grower MF, Gamer GD. A metalloproteinases and their inhibition in peri- comparison of the glucose and protein content odontal treatment. Curr Opin Periodont 1996; of gingival crevicular fluid from diabetics and 3: 8 5-96. nondiabetics. J Periodontal Res 1975;lO:171-5. 79. Birkedal-Hansen H. Role of matrix metallopro- 67. Nishimura F, Takahashi K, Kurihara M, et al. Peri- teinases in human periodontal disease. J Peri- odontal disease as a complication of diabetes odontol 1993;64:474-84. mellitus. Ann Periodontol 1998;3:20-9. 80. Ramamurthy NS, Golub LM. Diabetes increases 68. Frantzis TG, Reeve CM, Brown AL. The ultra- collagenase activity in extracts of rat gingiva and structure of capillary basement membranes in skin. J Periodontal Res 1983;18:23-30. the attached gingiva of diabetic and non-diabet- 81. Golub LM, Lee HM, Lehrer G, et al. Minocycline ic patients with periodontal disease. J Periodon- reduces gingival collagenolytic activity during to1 1971;42:406-11. diabetes: preliminary observations and a pro- 69. Listgarten MA, Ricker FH, Laster L, et al. Vascular posed new mechanism. J Periodontal Res 1983; basement membrane lamina thickness in the normal and inflamed gingiva of diabetics and 18516-26. nondiabetics. J Periodontol 1974;45:676-84. 82. McCulloch CAG, Birek Overall C, et al. Ran- 70. Seppala B, Sorsa T, Ainamo J. Morphometric domized controlled clinical trial of doxycycline analysis of cellular and vascular changes in gin- in prevention of recurrent periodontitis in high gival connective tissue in long-term insulin- risk patients: antimicrobial activity and collage- dependent diabetes. J Periodontol 1997;68: nase inhibition. J Clin Periodontol 1990;17: 123745. 6 16-22. 71. Schmidt AM, Weidman E, Lalla E, et al. Advanced 83. Golub LM, Lee HM, Greenwald RA, et al. A glycosylation endproducts (AGES) induce oxi- matrix metalloproteinase inhibitor reduces dant stress in the gingiva: a potential mecha- bone-type collagen degradation fragments and nism underlying accelerated periodontal disease specific collagenases in gingival crevicular fluid associated with diabetes. J Periodontal Res during adult periodontitis. Inflamm Res 1997; 1996; 31:508-15. 46:310-9. 72. Manoucher-Pour M, Spagnuolo PJ, Rodman HM, 84. Bain S, Ramamurthy NS, Impeduglia T, et al. Bissada NF. Comparison of neutrophil chemo- Tetracycline prevents cancellous bone loss and tactic response in diabetic patients with mild maintains near-normal rates of bone formation and severe periodontal disease. J Periodontol in streptozotocin diabetic rats. Bone 1997;21: 1981;52:410-5. 147-53. 73. McMullen JA, van Dyke TE, Horoszewicz HU, 85. Greenwald RA, Golub LM, Ramamurthy NS, et al. Genco RJ. Neutrophil chemotaxis in individu- In vitro sensitivity of the three mammalian col- Diabetes Mellitus 149

lagenases to tetracycline inhibition: relationship Research Group. The Diabetes Control and to bone and cartilage degradation. Bone 1998; Complications Trial (DCCT): design and 22: 33-8. methodologic considerations for the feasibility 86. Caton J, Ciancio S, Crout R, et al. Adjunctive use phase. Diabetes 1986;35:530-45. of subantimicrobialdoxycycline therapy for peri- 101. Diabetes Control and Complications Trial odontitis (Abstract).J Dent Res 1998;77:1001. Research Group. The effect of intensive treat- 87. Taylor GW, Burt BA, Becker ME et al. Severe peri- ment of diabetes on the development and pro- odontitis and risk for poor glycemic control in gression of long-term complications in insulin- patients with non-insulin-dependent diabetes dependent diabetes mellitus. N Engl J Med mellitus. J Periodontol 1996;67:1085-93. 1993;329:977-86. 88. Thorstensson H, Kuylensteirna J, Hugoson A. Med- 102. Diabetes Control and Complications Trial ical status and complications in relation to peri- Research Group. Progression of retinopathy odontal disease experience in insulin-dependent with intensive versus conventional treatment in diabetics. J Clin Periodontol 1996;23:194-202. the Diabetes Control and Complications Trial. 89. Loe H. Periodontal disease. The sixth complication Ophthalmology 1995;102:647-61. of diabetes mellitus. Diabetes Care 1993;16 103. Diabetes Control and Complications Trial (Suppl 1):329-34. Research Group. Effect of intensive diabetes 90. Williams RC, Mahan CJ. Periodontal disease and management on macrovascular and microvascu- diabetes in young adults. JAMA 1960;172: lar events and risk factors in the Diabetes Con- 776-8. trol and Complications Trial. Am J Cardiol 91. Miller LS, Manwell MA, Newbold D, et al. The 1995;75:894-903. relationship between reduction in periodontal 104. American Diabetes Association Position Statement. inflammation and diabetes control: a report of 9 Implications of the Diabetes Control and Compli- cases. J Periodontol 1992;63:843-8. cations Trial. Diabetes Spectrum 1993;6:225-7. 92. Grossi SG, Skrepcinski FB, DeCaro T, et al. 105. Diabetes Control and Complications Trial Response to periodontal therapy in diabetics Research Group. Lifetime benefits and costs of and smokers. J Periodontol 1996;67:1094-102. intensive therapy as practiced in the Diabetes 93. Grossi SG, Skrepcinski FB, DeCaro T, et al. Treat- Control and Complications Trial. JAMA ment of periodontal disease in diabetics reduces 1996;276:1409-15. glycosylated hemoglobin. J Periodontol 1997; 106. Thompson CJ, Cummings JF, Chalmers J, et al. 68:713-9. How have patients reacted to the implications 94. Aldridge JC Lester V, Watts TLC et al. Single-blind of the DCCT? Diabetes Care 1996;19:876-9. studies of the effects of improved periodontal 107. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive health on metabolic control in type 1 diabetes insulin therapy prevents the progression of dia- mellitus. J Clin Periodontol 1995;22:271-5. betic microvascular complications in Japanese 95. Sammalkorpi K. Glucose intolerance in acute patients with non-insulin-dependent diabetes infections. J Intern Med 1989;225:15-9. mellitus: a randomized prospective 6-year study. 96. Yki-Jarvinen H, Sammalkorpi K, Koivisto VA, Diabetes Res Clin Pract 1995;28:103-17. Nikkila EA. Severity, duration and mechanism 108. Andersson DKG, Svardsudd K. Long-term of insulin resistance during acute infections. glycemic control relates to mortality in type I1 J Clin Endocrinol Metab 1989;69:317-23. diabetes. Diabetes Care 1995;18:1534-43. 97. Grossi SG, Genco RJ. Periodontal disease and dia- 109. Scheen AJ, Lefebvre PJ. Oral antidiabetic agents. betes mellitus: a two-way relationship. Ann A guide to selection. Drugs 1998;55:225-36. Periodontol 1998;3:51-61. 110. Wolffenbuttel BHR, Nijst L, Sels JPJE, et al. 98. Nevins ML, Karimbux NY, Weber HE et al. Effects of a new oral hypoglycaemic agent, Wound healing around endosseous implants in repaglinide, on metabolic control in sulfony- experimental diabetes. Int J Oral Maxillofac lurea-treated patients with NIDDM. Eur J Clin Implants 1998;13:620-9. Pharmacol 1993;45:1 13-6. 99. Takeshita F, Murai K, Iyama S, et al. Uncontrolled 11 1. Lebovitz HE: Oral antidiabetic agents. In: Kahn diabetes hinders bone formation around titani- CR, Weir GC, editors. Joslin’s diabetes mellitus, um implants in rat tibiae. A light and fluores- 13th ed. Malvern (PA): Lea & Febiger; 1994. cence microscopy, and image processing study. J 112. Peterson KA, Smith CK. The DCCT findings and Periodontol 1998; 69:314-20. standards of care for diabetes. Am Fam Physi- 100. Diabetes Control and Complications Trial cian 1995;2:1092-8. 15 0 Periodontal Medicine

113. Diabetes Control and Complications Trial Periodontics. Periodontal implications: medical- Research Group. Epidemiology of severe hypo- ly compromised patients. Ann Periodontol glycemia in the Diabetes Control and Compli- 1996; 1:256-32 1. cations Trial. Am J Med 1991;90:450-9. 117. Galili D, Findler M, Garfunkel AA. Oral and den- 114. Diabetes Control and Complications Trial tal complications associated with diabetes and Research Group. Hypoglycemia in the Diabetes their treatment. Compend Contin Educ Dent Control and Complications Trial. Diabetes 1994;15496-509. 1997;46:271-86. 118. Heller SR, Herbert M, MacDonald IA,Tattersall 115. Rees TD. The diabetic dental patient. Dent Clin RB. Influence of sympathetic nervous system on North Am 1994;38:447-63. hypoglycemic warning symptoms. Lancet 116. Mealey BL. 1996 World Workshop in Clinical 19 87;2: 3 59-63. CHAPTER9

PERIODONTALMEDICINE AND THE FEMALEPATIENT

Joan Otomo-Corgel, DDS, MPH Barbara J. Steinberg, DDS

Women's life cycle changes present unique chal- observed during puberty.2 Recent studies associat- lenges to the oral health care profession. Hormon- ed with puberty gingivitis indicate proportionately al influences associated with the reproductive elevated motile rods, spirochetes, and Prevotellu process alter periodontal and oral-tissue responses intermediu. Statistically significant increases in to local factors creating diagnostic and therapeutic gingival inflammation and in the proportion of dilemmas. It is imperative, therefore, that the clin- Prevotellu intermediu and Prevotelh nigrescens were ician recognize, customize, and vary periodontal seen in puberty gingi~itis.~ therapy according to the individual female and the Clinically, during puberty, there may be a stage of her life cycle. nodular hyperplastic reaction of the gingiva in areas This chapter will deal with phases of the where food debris, materia alba, plaque, and calcu- female life cycle during the reproductive years: lus are deposited. The inflamed tissues are erythe- puberty, menses, and pregnancy. Oral contracep- matous and may be lobulated and retractable (Fig- tives, periodontal manifestations, systemic effects, ure 9-1). Bleeding may occur with brushing or and clinical management will also be discussed. mastication. Histologically, the appearance is consistent with inflammatory hyperplasia.

PUBERTY Managemen t

Periodontal Manifestations Preventive care, including a vigorous program of oral hygiene, is vital. Milder gingivitis cases During puberty, the female experiences an increase respond well to scaling and root planing with fre- in the production of sex hormones (estrogen and quent oral hygiene instruction^.^ Severe cases of progesterone) that remains relatively constant fol- gingivitis may require microbial culturing, antimi- lowing puberty throughout the normal female life- crobial mouthwashes and local site delivery, or time reproductive phase. There is also an increase in the prevalence of gingivitis without an increase in the amount of plaque.' Gram-negative anaerobes, especially Prevotellu intermediu, have been implicated in association with puberty gingivitis. Kornman and Loesche postulated that this anaerobic organism may use ovarian hormone as a substitute for vitamin K growth factor.' Delaney and Kornman suggest that levels of black-pigmented bacteroides, especially Bucteroides intermedius, increase with increased levels of gonadotrophic hormones in puberty. Cupno- cytophugu species also increase in incidence as well as in proportion. These organisms have been implicated in the increased bleeding tendency Figure 9-1. Puberty gingivitis. 15 2 Periodontal Medicine antibiotic therapy. Supportive periodontal therapy progesterone to prepare the uterus for implanta- visits may need increased frequency. Whenever tion of the egg. There are two phases of the month- possible, involvement of a parent or caregiver with ly reproductive cycle. During the follicular phase I, home care procedures is recommended. estrogen causes cellular proliferation of the stroma cells, blood vessels, and glands of the endometri- Eating Disorders um. Phase I1 is called the luteal phase. Note that estrogen peaks to 0.2 ng/mL and progesterone to This age group also is susceptible to eating disor- 10.0 ng/mL to complete the rebuilding of the ders, bulimia nervosa, and anorexia nervosa. The endometrium for fertilized egg implantation. The clinician should recognize the intraoral effects of corpus luteum involutes, ovarian hormone levels chronic regurgitation of gastric contents on intrao- drop, and menstruation ensues. ral tissues. Perimylolysis, or smooth erosion of the The concept that ovarian hormones may enamel and dentin, typically on the lingual surfaces increase inflammation in gingival tissues and exag- of maxillary anterior teeth, varies with the duration gerate the response to local irritants has been pos- and frequency of the behavior.' Also, parotid gland tulated by several studies. Gingival inflammation enlargement (occasionally, sublingual glands) has seems to be aggravated by an imbalance and/or been estimated at between 10 to 50 percent in the increase in sex hormones.'-' patient who binges and purges.' Therefore, there Progesterone has been associated with increased may also be a diminished salivary flow rate, which permeability of the microvasculature, altering the will increase oral mucous membrane sensitivity and rate and pattern of collagen production in the gin- gingival erythema. One should also rule out other giva;' increasing folate metaboli~m,~>'~and altering etiologies that alter salivary flow, that is, systemic the immune response. During menses, proges- conditions or medications. terone increases from the second week, peaks at approximately 10 days, and dramatically drops prior to menstruation. (Note that this is based on a MENSES 28-day cycle and individual cycles are variable.) Progesterone plays a role in stimulating the produc- Periodontal Manifestations tion of prostaglandins that mediate the body's response to inflammation. Prostaglandin E2 (PGE2) During the reproductive years, there are ongoing is one of the major secretory products of monocytes changes in the concentration of the gonadotrophins and is higher in inflamed gingiva." Miyagi and col- and ovarian hormones during the monthly men- leagues found that the chemotaxis of polymor- strual cycle (Figure 9-2). Estrogen and proges- phonuclear leukocytes (PMNs) was enhanced by terone are steroid hormones produced by the progesterone, whereas it was reduced by estradiol.l1 ovaries during the menstrual cycle. The gonado- Testosterone did not have a measurable effect on trophins follicle-stimulating hormone (FSH) and PMN chemotaxis. They suggested that the altered luteinizing hormone (LH) influence estrogen and PMN chemotaxis associated with gingival inflammation may be due to the effects of sex hormones. Gingival tissues have been reported to be more edematous and erythematous preceding the onset of menses in some individuals. In addition, an increase of gingival exudate has been observed during the menstrual period and is sometimes associated with a minor increase in tooth mobility.12 Intraoral recurrent aphthous ulcers,13 herpes labialis lesions, and Candidae infections occur in some women as a cyclic pattern associated with the luteal phase of their cycle when progesterone is the highest. Because the esophageal sphincter is relaxed by progesterone, women may be more susceptible to gastroesophageal reflux disease (GERD) during Figure 9-2. Female reproductive cycle. Note peak of progres- this time of the cycle as well. Symptoms of GERD terone and estrogen to follicle-stimulating hormone (FSH) include heartburn, regurgitation, and chest pain; and luteinizing hormone (LH). when reflux is severe, some people will develop Periodontal Medicine and the Female Patient 15 3 unexplained coughing, hoarseness, sore throat, I O most-prescribed medications in the United gingivitis, or asthma. States in the late 1990s. The clinician should be During the peak level of progesterone (about aware that patients on fluoxetine will have increased 7 to 10 days prior to menstruation), premenstrual side effects with highly protein-bound drugs (eg, syndrome (PMS) also occurs. There appears to be aspirin) and the half-life of diazepam and other no significant differences in estrogen and proges- central nervous system (CNS) depressants will be terone levels between women who suffer from increased. Other common selective serotonin reup- PMS and women who do not. Yet, women with take inhibitors are sertraline and peroxetine. PMS seem to have lower levels of certain neuro- The PMS patient may be difficult to treat due transmitters such as enkephalins, endorphins, y- to emotional and physiologic sensitivity. Treat the aminobutyric acid (GABA) and serotonin. gingival and oral mucosal tissues gently. Moisten Depression, irritability, mood swings, and diffi- gauzes or cotton rolls with a lubricant, chlorhexi- culty with memory and concentration may be dine rinse, or water before placing them in the symptoms of neurotransmitter reduction. aphthous prone patient. Carehl retraction of the oral mucosa, cheeks, and lips will be necessary in Management both the aphthous and herpetic prone patient. Since the hypoglycemic threshold is elevated, For the women who have increased gingival bleed- advise the patient to have a light snack prior to her ing and tenderness associated with the menstrual appointment. Note that 70 percent of menstruat- cycle, adherence to 3 to 4-month supportive peri- ing women have PMS symptoms, but only 5 per- odontal therapy appointments is recommended. cent meet the strict diagnostic criteria. Antimicrobial mouthrinses prior to cyclic inflammation may be indicated. Particular emphasis should be placed on oral hygiene. PREGNANCY During PMS, physical symptoms may include fatigue, sweet and salty food cravings, abdominal Pregnancy provides unique diagnostic and treat- bloating, swollen hands or feet, headaches, breast ment challenges to the periodontal clinician. It is tenderness, and nausea or gastrointestinal upset. l4 an opportunity to individualize care at a time Gastroesophageal reflux disease may make it more when the patient may experience the most pro- uncomfortable for the patient to lay hlly supine, found physiologic and psychologic changes in her especially within the hours immediately after con- life. Awareness exists regarding pregnancy and its sumption of a meal. Care should be taken during effect on periodontal disease; however, recent evi- dental treatment to prevent stimulating the more dence indicates an inverse relationship to systemic sensitive gag reflex. The clinician should be aware disease. Current research implies that periodontal that nonsteroidal anti-inflammatory medication, disease may alter the systemic health of the patient infection, and acidic foods exacerbate GERD. as well as adversely effect the well-being of the Patients taking over-the-counter antacids, H2 fetus by elevating the risk of low-birth-weight, receptor antagonists (cimetidine, famotidine, niza- preterm infants. tidine, and ranitidine), prokinetic agents (cisapride and metclopramide), and proton pump inhibitors Periodontal Manifestations (lansoprazole and omeprazole) may be GERD candidates. l5 The aforementioned medications have Periodontal Diseases interactions with some antibiotics and antifungal In 1877, Pinard recorded the first case of “preg- medications, therefore, review of the pharmacolo- nancy gingivitis.”16 Only recently has periodontal gy is necessary if they are used in periodontal ther- research began to focus on causative mechanisms. apy. Fluoride rinses and/or trays, frequent peri- Pregnancy gingivitis is extremely common, occur- odontal dkbridement, and avoidance of mouth- ring in approximately 30 to 75 percent of all preg- washes with high alcohol content may reduce the nant women.17-19 It is characterized by erythema, associated gingival and caries sequelae. edema, hyperplasia, and increased bleeding. Histo- It is common for physicians to treat PMS by logically, the description is the same as gingivitis. increasing the levels of deficient neurotransmitters. The etiologic factors, however, are different despite Alprazolam mimics GABA. Fluoxetine increases clinical and histologic similarities. Cases range the amount of serotonin in the circulation and has from mild inflammation (Figure 9-3) to severe a reported 70 percent response rate. It is one of the hyperplasia, pain, and bleeding (Figure 9-4). 15 4 Periodontal Medicine

Figure 9-3. Mild to moderate pregnancy gingivitis.

Alterations in immunocompetency during preg- Pyogenic granulomas occur during pregnancy nancy may create an exaggerated response in peri- at a prevalence of 0.2 to 9.6 percent. The “preg- odontal supporting structures (Figure 9-5). Peri- nancy tumor” or “pregnancy epulis” are clinically odontal status prior to pregnancy may influence and histologically indistinguishable from pyogenic the progression or severity as the circulating hor- granulomas occurring in women who are not preg- mones fluctuate. The anterior region of the mouth nant or in men. They appear most commonly dur- is more commonly affected, and interproximal ing the second or third month of pregnancy. The sites tend to be most involved.20 Increased tissue gingiva is the most common site involved (approx- edema may lead to increased pocket depths and imately 70% of all cases), followed by tongue and relate to a transient tooth mobility21 Anterior site lips, buccal mucosa, and palate.22 inflammation may be exacerbated by increased Clinically, pregnancy tumors appear to be mouthbreathing, primarily in the third trimester tumorlike growths that generally appear on the from “pregnancy rhini tis. ” interdental papillae of maxillary anterior teeth.

Figure 9-4. Severe pregnancy gingivitis with hyperplasia in a patient with non-insulin-dependent diabetes mellitus in poor control. Periodontal Medicine and the Female Patient 155

They usually grow rapidly, bleed easily, and of localized inflammation by down-regulation of become hyperplastic and nodular. They may be IL-6 production, rendering the gingiva less effi- sessile or pedunculated and may be ulcerated. cient at resisting the inflammatory challenges pro- Color ranges from purplish red to deep blue, duced by the bacteria.31 depending on the vascularity of the lesion and the Also, ovarian hormone stimulates the produc- degree of venous stasis. The lesion classically occurs tion of prostaglandins, mediators of the inflammato- in an area of gingivitis and is associated with poor ry response. With the prostaglandin acting as an oral hygiene. Often calculus is present. Osseous immunosuppressant, gingival inflammation may destruction is not usually associated with pyogenic increase when the mediator level is high.32,33Kinnby granulomas of pregnancy. and colleagues found that high progesterone during pregnancy influenced plasminogen activator Etiologic Factors inhibitor type 2 (PAI-2)and disturbed the balance of Despite the clinical/histologic diagnoses of gin- the fibrinolytic system.34Because PAI-2serves as an givitis or pyogenic granuloma, a variety of other etiologic factors contribute to these periodontal conditions during pregnancy (Table 9-1). Alter- ations in the composition of subgingival plaque, maternal immunoresponsiveness, and sex hormone concentrations create a myriad of responses in the periodontium. Subgingival Plaque Composition. There is an alteration in the composition of subgingival plaque during pregnancy. Kornman and Loesche found that during the second trimester there was an increase in gingivitis and gingival bleeding without an increase in plaque levels.23 Bacterial anaerobic-to-aerobic ratios increased, as well as Bucteroides mehninogenicus, and Prevotelh intermedid proportions (2.2 to 10.1Yo) . There was also an increase in Porphyromonus gingivulis. These authors suggested that estradiol or progesterone can substitute for menadione (vitamin K) as an essential growth factor for I! intermedid but not I! gingivulis or Bucteroides coherences. Maternal Immunoresponse. Recent studies support alteration of immunocomponents during pregnancy. These changes in maternal immunoresponsiveness suggest increased susceptibility to gingival inflammation. In one study, gingival index was higher, but percentages of T3, T4, and B cells appear to decrease in peripheral blood and gingival tissues during pregnancy as compared to a control group.24 Other studies report decreased neutrophil chemotaxis, depression of cell-mediated immunity and phagocytosis as well as a decreased T-cell response with elevated levels of ovarian hormone, especially pr~gesterone.~~A decrease in in vitro responses of peripheral blood lymphocytes to several bacterial antigens has been reported26-28and there is evidence for a decrease in the absolute numbers of CD4-positive cells in peripheral blood during pregnancy as compared to the number of these cells post part~m.~~.~'La PP and colleagues suggest that high levels of proges- Figure 9-5. Pregnant (5l/2 months) patient with severe terone duringUL pregnancy U affect the development hyperplasia and acute monocytic leukemia. 15 6 Periodontal Medicine important inhibitor of tissue proteolysis, the research Sex Hormone Concentration. During preg- by Kinnby and colleagues implies that components nancy, progesterone reaches levels of 100 ng/mL, 10 of the fibrinolytic system may be involved in the times the peak luteal phase of menses. Estradiol in development of pregnancy gingivitis. the plasma may be 30 times higher than that during the reproductive cycle. Estrogens and progesterones have different roles. Estrogen may regulate cellular proliferation, differentiation, and keratinization, TABLE 9- I. Etiology of Gingival Responses while progesterone influences the permeability of to Elevated Estrogen and Progesterone the microva~culature,~~>~~alters the rate and pattern during Pregnancy of collagen production, and increases the metabolic Subgingival Plaque Composition breakdown of folate (necessary for tissue mainte- Anaerobic-to-aerobic ratio increases nan~e).~~A high concentration of sex hormones in Higher concentrations of Prevotela intermedia gingival tissues, saliva, serum, and crevicular fluid (substitutes sex hormone for vitamin K growth may exaggerate the response as well. Vittek and col- factor) leagues have demonstrated specific estrogen and Higher concentrations of Bacteroides mehninogenicus progesterone receptors in gingival tissues.38This is Higher concentrations of Porpbyromonas gingivalis direct biochemical evidence that this tissue may Maternal Immunoresponse hnction as a target organ for sex hormones. Mura- Depression of cell-mediated immunity matsu and Takaesu found increasing concentration Decreased neutrophil chemotaxis of sex hormones in saliva from the first month of Depression of antibody and T cell responses gestation, peaking in the ninth month along with Decrease in the ratio of peripheral T helper cells increasing percentages of Prevotelh intermediu.With to T suppressor-cytotoxic cells (CD4/CD8 ratio) increasing depth, the number of gingival sites with Cytotoxicity directed against macrophages and p cells bleeding and redness increased until I month post may result in diminished immunoresponsiveness part~m.~~There is also evidence of sex hormone Decrease in absolute numbers of CD3-, CD4- and concentration in crevicular fluid, providing a CD 19-positive cells in peripheral blood during growth media for periodontal pathogens. pregnancy versus post partum Periodontal Disease and Preterm Low-Birth- Stimulation of prostaglandin production weight Births. Due to the pioneering research of Sex Hormone Concentration Offenbacher and co-workers, evidence exists that Estrogen untreated periodontal disease in pregnant women Increases cellular proliferation in blood vessels may be a significant risk factor for preterm (< 37 weeks) low-birth-weight (< 2,500 g) babies.40The (known in the endometrium) relationship with genito-urinary tract infection Decreases keratinization while increasing and preterm low birth weight (PLBW) is well doc- epithelia1 glycogen umented in human and animal studies. Periodon- Specific receptors are found in gingival tissues tal researchers suspecting periodontal disease as Progesterone another source of infection found that mothers of Increases vascular dilation and thus increases low-birth-weight infants, otherwise having low permeability (results in edema and accumula- risk, had significantly more periodontal attachment tion of inflammatory cells) loss than control mothers having normal-weight Increases proliferation of newly formed capillaries infants at birth. The current opinion is that PLBW in gingival tissues (increased bleeding tendency) occurs as a result of infection and is mediated indi- Alters rate and pattern of collagen production rectly, principally by the translocation of bacterial Increases metabolic breakdown of folate products such as endotoxin (lipopolysaccharide (a deficiency can inhibit tissue repair) [LPS]) and by the action of maternally produced Specific receptors are found in gingival tissues inflammatory mediat01-s.~~Biologically active mol- Decreases plasminogen activator inhibitor factor ecules such as prostaglandin E2 (PGE2) and tumor type 2 and thus increases tissue proteolysis necrosis factor (TNF), which are involved in nor- Estrogen and Progesterone mal parturition, are raised to artificially high levels Affect ground substance of connective tissue by by the infection process, which may foster prema- increasing fluidity ture lab~r.~~Gram-negative bacteria in periodontal Concentrations increase in saliva and fluid diseases, therefore, may permit selective over- with increased concentrations in serum growth or invasion of gram-negative bacteria with- Periodontal Medicine and the Female Patient 15 7 in the genito-urinary tract. Recently, gingival ous miscarriages, recent cramping, spotting, or per- crevicular fluid levels of PGE2 were positively asso- nicious vomiting. If possible, the next step is to con- ciated with intra-amniotic PGE2 levels, suggesting tact the obstetrician to discuss the patient’s medical that gram-negative periodontal infection may pre- status, dental needs, and proposed treatment plan. sent a systemic challenge sufficient to initiate the The most important objectives in planning onset of premature labor as a source of LPS and/or dental treatment for the pregnant patient are to through stimulation of secondary inflammatory establish a healthy oral environment and to obtain mediators such as PGE2 and interleukin-1 beta optimum oral hygiene levels. These are achieved by (IL- 1p) .43 There is ongoing research supporting the means of a good preventive dental program, consist- association of periodontal disease and PLBW.44>45 ing of nutritional counseling and rigorous plaque Offenbacher has recently published data suggesting control measures in the dental office and at home. a dose-response relationship for increasing gingival crevicular fluid PGE2 as a marker of current perio- Preventive program dontal disease activity and decreasing birth weight. Nutrition. The quality of the diet affects caries Four organisms associated with mature plaque and formation and pregnancy gingivitis. Diet is also progressing per io don t it is (Bucteroidesfo rsythus, POr- important for the developing dentition in the phyromonus gingivulis, Actinobucillus uctinomycetem- fetus. Pregnant patients normally receive nutrition- comituns, and Seponemu denticoh) were detected at al guidance from their obstetricians, which may be higher levels in PLBW mothers, as compared to re-inforced by the dental team. It is imperative that normal birth weight control^.^' Further longitudi- the mother’s diet supplies sufficient levels of need- nal studies and intervention trials are needed to ed nutrients, including vitamins A, C, and D, pro- clarify the relationship between periodontal infec- tein, calcium, and phosphorus (Table 9-2 ). tion and PLBW. Patients should select nutritious snacks, but because so many foods contain sugars and starches Other Oral Manifestations of Pregnancy that can contribute to caries development, it is Perimylolysis or acid erosion of teeth may occur if advisable to limit the number of times they snack “morning sickness” or esophageal reflux is severe between meals. and involves repeated vomiting of gastric contents. Plaque Control. The pregnant patient should Severe reflux may cause scarring of the esophageal be provided with a comprehensive plaque control sphincter, and the patient may become a more like- program to minimize the exaggerated inflammato- ly candidate for GERD later in life. ry response of the gingival tissues. The heightened Xerostomia is a frequent complaint among tendency for gingival inflammation may be clearly pregnant women. One study found this persistent explained to the patient so that acceptable oral dryness in 44 percent of pregnant participant^.^' hygiene techniques may be taught, re-inforced, and A rare finding in pregnancy is ptyalism, or sial- monitored throughout pregnancy. Scaling, polish- orrhea. This excessive secretion of saliva usually ing, and root planing may be performed whenever begins at 2 to 3 weeks of gestation and may abate necessary throughout the pregnancy. Some practi- at the end of the first trimester. While its etiology tioners avoid the use of high-alcohol-content has not been identified, ptyalism may result from antimicrobial mouthrinses in pregnant women and the inability of nauseated gravid women to swallow prefer to use non-alcohol-based mouthrinses. normal amounts of saliva rather than from a true increase in the production of saliva.48 Because pregnancy places the woman in an immunocompromised state, the clinician must be aware of the total health of the patient (see Figure 9-4). Gestational diabetes, leukemia, and other medical conditions may appear during pregnancy.

Manage ment

The periodontal evaluation of the pregnant patient begins with a thorough medical history. This history should note any complications the patient has encountered in the pregnancy and record any previ- Figure 9-6. Pregnancy tumor. 15 8 Periodontal Medicine

Prenatal Fluoride. The prescribing of prenatal position as well. The American Academy of Pedi- fluoride supplements has been an area of controver- atrics has no stated position on prescribing prena- sy for quite some time. Although two studies have tal fluorides. claimed beneficial result~,4~>~~others suggest that the Baby-Bottle Tooth Decay. When discussing clinical efficacy of prenatal fluoride supplements is preventive oral health with the patient, it is advisable uncertain and that the mechanism by which prena- to mention the condition known as baby-bottle tal fluorides might impart cariostasis is unclear.51 tooth decay (BBTD) for the benefit of the mother The American Dental Association (ADA) does and other caregivers. Baby-bottle tooth decay is an not recommend the use of prenatal fluoride, because easily preventable condition affecting primary teeth. its efficacy has not been demonstrated. The Amer- It is caused by frequent and prolonged exposure of ican Academy of Pediatric Dentistry supports this the primary teeth to fluids containing sugars, such as milk, formula, fruit juice, and other sweetened liquids provided in baby bottles. TABLE 9-2. Guidelines for Daily Food Choices for Pregnant Women Treatment

Breads, cereals, and other whole-grain and enriched Elective Dental Treatment products It is prudent to avoid elective dental care other 1 slice bread than good plaque control during the first trimester 1/z hamburger bun or English muffin and the last half of the third trimester if possible. 34small or 2 large crackers The first trimester is the period of organogenesis, 1/z cup cooked cereal, pasta, or rice when the fetus is highly susceptible to environ- 1 oz ready-to-eat cereal mental influences. In the last half of the third Fruits trimester, there is a hazard of premature delivery 2-4 servings (include at least one citrus fruit or juice) because the uterus is very sensitive to external stim- 3/4 cup juice uli. Prolonged chair time may need to be avoided 1 medium apple, banana, or other fruit because the woman is most uncomfortable at this 1/z cup fresh, cooked, or canned fruit time. Further, there is a possibility that supine Vegetables hypotensive syndrome may occur. In a semi-reclin- 3-5 servings (include at least two servings of dark ing or supine position, the great vessels, particular- green lea@, yellow, or orange vegetables) ly the inferior vena cava, are compressed by the gravid uterus. By interfering with venous return, 1/z cup cooked or chopped raw vegetables 1 cup leafjr raw vegetables this compression will cause maternal hypotension, decreased cardiac output, and eventual loss of con- Meat, poultry, fish, and alternates sciousness. Supine hypotensive syndrome can usu- 2-3 servings ally be reversed by turning the patient on her left Total of 6-7 oz cooked lean meat, poultry, fish, or side, thereby removing pressure on the vena cava other protein sources daily and allowing blood to return from the lower 1 oz = 1 egg extremities and pelvic area. 1/z cup cooked beans The second trimester is the safest period for 2 tablespoons peanut butter providing routine dental care. The emphasis at this Milk, cheese, and yogurt time is on controlling active disease and eliminating 4 servings potential problems that could arise in late pregnan- 1 cup milk cy. Extensive reconstruction procedures and major 1 cup buttermilk oral or periodontal surgery should be postponed 8 oz yogurt until after delivery. Pregnancy tumors that are 1/z oz Natural cheese painful, interfere with mastication, or continue to 2 oz processed cheese bleed or suppurate after mechanical dkbridement Fats, sweets, and alcohol may require excision and biopsy prior to delivery. Limited fadsweets Emergency Dental Treatment Avoid alcoholic beverages Dental emergencies should be dealt with as they Adapted from United States Department of Agriculture arise throughout the entire pregnancy to manage Home & Garden Bulletin No.232-8 pain and treat infection that otherwise could result Periodontal Medicine and the Female Patient 15 9 in increased stress for the mother and endanger- of drugs presented here are considered to be gener- ment of the fetus. Emergency treatment calling for al guideline^.^^ Obviously, drugs in categories A or general anesthesia necessitates consultation with B are preferable for prescribing. However, many the patient’s obstetrician, as does any uncertainty drugs that fall into category C are sometimes about prescribing medication or pursuing a partic- administered during pregnancy. These drugs pre- ular course of treatment. sent the greatest challenge to the dentist and physician in terms of therapeutics and medicolegal deci- Dental Radiographs sions. It should be recognized that physicians may Dental radiography is one of the more controver- advise against the use of some of the approved sial areas in the management of a pregnant patient. drugs or conversely may suggest the use of ques- It is most desirable not to have any irradiation dur- tionable drugs. An example of the occasional use of ing pregnancy, especially during the first trimester, a questionable drug would be a narcotic for a because the developing fetus is particularly suscep- patient in severe pain. Consulting the patient’s tible to radiation damage.52However, the safety of physician may be advisable prior to prescribing any dental radiography has been well established, pro- medications during pregnancy. vided features such as high-speed film, filtration, collimation, and lead aprons are used. Of all aids, the most important for the patient is the protective TABLE 9-3. Food and Drug Administration lead apron. Studies have shown that when an Classification System* apron is used during contemporary dental radiography, gonadal and fetal radiation is virtually A Controlled studies in women fail to demonstrate ~nmeasurable.~~ a risk to the fetus in the first trimester (and there Even in light of the obvious safety of dental is no evidence of a risk in later trimesters), and radiography, radiographs should be used selective- the possibility of fetal harm appears remote. ly during pregnancy and only when necessary and B Either animal reproduction studies have not appropriate to aid in diagnosis and treatment. In demonstrated a fetal risk and there are no con- most instances, only bite-wing, panoramic, or trolled studies in pregnant women, or animal selected periapical films are indicated. reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not Medications confirmed in controlled studies in women in the Another area of controversy involves drug therapy first trimester (and there is no evidence of a risk in because drugs given to a pregnant woman can later trimesters). affect the fetus by diffusion across the placenta. A C Either studies in animals have revealed adverse conservative approach is prudent, the dentist pre- effects on the fetus (teratogenic or embryocidal, scribing only the minimum effective dose and or other) and there are not controlled studies in duration absolutely essential for the pregnant women, or studies in women and animals are not patient’s well-being and only after careful consider- available. Drugs should be given only if the poten- ation of potential side effects. The dentist may tial benefit justifies the potential risk to the fetus. need to be familiar with the classification system D There is positive evidence of human fetal risk, established by the Food and Drug Administration but the benefits from use in pregnant women (FDA) in 1979 to rate fetal risk levels associated may be acceptable despite the risk (eg, if the drug with many prescription drugs (Table 9-3). The is needed in a life-threatening situation or for a prudent practitioner should consult references serious disease for which safer drugs cannot be such as Briggs and colleagues’ Drugs in Pregnuncy used or are ineffective). und Lu~tution~~or Drug Fucts und Comp~risons~~ X Studies in animals or human beings have demon- for information on the FDA pregnancy risk factor strated fetal abnormalities or there is evidence of associated with prescription drugs. Ideally, no drug fetal risk based on human experience, or both, should be administered during pregnancy, especial- and the risk of the use of the drug in pregnant ly the first trimester.52 However, it is sometimes women clearly outweighs any possible benefit. impossible to adhere to this rule. It is, therefore, The drug is contra-indicated in women who are fortunate that most of the commonly used drugs in dental practice can be given during pregnancy with or may become pregnant. relative safety although there are a few important *The five-category system used to classify drugs based on exceptions (Tables 94a, 94b, 94c). The tables their potential for causing birth defects. 160 Periodontal Medicine

In periodontal therapy, the use of antimicro- both mother and fetus. Antibiotics with systemic bial agents is common. During pregnancy, the effects cross the placenta and reach the fetus. The clinician must weigh the benefits and the risks to effect of a particular medication on the fetus

TAB LE 9-4a. Local Anest het ic/Analgesic Administration d uri ng Pregnancy Drug FDA Categoy (Prescription Drug) During Prepancy Local Anesthetics * Lidocaine Yes Mepivacaine Use with caution; consult physician Prilocaine Yes Bupivacaine Use with caution; consult physician Etidocaine Yes Procaine Use with caution; consult physician Analgesics Aspirin C/D 3rd trimester Caution; avoid in 3rd trimester Acetaminophen B Yes Ibuprofen B/D 3rd trimester Caution; avoid in 3rd trimester Codeine C Use with caution; consult physician Hydrocodone B Use with caution; consult physician Oxycodone B Use with caution; consult physician Propoxyphene C Use with caution; consult physician

*Can use vasoconstrictors if necessary. Avoid prolonged use.

TABLE 9-4b. Antibiotic Administration during Pregnancy FDA Categoy During Drug (Prescription Drug) Prepancy Risks Penicillins B Yes Diarrhea Erythromycin B Yes; avoid estolate form Intrahepatic jaundice in mother Clindamycin B Yes (with caution) Drug concentrated in fetal bone, spleen, lung, and liver Cephalosporins B Yes Limited information Tetracycline D Avoid Depression of bone growth, enamel hypoplasia, grey-brown tooth discoloration Ciprofloxacin C Avoid Possible developing cartilage erosion Metronidazole B Avoid (controversial) Theoretical carcinogenic data in animals Gentamicin C Caution; consult physician Limited information; ototoxicity Vanocomycin C Caution; consult physician Limited information Clarithromycin D Avoid; use only if the Limited information; adverse effects on potential benefit justifies pregnancy, outcome, and embryofetal the risk to the fetus development in animals

TABLE 9-4c. Sedative-Hypnotic Drug Administration during Pregnancy Drug FDA Categoy During Pregnancy Benzodiazepines D Avoid Barbiturates D Avoid Nitrous oxide Not assigned Avoid in 1st trimester; otherwise use with caution; consult physician Periodontal Medicine and the Female Patient 16 1 depends on the type of antimicrobial, the dosage, Prostaglandin E is a potent mediator of inflamma- the trimester, and the duration of the course of ti01.1.~~ Jensen and colleagues found dramatic therapy.57At this date, there is inadequate research microbial changes in pregnant and OC user groups in relation to subgingival irrigation and local site as compared with a nonpregnant A 16- delivery in relation to the developing fetus. fold increase in Bdcteroides species was noted in the OC user group versus the nonpregnant group Dental Drugs During Breast-Feeding despite the lack of statistically significant clinical Another perplexing problem for the dentist arises differences in gingival index or crevicular fluid flow. when a nursing mother requires a drug during den- The researchers state that the increased female sex tal treatment. There is a risk that the drug can enter hormones substituting for the napthaquinone the breast milk and be transferred to the nursing requirement of certain Bdcteroides species were most infant, in whom exposure could have adverse effects. likely responsible for this increase in Bdcteroides. Unfortunately, there is little conclusive information There have been reports that the oral contra- about drug dosage and effects via breast milk. How- ceptive-associated gingival inflammation may ever, retrospective clinical studies and empirical become chronic (as opposed to the acute inflam- observations coupled with known pharmacologic mation of pregnancy) due to the extended periods pathways allow recommendations to be made.52 of time women are exposed to elevated levels of The amount of drug excreted in breast milk is usu- estrogen and proge~terone.~~>~~Some have report- ally not more than I to 2 percent of the maternal ed that the inflammation increases with prolonged dose; therefore, it is highly unlikely that most drugs use of OCs. Kalkwarf did not find that duration of have any pharmacologic significance for the use made a significant difference, however, the infant.58>59Tables 9-5a and 9-5b compile recom- “brand of OC caused different responses. Further mendations regarding administration of common- studies need to be performed in relation to dosage, ly used dental drugs during breast-feeding. These duration, and type of OC used in association with recommendations are general guidelines only. As the periodontium. One should note that the con- with drug use in pregnancy, individual physicians centration of female sex hormones in OCs of the may wish to modifi- these suggestions. 2000s will be significantly less than in those of the In addition to choosing drugs carefully, it is 1970s, yet the OCs of the 2000s will have the same desirable for the mother to take the drug just after level of contraceptive efficacy. breast-feeding and then to avoid nursing for 4 Other intraoral effects of oral contraceptives hours or more if po~sible.~~,~~This markedly are changes in salivary composition. A decreased decreases the drug concentration in breast milk. concentration of protein, sialic acid, hexosamine hcose, hydrogen ions, and total electrolytes has been reported. Salivary flow rates have been report- ORAL CONTRACEPTIVES ed to be increased in one and decreased in 30 percent of subjects in another study.68 ( Note Periodontal Manifestations that these studies were conducted in the 1970s.) The dental literature reports that women tak- Because oral contraceptive (OC) use mimics hor- ing oral contraceptives experience a twofold to monal levels of pregnancy, clinical manifestations threefold increase in the incidence of localized are similar. Gingival tissues may have an exaggerat- osteitis following extraction of mandibular third ed response to local irritants. Inflammation ranges molars.69 The higher incidence of osteitis in these from mild edema and erythema to severe inflam- patients may be attributed to the effects of OCs mation with hemorrhagic or hyperplastic gingival (estrogens) on clotting factors. There are, however, tissues. It has been reported that there is more exu- a number of studies that refute these findings.70 date in inflamed gingival tissues of OC users than Evidence at this date is inconclusive with regard to in those of pregnant osteitis following third molar extractions and the Investigators have reported several mechanisms use of OCs. for the heightened response in gingival tissues. Also, it has been reported in the medical liter- Kalkwarf reported that the response may be due to ature that there may be a spotty melanotic pig- alteration of the microvasculature, increased gingi- mentation of the skin with the use of OCs. This val permeability, and increasing synthesis of suggests a relationship between the use of OCs and prostaglandgin.62 Prostaglandin E2 appears to rise the occurrence of gingival melanosis, especially in significantly with increasing sex hormone. fair-skinned individuals. 162 Periodontal Medicine

Management tives during antibiotic therapy and advised to use additional forms of contraception during short- A comprehensive medical history and an assess- term antibiotic therapy. During long-term antibi- ment of vital signs (particularly blood pressure) are otic therapy, they should consult with their physi- extremely important in this group of patients. cian about using high-dose oral contraceptive Treatment of gingival inflammation exaggerated by preparation^.^^ Although research regarding oral oral contraceptives should include establishing an manifestations attributed to oral contraceptives has oral hygiene program and eliminating local predis- been reported in the literature, presumably the posing factors. It is also imperative that the patient same effects could occur with the use of contra- be informed of their heightened risks and the need ceptive implants (eg, Norplant@).Along the same for meticulous home care and compliance with lines, the remote possibility exists of reduced effi- supportive periodontal therapy visits. Periodontal cacy of the contraceptive implant with concurrent surgery may be indicated if there is inadequate res- antibiotic administration, and the same precau- olution after initial therapy (scaling and root plan- tions can be adhered to as with oral contraceptives. ing). Antimicrobial mouthwashes may be indicated as part of the home care regimen. It may be advisable to perform extraction of teeth (especially CONCLUSION of third molars) on non-estrogenic days (days 23 to 28) of the pill cycle, to reduce the risk of a postop- There is increasing evidence that the female erative localized o~teitis.~~However, evidence of patient frequently presents with unique periodon- this association is inconclusive and warrants fur- tal and systemic manifestations that alter the ther investigation. course of conventional periodontal therapy. The Although the results from animal studies have cyclic nature of the female sex hormones is often demonstrated antibiotic interference adversely reflected in gingival tissue changes. It is the affecting contraceptive sex hormone levels, several responsibility of those who treat the oral cavity to studies involving human subjects have failed to realize that they are treating the total health of the support such an intera~tion.~~~~~This issue is con- patient (and possibly the unborn fetus), not just a troversial, and there may be a possibility that localized site infection. antibiotics could render oral contraceptives ineffi- Thorough medical histories in the female cacious in preventing pregnancies. In 1991, an patient should include questions regarding men- ADA Health Foundation report stated that all strual regularity, oral contraceptive use, hormone women of childbearing age should be informed of replacement therapy, fertility medications, preg- possible reduced efficacy of oral steroid contracep-

TABLE 9-5b. Dental Drug Administration TABLE 9-5a. Dental Drug Administration during Breast-Feeding during Breast-Feeding DT During Breast-Feeding Drug During Breast-Feeding Antibiotics* Local anesthetics Penicillins Yes Lidocaine Yes Erythromycin Yes Mepivacaine Yes Clindamycin Yes (with caution) Priolocaine Yes Cephalosporins Yes Bupivacaine Yes Tetracycline Avoid Etidocaine Yes Ciprofloxacin Avoid Procaine Yes Metronidazole Avoid Analgesics Gentarnicin Avoid Aspirin Avoid Vancomycin Avoid Acetaminophen Yes Sedative-hypnotics Ibuprofen Yes Benzodiazepines Avoid Codeine Yes Barbiturates Avoid Hydrocodone No data Nitrous oxide Yes Oxycodone Yes *Antibiotics have the risk of diarrhea and sensitization in the Propoxyphene Yes mother and infant. Periodontal Medicine and the Female Patient 163 nancy, breast-feeding, cyclic problems that may be systemic folic acid supplementation on gingivi- associated with manifestations of the sex hor- tis in pregnancy. J Clin Periodontol 1980;7: mones, as well as any question that may enhance 402-14. the quality of care for the individual patient and 11. Miyagi M, Aoyama H, Morishita M, Iwamoto Y. determine her particular needs. It is possible to Effects of sex hormones on chemotaxis of poly- control the periodontal health of the patient by morphonuclear leukoctyes and monocytes. J educating her about the profound effects of the sex Periodontol 1992;63:28-32. hormones, especially progesterone, and the impor- 12. Grant D, Stern J, Listgarten M. The epidemiology, tance of consistent removal of local irritants. etiology and public health aspects of periodon- In the late 1990s, there has been a resurgence tal disease. In: Grant D, Stern J, Listegarten M. of curiosity relating to female issues and med- editors. Periodontics. St. Louis (MO): Mosby ical/periodontal therapy. There should be light 1988. p. 229,332-5. shed on the specific management and etiology of 13. Ferguson MM, Carter J, Boyle E An epidemiolog- sex hormone-mediated infections in the near ical study of factors associated with recurrent future. It is also imperative that we disseminate this apthae in women. J Oral Med 1984:39(4):212. knowledge to other health care providers and to 14. Robb-Nicholson C. PMS: it’s real. Harvard the community. Women’s Health Watch 1994; July 1(11):2-3. 15. Robb-Nicholson C. Gastroesophageal reflux disease. Harvard Women’s Health Watch;4(6):4-5. REFERENCES 16. Pinard A. Gingivitis in pregnancy. Dent Register 187731~258-9. 1. Kornman K, Loesche WJ. Direct interaction of 17. Levin W. Pregnancy gingivitis. Maryland State estradiol and progesterone with Bacteroides Dental Association 1987;30:27. mehninogenicus. J Dent Res 1979;58A:10. 18. Hanson L, Sobol SM, Abelson T. The otolaryngo- 2. Gusberti FA, Mombelli A, Lang NE Minder CE. logic manifestations of pregnancy. J Fam Pract Changes in subgingival microbiota during 19 86;23: 5 1-5. puberty. J Clin Periodontal 1990;17:685-92. 19. DeLiefde B. The dental care of pregnant women. 3. Mombelli A, Rutar A, Lan NE Correlation of the NZ Dent J 1984;80:41-3. periodontal status 6 years after puberty with 20. Loe H, Silness J. Periodontal disease in pregnancy. clinical and microbiological conditions during 1. Prevalence and severity. Acta Odontol Scand puberty. J Clin Periodontol 1995;22(4):300-5. 1984;21:533-5 1. 4. Nakagawa S, Fujii H., Machida Y, Okuda K. A lon- 21. Raber-Durlacher JE, van SteenbergenTJM, van der gitudinal study from prepuberty to puberty of Velden U. Experimental gingivitis during preg- gingivitis. Correlation between the occurrence nancy and post-partum; clinical, endocrino- of PrevoteZh intermedia and sex hormones. J Clin logical and microbiological aspects. J Clin Perio- Periodontal 1994;21(10):658-6. dontol 1994;21:549-58. 5. American Dental Association. Women’s Oral Health 22. Bhashkar SN, Jacoway JR. Pyogenic granuloma: Issues 1995; Dec. clinical features, incidence, histology, and results 6. Brown S, Bonifaz DZ. An overview of anorexia and of treatment. Report of 242 cases. J Oral Surg bulimia nervosa and the impact of eating disor- 1966;24: 39 1-8. ders on the oral cavity. Compend Contin Educ 23. Kornman KS, Loesche WJ. The subgingival flora Dent 1993;14( 12): 1594-1 608. during pregnancy. J Periodontol 1980; 15: 7. Mandel L, Kaynar A. Bulimia and parotid swelling: 111-22. a review and case report. J Oral Maxillofac Surg 24. Aboul-Dahab OM, el-Sherbiny MM, Abdel-Rah- 1992;50:1122-5. man R, Shoeb M. Identification of lymphocytes 8. Lundgren D, Magnssen B, Lindhe J. Connective subsets in pregnancy. Egyptian Dental J 1994; tissue alterations in gingiva of rats treated with 40( 1):653-6. estrogens and progesterone. Odontol 1973;24: 25. Raber-Durlacher JE, Leene W, Palmer-Bouva 49-58. CCR, et al. Experimental gingivitis during preg- 9. Thomson ME, Pack ARC. Effects of extended sys- nancy and post partum: immunohistochemical temic and topical folate supplementation on aspects. J Periodontol 1993;64:211-18. gingivitis in pregnancy. J Clin Periodontol 26. O’Neil TCA. Maternal T-lymphocyte response and 1982;9:275-80. gingivitis in pregnancy. J Periodontol 197950: 10. Pack ARC, Thomson ME. Effects of topical and 178. 164 Periodontal Medicine

27. Brabin, BJ. Epidemiology of infection in pregnancy. 42. American Academy of Periodontology Position Rev Infect Dis 1985;7:579. Paper. Periodontal disease as a potential risk fac- 28. Lopatin DE, Kornman KS, Loesche WJ. Modula- tor for systemic disease. J Periodontol 1998; tion of immunoreactivity to periodontal disease- 69(7):84 1-50. associated microorganisms during pregnancy. 43. Damare SM, Wells S, Offenbacher S. Eicosanoids Infect Immun 1980;28:713-18. in periodontal diseases: potential for systemic 29. Sridama V, Pacini F, Yang SL, et al. Decreased lev- involvement. Adv Exp Med Bio 1997;433:23-5. els of helper T cells. A possible cause of immun- 44. Davenport ES, Williams CE, Sterne JA, et al. The odeficiency in pregnancy. N Engl J Med 1982; East London study of maternal chronic peri- 307:352. odontal disease and preterm low birth weight 30. Raber-Durlacher JE, Zeylemaker WE Meinesz infants: study design and prevalence. Ann Perio- M,Abraham-Lipijn L. CD4 to CD8 ratio and dontol 1998;3(1):213-2 1. in vitro lymphoproliferative responses during 45. Dasanayake AE Poor periodontal health of the experimental gingivitis in pregnancy and post- pregnant woman as a risk. Ann Periodontol partum. J Periodontol 1991;62:663-7. 1998;3(1):206-12. 31. Lapp CA, Thomas ME, Lewis JB. Modulation by 46. Offenbacher S, Jared HL, O’Reilly PG, et al. progesterone of interleukin-6 production by Potential pathogenic mechanisms of periodonti- gingival fibroblasts. J Periodontol 1995;66(4): tis associated pregnancy complications. Ann Periodontol 1998;3(1):233-50. 279-84. 47. El-Ashiry G. Comparative study of the influence of 32. El-Attar TMA. Prostaglandins F2 in human gingiva pregnancy and oral contraceptives on the gingi- in health and disease and its stimulation by female vae. Oral Surg 1970;30:472-5. sex steroids. Prostaglandins 1976;1 :33 1-4 1. 48. Cruikshank 0, Hayes PM. Maternal physiology. In: 33. Ojanotko-Harri AO, Harri MOC Hurrita HE Gabbe S, Niebyl JR, Simpson JL, editors. Preg- Altered tissue metabolism of progesterone in nancy in obstetrics: normal and problem preg- pregnancy gingivitis and granuloma. J Clin Peri- nancies. Livingstone (NY): Churchill Livingstone; odontol 1991;8:262-6. 1986. 34. Kinnby B, Matsson L, Astedt B. Aggravation of 49. Glenn FB. Immunity conveyed by a fluoride sup- gingival inflammatory symptoms during preg- plement during pregnancy. J Dent Child 1977; nancy associated with the concentration of acti- 44:391-5. vator inhibitor type 2 (PAI-2) in gingival fluid. 50. Glenn FB, Glenn WD 111, Duncan RC. Fluoride J Periodontal Res 1996;31 (4):271-7. tablet supplementation during pregnancy for 35. Lindhe J, Branemark E Changes in vascular per- caries immunity: a study of the offspring pro- meability after local application of sex hor- duced. Am J Obstet Gynecol 1982;143:560-4. mones. J Periodontal Res 1967b;2:259-265. 51. Reference manual. Pediatr Dent 1994-95: 16(7). 36. Lindhe J, Branemark E Changes in microcircula- 52. Little JW, Falace DA. Dental management of the tion after local application of sex hormones. J medically compromised patient. 4th edition. Periodontal Res 1967a;2: 185-93. St. Louis (MO): Mosby;1993:383-9. 37. Zachariasen RD. Ovarian hormones and oral 53. Bean LR Jr, Devore WD. The effects of protective health: pregnancy gingivitis. Compend Contin aprons in dental roentgenography. 1969;28: Educ Dent 1989;10(9):508-12. 505-8. 38. Vittek J, Gordon G, Rappaport C, Munangi 54. Briggs GG, Freeman RK, Yaffe SJ. Drugs in preg- Southern A. Specific progesterone receptors in nancy and lactation. 4th ed. Baltimore (MD): rabbit gingiva. J Periodontal Res 1982;17:657. Williams and Wilkins; 1994. 39. Muramatsu Y, Takaesu Y. Oral health status related 55. Olin BR, editor. Drug facts and comparisons. St. to subgingival bacterial flora and sex hormones Louis (MO): Walters Kluwer; 1994. in saliva during pregnancy. Bull Tokyo Dent 56. Reese RE, Betts RF. Handbook of antibiotics. 2nd College 1994;35(3):139-5 1. ed. Boston (MA): Little, Brown, and Co.:1993. 40. Offenbacher S, Katz V, Fertik G, et al. Periodontal 57. Otomo-Corgel J. Systemic considerations for infection as a possible risk factor for preterm low female patients. In: Antibiotics/antimicrobial birthweight. J Periodontol 1996;67(10 Suppl): use in dental practice. Tokyo: Quintessence 1103-13. Publishing Co.; 1990. p. 217-21. 41. Gibbs RS, Romero R, Hillier SL, et al. A review of 58. Steinberg, BJ. Sex hormonal alterations. In: Rose LD, premature birth and subclinical infections. Am Kay D, editors. Internal medicine for dentistry. J Obstet 1992;166:1515-28. 2nd ed. St. Louis (MO): Mosby;1990. p. 1073-7. Periodontal Medicine and the Female Patient 1 6 5

59. Wilson JT, Brown RD, Cherek DR, et al. Drug Effects of oral contraceptives on the gingiva. excretion in human breast milk: principles, J Periodontol 1971; 42:273-5. pharmacokinetics and projects consequences. 69. Sweet JB, Butler DE Increased incidence of postop- Clin Pharmacokinet 1980;5:1-66. erative localized osteitis in mandibular 3rd molar 60. Zachariasen, RD. The effects of elevated ovarian surgery associated with patients using oral con- hormones on periodontal health: oral contra- traceptives. Am J Obstet Gynecol 1977;127:518. ceptives and pregnancy. Women Health 1993; 70. Cohen ME, Simecek JW. Effects of gender-related 20(2):21-30. factors on the incidence of localized alveolar 61. Sooriyamoorthy M, Gower DB. Hormonal influ- osteitis. Oral Surg Oral Med Oral Path Oral ences on gingival tissues: relationship to perio- Radio1 Endod 193579(4):4 16-22. dontal disease. J Clin Periodontol 1989;16: 71. Hertz RS, Beckstead PC, Brown WJ. Epithelial 201-8. melanosis of the gingiva possibly resulting from 62. Kalkwarf KL. Effect of oral contraceptive therapy the use of oral contraceptives. J Am Dent Assoc on gingival inflammation in humans. J Perio- 1980;100:(5): 173. dontol 1978;49:560-3. 72. Fleisher AB Jr, Resnick SD. The effect of antibi- 63. El-Attar TMA, Roth GD, Hugoson A. Compara- otics in the efficacy of oral contraceptives. Arch tive metabolism of 4-C progesterone in normal Dermatol 1980;125:1582-4. and chronically inflamed human gingival tissue. 73. Back DJ, Orme MLIE. Pharmacokinetic drug J Periodontol Res 1973;8:79. interactions with oral contraceptives. Clin Phar- 64. Jensen J, Lilijmack W, Blookquist C. The effect of macokinet 1990;18(6):472-84. female sex hormones on subgingival plaque. J 74. Fraser IS, Jansen WS. Why do inadvertent preg- Periodontol 1981;52( 10): 599-602. nancies occur in oral contraceptive users? Effec- 65. Knight GM, Wade AB. The effects of oral contra- tiveness of oral contraceptive regimens and inter- ceptives on the human periodontium. J Perio- fering factors. Contraception 1983;27:531-5 1. dontal Res 1974;9:18-22. 75. Murphy AA, Zacur HA, Charache et al. The 66. Pankhurst CL. The influence of oral contracep- effect of tetracycline on levels of oral contraceptive therapy on the periodontium-duration tives. Am J Obstet Gynecol 1991;164:28-33. of drug therapy. J Periodontol 1981;52:617- 76. Neely JL, Abate M, Swinker M, et al. The effect of 620. doxycycline on serum levels on ethinyl estradiol, 67. Magnusson T, Ericson T, Hugoson A. The effect of norethindrone, and endogenous progesterone. oral contraceptives on some salivary substance Obstet Gynecol 199 1;77:4 10-1 6. in women. Arch Oral Biol 197520:1 19. 77. Antibiotic interference with oral contraceptives. 68. El-Ashiry G, El-Kafrawy AH, Nasr MF, Younis N. J Am Dent Assoc 1991;122:79. CHAPTER10

0STEO PENIA, 0STEO PORO s IS AND ORAL DISEASE

Sara G. Grossi, DDS, MS Marjorie K. Jeffcoat, DMD Robert J. Genco, DDS, PhD

Normal bone is among the most metabolically tions, including replication of undifferentiated active of human tissues. Once formed, bone is con- cells and recruitment and cell differentiation in tinuously changing throughout life, constantly both cortical and trabecular bone.3 This concert of responding to various metabolic demands. In a bone cells is referred to as the basic multicellular process known as remodeling, bone shapes itself, unit (BMU) or bone remodeling unit and consti- creating an organ with maximal compressive tutes the smallest hnctional unit of bone cells strength, able to hlfill its role as the load-bearing capable of undergoing the remodelling process.* structure of the body. The human skeleton consists Four distinct phases are recognizable in the bone of two different tissues: trubecuhr bone, concentrat- remodeling cycle: activation, resorption, reversal, ed mostly in vertebrae, the pelvis and other flat and formation. A cycle is completed in approxi- bones, and corticul bone, which overlays trabecular mately 8 months. The process is under tight con- bone and occupies mostly the shafts of long bones.’ trol by both systemic and local factors. Cortical bone is a more dense tissue than trabecular Systemic factors regulating bone remodeling bone, as the cells are in closer proximity with less include: ( 1) the calcium-regulating hormones: intercellular space and matrix. Trabecular bone is parathyroid hormone (PTH), I ,25-dihydroxyvita- metabolically more active than cortical bone, likely min D (1,25(OH)2D3), and calcitonin (CT); and because of its greater surface-to-volume ratio. (2) the systemic growth-regulating hormones: To maintain this phenomenally strong load- growth hormone, glucocorticoids, thyroid hor- bearing structure, young bone is constantly renew- mone, and sex hormone^.^ Parathyroid hormone is ing itself. That is, “old bone is constantly removed a polypeptide with complex effects on bone metab- and replaced with “new bone,” a process known as olism. The most important hnction of PTH is to bone remodeling. In this process, bone is constant- maintain serum ionized calcium concentration, ly resorbed on a particular bony surface, followed accomplished by stimulation of bone resorption, by a phase of bone formation. It is etimated that renal resorption of calcium, and increased synthesis the entire skeleton is completely turned over every of 1,25(OH)2D3, which, in turn, results in 7 to 10 years. Remodeling occurs at both trabecu- increased intestinal calcium absorptioa6 Parathy- lar and cortical sites. In the normal adult skeleton, roid hormone has a dual effect on bone metabo- bone resorption is coupled with bone formation, lism, stimulating both resorption and f~rmation.~>~ so that bone balance is maintained.2 In this man- The bone resorbing effect is dependent on the pres- ner, the skeleton is maintained throughout the life ence of osteoblasts or osteoblast-derived factors. of the individual. Vitamin D (1,25(OH)2D3), a hormone synthesized primarily by the kidney, has similar hnctions as PTH. It stimulates bone resorption and has effects BONE REMODELING on bone f~rmation.~The major function of vitamin D, however, is to maintain the supply of calcium Bone remodeling is a complex and dynamic and phosphate by stimulating intestinal absorp- process aimed at the maintenance of a mineralized tioa8 Vitamin D is important in cell differentia- bone matrix. It involves a number of cellular function, formation of osteoclasts, and the differentiat- 168 Periodontal Medicine ed hnction of osteoblasts. Calcitonin is a potent osteoclast recruitment and differentiation from inhibitor of bone resorption. Unlike PTH, the bone marrow precursors. Moreover, 17-B estradiol effect of calcitonin on bone metabolism is indepen- appears to stimulate the production of alkaline dent from osteoblasts. Accordingly, osteoclasts phosphatase and collagen IGF-1 by bone cells.’‘ In express receptors for calcitonin on their membrane addition, estrogen may affect bone turnover indi- and not for PTH.‘ rectly by acting as an antagonist to PTH. The bone- Insulin and growth hormone (GH) are sparing effect of estrogen may be explained by its polypeptide hormones with counter-regulation. hndamental ability to interact with bone cells and While GH is the major regulator of somatic modulate the cytokine circuitry that controls bone growth, it acts indirectly by stimulating the pro- remodeling.l7 duction of circulating and local insulin-like growth Other local factors regulating bone remodeling factor (IGF-I) by skeletal cells,9 which, in turn, are synthesized by skeletal cells and include growth mediates some of the effects of insulin on bone factors and prostaglandins. Polypeptide growth fac- metabolism and skeletal growth. ‘O Insulin stimu- tors include IGF-1 and -2,18 TGF-fl,” fibroblast lates bone matrix formation and mineralization. growth factor (FGF),20 platelet-derived growth fac- This stimulatory effect on matrix synthesis is due tor (PDGF),21 and bone morphogenic proteins to an effect on osteoblast differentiation rather (BMPs).~~These factors have effects on cells of the than an increase in collagen-producing cells. ’’ same class (autocrine effect) or other cells within the Glucocorticoids are steroid hormones with tissue (paracrine effect). Prostaglandins are currently direct and indirect effects on bone metabolism. the only known regulators of bone remodeling that The indirect effects include inhibition of intestinal do not have a polypeptide structure. absorption of calcium and GH secretion. The Growth factors are also present in circulation direct effects include inhibition of bone collagen and may act as systemic regulators of skeletal and synthesis, probably due to a decrease in osteoblast nonskeletal metabolism but the locally produced repli~ation,~and increased response to other sys- factor has a more direct and possibly important temic hormones such as PTH and IGF,‘possibly hnction in cell growth. Circulating hormones may by increasing receptor binding. This could be one act on skeletal cells either directly or indirectly, of the mechanisms involved in steroid-induced modulating the synthesis, activation, and receptor osteoporosis.l2 binding of local growth factor. This, in turn, stim- Sex hormones, both estrogen and androgens, ulates or inhibits bone formation or bone resorp- play a central role in skeletal development and bone tion. It is likely that hormones are important in the loss. The increase in sex hormones at puberty is targeting of growth factors to tissues expressing spe- partly responsible for the events leading to acceler- cific hormonal receptors. Growth factors may play ation of cartilage growth, increased bone turnover, a critical role in the coupling of bone formation and increased bone mass. Both estrogen and andro- with bone resorption and possibly in pathophysio- gen receptors are present in bone cells, pointing to logic processes.23 the direct effects of these hormones on bone metabolism as well. Estrogen regulates bone remodeling by Peak Bone Mass modulating the production of cytokines and growth factors, which, in turn, act as local regulators of the Bone mass increases during early childhood and remodeling process. Cytokines under estrogen regu- adolescence by linear growth of the endochondrial lation with direct effects on bone cells include inter- growth plates and by radial growth due to periosteal leukin- 1 (IL-1), tumor necrosis factor-a (TNF-a), apposition. After closure of the growth plate around granulocyte-macrophage colony-stimulating factor age 20 years, radial growth continues for about 10 (GM-CSF) secreted by monocytes, and IL-6 and to 15 years. Peak bone mass is therefore reached colony-stimulating factor (CSF) secreted by osteo- sometime between the third and early part of the b1a~ts.l~Interleukin-1 induces the synthesis of IL-6, fourth decade of life, declining progressively there- which increases bone resorption through osteoclast after (Figure 10-1).1>2Peak bone mass constitutes recruitment. Colony-stimulating factor plays a role the summation of growth and turnover during what in the maturation of osteoclasts. Interleukin-1 fl and is known as the “calcium building years.” Sometime TNF-a stimulate mature osteoclasts, modulate after age 40 years, a slow age-dependent phase of bone cell proliferation, and induce bone resorption bone loss ensues. This calcium depletion phase in vivo.’*J5 In addition, IL-1, TNF-a, and GM- results in similar losses of cortical and trabecular CSF contribute to bone resorption by promoting bone, with roughly similar rates in men and women. Osteopenia, Osteoporosis, and Oral Disease 169

In addition, postmenopausal women experience yet another phase of bone loss, that is, an accelerated loss as a consequence of the estrogen deficiency associated with menopause. Trabecular bone, being more metabolically active than cortical bone, is lost at a disproportionately faster rate during this postmenopausal phase of bone loss. Peak bone mass has strong genetic determinants. Morrison and colleagues2*have shown that bone mass, one of the main determinants of osteoporotic fractures, has a genetic component linked to an allellic change in the receptor for vitamin D, one of the hormones controlling calcium metabolism. 20 40 60 80 100 However, nutritional factors, such as level of dietary Age (years) calcium during skeletal growth, and environmental Figure 10-1. Changes that occur in bone mass with growth factors, such as physical activity, modulate the and aging in men and women. Factors involved in determin- genetic disposition and contribute to the achieve- ing peak bone mass are genetic and nongenetic (nutrition, ment of peak bone mass.25 Failure to achieve peak smoking, exercise). Factors increasing rate of bone loss later in bone mass predisposes to fractures later in life as age- life include aging, estrogen deficiency, and lifestyle factors related bone loss ensues. Genetically determined dif- (smoking, alcohol). Results of Morrison and colleagues ferences in peak bone mass may explain, in part, the (1994) suggest that bone mass is under genetic control, racial and gender differences in the incidence of linked to polymorphism in the gene for vitamin D receptor. osteoporosis. Caucasian women have the least bone mass and African American men have the most, while Caucasian men and African American women A Consensus Development Conference defined have intermediate bone mass. Thus, assuming a osteoporosis as “a systemic skeletal disease charac- constant rate of bone loss with age, Caucasian terized by low bone mass and microarchitectural women with the lowest peak bone mass are at great- deterioration with a consequent increase in bone est risk for osteoporosis and fractures later in fragility and susceptibility to This definition, though descriptive, provides little usehlness for diagnosis and clinical management. OSTEOPOROSIS Microarchitectural deterioration is not amenable to clinical measurement, whereas bone mass can be Osteoporosis means literally “porous bone,” a con- measured with accuracy and precision with dual x- dition where there is “too little bone” to provide ray absorptiometry (DXA). Thus, a World Health mechanical support. Osteopenia, on the other Organization panel has operationally defined hand, is a reduction in bone mineral density osteoporosis as a BMD (T score) that is 2.5 SD (BMD) below a predefined level. Osteoporosis is below the mean peak value in young adults (Table characterized by a reduction in BMD to a level 10-1) .29 This definition too, has limitations since below what is required for mechanical s~pport.~~>~~BMD values are applicable to Caucasian women

TABLE 10- I. World Health Organization (WHO) Diagnostic Guidelines for Interpretation of Bone Mass Measurements in Caucasian Women Severe osteoporosis Bone mineral density (BMD) more than 2.5 standard deviations (SD) below the mean value of peak bone mass in young normal women and the presence of fractures. Osteoporosis BMD more than 2.5 SD below the mean value of peak bone mass in young normal women. Low bone mass (osteopenia) BMD within -1 SD and -2.5 SD of the mean value of peak bone mass in normal young women. Normal BMD not more than 1SD below mean value of peak bone mass in young normal women. 170 Periodontal Medicine

after menopause (see Figure 10-1). Thus, type 1 TABLE 10-2. Classification of Osteoporosis osteoporosis is characterized by a disproportionate Primary loss of trabecular bone resulting in fractures at those Idiopathic Juvenile skeletal sites with a high volume of trabecular bone, Adult including the vertebrae, distal forearm (Colles’ fractures), and distal ankle. Clinical symptoms of the Involutional Type I (postmenopausal) disease include bone pain (mostly from vertebral Type I1 (age-related) compression), loss of height and consequent defor- Secondary mation of the skeleton leading to dorsal kyphosis Endocrine disorders (“dowager‘s hump). Diabetes mellitus Type I osteoporosis is related to the estrogen Gastrointestinal and malabsorption syndromes deficiency associated with menopause, leading to a Myeloproliferative disorders cascade of accelerated bone loss, decreased secre- Multiple myeloma tion of parathyroid hormone, increased secretion Connective tissue diseases of calcitonin, and decreased calcium absorption, Marfan syndrome which hrther aggravates bone loss. In addition, Ehlers-Danlos syndrome patients with type osteoporosis and high bone Chronic obstructive pulmonary disease I turnover have increased production of IL-I by stimulated monocytes, as compared with age- only. Their relevance to other ethnic groups and to matched controls, which also contributes to men is currently unknown. increased bone resorption. Osteoporosis affects more than 25 million peo- Type I1 (age-related) osteoporosis appears to ple in the United States (about 10% of the total pop- affect virtually the entire population of aging men ulation), including I in 3 postmenopausal women, and women, although it is twice as common in and a substantial number of men. It is responsible for women. Bone loss starts around the third decade more than 2 million fractures annually, resulting in and continues through life and is characteized by health-care costs in excess of 20 billion U.S. dollars. slow bone loss due to decreased calcium absorp- The major portion of the social and economic bur- tion and secondary hyperparathyroidism. Bone den caused by fractures is due to hip fracture. The loss affects cortical and trabecular bone equally intangible costs to society due to pain and suffering with a rate of about 0.3 to 0.5% per year (see Fig- associated with morbidity, need for long-term care, ure 10-1). These two types of bone loss result in and mortality as a result of osteoporotic fractures distinct fracture patterns. While postmenopausal add to the financial burden. Osteoporosis is clearly osteoporosis manifests mostly in Colles’ and verte- a major public health problem. bral fractures, age-related osteoporosis results in hip fractures in both men and women of older Classification age. However, fractures of the humerus, proximal fibula, and pelvis are also common. Osteoporosis occurs either as a primary disorder, or it may be secondary to other diseases or conditions Secondary Osteoporosis (Table 10-2). Primary osteoporosis includes idiopathic (juvenile or adult) and involutional forms. Osteoporosis may be associated with a number of Idiopathic forms of osteoporosis are rare and affect endocrine diseases. Hypogonadism in either sex men and women equally. Involutional osteoporo- increases the incidence of osteoporosis. Hyperthy- sis, by far the most common form, includes two roidism consistently increases bone turnover but in patterns: type I (postmenopausal) and type I1 (age- most patients, formation and resorption remain cou- related) osteoporosis. pled. Osteoporosis may also be associated with gas- Type I (postmenopausal) osteoporosis occurs in trointestinal diseases, and malabsorption syndromes peri- and postmenopausal women. Bone loss in pre- that impair absorption of calcium and vitamin D. menopausal women is slow and approximately equal Multiple myeloma and other myeloproliferative dis- to that of men (0.3 to 0.5% per year). With the orders produce d&se osteoporosis in about 10% of onset of menopause in females, an accelerated rate patients. D&se osteoporosis may also occur when of cortical bone loss of 2 to 3% per year ensues for disseminated carcinoma invades the bone marrow. about 8 to 10 years. Trabecular bone is lost at a rate An unusually severe form of osteoporosis may occur of about 5% per year during the first 5 to 8 years in connective tissue diseases such as osteogenesis Osteopenia, Osteoporosis, and Oral Disease 17 1 imperfecta. Marfan and Elders-Danlos syndromes ORAL BONE AND may also be associated with vertebral osteopenia, but OSTEOPENIA/OSTEOPOROSIS less frequently include vertebral fiactures. Other causes of osteoporosis include total After having reviewed the biology of bone remod- immobilization, such as in traumatic quadriplegia. eling and the basis of imbalance in coupling Significant bone loss also occurs during total bed responsible for the onset of skeletal osteopenia and rest among nonparalyzed individuals and in astro- ultimately osteoporosis, the implicit question is, to nauts during gravitational weightlessness. Osteo- what extent is oral bone affected by remodeling porosis is also associated with chronic obstructive imbalance, and does it contribute to oral bone loss? pulmonary disease. Whether this is related to the In addition to the academic relevance of this ques- underlying consumption of tobacco or to the pul- tion, it is fundamental to proper clinical manage- monary disease itself is unknown. ment of dentate and edentulous patients suffering from both osteopenia and osteoporosis. A rational Patho ph ysiol ogy dental treatment plan in such patients is not complete if proper management of systemic bone loss The pathophysiology of osteoporosis is poorly is not included. understood. Bone mass at any given time is related to peak bone mass and bone loss that has occurred Relationship of Skeletal Osteopenia since peak mass was attained. Bone is continuous- to Mandibular Bone Density ly remodeled throughout the life of an individual, and the rate of remodeling is increased in older It has long been postulated that mandibular bone adults. With the increased rate of remodeling in density may be indicative of systemic bone miner- older age, there is uncoupling of the remodeling al density. In a classic series of studies, Kribbs and cycle, that is, the rate of resorption exceeds the rate colleagues (Table 10-3) addressed this relationship of f~rmation.~'>~lThis results in a remodeling in both normal and osteoporotic women. In an imbalance with net bone loss, lower bone mass, early total body calcium as assessed by neu- and ultimately increased risk for fractures. Such an tron activation analysis, was found to be associated imbalance would be even greater if the rate of ini- with mandibular density as measured by quantita- tiation of new bone remodeling cycles were to tive analysis of intraoral radiographs. A later increase. Therefore, genetically determined bone study33 in normal, nonosteoporotic women, mass and age constitute the major determinants of revealed that bone mass was not affected by age but risk of osteoporosis and osteoporotic fractures. was significantly associated with skeletal bone mass

TABLE 10-3. Relationship between Systemic and Mandibular Bone Mineral Density Authors Popuhtion Major Result Type of Study Jeffcoat et al, 200 subjects from Women's Correlation between basal Baseline data from [In press] Health Initiative bone mineral density and longitudinal Postmenopausal women hip bone mineral density study Von Wowern et al, 12 women with osteoporotic Osteoporotic subjects had less Cross-sectional 1994 fracture bone mineral content and study 14 normal women more loss of attachment compared with normals Kribbs et al, 1990 50 normal women, aged 20 Mandibular bone mass correlated Cross-sectional to 90 years with bone mass as spine and wrist study Kribbs et al, 1990 85 osteoporotic and 27 Osteoporotic group had less Cross-sectional normal women, aged 50 mandibular bone mass and study to 85 years density Kribbs et al, 1989 85 osteoporotic women Total body calcium, bone mass at Cross-sectional radius, and bone density at spine study correlated with mandibular mass Kribbs et al, 1983 30 postmenopausal women Total body calcium associated with Cross-sectional mandibular bone density study 172 Periodontal Medicine at the spine and wrist. A comparison of 85 osteo- related with tooth loss for women in their sixties. In porotic women with 27 normal women showed a study of 329 healthy postmenopausal women, for less mandibular bone mass and density and a thin- each additional tooth present, spinal BMD increased ner cortex at the gonion in osteoporotic compared 0.003 g per cm2.42In a 7-year longitudinal study, with nonosteoporotic Similarly, von rate of systemic bone loss was a predictor of tooth Wowern and colleagues36reported that 12 osteo- loss in postmenopausal w0men.4~For each 1% per porotic subjects with a history of fractures had less year decrease in whole body BMD, the risk for tooth mandibular bone mineral content as measured by loss more than quadrupled. Decreases in BMD at dual photon absorptiometry than 14 normal the femoral neck and spine resulted in a 50% and women. It is noteworthy that all reports Kribbs 45% increased risk of tooth loss respectively. Collec- and colleague^^^-^^ and von Wowern and col- tively, this evidence indicates that osteoporotic league~~~described are cross-sectional studies. women have lost significantly more teeth, and more The Women's Health Initiative (WHI), in the are edentulous compared with nonosteoporotic United States, is an unprecedented study of wornen.4Oa Thus, women that are at risk for or suf- women's health after menopause. Specific risk fac- fer fiom osteoporosis are also at risk for tooth loss. tors for diseases including heart disease and osteoporosis are being addressed nationwide. The Uni- Periodontal Disease and versity of Alabama at Birmingham and the State OsteopenidOsteoporosis University of New York at Buffalo are conducting oral studies ancillary to the WHI to determine Unlike the clear relationship between osteoporosis whether image analysis of intraoral radiographs and tooth loss, controversy still exists concerning the could be used to determine if basal mandibular association between osteopenia/osteoporosis and BMD is correlated with hip BMD determined by periodontal disease. Conflicting results among dif- DXA. Comprehensive medical histories and exam- ferent studies account for much of the controversy. inations performed as part of the parent study were Small sample size and hndamental differences in linked with results of oral examinations and quan- study design, population examined (ie, women only titative digital intraoral radi~graphy.~~.~~A region versus men and women), age of population studied, of interest in the area of the basal bone of the first and methodology to assess periodontal disease and mandibular molar was selected for measurements skeletal osteopenia and osteoporosis prevent inter- of mandibular BMD. General linear models of pretation and comparability of results. mandibular basal BMD, hip BMD, midroot den- Wactawski-Wende and c0lleagues,4~in a study sity, age, race, hormone replacement therapy, and of 70 postmenopausal women, found a significant calcium supplements were created. Preliminary relationship between alveolar crestal bone height as analyses from the University of Alabama cohort a measure of periodontitis and skeletal osteopenia used data from the first 200 subjects in the (femur and lumbar spine) measured by DXA. This Significant correlations were found between relationship was seen after controlling for possible mandibular basal BMD and hip BMD (r = 0.74, confounders such as dental plaque, years of meno- p c .OOl). These findings are consistent with evi- pause, and smoking. In addition, there was a rela- dence that supports the concept that BMD of the tionship between osteopenia at the hip and probing mandible is indeed correlated with skeletal BMD. attachment loss in this same group. Similarly, von Wowern and colleague^,^^ in a case-control study Tooth Loss and Osteoporosis comparing I2 female patients with osteoporotic fractures and 14 normal women, reported signifi- Several studies have demonstrated a relationship cantly greater periodontal attachment loss in the between tooth loss and systemic osteoporosis in both osteoporotic women compared with the normal dentate and edentulous individuals. Daniel1 and col- women. They found that the osteoporotic women league~~'suggested that systemic bone loss was a risk had less mandibular bone mineral content, as mea- factor for edentulism. Women with severe osteo- sured by dual photon absorptiometry, than the 14 porosis, defined as extreme thinning of the normal women. The mandibular bone mineral metacarpal cortical area, were three times more like- content values were 2 SD below the mandibular ly (44% versus 15%) to have no teeth compared bone content for young reference (normal) women with healthy, age-matched controls. Taguchi and col- in 92% of the osteoporotic group and in 64% of leagues4' showed that a decrease in mandibular bone the control group, suggesting that a high propor- density, estimated as mandibular cortical width, cor- tion of the control group also suffered from Osteopenia, Osteoporosis, and Oral Disease 173 mandibular osteopenia. The relationship between osteopenia and severity of periodontal disease was Femoral neck also examined in a sample from the Third Nation- al Health and Nutrition Examination Survey A b (NHANES 111) of 11,247 individuals 20 to 90 Trochanter I 4 v years of age.46Osteopenia of the hip was significantly associated with severity of periodontal dis- lntertrochanter - ease (mean attachment loss 2 1.5 mm) in females and males alike (Figure lO-2), independently of the Ward's triangle 4 -1 b confounding effects of age, gender, smoking, or intake of dietary calcium. This association was Total hip increased even further in postmenopausal females. - Hence, though limited, the evidence suggests an association between osteopenia, osteoporosis, and I I I 1 periodontal disease. Estrogen deficiency may explain, in part, the nature of this association.

CO-RISK FACTORS FOR OSTEOPOROSIS AND PERIODONTAL DISEASE

Osteoporosis and periodontal disease are chronic, multifactorial diseases. It is not surprising, therefore, that both diseases share common risk factors. Skeletal bone loss can be slowed or even Risk factors common to both osteoporosis and reversed if modifiable environmental and dietary periodontal disease are listed under the categories risk factors, such as physical inactivity, cigarette of genetic, dietary, environmental, and systemic smoking, low dietary calcium intake, and excessive factors (Table 10-4). Strong evidence indicates use of caffeine and alcohol, are identified and that genetic and lifestyle factors are important risk reversed. A report from the National Osteoporosis factors for osteopor~sis.~~~~Family history of Foundation concluded that the following factors osteoporosis or fractures, thin body build, genetics, were usehl in identifying women at risk for fracture: race, and advancing age constitute nonmodifiable low body weight (< 58 kg), current smoking, first- risk factors for osteoporosis. degree relative with low-trauma fracture, and per-

TABLE 10-4. Risk Factors for Osteoporosis and Periodontal Disease Osteoporosis Periodontal Disease Hereditary/genetics Female gender 4F Caucasian or Asian race Race Family history Familial aggregation Menopause IL-1 polymorphism Petite body build Suboptimal peak bone Dietary factors Low intake calcium Low intake calcium Low intake vitamin D Low intake vitamins C, E, A, selenium High intake caffeine, protein, salt, phosphate Environment Smoking Smoking Alcohol Alcohol Physical inactivity Stress Systemic factors Diabetes mellitus Diabetes mellitus Multiple myeloma Osteoporosis Connective tissue diseases Hormone changes 174 Periodontal Medicine

bar spine bone mineral density and increased inci- TABLE 10-5. Risk Factors to Identify dence of fractures of the vertebrae and hip.5G58 Women at Risk for Fracture (Recommended Estrogen regulates bone remodeling by modulating by the National Osteoporosis Foundation) the production of cytokines and growth factors, Low body weight (c 58 kg) especially IL-lp, TNF-a, GM-CSF, and M-CSF Current smoking from bone cells.13 Interleukin-1 fland TNF-a stim- First-degree relative with low-trauma fracture ulate mature osteoclasts, modulate bone cell prolif- Personal history of low-trauma fracture eration, and induce bone resorption in vivo.14J5 In addition, IL- 1, TNF-a, and GM-CSF contribute to bone resorption by promoting osteoclast recruit- sonal history of low-trauma fracture (Table 10-5). ment and differentiation from bone marrow precur- These risk factors are simple and easy to ascertain sors. Osteoblast precursors respond to the loss of and effective in identifying women at increased risk. estrogen by secreting IL-6, which then induces Recent evidence indicates that genetics may osteoclastogenesis.l6 The loss of estrogen accompa- play an important role in the severity of periodontal nying menopause results in an increase of cytokines disease as well5' Environmental factors such as in the bone remodeling circuitry. Subjects with smoking and excessive alcohol consumption are "high turnover" osteoporosis secrete increased important modifiable risk factors for periodontal amounts of IL-I that is blocked by estrogen/proges- disea~e.~l>~~Stress and inadequate coping are also terone therapy.59This association, apparently, is not equally predictive for both periodontal disease and restricted to IL-I but also affects other major osteopor~sis.~~Largescale population-based studies mononuclear cell secretory products, such as TNF- indicate that inadequate intake of specific nutrients a and GM-CSF. Cytokine production by peripher- is also associated with severe periodontal di~ease.~~>~~al blood monocytes (PBM) from ovariectomized women that receive no estrogen therapy steadily Estrogen Deficiency increases. Moreover, in vitro treatment of human monocytes with estrogen has been shown to regulate Estrogen deficiency is the factor most closely associ- both IL- 1 and TNF." Accordingly, HorowitzG1pro- ated with postmenopausal osteoporo~is?~>~~Defi- posed that the antiosteoporotic effect of estrogen is ciency of estradiol in postmenopausal and oophorec- exerted through downregulation of cytokine synthe- tomized women is associated with decreased lum- sis and secretion by osteoblasts and other cells.

TABLE I 0-6. Relationship between Estrogen Status and Periodontal Disease Authors Study Desip/Popuhtion Results Conclusion Norderyd et al, Cross-sectional Gingival bleeding significantly ERT associated with 1993 234 postmenopausal women lower in ERT vs. non-ERT less gingivitis in (57 ERT; 177 non-ERT) Lower levels of plaque and postmenopausal Capnocytopbaga sp. women Less attachment loss in ERT group vs. non-ERT Payne et al, Longitudinal 1 year Estrogen-sufficient group showed Estrogen status may 1997 24 postmenopausal women mean net gain in alveolar bone influence alveolar (10 estrogen sufficient; density bone density status 14 estrogen deficient) Estrogen-deficient group showed mean net loss in alveolar bone density Jacobs et al, Longitudinal 5 years Moderate relationship between Estrogen status 1996 69 women, 36 to 64 years old BMC of mandible and lumbar directly related to Natural and surgical menopause spine mandibular Receive estrogen therapy Positive effect of estrogen therapy bone mass on mandibular bone mass

ERT = estrogen replacement therapy; BMC = bone mineral content. Osteopenia, Osteoporosis, and Oral Disease 175

Three studies have directly examined the rela- estrogen defieciency as a risk factor for alveolar tionship of estrogen status/deficiency and peri- bone density loss. Thus, in the estrogen deficient odontal disease (Table 10-6). Norderyd and col- state, the governor controlling cytokines and bone leagues62reported lower, although not statistically remodelling is lost, resulting in increased bone significant, levels of clinical attachment loss in post- resorption and net skeletal and alveolar bone loss. menopausal women receiving estrogen supplemen- Hence, consistent evidence supports the rela- tation compared with estrogen-deficient post- tionship between estrogen status, periodontal dis- menopausal women. In addition, gingival bleeding ease, and mandibular bone density. Results from was statistically significantly reduced in the estro- three independent studies clearly suggest that gen-treated postmenopausal women compared estrogen deficiency plays an important role in with the estrogen-deficient group, after controlling mandibular bone loss and is likely an important for levels of supragingival plaque and frequency of factor modifi-ing the severity of periodontal disease dental treatment. A 5-year longitudinal study of 69 in postmenopausal women. women with surgical or natural menopause receiving hormone replacement therapy compared lum- Smo ki ng bar spine BMD, measured by dual photon absorptiometry, with mandibular bone mass assessed by A meta-analysis of 29 studies including 2,156 smok- quantitative measures of standardized intraoral ers and 9,750 nonsmokers examined the effect of radiograph^.^^ A statistically significant but moder- cigarette smoking on skeletal bone mineral densi- ate correlation was observed between mandibular ty.65While bone density in premenopausal women and lumbar spine bone mass and that estrogen was comparable in smokers and nonsmokers, in replacement therapy after surgical or natural postmenopausal women bone loss was greater in menopause had a positive effect on bone mass not current smokers compared with nonsmokers. The only of the lumbar spine but the mandible as well.63 cumulative risk for hip fractures in women was 19% Payne and colleagues6*showed, in a I-year longitu- in smokers and 12% in nonsmokers. Among all dinal study of 24 postmenopausal women, that women, one in eight hip fractures was attributable estrogen-deficient women displayed a mean net loss to smoking. Limited data was available for men; in alveolar bone density compared with estrogen- however, a similar proportionate effect of smoking sufficient women, who displayed a mean net gain was observed. The meta-analysis concluded that in alveolar bone density. The authors proposed smoking may have a direct effect on bone metabo-

(mm) Current smokers Nonsmokers Attachment loss Bone loss 4m01 Attachment loss Bone loss -**

+I I MF MF

0.0 1 - Males Females Males Females Figure 10-3. Analysis of the Erie County Study reveals that for the entire population of 1,426 individuals 25 to 74 years old, men show more severe periodontal disease than women. However, male and female nonsmokers have the same levels of alveolar bone loss. Among current smokers, on the other hand, males have significantly @ = .03) more alveolar bone loss compared with females, suggesting that the difference in disease severity is explained, in part, by a reduced response to smoking in females, mediated possibly by estrogen status. 176 Periodontal Medicine lism, since the association between smoking and independent of the effects of age, socioeconomic BMD was not explained by smokers being thinner, factors, diabetes mellitus, or dental plaque." Fur- younger at menopause, exercising less, or tobacco thermore, the risk is cumulative and dose depen- smoke having a direct effect on estrogen. dent in that the severity of periodontal disease is The direct effect of smoking on skeletal bone related to the duration and amount of ~moking.~' is modulated by gender and estrogen. Analysis of When alveolar bone loss is used as the outcome BMD at the hip, spine, and radius of the Framing- measure, the risk is even greater.69 This increased ham cohort showed that men smokers had 4 to negative effect on alveolar bone may be explained 15% lower BMD compared with nonsmokers, by the direct effect of smoking on bone metabolism independent of weight, alcohol, or caffeine use," and bone resorption. In a manner similar to skele- implying other mechanisms for the effect of smok- tal BMD, the effect of smoking on alveolar bone is ing on bone. Smoking did not affect skeletal BMD modulated by gender and estrogen. in women that had not taken estrogen. However, Analysis of the Erie County Study cohort reveals lower BMD was seen among women that had that the greater severity in periodontal disease seen in taken estrogen supplementation and were smokers males is explained in part by smoking. That is, if only compared with nonsmokers, suggesting that smok- nonsmokers are examined, disease levels measured as ing negates the bone-sparing effect of estrogen. alveolar bone loss are comparable between both gen- Smoking also accelerated the rate of bone loss at ders. However, when only smokers are examined, the femoral neck and total body in some elderly males exhibit greater alveolar bone loss compared men and women, who participated in a 3-year with females (Figure 10-3). Therefore, the greater placebo-controlled study of calcium and vitamin severity of periodontal disease seen in males appears D s~pplementation.~'Less efficient absorption of to be related to a gender response to smoking. The calcium was proposed as a possible mechanism for lesser severity of periodontal disease in pre- the smoking-related accelerated bone loss. menopausal women that smoke could be explained Smoking is the single most important modifi- by the bone protective effects of estrogen. When the able risk factor for periodontal disease and osteo- levels of periodontal disease in postmenopausal porosis. A meta-analysis of available literature indi- women are examined, nonsmoking women that cates that smokers have 2.5 times the risk for severe receive estrogen supplementation through hormone periodontal disease compared with nonsmokers, replacement therapy (HRT) exhibit less alveolar

Figure 10-4. The effect of smoking and estrogen on alveolar bone loss is seen in women from the Erie County Study. Among nonsmokers, postmenopausal HRT women have levels of alveolar bone loss no different compared with premenopausal (PM) women. Non-HRT women, on the other hand, have bone loss levels significantly greater (p = .04) than PM and HRT counterparts, suggesting a protective effect of estrogen on alveolar bone loss. Among women who smoke, however, both HRT and non-HRT groups have levels of bone loss significantly greater than premenopausal women, suggesting that smoking reduces the protective effect of estrogen. HRT = hormone replacement therapy; PM = premenopausal. Osteopenia, Osteoporosis, and Oral Disease 177 bone loss compared with women that do not take 1,25(OH)2D3, which is the final product of vitamin estrogen (non-HRT) (Figure 10-4).70 In fact, alve- D metabolism. Excess protein intake is related to olar bone loss levels in postmenopausal women increased calcium excretion. Fluoride is a powerhl taking HRT are no different from the levels in pre- stimulator of bone formation, resulting in a major menopausal women. Postmenopausal women that increase in trabecular bone mass. However, cortical smoke and take HRT have levels of alveolar bone fractures have been associated with high fluoride loss comparable with those women that do not levels, which may be related to the fact that fluoride take HRT. Thus, in a manner analogous to skeletal decreases the elasticity of bone. Caeine is correlat- bone density, estrogen has a bone-sparing effect on ed with decreased bone density. In addition, studies alveolar bone, which is negated by current smok- in ovariectomized Sprague-Dawley rats fed a soy- ing (see Figure 104). Similar findings are evident protein diet showed a bone-sparing effect mediated when tooth loss is examined in this population of by isoflavones in ~oy-protein.~~ women, that is, estrogen supplementation is pro- A series of recent studies examining the data tective in postmenopausal tooth loss, and current fiom NHANES I11 demonstrate the significant smoking negates this protective effect as well.71 effect of nutrition as a risk factor for periodontal disease. Trained nutritionists conducted interviews on a Dietary Factors 24-hour diet recall on a nationwide probability sample of approximately 40,000 individuals I to 90+ Peak bone mass is attained at around 30 to 35 years years old. Individuals with diets deficient in calcium of age as the summation of genetically determined had statistically higher levels of periodontal disease factors modulated by dietary and environmental compared with those with calcium sufficient diets.54 factors.72Adequate dietary calcium is essential for This association was especially strong in younger and the growth and development of a normal skele- premenopausal women. Individuals with diets defi- Insufficient calcium intake during childhood cient in vitamins C, A, alpha-carotenoids, selenium, and adolescence can reduce peak bone mass and and lutein also showed increased risk for periodontal enhance postmenopausal and age-related osteo- disease, independently of the confounding effects of por~sis.~~Dietary calcium supplementation has age, dental plaque, and smoking.55Therefore, a diet been shown to increase bone mass in children and complete in vitamins and minerals plays an impor- adolescents and to reduce age-associated bone loss. tant role, not only in ensuring achievement of peak Not surprisingly, osteoporosis has been defined bone mass and protection from age-related bone loss, as a “pediatric disease.” Radial BMD was correlated but it also likely protects against the destruction of with current calcium intake in young women (20 to connective tissue and alveolar bone resulting from 23 years A study of young women failed to periodontal infection. find an association between BMD and calcium intake.76 However, the mean calcium intake for the Genetic Factors study group was 909 mg, high enough to obscure any possible difference. A study of about 18,000 Osteoporosis is likely a multifactorial, polygenic con- Japanese men and women, 30 to 69 years old, found dition involving mutiple genes regulating the attain- that even one glass of milk per day was protective ment of peak bone mass and possibly the control of against osteoporosis in calcium-deficient individual~.~~The National Institutes of Health (NIH), 1994 Conference on Optimal Calcium recommends a TABLE 10-7. National Institutes of dose of 1,000 mg per day for premenopausal Health (NIH) Consensus Conference women, and 1,500 mg per day for estrogen-deficient Recommendation for Optimum Calcium women (Table 10-7). These recommendations are Intake for Caucasians. Requirements for other ethnic groups, as well as for persons with lower protein Premenopausal women 1,000 mg/d intakes and small skeletal size may differ. (25 to 50 years old) The role of phosphorous, vitamin D, protein, Postmenopausal women 1,000 mg/d fluoride, and caffeine on bone mass have been stud- (estrogen therapy) ied as well.78Vitamin D or its metabolites increase Postmenopausal women 1,500 mg/d intestinal calcium absorption, suppress PTH levels, (no estrogen therapy) and increase bone density; their amount and action Men (25 to 65 years old) 1,000 mg/d decrease with age. Osteoblasts have receptors for Women and men > 65 years old 1,500 mg/d 178 Periodontal Medicine turnover. Early studies showed that monozygotic the likelihood that bone mass is maintained over a twins exhibited less variation in bone mass than dizy- lifetime, load-bearing exercise is also necessary. gotic twins.80 A landmark study by Morrison and Like periodontal disease, smoking is a major risk colleagues24reported that bone mass had a genetic factor for osteoporosis and avoidance of smoking component that could be ascribed to an allelic or smoking cessation contributes to osseous health. change in the receptor for 1,25 dihydroxy vitamin There is a limited amount of evidence that cal- D. The vitamin D receptor (VDR) is required for cium supplementation may be beneficial in reduc- normal calcium absorption fiom the gut. It is esti- ing tooth loss. In a 7-year study of 189 post- mated that common allelic variants in the gene menopausal women not taking HRT, subjects were encoding the VDR account for up to 75% of the assigned to receive either placebo, calcium supple- total genetic effect on bone density in healthy Cau- mentation, or vitamin D plus calcium supplemen- casian adults24 and predicts the density of femoral tati~n.~~Four times as many (12%) placebo-treat- and vertebral bone in prepubertal American girls of ed women lost teeth during the study period com- Mexican descent.81Other polymorphisms imparting pared with 3% in the calcium-supplemented susceptibility to osteoporosis include the binding site group. No effect was observed with vitamin D. in collagen type I alpha I (COLIA 1) gene,82.83trans- Bone loss in women occurs most rapidly in the forming growth hctor-beta (TGF-P) gene,84 the years immediately following menopause when nat- estrogen re~eptor,~~the vitamin D promoter region ural levels of estrogen are greatly reduced. Hormone of the osteocalcin gene,86as well as genes regulating replacement therapy is designed to replace estrogen cytokines involved in bone turnover. after menopause since this immediate post- Susceptibility to periodontal infection and the menopausal period is a time of rapid loss of bone inflammatory responses to the infecting organism mineral den~ity.~O-~~For women with a uterus, a appear to be under genetic regulation as well.87 It is combination of estrogen and progesterone is used; possible that periodontal disease is also a polygenic while in women without a uterus, estrogen replace- condition. Candidate genes for susceptibility to peri- ment therapy (ERT) alone is employed. Many stud- odontal disease include genes defining the FcyRII ies have reported that HRT and ERT are efficacious receptor, genes regulating immunoglobulin synthe- in sparing bone mineral and reducing fracture~.~O-~~ sis, especially IgG2, and genes regulating cytokine Few studies have directly assessed the relation- synthesis. Specific genotypes of polymorphic IL- I P ship between periodontal disease and its sequelae in genes are associated with increased IL- I production women receiving HRT. Most of these studies have and associated with severity of periodontal disease in involved HRT with either estrogen or estrogen plus nonsmoker^.^^ This IL-I genotype was found to progesterone, and assessed tooth loss, alveolar bone accurately predict prognosis and tooth survival in loss, or other measures of periodontal health. In a individuals affected by periodontal disease.88Current longitudinal, unblinded study of 69 women receiv- predictive models for both periodontal disease and ing HRT, Jacobs and colleagues63compared lumbar osteoporosis do not account for all the observed vari- spine bone mineral density, measured by dual pho- ability in disease expresssion. Genetically determined ton absorptiometry, with mandibular bone mass individual susceptibility to both conditions may in assessed by quantitative measures of standardized part explain some of the unaccounted variability. intraoral radiographs. The average length of study was 5.1 years. A significant but moderate correlation was observed at the second examination. COMMON TREATMENT STRATEGIES Estrogen replacement therapy was associated with FOR OSTEOPOROSISAND less gingival bleeding after correcting for age,62less PERIODONTAL DISEASE alveolar bone and less tooth than in Avoidance of the morbidity of osteoporosis begins women without estrogen supplementation. with prevention. Adequate calcium intake during Major cohorts of women have been examined adolescence and early adulthood is critical to formin two longitudinal studies in an attempt to deter- ing peak bone mass. The 1994 NIH Conference mine if HRT has reduced the number of lost teeth on Optimal Calcium Intake recommended that in postmenopausal women. These include the 3- daily calcium intake of 1,000 mg of calcium per year study of 42,171 postmenopausal women in day for premenopausal, and 1,500 mg per day for the Nurses Health Cohort95and the 10-year study postmenopausal women (see Table 10-7) should of 3,921 women living in a retirement community be maintained until additional research warrants in the Leisure World Cohort.96The Leisure World revisions to such recommendations. To maximize Cohort taking estrogen experienced a 36% reduc- Osteopenia, Osteoporosis, and Oral Disease 179 tion in tooth loss and the Nurses Health Cohort partial agonisdantagonists of estrogen, which could showed an inverse relationship between HRT and uniquely influence receptor conformation. Thus, loss of teeth, after correcting for smoking and age. research to elucidate the tertiary structure of estro- One potential source of bias in these studies (and, gen receptors will aid in developing “designer estro- in fact, addressed in the reports) is the fact that the gens.” Clearly, much more research into the bone same patients that seek to prevent osteoporosis formation process is needed as well, with the ulti- may seek preventive dental care as well. Both these mate goal of identifi-ing agents capable of promot- populations are large but composed of relatively ing bone formation. Suitable agents at present are well-educated, higher socioeconomic groups. In a fluoride and PTH, each of which is a substantial third study, 488 women aged 72 to 95 years par- promoter of bone formation. ticipating in the Framingham Heart Study were Longitudinal studies are needed to definitively examined.97Estrogen users had more teeth remi- elucidate the contribution of systemic osteopenia to ning than had nonusers, after controlling for age, periodontal disease, alveolar bone loss, alveolar ridge smoking status, and education. resorption, and tooth loss. Additional research is Therapy for osteoporosis is a rapidly changing needed to identify and test, in clinical trials, agents field. The latest generation of bisphosphonate drugs, with effects on reducing skeletal and oral bone such as alendronate, deposit onto bone decreasing resorption. Evidence-based treatment approaches to osteoclast numbers and activity, thereby decreasing manage individuals suffering from both periodontal bone resorption. Alendronate has been shown to disease and systemic osteopenia are urgently needed. inhibit loss of bone density and decrease the risk of Preservation of alveolar bone and alveolar ridge in fracture, without disturbance of bone healing combination with the prevention of fracture is observed with earlier drugs.98 In a pilot clinical essential to provide the quality of life in our older trial, the efficacy of alendronate in slowing alveolar population. Biomedical research needs to ensure bone loss due to periodontitis was in~estigated.~~that the quality of life and well being of this rapidly This %month, double-blind, placebo-controlled, growing segment of our population will continue randomized clinical trial (RCT) measured loss of well into older age. bone height and density using digital subtraction Finally, the first genetic clue to susceptibility radiography. Alendronate reduced the risk of pro- to osteoporosis came from work with the vitamin gressive loss of alveolar bone. The relative risk of D receptor gene. Since then, other candidate genes progressive loss of bone height and density was 0.45 and genetic polymorphisms conferring susceptibil- for the alendronate-treated patients compared with ity to osteoporosis have been identified, establish- placebo-treated patients. ing osteoporosis as a polygenic disease. Additional research is needed to fully unravel the genetic make-up of osteopenia/osteoporosis. Additionally, FUTURE RESEARCH interactions between genetic, nutritional, and lifestyle factors, such as smoking and alcohol Although considerable research has been done in intake, are important targets for future research. the last 10 years in understanding the functions Genetic studies in osteoporosis and periodontal and control mechanisms of bone cells, much work disease will lead to ways of not only identifying still remains to be done in the field of bone cell individuals susceptible to these two crippling dis- biology. New treatments addressing the multifac- eases but also to understanding how the environ- torial nature of osteoporosis will require funda- ment may contribute to modulating the suscepti- mental advances in knowledge in the field of bone bility to both diseases. Future research will provide cell and molecular biology. ways of identifying susceptible individuals likely to Further research is needed on the therapeutic benefit from prevention of both osteopenial control of bone resorption, including the nature of osteoposis and periodontal disease. the cellular and molecular mechanisms by which osteoblasd stromal cells influence progression from hematopoietic precursors to differentiated osteo- REFERENCES clasts. Either the factor(s) responsible or the cascade of events leading to this differentiation will provide 1. Eggs BL. Overview of osteoporosis. West J Med important therapeutic alternatives. Substantial evi- 1991;154:63-77. dence supports the antiosteoporotic effect of estro- 2. Parfitt AM. Bone remodeling: relationship to the gen. However, significant research interest exists in amount and structure for bone, and the patho- 1 8 0 Periodontal Medicine

genesis and prevention of fractures. In: Eggs replication and collagen synthesis in osteoblast- BL, Melton LJ 111, editors. Osteoporosis: etiolo- enriched cell cultures from fetal rat bone. J Biol gy, diagnosis and management. New York: Chem 1987;262:2869-74. Raven Press; 1988. p. 45-93. 20. Canalis E, Centrella M, McCarthy T. Effects of 3. Vaanamen HK. Mechanisms of bone turnover. basic fibroblast growth factor on bone forma- Ann Med 1995;25:353-9. tion in vitro. J Clin Inv 1988;81:1572-7. 4. Parfitt AM. The physiological and clinical signifi- 21. Canalis E, Centrella M, McCarthy T. Effects of cance of bone histomorphometric data. Bone platelet-derived growth factor on bone forma- histomorphometry: techniques and interpretation in vitro. J Cell Physiol 1989;140:530-7. tion. Boca Raton, FL; 1983. p. 143-223. 22. Wozney M, Rosen V, Celeste A, et al. Novel regu- 5. Canalis E. The hormonal and local regulation of lators of bone formation; molecular clones and bone formation. Endocr Rev 1983;4:62-77. activities. Science 1988;242:1528-34. 6. Raisz LG. Local and systemic factors in the patho- 23. Canalis E , McCarthy T, Centrella M. Growth fac- genesis of osteoporosis. N Engl J Med 1988;318: tors and cytokines in bone cell metabolism. Ann 8 18-27. Rev Med 1991;42:17-24. 7. DeLuca H. Vitamin D visited. Clin Endocrinol 24. Morrison NA, Qi JC, Tokita A, et al. Prediction of Metab 1980;9:1-26. bone density from vitamin D receptor alleles. 8. Raisz LG, Kream BE. Regulation of bone forma- Nature 1994;367:284-7. tion. N Engl J Med 1983:309:29-35. 25. Nordin BEC, Morris HA. The calcium deficiency 9. Raisz LG. Recent advances in bone cell biology: model for osteoporosis. Nutr Rev 1989;47: interactions of vitamin D with other local and 65-72. systemic factors. Bone Mineral 1990;9:19 1-7. 26. Marcus R The nature of osteoporosis. J Clin 10. Canalis E, Centrella M, Burch W, McCarthy T. Endocrinol Metab 1995;81(1):1-5. Insulin-like growth factor I mediates selective 27. Kanis JA, et al. The diagnosis of osteoporosis. J anabolic effects of parathyroid hormone in bone Bone Miner Res 1994;9(8):1137-41. cultures. J Clin Invest 1989;83:60-5. 28. Conference Report. Consensus Development Con- 11. McCarthy T, Centrella M, Canalis E. Regulatory ference: diagnosis, prophylaxsis, and treatment effects of insulin-like growth factor I and I1 on of osteoporosis. Am J Med 1993;94:646-50. bone collagen synthesis in rat calvarial cultures. 29. World Health Organization. Assessment of fracture Endocrinology 1989;124:301-9. risk and its application to screening for post- 12. Lukert BE Raisz LG. Glucocorticoid-induced menopusal osteoporosis. Technical Report osteoporosis: pathogenesis and management. Series. Geneva: WHO; 1994. Ann Intern Med 1990;112:352-64. 30. Parfitt AM. Trabecular bone architecture in the 13. Pacifici R. Estrogen, cytokines and pathogenesis of pathogenesis and prevention of fracture. Am J postmenopausal osteoporosis. J Bone Miner Res Med 1987;82:68-72. 1996;ll: 1043-5 1. 31. Eriksen EF. Normal and pathological remodeling 14. Pacifici R. Is there a causal role for IL-1 in post- of human trabecular bone: threee dimensional menopausal bone loss? Calcif Tissue Int 1992; reconstruction of the remodeling sequence in 50~295-9. normal and in metabolic disease. Endocr Rev 15. Tatakis DN. Interleukin-1 and bone metabolism. A 1986;7:379-408. review. J Periodontol 1993;64:416-31. 32. Kribbs PJ, Smith DE, Chesnut CH. Oral findings 16. Girasole G, Jilka RL, Passeri G, et al. 17b-Estradi- in osteoporosis. Part 11. Relationship between 01 inhibits interleukin-6 production by bone residual ridge and alveolar bone resorption and marrow-derived stromal cells and osteoblasts in generalized skeletal osteopenia. J Prosthet Dent vitro: a potential mechanism for the antiosteo- 1983;50:719-24. porotic effect of estrogens. J Clin Invest 1992; 33. Kribbs PJ, Chesnut CH, Ott SM, Kilcyne RF. Rela- 89: 8 83-9 1. tionships between mandibular and skeletal bone 17. Horowitz MC. Cytokines and estrogen in bone: in a population of normal women. J Prosthet anti-osteoporotic effects. Science 1993;260: Dent 1990;63:86-9. 626-7. 34. Kribbs PJ, Chesnut CH. Relationships between 18. McCarthy T, Centrella M, Canalis E. Cortisol mandibular and skeletal bone in an osteoporot- inhibits the synthesis of insulin-like growth fac- ic population. J Prosthet Dent 1989;62:703-7. tor I in skeletal cells. Endocrinology 1990;126: 35. Kribbs PJ. Comparison of mandibular bone in nor- 1569-75. mal and osteoporotic women. J Prosthet Dent 19. Centrella M, McCarthy T, Canalis E. Transforming 1990;63:218-22. growth factor beta is a bifunctional regulator of 36. von Wowern N, Klausen B, Kollerup G. Osteo- Osteopenia, Osteoporosis, and Oral Disease 18 1

porosis: a risk factor in periodontal disease. J of alcohol consumption on periodontal disease. Periodontol 1994;65:1134-8. J Periodontol 1999. [In Press] 37. Jeffcoat MK, Reddy MS, Magnusson I, et al. Efi- 53. Genco RJ, Ho AW, Kopman J, et al. Models to cacy of quantitative digital subtraction radiogra- evaluate the role of stress in periodontal disease. phy using radiographs exposed in a multicenter Ann Periodontol 1998;3(1):288-302. trial. J Periodontal Res 1996;3 1: 157-60. 54. Nishida M, Grossi SG, Dunford RG, et al. Nutrition 38. Jeffcoat MK, Reddy MS. Alveolar bone loss and and risk for periodontal disease. I. Dietary and osteoporosis: evidence for a common mode of serum calcium. J Periodontol 1999. [In Press] therapy using the bisphonate alendronate. In: 55. Nishida M, Grossi SG, Dunford RG, et al. Nutri- Davidovitch 2, editor. The biologic mechanism tion and risk for periodontal disease. I1 .Dietary of tooth resorption and replacement by vitamin C. J Periodontol 1999. [In Press] implants. Boston: Harvard Society for the 56. Utian WH. Biosynthesis and physiologic effects of Advancement of Orthodontics; 1996. estrogen and pathophysiologic effects of estro- 39. Jeffcoat MK, Lewis CE, Reddy MS, et al. Post- gen deficiency: a review. Am J Obstet Gynecol menopausal bone loss and its relationship to 1989;161: 1828-3 1. oral bone loss. Periodontol2OOO. [In press] 57. Lindsay R, Aitken J, Anderson J. Long term pre- 40. Daniel1 Hw.Postmenopausal tooth loss. Contribu- vention of postmenopausal osteoporosis by tions to edentulism by osteoporosis and cigarette estrogen. Lancet 1976; 1: 1038-41. smoking. Arch Intern Med 1983;143: 1678-82. 58. Horsman A, Jones M, Francis R. The effect of 41. Taguchi A, Tanimoto K, Suei Y et al. Tooth loss estrogen dose on postmenopausal bone loss. N and mandibular osteopenia. Oral Surg Oral Engl J Med 1983;309:1404-7. Med Oral Pathol Oral Radio1 Endod 1995;79: 59. Pacifici R, Brown C, Puscheck E, et al. Effect of 127-32. surgical menopause and estrogen replacement 42. Gall EA, Dawson-Hughes B, Papas A, et al. Tooth on cytokine release from human blood loss and skeletal bone density in healthy post- mononuclear cells. Proc Natl Acad Sci U S A menopausal women. Osteoporosis Int 1994;4: 1991;88: 5134-8. 104-9. 60. Cohen-Sold ME, Graulet AM, Denne MA, et al. 43. Gall EA, Garcia RI, Dawson-Hughes B. Increased Peripheral monocyte culture supernatants of risk of tooth loss is related to bone loss at the menopausal women can induce bone resorption: whole body, hip, and spine. Calcif Tissue Int involvement of cytokines. J Clin Endocrinol 1996;59:433-7. Metab 1993;77: 1648-53. 44. Hirai T, Ishijima T, Hashikawa Y, et al. Osteoporo- sis and reduction of residual ridge in edentolous 61. Horowitz MC. Cytokines and estrogen in bone: anti- patients. J Prosthet Dent 1993;69:49-56. osteoporotic effects. Science 1993;260:626-7. 62. Norderyd OM, Grossi SG, Machtei EE, et al. 45. Wactawski-Wende J, Grossi SG, Trevisan M, et al. The role of osteopenia in periodontal disease. J Periodontal status of women taking post- Periodontol 1996;67:1076-84. menopausal estrogen supplementation. J Perio- 46. Grossi SG, Nishida M, Wactawski-Wende J, et al. dontol 1993;64:957-62. Skeletal osteopenia increases the risk for peri- 63. Jacobs R, Ghyselen J, Konincla van Steenberghe odontal disease. J Dent Res 1998;77:Abstract D. Long term bone mass evaluation of #2 140. mandible and lumbar spine in a group of 47. Kanis JA, McCloskey. Risk factors in osteoporosis. women receiving hormone replacement therapy. Maturitas 1998;30(3):229-33. Eur J Oral Sci 1996;104:10-6. 48. Ross PD. Risk factors for osteoporotic fracture. 64. Payne JB, Zachs NR, Reinhardt RA, et al. The Endocrinol Metab Clin North Am 1998;27(2): association between estrogen status and alveolar 289-30 1. bone density changes in postmenopausal 49. Cumming SR. Treatable and untreatable risk fac- women with a history of periodontitis. J Perio- tors for hip fracture. Bone 1996;18(3 Suppl): dontol 1997;68:24-3 1. 16%-167s. 65. Law MR, Hackshaw AK. A meta-analysis of ciga- 50. Kornman KS, Crane A, Wang H-Y, et al. The inter- rette smoking, bone mineral density and risk of leukin-1 genotype as a severity factor in adult hip fracture: recognition of a major effect. BMJ periodontal disease. J Clin Periodontol 1997; 1997;315:841-6. 24: 72-7. 66. Kiel Dc Zhang Y, Hannan MT, et al. The effect of 5 1. Grossi SG, Zambon JJ, Ho AW, et al. Assessment of smoking at different life stages on bone mineral risk for periodontal disease. I. Risk indicators for density in elderly men and women. Osteoporo- attachment loss. J Periodontol 1994;65:260-7. sis Int 1996;6:240-8. 52. Tezal M, Grossi SG, Ho AW, Genco RJ. The effcet 67. Gall EA, Dawson-Hughes B. Smoking increases 182 Periodontal Medicine

bone loss and decreases intestinal calcium absorp- premenopausal women with diabetes mellitus. tion. J Bone Miner Res 1999;14(2):215-20. Diabetologia 1998;41(11):1314-20. 68. Papapanou PN. Periodontal diseases; epidemiolo- 84. Yamada Y, Miyauchi A, Goto J, et al. Association of gy. Ann Periodontol 1996;1 : 1-36. polymorphism of the transforming growth factor 69. Grossi, SG, Genco RJ, Machtei EE, et al. Assess- beta 1 gene with genetic susceptibility to osteo- ment of risk for periodontal disease. 11. Risk porosis in posunenopausal Japanese women. indicators for alveolar bone loss. J Periodontol J Bone Miner Res 1998;13( 10); 1569-76. 1995;66:23-9. 85. Grant SFA, Ralston SH. Genes and osteoporosis. 70. El-Ghorab N, Grossi SG, Dunford R, et al. Effect Trends Endocrinol Metab 1997;8:232-6. of smoking and estrogen supplementation on 86. Wood RJ, Fleet JC. The genetics of osteoporosis: interproximal alveolar bone loss in women. vitamin D receptor. Ann Rev Nutr 1998;18: J Dent Res 1996;75:Abstract 244. 223-58. 71. Ferreira C, Grossi SG, Ho AW, et al. Tooth loss in 87. Michalowicz BS. Genetic and heritable risk factors women: relationship to estrogen supplementation in periodontal disease. J Periodontol 1994;65: and smoking. J Dent Res 1996:75:Abstract 245. 479-88. 72. Eisman JA. Genetics, calcium intake and osteo- 88. McGuire MK, Nunn ME. Prognosis vs. actual out- porosis. Proc Nutr SOC1998;57(2): 187-93. come. W. The effectiveness of clinical parame- 73. Faine MI? Dietary factors related to preservation of ters and IL-1 genotype in accurately predicting oral and skeletal bone mass in women. J Pros- prognoses and tooth survival. J Periodontol thet Dent 1995;73(1):65-72. 1999;70:49-56. 74. National Institutes of Health. Consensus Develop- 89. Krall EA, Garcia RI, Dawson-Hughes B. Increased ment Conference. JAMA 1984;252:799-802. risk of tooth loss is related to bone loss at the 75. Fehily AM, Coles RJ, William DE, Elwood PC. whole body, hip and spine. Calcif Tissue Int Factors affecting bone density in young adults. 19 96; 5 9 :43 3-7. Am J Clin Nutr 1992;56:579-86. 90. Christiansen C, Christensen MS, Transbol I. Bone 76. Mazess RB, Barden HS. Bone density in pre- mass in posunenopausal women after withdraw- menopausal women: effect of age, dietary al of oestrogedgestagen replacement therapy. intake, physical activity, smoking and birth con- Lancet 1981;i:459-6 1. trol pills. Am J Clin Nutr 1991;53:132-42. 91. Ettinger B, Genant HK, Cann C. Long-term estro- 77. Yoshida H, Nagaya T, Hayashi T, et al. Milk con- gen replacement therapy prevents bone loss and sumption decreases activity of human serum fractures. Ann Intern Med 1985;102:319-24. alkaline phosphatase: a cross-sectional study. 92. Felson DT, Zhang Y, Hannan MT, et al. The effect Metab Clin Exp 1995;44(9):1190-3. of postmenopausal estrogen therapy on bone 78. Heaney W, Recker RR. Effects of nitrogen, phos- density in elderly women. N Engl J Med 1993; phorus and caffeine on calcium balance in 329: 114146. women. J Lab Clin Med 1982;99:46-55. 93. Lindsay R. Estrogens, bone mass and osteoporotic 79. Arjmandi BH, Birnbaum R, Goyal W,et al. Bone fracture. Am J Med 1991;91:10S-13S. sparing effect of soy protein in ovarian hor- 94. Naessen T, Persson I, Adami HO, et al. Hormone mone-deficient rats is related to its isoflavone replacement therapy and the risk for first hip content. Am J Clin Nutr 1998;68(6 Suppl): fracture. A prospective, population-based cohort 1364s-8s. study. Ann Intern Med 1990;113:95-103. 80. Pocock N, Eisman J, Mazess R Genetic determi- 95. Grodstein F, Colditz G, Stampfer G. Post- nants of bone mass in adults: a twin study. J menopausal homone use and tooth loss: a Clin Invest 1987;80:706-10. prospective study. J Am Dent Assoc 1996;127: 81. Sainz J, Van Tornout JM, Loro ML, et al. Vitamin- 370-7. D receptor gene polymorphisms and bone den- 96. Paganini-Hill A. Benefits of estrogen replacement sity in prepubertal American girls of Mexican therapy on oral health: the leisure world cohort. descent. N Engl J Med 1997;337:77-82. Arch Intern Med 1995;155:2325-9. 82. Langdahl BL, Ralston SH, Grant SF, Erikson EF. 97. Krall E, Dawson-Hughes B, Hannan M, et al. Post- An Spl binding site polymorphism in the menopausal estrogen replacement and tooth COLIAl gene predicts osteoporotic fractures in retention. Am J Med 1997;102:536-42. both men and women. J Bone Miner Res 1998; 98. Papapoulos SE. Bisphosphonates. Pharmacology 13(9):1384-9. and use in the treatment of osteoporosis. In Mar- 83. Hampson G, et al. Bone mineral density, collagen cus RE, Feldman D, Kelsey J, editors. Osteo- type 1 alpha 1 genotypes and bone turnover in porosis. San Diego: Academic Press; 1996. CHAPTER11

HIV INFECTION AND PERIo D ONTAL D IS EAS ES

Michael Glick, DMD Palle Holmstrup, PhD, Dr. Odont

The human immunodeficiency virus (HIV) epi- The body's natural immune system cannot demic is not abating. By the end of 1998, an esti- detect and eliminate cells latently infected with mated 34 million individuals worldwide were HIV, as these cells lack the expression of viral anti- infected. Eleven men, women, and children, half gens on the cell surface. Furthermore, as the provi- of these aged 15 to 24 years, acquire a new infec- ral DNA is already integrated into the cellular tion every minute. Approximately four people suc- genome, it cannot be targeted by existing antiretro- cumb to this disease every minute. Although the viral medications which inhibit the RNA reverse death rate from HIV infection has slowed down in transcriptase of HIV. Therefore, elimination of the United States and Western Europe due to new HIV can only be accomplished by activating latent- and improved therapies, 75,000 new infections are ly infected cells in combination with potent anti- still recorded annually.' This changing face of the retroviral therapy. This will create a situation where epidemic suggests an increasing number of people latently infected cells are induced into a state of living with HIV disease requiring health services. productive infection and die, while the antiretrovi- As with all chronic diseases, a multidisciplinary ral therapy prevents infectious viruses released from approach to care results in improved quality of life these cells from infecting new cells. and decreased morbidity and mortality. This chap- Another concern for infected individuals is the ter focuses on oral lesions and conditions affecting state of their debilitated immune system. Thus, in the periodontium that are found in individuals concert with targeting infected cells, immune with HIV infection and also explores the possible reconstitution also needs to be addressed. The connection between the propagation of periodon- hallmark of HIV disease is the infection and sub- tal infection and the propagation of HIV infection. sequent depletion of CD4+ Tcells. After successful As periodontal manifestations have shown to institution of antiretroviral therapy, a sharp rise be markers for immune deterioration and HIV dis- of CD4+ T cells can be noticed.* However, this ease progression, early recognition of these lesions increase apparently occurs as a result of the redis- and an understanding of their significance in the tribution of memory cells. These T cells are severe- course of HIV disease will impact on the overall ly limited in their ability to recognize different systemic care for infected individuals. New insights antigens. The appearance of nalve CD4+ T cells, into the pathogenesis of HIV infection have with specificities that had previously been lost, revealed much about the fate of, as well as the may occur only after several months. Thus, the immune response to, the virus. Until recently, it immunologic repertoire during the course of HIV was generally believed that HIV was constantly disease predisposes to increased susceptibility to replicating, notwithstanding clinical asymptomatic opportunistic infections. The level of immune periods. Therapeutic interventions focused on deterioration or reconstitution determines the slowing down the replication rate as well as the individual's susceptibility to specific infections. transcription of viral proteins. However, new The influence of periodontal infection on the research has discovered the existence of latently pathogenesis of HIV disease has not been elucidat- infected CD4+ T cell^.^>^ This phenomenon poses ed. However, the immune system weakened by a significant problem both for an effective immune HIV may have a direct influence on the pathogen- response and for drug therapy. esis of periodontal disease. 184 Periodontal Medicine

Individuals infected with HIV exhibit oral The classification includes three groups of conditions and lesions often associated with lesions (Table 11-1): (1) lesions strongly associat- immune ~uppression.~These oral manifestations ed with HIV infection, (2) lesions less commonly may reflect systemic conditions or could compli- associated with HIV infection, and (3) lesions seen cate systemic disease. Among HIV-infected indi- in HIV infe~ti0n.l~Most characteristic among the viduals, no oral lesions are found that are directly lesions listed in the latter category are the types of caused by HIV. Instead, lesions are mostly associ- infection which are extremely rare in noninfected ated with immune suppression and opportunistic individuals. These include Histophsmu cupsuhtum pathogens and can therefore be found among other and fungal infections other than candidiasis. immunosuppressed individuals as well. For a lesion Although a number of these diseases may affect the to be classified as “HIV-associated,” the lesion periodontal tissues, they are outside the scope of needs to be more common or exhibit a different the present chapter. However, conventional forms clinical course and appearance than those in indi- of periodontal diseases affect HIV-infected individuals not infected with HIV. viduals but may differ in their clinical course. This A multitude of lesions that affect the perio- aspect will be discussed below in the section dontium have been described. Moreover, aggres- “lesions seen in HIV infection.” sive periodontal lesions may be the first clinical expression of the HIV Bacterial, viral, fungal, or parasitic infections can all affect LESIONS STRONGLY ASSOCIATED the course of HIV disease as well as take on differ- WITH HIV INFECTION ent clinical manifestations and severity or require different treatment modalities than in non-HIV- Three periodontal disease entities can be consid- infected individuals. Due to the impaired immune ered to be strongly associated with HIV infection. system characteristic of HIV disease, infections often These are linear gingival erythema (LGE), necro- present a more serious course compared with tizing gingivitis (NG) or necrotizing ulcerative gin- immunocompetent individuals. This is also found givitis (NUG), and necrotizing periodontitis (NP) with infections of the periodontal tissues. Com- or necrotizing ulcerative periodontitis (NUP). l5 It parative studies attempting to assess the association is important to note that similar lesions may occur of periodontal disease entities with HIV infection in non-HIV-infected individuals16-18 even with are often limited by several factors. They include similar prevalence.19-23 Consequently, although the lack of specific diagnostic criteria, the use of the initial descriptions of these lesions referred to various HIV treatment regimens, and lack of infor- them as HIV-associated gingivitis and HIV-associ- mation on the immune status of the HIV-infected ated periodontitis, the more descriptive terminolo- individual. An additional problem is biased study gy of the lesions is used today. In the list of lesions populations, frequently selected on the basis of strongly associated with HIV (Table 11-l), a few institutional affiliation. This means that usually supplementary disease entities that may also affect the groups of HIV-infected subjects under investi- the periodontium are included. These entities are gation are more seriously affected by HIV disease candidiasis, Kaposi’s sarcoma, and non-Hodgkin’s than the entire group of HIV-infected individuals. lymphoma.

Linear Gingival Erythema TERMINOLOGY Diagnosis and Clinical Presentation A wide spectrum of terms have been used to Linear gingival erythema presents as a fiery red describe soft and hard tissue inflammatory and/or band of the marginal gingiva, characterized by a destructive conditions of the periodontium, pre- disproportional inflammatory intensity in relation sumably associated with HIV infection. 12-14 An to the amount of plaque present. There are no internationally accepted classification of the oral ulcerations and no evidence of pocketing or attach- manifestations of HIV infection and their diag- ment loss. A further characteristic of this type of nostic criteria has been established by the EC- lesion is its lack of response to improved oral Clearinghouse on Oral Problems Related to HIV hygiene and to ~caling.’~ Infection and the WHO Collaborating Centre on The first description of LGE included a dis- Oral Manifestations of the Immunodeficiency tinctive erythema of the free gingiva, attached gin- Virus (EC-WHO) at a meeting in 1993.15 giva, and alveolar mucosa in individuals with HIV HIV Infection and Periodontal Diseases 18 5

TABLE I I- I. Revised Classification of Oral Lesions Associated with HIV Infection Group 1: Lesions strongly associated with HIV infection Candidiasis Erythematous Pseudomembranous Hairy leukoplakia Kaposi’s sarcoma Non-Hodgkin’s lymphoma Periodontal disease Linear gingival erythema Necrotizing (ulcerative) gingivitis Necrotizing (ulcerative) periodontitis Group 2: Lesions less commonly associated with HIV infection Bacterial infections Mycobacterium avium-intracelluhre Mycobacterium tuberculosis Melanotic hyperpigmentation Necrotizing (ulcerative) stomatitis Salivary gland disease Dry mouth due to decreased salivary flow rate Unilateral or bilateral swelling of major salivary glands Thrombocytopenic purpura Ulceration NOS (not otherwise specified) Viral infections Herpes simplex virus Human papillomavirus (warty-like lesions) Condyloma acuminatum Focal epithelial hyperplasia Verruca vulgaris Varicella-zoster virus Herpes zoster Varicella Group 3: Lesions seen in HIV infection Bacterial infections Actinomyces israelii Escbericbia coli Klebsielh pneumoniae Cat-scratch disease Drug reactions (ulcerative, erythema, multiforme, lichenoid, toxic epidermolysis) Epithelioid (bacillary) angiomatosis Fungal infection other than candidiasis Cyptococcus neofo mans Geotricbum candidum Histophsma capsuhtum Mucoraceae (Mucormycosis/zygomycosis) Asperigillus&vus Neurologic disturbances Facial palsy Trigeminal neuralgia Recurrent aphthous stomatitis Viral infections Cytomegalovirus Molluscum contagiosum

With permission from EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus. Classification and diagnostic criteria for oral lesions in HIV infection. J Oral Pathol Med 1993;22:289-91. 1 8 6 Periodontal Medicine disease.24Free gingival erythema, appearing as an some studies have revealed microflora comprising intense linear band extending 2 to 3 mm apically both Cundidd ulbicuns and a number of perio- from the free gingival margin was seen in more dontopathic bacteria consistent with those seen in than 50% of cases. Punctate or difhse erythema of conventional periodontitis, that is, Porpbyromonus the attached gingiva was another prominent fea- gingivulis, Prevotellu intermediu, Actinobucillus ture. The lesions were associated with pain in some uctinomycetemcomituns, Fusobucterium nucleutum, instances and most frequently involved the entire and Cumpylobucter rectus.33,34 Studies using DNA mouth with an equal distribution to all quadrants. probes have suggested the percentage of A. uctino- Sometimes they were limited to one or two teeth, mycetemcomituns-positive sites in HIV-associated and the changes were present even with little or no gingivitis and matched gingivitis sites of HIV- plaque accumulations. The extent of gingival seronegative patients to be 23% and 7%, respec- banding measured by the number of affected sites tively. Furthermore, positive sites were 52% and was later suggested to depend on tobacco 17% for I? gingivulis, 63% and 29% for I? inter- While 15% of affected sites were originally report- mediu, and 50% and 14% for C. rectus, respec- ed to bleed on probing and I I% exhibited sponta- ti~ely.~~”~C. ulbicuns has been isolated by culture neous bleeding,24 a key feature of linear gingival in about 50% of HIV-associated gingivitis sites, in erythema is now considered to be lack of bleeding 26% of unaffected sites of HIV-seropositive on probing. l4 patients, and in 3% of healthy sites of HIV- seronegative patients. The frequent isolation and Prevalence the pathogenic role of C. ulbicuns may be related A few studies of unbiased groups of patients have to the high levels of the yeast in the saliva and oral indicated that gingivitis with bank-shaped or mucosa of HIV-infected patients.35 punctate marginal erythema may be relatively rare The significance of CD4+ T cell depletion in in HIV-infected patients and probably represents the pathogenesis of LGE is uncertain. A study of a clinical finding which is not more frequent than 25 patients with so-called HIV-associated gingivi- in the general population.20.2’ Other studies of tis showed CD4/CD8 ratios within the low nor- various groups of HIV-infected patients have mal range.24In another study of the red banding of revealed the prevalence of gingivitis with band- the gingiva, it was concluded that the condition shaped patterns in 0.5 to 49%.25-29These preva- was not related to immunosuppression, as equal lence values reflect some of the problems with number of cases had CD4+ T cell counts above non-standardized diagnosis and selection of study and below 400/mrn3.l9 A similar result has been groups as mentioned above. There is no doubt that obtained by others.25 However, a more recent several studies comprise cohorts of patients with study comprising 396 HIV-seropositive individu- poor oral h~giene,~‘>~~and the degree to which the als classified according to their peripheral CD4+ reported inflammatory processes respond to con- lymphocyte counts revealed linear gingival erythe- ventional therapy is currently unknown. A prepon- ma in 2 patients with less than 200 CD4 derance of HIV-associated red banding was not cells/mm3 as opposed to none among patients with noted in a recent British study, while diffuse and 200 CD4 cells/mm3 or more.‘ punctate erythema was significantly more preva- An interesting histopathologic finding in biop- lent in HIV-infected than in non-HIV-infected sy specimens from the banding zone has revealed individual^.^^ Red gingival banding as a clinical no inflammatory infiltrate but an increased number feature alone is, therefore, not strongly associated of blood vessels, which explains the red color of the with HIV infection. lesion^.^' The incomplete inflammatory reaction of While several studies are available on HIV- the host tissue may be the cause of the lack of infected adults, few reports describe HIV-related response to conventional treatment. diseases among children. In two studies, however, as many as 30% and 37%, respectively, were diag- Differential Diagnosis nosed with so-called HIV-gingivitis, which is syn- A number of diseases present clinical features onymous with LGE.30>31 resembling those described above and which, accordingly, do not resolve after improved oral Etiology and Pathogenesis hygiene and dkbridement. Oral lichen planus is There are suggestions that candidal infection is frequently associated with a similar inflammatory the etiologic agent in some cases of gingival red band of the attached gingi~a,~~and mucous inflammation, including LGE.23>24>32However, membrane pemphigoid may also have this appear- HIV Infection and Periodontal Diseases 187 an~e.~~Geotrichum cundidum infection39 and mucogingival junction would have qualified for hypersensitivity reactions manifesting as plasma the diagnosis of NS,41 but the description of NP cell gingivitis40 are other rare differential diagnoses. as proposed by EC-WHO incorporates tissue In rare instances, gingivitis-like changes may also destruction extending across the mucogingival be the result of thr~mbocytopenia.~’ border. Consequently, the differential diagnosis between NP and NS is not always clear, as NS is Treatment sometimes described as extending from areas of Important characteristics of the originally described NI?l5 Necrotizing stomatitis is mentioned below entity of LGE included a temporal lack of response in the section on “lesions less commonly associat- to plaque removal and an erythematous appeared with HIV infection.” ance disproportional to the amount of plaque. There is considerable variation in the clinical Reports of different therapeutic results may be due manifestations ranging from initial lesions with to the varied definition of LGE. Conventional necrosis limited to the top of the interdental papil- therapy with 0.12% chlorhexidine gluconate lae, to moderate manifestations with involvement mouth rinses twice daily has been reported to show of the entire attached gingiva with tooth mobility significant improvement after 3 months.42Howev- and sequestration of parts of the crestal bone, to er, HIV-associated free gingival erythema did not severe cases with extensive bone loss and necrosis respond to removal of plaque by intense scaling of supporting tissues. Fetor oris evolves in most and root planing and improved plaque control cases as a characteristic feature. measures, alone or supplemented with povidone- The initial lesion typically presents with iodine irrigation 3 to 5 times daily. There was no changes in gingival contour, such as interproximal significant improvement in clinical features or necrosis, ulceration, and cratering. The most dis- indices after I and 3 months of treatment. Howev- tinguishing feature is soft tissue necrosis and the er, the povidone-iodine irrigation substantially rapid destruction of periodontal attachment and reduced pain reported to be associated with the bone. Severe cases can affect all teeth, but more fre- lesions examined. quently, several localized areas are affected inde- As mentioned above, LGE may in some cases pendently, and all regions appear to have similar be related to the presence of C. ulbicuns. In accor- chances of being affected. The lesions are not dance with this finding, clinical observations indi- always associated with deep pocket formation, as cate that improvement is frequently dependent on extensive gingival necrosis often coincides with loss successful eradication of intraoral C. ulbicuns, of crestal alveolar bone. On the other hand, the which results in the disappearance of the charac- rapid progression of the soft tissue necrosis some- teristic features.24Consequently, attempts to iden- times leads to the exposure of the alveolar bone, tify the presence of hngal infection either by cul- which becomes sequestrated and leaves deep inter- ture or smear are recommended, followed by dental Frequently, such defects are locat- antimycotic therapy in C. ulbicuns-positive cases. ed in the molar/premolar region. Severe pain has been mentioned as a distin- Necrotizing (Ulcerative) Gingivitis guishing feature of HIV-associated periodonti- and Periodontitis ti~~~,~~,~~,~and the chief reason for patients seeking treatment. Bleeding on probing is a prominent fea- Diagnosis and Clinical Presentation ture, and about 50% of involved sites bleed spon- The necrotizing (ulcerative) diseases NG, NP, and tane~usly.~~The number of sites affected by papil- necrotizing stomatis (NS) are the most severe perio- lary destruction have been shown to be significant- dontal disorders, presumably caused by bacteria. ly determined by tobacco About 85% of These entities may represent various stages of sim- individuals with HIV-associated periodontitis ilar disease process.43The distinction between NG lesions have been described to be aware of their and periodontitis is parallel to the distinction serostatus at their initial visit.23 between gingivitis and periodontitis. Thus, NG should be limited to lesions only involving gingi- Prevalence val tissue with no loss of periodontal attach- Meaningful comparisons of prevalence data In most patients, however, the disease among the available studies remain unavailable process rapidly results in loss of attachment, in because of the diversity in the study methods and which case NP is the correct terminology. Previ- diagnostic criteria and the variance in groups ously, progression of the disease process across the under investigation. One major problem is the 1 8 8 Periodontal Medicine lack of a clear distinction between NG and NP in that I? gingivulis was more prevalent in conven- the majority of the literature. However, even tak- tional peri~dontitis.~~>~~>~~Greater numbers of ing these limitations into account, studies show I? gingivulis have been revealed in samples from that NG is more common among HIV-seroposi- non-HIV-infected subjects with healthy periodon- tive individuals than in the general population. tium than in samples from HIV-associated perio- The prevalence in these studies ranges from 5 to dontiti~.~'Other findings have indicated that sub- I 1%.8J9,27,4547In contrast, other more recent gingival plaque in acquired immunodeficiency studies have either found low prevalence (0 to syndrome (AIDS) patients with periodontitis can 0.7%)23,29*48or no significant difference between harbor high proportions of the same periodontal cohorts of HIV-seropositive and HIV-negative pathogens as are associated with periodontitis in patients.22 The anterior gingiva is most common- non-HIV-infected individuals, but additional high ly which agrees with NG in HIV- proportions of other opportunistic pathogens like seronegative patients.49 Gingival ulceration may Clostridium, Enterococcus, and C. ulbicuns.52 The affect individual teeth or extend to several areas of suggestion that the predominant subgingival the jaws.8 microflora in HIV-associated periodontitis is in Necrotizing periodontitis has been described in many ways similar to that of progressing periodon- 88% among 136 HIV-infected patients.28However, titis lesions in systemically healthy adults has been most studies have shown considerably lower preva- supported by others.53 On the other hand, this lence values of NP among HIV-infected individuals, investigation of HIV-associated periodontitis such as 6.3% of 700 HIV-seropositive patients5' lesions also revealed organisms rarely associated and in 1% of 200 HIV-seropositive patients.29Yet, with common types of periodontitis. Higher pro- other studies have suggested that HIV-associated portions of C. ulbicuns and C. rectus were charac- periodontitis with ulceration and tissue necrosis teristic of HIV-associated periodontitis, the quali- may be relatively rare and that the prevalence may, tative profiles of HIV-associated gingivitis and in fact, not differ significantly from that of similar HIV-associated periodontitis being similar and lesions of the general p~pulation.'~-~' only C. rectus showing major quantitative differences. None of the available studies answer the Etiology and Pathogenesis important question whether other pathogens cause Established knowledge of the pathogenic back- tissue breakdown in HIV-associated disease unlike ground of tissue necrosis in NG and NP is limited. in non-HIV associated disease. Necrotizing gin- One of the most interesting questions is whether less givitis has been associated with peripheral CD4+ pathogenic organisms can cause tissue necrosis in lymphocyte depletion in a few st~dies.~>~~Howev- HIV-infected as compared with non-HIV-infected er, the disease has also been found to be unrelated individuals. Data on the microflora associated with to immunosuppression, with equal numbers of necrotic periodontal lesions are unfortunately com- patients having CD4+ T cell counts above and promised by frequent lack of precise description of below 400/mm3.l9 the sites from which the microbiologic samples were The severity of periodontal destruction has obtained. There is no doubt that many samples are been associated with the progression of HIV dis- obtained from deep pockets, and consequently, the ease in several ~tudie~.~~~~~~~~~~~~~~~~~~~~-~~The cause findings may not be directly related to tissue necro- mentioned in these studies is that the progressive sis. No clear distinction can therefore be drawn depletion of immune effector and regulatory cells between NP and other forms of HIV-associated in HIV-seropositive patients compromises the periodontitis in the description of the microbiolog- local host defense to such an extent that the sus- ic profile. A hrther complication is that the avail- ceptibility to periodontal disease increases. One able information on the microbiology of HIV-asso- study even suggested that NP was a stronger pre- ciated NG is very limited. The isolated organisms dicator of HIV disease progression and immune include Borreliu, gram-positive cocci, P-hemolytic suppression than established AIDS defining ill- streptococci, and C. ulbicuns.8 ne~ses.~'A temporal relationship between NP and The occurrence of I? gingivulis, spirochetes, poor survival was also suggested, where almost and motile eubacteria in periodonitis has been 60% of patients with NP died within 18 months found to be the same in HIV-infected patients and of the periodontal diagnosis. However, other stud- in systemically healthy adult^.^' Also, the microflo- ies have indicated that the association between ra isolated from HIV-associated periodontitis was HIV-related immune depletion and periodontal similar to that of classic adult periodontitis, except destruction is less ~trong.~~~~~ HIV Infection and Periodontal Diseases 1 8 9

Differential Diagnosis were not detectable in samples obtained at 30 min- A number of oral mucosal diseases can be con- ute~.~~Removal of sequestra does not always fused with NG and NP. These include bullous appear to require antibiotic coverage.65 lesions of benign mucous membrane pemphigoid and erythema multiforme exudativum, but the progressive nature and the localized occurrence LESIONS LESS COMMONLY of NG and NP usually distinguish these diseases ASSOCIATED WITH HIV INFECTION from bullous mucosal diseases. Acute forms of leukemia may be associated with necrotizing gin- A number of lesions less commonly associated with gival ulcers of the oral mucosa, which sometimes HIV infection may affect the periodontal tissues. manifest in the marginal gingiva.17J8The gingi- Necrotizing stomatitis is among the most serious, val lesions are often bluish red and edematous. but other important diseases are lesions caused by Medical examination will reveal the cause in sus- herpes simplex virus, human papilloma virus, and pect cases. Since serologic/hematologic examina- varicella-zoster virus. These lesions, however, are tion usually is necessary for patients unaware of a not included in this chapter. possible HIV infection or another cause of the necrotizing periodontal disease, a possible sup- Nec roti zi ng Sto mat i t is plementary blood examination to look for leukemia is justifiable. Necrotizing stomatitis (NS) is defined as a localized, acutely painful ulceronecrotic lesion of the Treatment oral mucosa, exposing underlying bone or pene- The treatment aspects of NG and NP are similar. trating or extending into contiguous tissues. The In HIV-infected patients, the diseases do not rou- lesions may extend from areas of NI?15 tinely respond to conventional treatment with seal- ing and improved oral hygiene.24 However, the Diagnosis and Clinical Presentation adjunctive use of metronidazole in these patients is The clinical aspects of NS resemble those of NG reported to be extremely effective in reducing acute and NI? Necrotizing stomatitis is the most severe pain and promoting rapid healing.50>60Due to the and is not as common as NG and NP5The exten- susceptibility of HIV-infected patients to candidal sively destructive lesions are rapidly progressive, infections," simultaneous treatment with appro- ulcerative, and necrotizing. In most cases, the priate antimycotic agents may be necessary. lesions extend from the gingiva into the adjacent Although it has been postulated that healing is mucosa and bone, causing destruction of both oral delayed in HIV-infected patients and pain may be soft tissues and underlying bone. The disease prolonged,8 other studies did not reveal increased appears to be related to the immune depletion incidence of delayed healing after extraction or caused by HIV infection." Importantly, it may be other complications even in severely immunocom- life threatening,67 and the clinical features of NS promised individuals. Therefore, prophylactic resemble noma as described by Tempest.68Progres- antimicrobials were not re~ommended.~~>~~Fre- sion of NP to NS may result in progressive osseous quent use of antibiotics may give rise to problems de~truction,~~with sequestration and/or the devel- due to microbial resistance; hence a restrictive atti- opment of oroantral fistula and o~teitis.~~The dif- tude is important. ferential diagnostic and treatment aspects for NS Follow-up care for HIV-associated necrotizing are similar to those of NG and NI?67 periodontal diseases is essential to ensure success in treatment. Inadequate plaque control in sites affected by NP is often associated with delayed LESIONS SEEN IN HIV INFECTION healing and continued rapid destruction. In many cases, extensive tissue destruction results in Individuals infected by HIV may suffer from com- residual defects, which may make it very difficult mon forms of periodontal diseases without tissue for the patient to maintain oral hygiene. Oral necrosis or other characteristic features of HIV hygiene in these areas often requires the use of infection as described above. These diseases with interproximal devices and soft, smaller brushes. less dramatic clinical features include adult peri- Antibiotic prophylaxis may not be necessary in odontitis20>21and rapidly progressive periodonti- relation to scaling, since bacteria were recovered tk8The most interesting aspect of these diseases in from venipuncture 15 minutes after scaling but HIV-infected populations is whether their preva- 19 0 Periodontal Medicine lence figures and progression of attachment loss are ~ania.~~However, when using clinical attachment similar to those encountered in non-HIV-infected loss and radiographic assessment of alveolar bone individuals. loss, definite trends are evident pointing to HIV infection being a risk indicator for progression of Conventional Adu It Periodo nt it isl peri~dontitis.~~ Rapidly Progressive Periodontitis Etiology and Pathogenesis Prevalence Reports of the microbiology of HIV-associated A number of studies among HIV-seropositive indi- periodontitis do not always state whether micro- viduals have reported high prevalence figures of bial samples have been obtained from lesions with severe attachment loss, but others have failed to or without necrosis. The available microbiologic show differences between HIV-seropositive and data are described above in relation to NG and NI? HIV-seronegative individual^.^^ The reported The reports on the significance of HIV-related prevalence figures of periodontitis among HIV- immune deterioration and loss of attachment are seropositive patients show considerable variation conflicting. However, most studies have revealed (5 to 69%), the variation being due to differences an association between progression of periodontitis in study groups. For instance, several studies com- and decreased number of peripheral T-helper cells. prise groups of patients who are selected on the One study has shown that periodontitis in patients basis of admission to hospitals or to the dental set- with more advanced stages of HIV infection was ting, but it is not possible to identify mechanisms related to severity of systemic disease and to of selection in all referred studies. decreasing numbers of CD4+ lymphocytes but not Severe periodontal destruction was revealed in to visible plaque index or occurrence of periodon- 11% of 44 HIV-seropositive patients45 and pro- tal pathogenic microorganism^.^^ A 20-month fol- gressive periodontitis comparable with rapidly pro- low-up study of I 14 homosexual and bisexual men gressive peri~dontitis~'was diagnosed with similar showed relative attachment loss of 3 mm or more frequency among 110 HIV-seropositive patients.8 occurring 6.16 times more frequently among sub- Twenty-seven percent of 200 HIV-seropositive jects with CD4+ counts < 200 compared with sub- patients had moderate or advanced adult perio- jects with counts of 200 or more. Among individ- dontiti~.~~In a study of 181 heterosexual men and uals aged 35 years and over, the incidence (33%) of women with AIDS, 92% of the patients being relative attachment loss of 3 mm or more was sig- intravenous drug users, the prevalence was much nificantly higher in more immunosuppressed indi- higher than in other studies. The clinical features viduals compared with the incidence (5%) in less were not reported in detail, and figures for patients immunosuppressed subjects. In 78 individuals without tissue necrosis could not be identified. seen at follow-up visits, mean gingival indices Early periodontitis was found in 24%, moderate in increased and were significantly higher in the 23%, and advanced in 22%. Significantly seropositive subjects compared with the seronega- increased severity of periodontitis was seen in tive ones, but gingival indices were not related to women as compared with men.26 CD4+ T cell counts within the seropositive group. A number of studies have shown limited The study suggested a greater sensitivity to plaque prevalence figures. Among 141 HIV-seropositive in the seropositive group. The authors concluded homosexual males, 5% had severe periodontitis as that immunosuppression, especially in combina- compared with 0.2% among 606 seronegative tion with older age, may be a risk for attachment homosexual males. The reported prevalence was loss, and HIV seropositivity, independent of markedly lower than that reported for severe perio- CD4+ T cell counts, may be a risk factor for gin- dontitis in adult males in the United States. No gival inflammati~n.'~In a study of 29 HIV- radiographic examination was available.22 Studies seropositive patients and 27 control patients, the based on the registration of periodontal indices HIV-seropositive patients had a higher mean per- have shown that loss of attachment associated with cent of sites exhibiting suppuration than the con- HIV infection is a relatively rare condition, at least trol group.59Among 3 12 men with HIV infection, in some cohorts of patients.20.21One of the most decreased CD4 lymphocyte counts predicted the recent studies revealed no significant differences in extent and severity of periodontal attachment loss bleeding on probing, pocket formation, or attach- but not pocketing, which was only related to HIV ment loss among HIV-seronegative and HIV- infection when compared with 260 men without seropositive individuals and AIDS patients in Tan- HIV.22 In contrast, a recent report from Tanzania HIV Infection and Periodontal Diseases 19 1 did not reveal any significant associations between 9. Schicat M, Pindborg JJ. AIDS and the oral cavity. periodontal indicies with regard to lymphocyte Epidemiology and clinical oral manifestations of and CD4+ T cell counts among the HIV-infected human immune deficiency virus infection: a individuals including AIDS patients.58 review. Int J Oral Maxillofac Surg 1987;16:1-14. 10. Scully C, Laskaris G, Pindborg JJ, et al. Oral man- Treatment ifestations of HIV infection and their manage- Since deterioration of the immune deficiency may ment. I. More common lesions. Oral Surg Oral be a risk factor for attachment loss, and HIV- Med Oral Pathol 199 1;7 1: 1 5 8-66. seropositivity may be a risk factor for gingival 11. Winkler JR, Robertson PB. Periodontal disease inflammation, it is particularly important that associated with HIV-infection. Oral Surg Oral HIV-infected individuals practice intensive oral Med Oral Pathol 1992;73:145-50. hygiene and receive frequent professional preven- 12. Holmstrup Westergaard J. Periodontal diseases in tive dental treatment.19 This supports the idea of HIV-infected patients. J Clin Periodontol 1994; providing intensive oral care programs to be initi- 2 1~270-80. ated as soon as the diagnosis of HIV infection is 13. Holmstrup Westergaard J. HIV infection and established. periodontal diseases. Periodonto12000 1998;18: 37-46. 14. Robinson PG, Winkler JR, Palmer G, et al. The REFERENCES diagnosis of periodontal conditions associated with HIV infection. J Periodontol 1994;65: 1. WHO End of year annual report on HIV and 236-43. AIDS. Geneva: WHO; 1998. 15. EC-Clearinghouse on Oral Problems Related to 2. Chun Tw, Stuyer L, Mizell SB, et al. Presence of HIV Infection and WHO Collaborating Centre inducible HIV- 1 latent reservoir during highly on Oral Manifestations of the Immunodeficien- active antiretroviral therapy. Proc Natl Acad Sci cy Virus. Classification and diagnostic criteria 1997;94:13193-7. for oral lesions in HIV infection. J Oral Pathol 3. Finzi D, Hermankova M, Peirson T, et al. Identifi- Med 1993;22:289-9 1. cation of a reservoir for HIV-1 in patients on 16. Mealey BL. Periodontal implications: medically highly active antiretroviral therapy. Science compromised patients. Ann Periodontol 1996; 1997;278:1295-300. 1:256-321. 4. Leandersson AC, Bratt G, Fredrikson M, et al. Spe- 17. Glick M, Garfunkel AA. Common oral findings in cific T-cell responses in HIV-infected patients two different diseases-leukemia and AIDS. aft er highly active anti re t r ovi ral therapy Part I. Compend Contin Educ Dent 1992;13: (HAART). Abstract 31 142. Geneva: 12th 432-50. World AIDS Conference; 1998. 18. Garfunkel AA, Glick M. Common oral findings in 5. Glick M, Muyka BC, Lurie D, Salkin LM. Oral two different diseases-leukemia and AIDS. manifestations associated with HIV disease as Part 11. Compend Contin Educ Dent 1992;13: markers for immune suppression and AIDS. Oral 550-62. Surg Oral Med Oral Pathol 1994;77:344-9. 19. Barr C, Lopez MR, Rua-Dobles A. Periodontal 6. Ceballos-Salobrena A, Aguirre-Urizar JM, Bagan- changes by HIV serostatus in a cohort of homo- Sebastian JV. Oral manifestations associated sexual and bisexual men. J Clin Periodontol with human immunodeficiency virus infection 1992; 19:794-80 1. in a Spanish population. J Oral Pathol Med 20. Drinkard CR, Decker L, Little JW, et al. Periodon- 1996;25 :523-6. tal status of individuals in early stages of human 7. Ficarra G, Berson AM, Silverman S, et al. Kaposi’s immunodeficiencyvirus infection. Comm Dent sarcoma of the oral cavity: a study of 134 Oral Epidemiol 1991;19:28 1-5. patients with a review of the pathogenesis, epi- 21. Friedman RB,Gunsolley J, Gentry A, et al. Perio- demiology, clinical aspects and treatment. Oral dontal status of HIV-seropositive and AIDS Surg Oral Med Oral Pathol 1988;66:543-50. patients. J Periodontol 199 1;62:623-7. 8. Reichart PA, Gelderblom HR, Becker J, Kuntz A. 22. Melnick SL, Engel D, Truelove E, et al. Oral AIDS and the oral cavity. The HIV-infection: mucosal lesions: association with the presence of virology, etiology, origin, immunology, precau- antibodies to the human immunodeficiency tions and clinical observations in 110 patients. virus. Oral Surg Oral Med Oral Pathol 1989; Int J Oral Maxillofac Surg 1987;16:129-53. 6 8 :37-43. 192 Periodontal Medicine

23. Robinson PG, Sheiham A, Challacombe SJ, dental plaque control on gingival lichen planus. Zakrzewska JM. The periodontal health of Oral Surg Oral Med Oral Pathol 1989;69: homosexual men with HIV infection: a con- 585-90. trolled study. Oral Dis 1996;2:45-52. 38. Pindborg JJ. Atlas of diseases of the oral mucosa. 24. Winkler JR, Grassi M, Murray PA. Clinical descrip- 5th ed. Copenhagen: Munksgaard; 1992. p.246. tion and etiology of HIV-associated periodontal 39. Heinic GS, Greenspan D, MacPhail LA, Greenspan disease. In: Robertson PB, Greenspan JS, edi- JS. Oral Geotricbum candidum infection associ- tors. Oral manifestations of AIDS. Proceedings ated with HIV-infection. A case report. Oral of First International Symposium on Oral Man- Surg Oral Med Oral Pathol 1992;73:726-8. ifestations of AIDS. Littleton: PSG Publishing 40. Serio FG, Siege1 MA, Slade BE. Plasma cell gin- Company; 1988. p.49. givitis of unusual origin. A case report. J Peri- 25. Swango PA, Kleinman DV, Konzelman JL. HIV odontol 199 1;62:390-3. and periodontal health. A study of military per- 41. EC-Clearinghouse on Oral Problems Related to sonnel with HIV. J Am Dent Assoc 1991;122: HIV Infection and WHO Collaborating Centre 49-54. on Oral Manifestations of the Human Immun- 26. Klein RS, Quart AM, Small CB. Periodontal disease odeficiency Virus. An update of the classifica- in heterosexuals with acquired immuno-deficiency tion and diagnostic criteria of oral lesions in syndrome. J Periodontol 1990;62:535-40. HIV-infection. J Oral Pathol Med 1991;20: 27. Laskaris G, Hadjivassiliou M, Stratigos J. Oral 97-1 00. signs and symptoms in 160 Greek HIV-infected 42. Grassi M, Williams, CA, Winkler JR, Murray PA. patients. J Oral Pathol Med 1992;21:120-3. Management of HIV-associated periodontal 28. Masouredis CM, Katz MH, Greenspan D, et al. diseases. In: Robertson PB, Greenspan JS, edi- Prevalence of HIV-associated periodontitis and tors. Perspectives on oral manifestations of gingivitis in HIV-infected patients attending an AIDS. Proceedings of First International Sym- AIDS clinic. J Acquir Immune Defic Syndr posium on oral manifestations of AIDS. Little- 19925 :479-83. ton: PSG Publishing Company; 1988. p.119. 29. Riley C, London Jc Burmeister JA. Periodontal 43. Horning GM, Cohen ME. Necrotizing ulcerative health in 200 HIV-positive patients. J Oral gingivitis, periodontitis, and stomatitis: clinical Pathol Med 1992;21 : 124-7. staging and predisposing factors. J Periodontol 30. San Martin T, Jandinski JJ, Palumbo I? Periodontal 199566: 990-8. diseases in children infected with HIV 44. Greenspan D, Schicadt M, Greenspan J, Pindborg [abstract]. J Dent Res 1992;71:366A. JJ. AIDS and the mouth. Copenhagen: Munks- 31. Schoen D, Murray Jandinski J. Periodontal sta- gaard; 1990. tus of HIV-positive children [abstract]. J Dent 45. Porter SA, Luker J, Scully C, et al. Orofacial man- Res 1994;73:2003A. ifestations of a group of British patients infected 32. Lamster IB, Grbic JT, Mitchell-Lewiss DA, et al. with HIV-1. J Oral Pathol Med 1989;18:47-8. New concepts regarding the pathogenesis of 46. Schulten EJAM, ten Kate RW, van der Waal I. Oral periodontal disease in HIV infection. Ann Peri- manifestations of HIV-infection in 75 Dutch odontol 1998;3:62-75. patients. J Oral Pathol Med 1989;18:42-6. 33. Murray PA, Grassi M, Winkler JR. The microbiol- 47. Thompson SH, Charles GA, Craig DB. Correla- ogy of HIV-associated periodontal lesions. J tion of oral disease with the Walter Reed staging Clin Periodontol 1989;16:636-42. scheme for HIV- 1-seropositive patients. Oral 34. Murray PA, Winkler JR, Peros WJ, et al. DNA Surg Oral Med Oral Pathol 1992;73:289-92. probe detection of periodontal pathogens in 48. Moniaci D, Greco D, Flecchia G, et al. Epidemiol- HIV-associated periodontal lesions. Oral ogy, clinical features and prognostic value of Microbiol Immunol 1991;6:34-40. HIV-1 related oral lesions. J Oral Pathol Med 35. Tylenda CA, Larsen J, Yeh C-K, et al. High levels 1990; 19:477-8 1. of oral yeasts in early HIV-infection. J Oral 49. Barnes Gc Bowles WF, Carter HG. Acute necro- Pathol Med 1989;18:520-4. tizing ulcerative gingivitis: a survey of 2 18 cases. 36. Glick M, Pliskin ME, Weiss RC. The clinical and J Periodontol 1973;44:35-42. histologic appearance of HIV-associated gingivi- 50. Glick M, Muyka BC, S&n LM, Lurie D. Necro- tis. Oral Surg Oral Med Oral Pathol 1990;69: tizing ulcerative periodontitis: a marker for 395-8. immune deterioration and a predictor of the diag- 37. Holmstrup Schicatz AW, Westergaard J. Effect of nosis of AIDS. J Periodontol 1994;65:393-7. HIV Infection and Periodontal Diseases 19 3

51. Gornitsky M, Clark DC, Siboo R, et al. Clinical 61. Holmstrup Samaranayake LE Acute and AIDS- documentation and occurrence of putative perio- related oral candidoses. In: Samaranayake LE dontopathic bacteria in human immunodeficiency MacFarlane Tw, editors. Oral candidosis. Lon- virus-associated periodontol disease. J Perio- don: Wright; 1990. p.133. dontol 1991;62: 576-85. 62. Robinson PG, Cooper H, Hatt J. Healing after den- 52. Zambon JJ, Reynolds HS, Genco RJ. Studies of the tal extractions in men with HIV-infection. Oral subgingival microflora in patients with acquired Surg Oral Med Oral Pathol 1992;74:426-30. immunodeficiency syndrome. J Periodontol 63. Glick M, Abel SN, Muzyka BC, DeLorenzo M. 1990;6 1:699-704. Dental complications after dental treatment of 53. Rams TE, Andriolo M, Feik D, et al. Microbiolog- patients with AIDS. J Am Dent Assoc 1994; ical study of HIV-related periodontitis. J Perio- 125296-301. dontol 1991;62:74-81. 64. Lucartorto FM, Franker CK, Maza J. Postscaling 54. Lucht E, Heimdahl A, Nord CE. Periodontal dis- bacteremia in HIV-associated gingivitis and ease in HIV-infected patients in relation to lym- periodontitis. Oral Surg Oral Med Oral Pathol phocyte subsets and specific micro-organisms. 1992;73: 5 5 04. J Clin Periodontol 199 1; 18:252-6. 65. Robinson E The management of HIV. Brit Dent J 55. Steigley KE, Thompson SH, McQuade MJ, et al. A 1991;171:287. comparison of T4:T8 lymphocyte ratio in the 66. Muzyka BC, Glick M. Necrotizing stomatitis and periodontal lesion of healthy and HIV-positive AIDS. Gen Dent 1994;42:66-8. patients. J Periodontol 1992;63:753-6. 67. Williams CA, Winkler JR, Grassi M, Murray PA. 56. Tomar SL, Swango PA, Kleinman DV, Burt B. Loss HIV-associated periodontitis complicated by of periodontal attachment in HIV-seropositive necrotizing stomatitis. Oral Surg Oral Med Oral military personnel. J Periodontol 1995;66:421-8. Pathol 1990;69:351-5. 57. Martinez-Canut Guarinos J, Bagin JV. Peri- 68. Tempest MN. Cancrum oris. Br J Surg 1966;53: odontal disease in HIV seropositive patients and 949-53. its relation to lymphocyte subsets. J Periodontol 69. SanGiacomo TR, Tan PM, Loggi DG, Itkin AB. 1996;67:33-6. Progressive osseous destruction as a complica- 58. Scheutz F, Matee MIN, Andsager L, et al. Is there tion of HIV-periodontitis. Oral Surg Oral Med an association between periodontal condition Oral Pathol 1990;70:476-9. and HIV infection?J Clin Periodontol 1997;24: 70. Felix DH, Wray D, Smith GLF, Jones GA. Oro- 5 80-7. antral fistula: an unusual complication of HIV- 59. Smith GLF, Cross DL, Wray D. Comparison of associated periodontal disease. Br Dent J 1991; periodontal disease in HIV seropositive subjects 171:61-2. and controls. I. Clinical features. J Clin Perio- 71. Page RC, Altman LC, Ebersole JL, et al. Rapidly dontol 199522:5 58-68. progressive periodontitis. A distinct clinical con- 60. Scully C, Porter SR, Luker J. An ABC of oral dition. J Periodontol 1983;54:197-209. health care in patients with HIV-infection. Brit Dent J 1991;171:149-50. CHAPTER12

PERIODONTAL DISEASEAND PERIODONTALMANAGEMENT IN PATIENTSWITH CANCER

Joel B. Epstein, DMD, MSD, FRCD(C)

PATIENTS WITH HEAD AND An additional consideration in preradiation NECK CANCER treatment planning is the finding that periodontal involvement of teeth in high-dose radiation of Radiation therapy that includes the oral cavity and some sites can lead to the development of osteo- salivary glands may have dramatic effects upon oral necrosis. l7 Periodontal attachment loss, particular- health. The acute effects of radiation therapy ly on the buccal aspect of teeth in a high-dose radi- include mucositis, altered salivary gland function, ated field, has been reported to represent a risk fac- and risk of mucosal infection. The long-term effects tor for the development of osteonecrosis.l8 include alteration in the vascularity of soft tissue and It is important to realize that periodontal bone, salivary gland damage, reduction in the cellu- attachment loss is greater in teeth in irradiated larity of bone and connective tissue, and risk of sites; l8 therefore, preradiation treatment planning increased collagen synthesis resulting in fibrosis should include consideration of the impact of (Figure 12-1). Cellular damage may lead to reduc- additional attachment loss over time on the ability tion in cellularity of tissue, fibrosis of connective tis- to retain teeth and, in particular, to maintain teeth sue, and vascular changes with intimal thickening, that may serve as abutment teeth for dental pros- endarteritis, and thrombosis. These changes result in theses. Statistically significant increase in attach- hypovascular, hypocellular, and hypoxic tissue. 'p4 ment loss occurs in teeth in the sites of high-dose The affected bone has a reduced capacity to remod- irradiation and is reflected in increased mobility of el and may be at increased risk of infection. The periodontium is sensitive to the effects of radiation at high doses.l-ll Blood vessels in the periodontium, periosteum, and the periodontal ligament' ,3,7,8 may be affected, leading to widening of the periodontal ligament space.'-' These changes may result in increased risk of periodontal disease and altered healing with impaired capacity of bone remodeling and repair.l>l2.l3Rampant periodontal destruction may occur in the absence of good oral hygiene.12 Because of the effects of therapeutic radiation, periodontal involvement of teeth to be included in the high-dose fields must be assessed prior to radiation therapy to identify teeth that cannot be maintained for a lifetime and may Figure 12-1. This photograph demonstrates exposure of require extraction prior to irradiation. l4>l It has bone in a patient following head and neck radiation therapy. been shown that preradiation extraction of teeth Radiation changes are seen involving the gingival tissues carries a lower risk of osteonecrosis than extraction extending into the floor of the mouth, and the necrotic, of teeth following radiation therapy. l6 stained area of the bone is exposed in the molar region. 19 6 Periodontal Medicine

long-term prognosis questionable or poor (Table TABLE I 2- I. Considerations for Preradiation Extraction of Teeth in the High-Dose Fraction 12-1). Periodontal considerations suggesting the possible need for extraction include probing depths Caries: nonrestorable teeth or attachment loss of > 5 mm, moderate to advanced Active periapical disease: symptomatic teeth alveolar bone loss, or advanced recession with or Moderate to advanced periodontal disease without mucogingival involvement. In patients with Lack of opposing teeth, compromised hygiene limited past dental care, poor oral hygiene, and evi- Partial impaction or incomplete eruption of teeth dence of past dental/periodontal disease, more Extensive periapical lesions (not if chronic or well aggressive management should be considered. The localized) recommendation for pretreatment extractions may be modified on the basis of the position of the teeth in question and should take into consideration the these teeth in irradiated fields.18 Also, following relative importance of individual teeth for hture radiation therapy, tooth loss is greater in fields of restoration and hnction, such as teeth that may serve irradiation. The increased periodontal involvement as abutments for prostheses. and loss of teeth in the high-dose fraction indicates Following radiation therapy, good oral care a local effect on the tissue, likely due to changes in and compliance with recommendations for oral the cellularity, vascularity, and reduced healing/ care are improved with regular post-treatment den- remodeling potential of the periodontium. tal visits for reinforcement of oral maintenance.22 Similarly, decreased saliva volume has been Periodontal treatment following radiation therapy shown in patients with Sjogren’s syndrome to result must be provided with knowledge of fields of irra- in increased risk of alveolar bone loss, attachment diation. Despite the potential for the development loss, and increased distance between the cemento- of osteonecrosis in high-dose volumes, if surgical enamel junction and the alveolar bone crest.19 In intervention is considered, it has been shown that patients with head and neck cancer and xerostomia, treatment including periodontal surgery is possi- the periodontal breakdown was comparable with ble, if necessary, and may be more easily tolerated the results reported in those with Sjogren’s syn- than e~traction.~~ drome. l8 However, more significant periodontal destruction was noted in the teeth within the irradiated bone, supporting the potential for irradia- PATIENTS RECEIVING HIGH-DOSE tion-induced changes in the periodontium to influ- CHEMOTHERAPY AND/OR BONE ence progression of periodontal involvement. Of MARROWTRANSPLANT course, the progression of the periodontal condition is also related to the patient’s home care. Periodontal manifestations of leukemia occur in The patient’s current periodontal status and some patients prior to the diagnosis of leukemia. the probability of continuing loss of periodontal The periodontal findings may occur as early man- attachment in general and greater attachment loss ifestations of disease or may develop during cancer within the fields of high-dose irradiation should be therapy (Figures 12-2, 12-3). Patients, especially considered in dental treatment planning prior to those with significant platelet dyshnction, may radiation therapy. A UK study found that only present with gingival bleeding. In some patients, 11.2% of patients who reported regular dental and more commonly in those with monocytic and office attendance prior to a diagnosis of oral cancer myelomonocytic leukemia, gingival infiltration had no dental conditions that required treatment may be seen (Figure 12-4). In patients with neu- before radiation therapy.20 The provider must be trophil dyshnction or neutropenia, the inflamma- knowledgeable and understand the basis of radia- tory response may be blunted or not seen, leading tion therapy, the nature of the planned radiation to nonhealing gingival ulceration and poor treatment for each patient (radiation dose, sched- response to tissue therapy following dental proce- ule, and fields) and the oral/dental/periodontal sta- dures. In patients with reduced red cell produc- tus in order to develop the best preradiation treat- tion, the oral tissues may appear pale (Figure ment plan.2’ 12-5). Thus, the presentation prior to diagnosis Teeth in the high-dose radiation field that and during treatment of leukemia may be variable, should be extracted prior to radiation therapy are ranging from significant oral changes that may lead those that are nonrestorable, and those with moder- to the diagnosis of leukemia to minimal findings ate to severe periodontal disease that makes their that are not suggestive of an underlying disease. Periodontal Disease and Periodontal Management in Patients with Cancer 19 7

Figure 12-2. This figure demonstrates gingival infiltration Figure 12-3. This figure represents gingival infiltration with minimal inflammatory response and some tissue pallor with soft tissue necrosis, minimal inflammatory response in a patient with progressive chronic lymphocytic leukemia. and some bleeding into tissues in a patient with progressing myelodysplastic syndrome, later diagnosed as chronic myelogenous leukemia. Prior to medical management, oral health assessment is conducted to identify oral conditions that may become symptomatic during medical compromised patients with blood dyscrasias, the therapy, particularly those that may represent risk frequency and severity of infection increases with sites of infection. Studies have shown that oral and the severity and duration of gran~locytopenia.”~-~~ periodontal assessment and management reduce Fifty-four percent of adult patients with leukemia the risk of infection and fever associated with oral develop oral lesions during ~hemotherapy.~~The condition^.^^-^^ The clinical diagnosis of oral infec- length of hospital stay is greater in patients who tion depends upon an accurate history of oral develop oral lesions, and in 25% of patients with symptoms and a thorough examination. Signs and positive blood cultures, an oral source is probable. symptoms may be minimized in neutropenic Increased length of hospitalization and alpha- patients, with reduced erythema, swelling, and hemolytic streptococcal septicemia have been pain in sites of infection. Careful appraisal of the reported in patients with oral ulcerative mucositis patient with cancer is needed, with understanding consistent with an oral source of infe~tion.~‘Thus, of pre-existing sites of periodontal involvement the oral cavity is a site of potential systemic infection and careful evaluation that includes an assessment in neutropenic patients. of tissue tenderness. While some have empirically raised concerns that periodontal probing and periodontal maintenance procedures may increase the risk of bacteremia in leukemic patients prior to medical management, this has not been seen in studies assessing the risk of fever or bacteremia following such procedure^.^^^^^^^^^^^ Patients may be febrile during neutropenia, and potential oral sources of infection must be carefully considered. The patient’s underlying systemic disease and its medical management are critical factors in determining the risk for infection. Oral infection is seen in approximately one-third of patients with acute leukemia or chronic leukemia in the blast phase.30 In patients receiving chemotherapy for solid tumors, 10% may develop oral infe~tion.~l>~~The complica- Figure 12-4. This figure demonstrates gingival hyperplasia, tions common in patients on intensive chemothera- with bleeding into the gingival margins, particularly at inter- py protocols for breast cancer (methotrexate, 5-flu- dental papillae. This was an individual with previous diag- orouracil, vincristine, and prednisone) include neu- nosis of myelodysplastic syndrome and the gingival involve- rotoxicity (65%), mucositis (2 1%, often associated ment was the initial finding of progression to acute myel- with neutropenia), and ~andidiasis.~~In immuno- ogenous leukemia. 19 8 Periodontal Medicine

existing periodontal disease. Gingivitis and periodontitis due to mixed bacterial infections are also common and have been reported in up to 25% of all infections in patients with acute nonlymphocytic leukemia." Patients with chronic periodontal disease receiving high-dose chemotherapy may develop acute exacerbations at pre-existing sites of disease during periods of ne~tropenia.~'~~Assessment of the periodontal flora during chemotherapy showed that a shift in the flora to increased gram-negative bacilli occurred in less than 50% of patient^.^"^' Of these, the Pseudornonus species predominated although was also pre~ent.~'Periodon- Figure 12-5. This photograph demonstrates mild gingival Klebsielh pneurnoniue hyperplasia in interdental regions and isolated areas of the tal disease and attachment loss was associated with gingival margins. There is tissue pallor and no evidence of recovery of staphylococci from supragingival sites hemorrhage. This patient was diagnosed with acute myel- but no correlation with yeast colonization was seen. ogenous leukemia (AML) type 4. In another study, the periodontal flora in leukemic patients were assessed in sites of exacerbation of periodontal disease.44In 24 patients, exacerbations Bacteremia due to oral sources has been well doc- developed during neutropenia in all but 2 cases. The umented in immunosuppressed potential pathogens identified were Stuphylococcus Bacterial infections may arise from oral sources in ep idemidis, Cu ndidu ulbicuns, Stuphylococcus u ureus, one-third of patients with acute leukemia. The bac- and Pseudornonus ueruginosu in primary infection or teria implicated include periodontal flora, strepto- mixed culture. The subgingival flora associated with cocci, and staphylococci (Figure 12-6). More these exacerbations were indigenous when com- recently, an increase in streptococcal bacteremia has pared with noncancer patients. In these patients, been reported in leukemic patient~."4:">"~' The inflammatory signs were suppressed, making detec- shift in the organisms identified in bacteremia may tion diffic~lt.~~>~O be due to use of systemic antibacterial prophylaxis Thus, pre-existing periodontal disease may with improved coverage of gram-negative organ- serve as a site for the development of infection in isms. Current antibiotic coverage may have an neutropenic An oral source of sep- impact on the potential for exacerbation of pre- ticemia was suspected in 25% of patients with acute leukemia who received dental care and scaling prior to chemotherapy, compared with 77% of patients without such dental care prior to ~hemotherapy.'~ The primary sources were pericoronitis or pre-existing periodontal infections. In a study of fever following oral examination with and without periodontal probing and scaling in leukemic patients, no differences were seen in the incidence of fever or bacteremia between groups.29 Oral preventive care has been shown to not result in increased risk of bacteremia or in fever and is associated with less severe oral muc~sitis.'~Thus, periodontal evaluation and treatment may reduce the potential for septicemia from periodontal sources. In patients who will become neutropenic, den- Figure 12-6. This patient was undergoing chemotherapy tal and periodontal treatment should be completed for acute myelogenous leukemia and developed an area of prior to chemotherapy. It is desirable to have a 2- tenderness between the incisors. Clinically, ulceration of the week healing period prior to the anticipated onset of interdental papillae with minimal erythematous reaction and possible extension of the ulceration along the attached gingi- neutropenia. In patients with solid tumors treated val tissue is seen. A culture identified Staphylococcus bacteria in with chemotherapy, the treatment schedules are this region. provided in a planned series, often on a 3 to 4 week Periodontal Disease and Periodontal Management in Patients with Cancer 19 9 basis for a number of treatments. In patients with solid tumors, chemotherapy may result in a short- term depression in white cell counts. Typically, blood counts improve prior to the next course of chemotherapy. Dental and periodontal treatment should be provided when the white cell counts are not suppressed, which is typically 2 to 3 weeks following a course of chemotherapy, just prior to the next dose of chemotherapy. Antibiotic coverage may be considered when the neutrophil counts are less than 500 cells/mL, if the treatment cannot be delayed until counts are higher than 1,000 cells/mL. Empiric antibiotic therapy for management of the febrile neutropenic patient is well established. Figure 12-7. This patient felt discomfort in the palatal gin- The antibiotic must be broad spectrum, bacterio- gival tissues. The clinical diagnosis was herpes simplex virus, cidal, and given in appropriate dose and schedule. and increasing acyclovir dose led to resolution. These lesions Metronidazole appears to be an important antimi- were confirmed as HSV on viral culture, and exfoliative crobial in the management of oral infection associ- cytology demonstrated the presence of HSV-like inclusions. ated with fever in neutropenic patients.52 In leukemic patients, who remain febrile despite broad-spectrum antibiotics, defervescence may to reduce the risk of mucositis and not increase the occur when metronidazole is added to the antibi- risk of fever or ba~teremia.~~ otic regimen.52 In leukemia/bone marrow transplant (BMT) The use of topical agents has not yet been patients, reactivation of latent herpes simplex virus shown to be effective in the prevention of coloniza- (HSV) infection occurs in the majority of carriers tion of the oropharynx and in the prevention of oro- in the “absence” of viral pro phyla xi^.^^-^^ In the mucosal infections. Chlorhexidine has been shown mouth, the lesions most commonly affect the ker- to reduce plaque formation and disperse established atinized mucosa of the gingiva, the palate, and the plaque; the agent may assist in managing gingivitis tongue, frequently beginning on the attached gin- and periodontal involvement, reduce caries risk, and giva as I- to Zmm, rounded ulcerations that can may decrease oral colonization by C~ndidu.~~>~~extend to form large confluent lesions (Figures In patients who will become neutropenic, 12-7, 12-8). A patient seropositive for HSV has a prior to myelosuppressive chemotherapy, elimination of pre-existing foci of infection is desired. The oral cavity, dentition, and periodontium must be examined thoroughly, including radiographic evaluation, when indicated, on the basis of the findings of the examination. If necessary, delaying the myelosuppressive therapy should be considered in order to manage a symptomatic dental infection. If asymptomatic periapical pathosis is present, dental treatment may be completed after chemotherapy, and the patient should be covered by appropriate systemic antibiotic therapy during myelosuppres- Local irritants such as calculus and rough irregular dental surfaces should be managed to reduce local tissue irritation. Dentures should be cleaned regularly, and removal of the appliance at night is recommended due to microbial coloniza- Figure 12-8. A patient during treatment for leukemia, with tion of the denture surface.58 In cancer patients, ulceration involving the gingival tissues, extending from the margin into the vestibular mucosa and bicuspid region, and pretreatment oral/dental management has been an extensive ulceration with the development of exophytic shown to decrease the length of hospital stay, and mass on the lip. Culture and tissue sampling identified her- to be associated with reduced oral complica- pes simplex virus, and treatment with acyclovir was associat- tion~.~~,~~-~~Good oral hygiene has been reported ed with improvement in the lesions. 20 O Periodontal Medicine high probability of viral reactivation during induc- 5. Arcuri MR, Schneider U. The physiological tion chemotherapy for leukemia or during effects of radiotherapy on oral tissue. J Prostho- BMT.65-67Since HSV infections in immunocom- dont 1992;1:37-4 1. promised patients are severe and can be associated 6. Fattore D, Straus R, Bruno J. The management of with high morbidity and mortality, chemoprophy- periodontal disease in patients who have received laxis with acyclovir and its analogs has become radiation therapy for head and neck cancer. Spec standard for seropositive patients during BMT.68-72 Care Dent 1987;7:120-3. Acyclovir-resistant HSV during prolonged treat- 7. Pappas GC. Bone changes in osteoradionecrosis ment has been reported although when this occurs, and their clinical significance. Oral Surg Oral increasing the dose of acyclovir or its analogs may Med Oral Pathol 1987;64:379-90. be effective, and foscarnet is also available.62>65,72-77 8. Beumer J, Curtis TZ. Radiation therapy of head Other antivirals are under de~elopment.~~>~~ and neck tumors. In: Beumer J, Curtis TA, Varicella-zoster infection is also common in Firtell DW, editors. Maxillofacial Rehabilita- immunocompromised patients, with the lesions tion. St Louis: CV Mosby, 1979. p. 43-89. initially confined to the dermatome distribution of 9. Fujita M, Tanimoto K, Wada T. Early radiographic the involved nerve branches. Cytomegalovirus changes in radiation bone injury. Oral Surg (CMV) causes up to 20% of post-transplant deaths, Oral Med Oral Pathol 1986;61:641-4. and reactivation occurs in up to 70% of seroposi- 10. Medals H, Burnett GW. The effect of x-ray irradi- tive patients.78Cytomegalovirus can present as per- ation on the oral tissues of the Macacus rhesus sisting oral mucosal ulcers and has been reported monkey. Oral Surg Oral Med Oral Patholl954; to cause gingival Diagnosis 7:778-86. requires suspicion of the potential causes of the 11. Chambers F, Ng E, Ogden H, et al. Mandibular lesion and is based on clinical findings and positive osteomyelitis in dogs following irradiation. Oral virus identification in the involved tissue. Surg Oral Med Oral Pathol 1958;11:843-59. Periodontal disease should be assessed and 12. Silverman S, Chierici G. Radiation therapy of oral managed prior to medical treatment of oropharyn- carcinomas. I. Effects on oral tissues and man- geal cancer and in patients in whom neutropenia agement of the periodontium. J Periodontol may develop during treatment. Oral and peri- 1965;36:478-84. odontal infection may exacerbate during cancer 13. Joyston-Bechal S. Prevention of dental diseases fol- therapy and may result in oral pain and infection lowing radiotherapy and chemotherapy. Int as well as systemic infection that results in morbid- Dent J 1992;42:47-53. ity and can lead to mortality. Pretreatment assess- 14. Consensus Development Panel. Consensus statement and management and maintenance of oral ment: oral complications of cancer therapies. hygiene have been shown to be effective in pre- NCI Monogr 19 9 0; 9 :3-8. venting oral and systemic complications during 15. Sonis ST, Woods PD, White A. Pretreatment oral treatment of patients with cancer. assessment. NCI Monogr 19 9 0; 9 :37-42. 16. Epstein JB, Rea G, Wong FLW, et al. Osteonecro- sis: study of the relationship of dental extraction REFERENCES in patients receiving radiotherapy. Head Neck Surg 1987;10:48-54. 1. Guglielmotti MB, Ubios AM, Cabrini U. Alveo- 17. Galler C, Epstein JB, Guze KA, et al. The develop- lar wound healing after x-irradiation: a histolog- ment of osteoradionecrosis from sites of peri- ic, radiographic and histometric study. J Oral odontal disease activity: report of 3 cases. J Peri- Maxillofac Surg 1986;44:972-6. odontol 1992;63:310-6. 2. Wright WE. Periodontium destruction with oncol- 18. Epstein JB, Lunn R, Le N, Stevenson-Moore E ogy therapy. Five case reports. J Periodontoll987; Periodontal attachment loss in patients follow- 5 8:5 59-63. ing head and neck radiation therapy. Oral Surg 3. Marx RE. Osteoradionecrosis: a new concept of its Oral Med Oral Pathol Oral Radiol Endod pathophysiology. J Oral Maxillofac Surg 1983; 1998;86(6): 673-7. 4 1:35 1-7. 19. Najera ME Al-Hashimi I, Plemons JM, et al. 4. Marx RE, Johnson W. Studies on the radiobiology Prevalence of periodontal disease in patients of osteoradionecrosis and their clinical signifi- with Sjogren’s syndrome. Oral Surg Oral Med cance. Oral Surg Oral Med Oral Pathol 1987; Oral Pathol Oral Radiol Endod 1997;83: 64: 379-90. 453-7. Periodontal Disease and Periodontal Management in Patients with Cancer 20 1

20. Lizi EC. A case for a dental surgeon at regional 33. Dreizen S, McCredie KB, Bodey GC Keating MJ. radiotherapy centres. Brit Dent J 1992;173: Quantitative analysis of the oral complications 24-6. of antileukemia chemotherapy. Oral Surg Oral 2 1. Stevenson-Moore E Essential aspects of a pretreat- Med Oral Pathol 1986;62:650-3. ment oral examination. NCI Monogr 1990;9: 34. Epstein JB, Gangbar SJ. Oral mucosal lesions 33-6. in patients undergoing treatment for leukemia. 22. Epstein JB, van der Meij EH, Lunn R, et al. Effects J Oral Med 1987;43:132-7. of compliance with fluoride gel application on 35. Navari RM, Buckner CD, Clift RA, et al. Prophy- caries and caries risk in patients after radiation laxis of infection in patients with aplastic ane- therapy for head and neck cancer. Oral Surg mia receiving allogeneic marrow transplants. Oral Med Oral Pathol Oral Radio1 Endod Am J Med 1984;76:564-72. 1996;82:268-75. 36. Ruescher TJ, Sodeifi A, Scrivani SJ, et al. The 23. Epstein JB, Corbett T, Galler C, Stevenson-Moore impact of mucositis on alpha-hemolytic strepto- E Surgical periodontal treatment in radiothera- coccal infection in patients undergoing autolo- py-treated head and neck cancer patient. Spec gous bone marrow transplantation for hemato- Care Dent 1994;14:182-7. logic malignancies. Cancer 1998;82:2275-8 1. 24. Borowski B, Benhamou E, Pico JL, et al. Preven- 37. Donnelly JE Bacterial complications of transplan- tion of oral mucositis in patients treated with tation: diagnosis and treatment. J Antimicrob high-dose chemotherapy and bone marrow Chemother 1995;36(B):59-72. transplantation: a randomised controlled trial 38. Donnelly JC Muus Horrevorts AM, et al. Failure comparing two protocols of dental care. Europ J of clindamycin to influence the course of severe Cancer, Oral Oncol 1994;30(B):93-7. oromucositis associated with streptococcal bac- 25. Greenberg MA, Cohen SG, McKitrick JC, Cas- teraemia in allogeneic bone marrow transplant sileth PA. The oral flora as a source of sep- recipients. Scand J Infect Dis 1993;25:43-50. ticemia in patients with acute leukemia. Oral 39. Donnelly JC Muus Schattenberg A, et al. A Surg Oral Med Oral Pathol 1982;53:32-6. scheme for daily monitoring of oral mucositis in 26. Overholser CD, Peterson DE, Williams LT, allogeneic BMT recipients. Bone Marrow Schimpff SC. Periodontal infection in patients Transplant 1992;9:409-13. with acute nonlymphocytic leukemia: preva- 40. Mossad SB, Longworth DL, Goormastic M, et al. lence of acute exacerbations. Arch Intern Med Early infectious complications in autologous bone 1982;14255 1-4. marrow transplantation: a review of 219 patients. 27. Peterson DE, Overholser CD, Schimpff SC, et al. Bone Marrow Transplant 1996;18:265-71. Relationship of intensive oral hygiene to sys- 41. Channock SJ, Pizzo PA. Infectious complications temic complications in acute nonlymphocytic of patients undergoing therapy for acute leukemia. Proc Am Fed Clin Res 1981;29:44OA. leukemia: current status and future prospects. 28. Levy-Polack ME Sebelli Polack NL. Incidence of Semin Oncol 1997;24:132-40. oral complications and application of a preven- 42. Peterson DE. Pretreatment strategies for infection tive protocol in children with acute leukemia. prevention in chemotherapy patients. NCI Spec Care Dent 1998;18:189-93. Monogr 1990;9:61-71. 29. Weikel DS, Peterson DE, Rubinstein LE, et al. 43. Overholser CD, Peterson DE, Williams LT, Incidence of fever following invasive oral inter- Schimff SC. Periodontal infection in patients ventions in the myelosuppressed cancer patient. with acute nonlymphocytic leukemia: preva- Cancer Nurs 1989;12:265-70. lence of acute exacerbations. Arch Intern Med 30. Dreizen S, McCredie KB, Keating MJ, Bodey GE 1982;14255 1-4. Oral infections associated with chemotherapy in 44. Peterson DE, Minah GE, Overholser CD, et al. adults with acute leukemia. Postgrad Med 1982; Microbiology of acute periodontal infection in 71: 133-46. myelosuppressed cancer patients. J Clin Oncol 31. Dreizen S, Bodey GC Valdivieso M. Chemothera- 1987;5:1461-8. py-associated oral infections in adults with solid 45. Stansbury DM, Peterson DE, Suzuki JB. Rapidly tumors. Oral Surg Oral Med Oral Pathol 1983; progressive acute periodontal infection in a 55~113-20. patient with acute leukemia. J Periodontol 32. McCarthy GM, Skillings JR. Orofacial complica- 198859544-7. tions of chemotherapy for breast cancer. Oral 46. Minah GE, Rednor JL, Peterson DE, et al. Oral Surg Oral Med Oral Pathol 1992;74:172-8. succession of gram-negative bacilli in myelosup- 202 Periodontal Medicine

pressed cancer patients. J Clin Microbiol 1986; 60. Sonis S. Mucositis as a biological process: a new 24:2 10-1 3. hypothesis for the development of chemotherapy- 47. Moore WEC, Holdeman LV, Cat0 EC et al. Bacte- induced stomatotoxicity. Oral Oncol 1998;34: riology of moderate (chronic) periodontitis in 39-34. mature adult humans. Infect Immun 1983;42: 61. Sonis S, Kunz A. Impact of improved dental ser- 510-155. vices on the frequency of oral complications of 48. Reynolds MA, Minah GE, Peterson DE, et al. Peri- cancer therapy for patients with non-head-and- odontal disease and oral microbial successions neck malignancies. Oral Surg Oral Med Oral during myelosuppressive cancer chemotherapy. Pathol 1988;65:19-22. J Clin Periodontol 1989;16: 185-9. 62. Epstein JB, Sherlock C, Page JL, et al. Clinical 49. Bodey GE Buckley M, Sathe YS, Freireich EJ. study of herpes virus infection in leukemia. Oral Quantitative relationships between circulating Surg Oral Med Oral Pathol 1990;70:38-43. leukocytes and infection in patients with acute 63. Epstein JB, Scully C. Herpes simplex virus in leukemia. Ann Intern Med 1966;64:32840. immunocompromised patients: growing evi- 50. Sickles EZ, Greene WH, Wiernik PH. Clinical dence of drug resistance. Oral Surg Oral Med presentation of infection in granulocytopenic Oral Pathol 1991;72:47-50. patients. Arch Intern Med 1975;135:715-9. 64. Epstein JB, Ransier A, Sherlock CH, et al. Acy- 51. Bergman OJ. Oral infections and septicemia in clovir prophylaxis of oral herpes virus during immunocompromised patients with hematolog- bone marrow transplantation. Oral Oncol, Eur ic malignancies. J Clin Microbiol 1988;26: J Cancer 1996;32(b):158-62. 2105-9. 65. Barrett N.A long-term prospective clinical study 52. Barrett N,Schifter M. Antibiotic strategy in orofa- of oral complications during conventional ciall head and neck infections in severe neu- chemotherapy for acute leukemia. Oral Surg tropenia. Oral Surg Oral Med Oral Pathol Oral Med Oral Pathol 1987;63:313-6. 1994;77:350-5. 66. Meyers JD, Flournoy N, Thomas ED. Infection 53. Fardal 0,Turnbull RS. A review of the literature on with herpes simplex virus and cell-mediated use of chlorhexidine in dentistry. J Am Dent immunity after marrow transplant. J Infect Dis Assoc 1986;112:863-9. 1980; 142:338. 54. Langslet A, Olsen I, Lie SO, Lokken NE Chlorhex- 67. Saral R, Ambinder RF, Burns WH, et al. Acyclovir idine treatment of oral candidiasis in seriously prophylaxis against recrudescent herpes simplex diseased children. Acta Paediatr Scand 1974;63: virus infections in leukemia patients: a random- 809-1 1. ized double-blind placebo controlled study. Ann 55. Overholser CD, Peterson DE, Bergman SA, Intern Med 1983;99:773-7. Williams LT Dental extractions in patients with 69. Larn MT, Pazin GJ, Armstrong JA, Ho M. Herpes acute nonlymphocytic leukemia. J Oral Surg simplex infection in acute myelogenous 1982; 40:296-8. leukemia and other hematologic malignancies: a 56. Peterson DE, Overholser CD, Williams LT. prospective study. Cancer 1981;48:2 168-71. Endodontic therapy in patients receiving myelo- 70. Rand KH, Kramer B, Johnson AC. Cancer suppressive chemotherapy. Proc J Dent Res 1982; chemotherapy-associated symptomatic stomati- 61:276. tis: role of herpes simplex virus (HSV). Cancer 57. Peters E, Monopoli M, Woo SB, Sonis S. Assess- 1982; 50:1262-5. ment of the need for treatment of postendodon- 71. Wade JC, Newton B, Flournoy N, Meyers JD. Oral tic asymptomatic periapical radiolucencies in acyclovir prophylaxis of herpes simplex virus bone marrow transplant recipients. Oral Surg infection after marrow transplant. Ann Intern Oral Med Oral Pathol 1993;76:45-8. Med 1984;100:823-7. 58. De Paola LG, Minah GE. Isolation of pathogenic 72. Cassady KA, Whitley RJ. New therapeutic microorganisms from dentures and denture approaches to alpha-herpesvirus infections. J soaking containers of myelosuppresed cancer Antimicrob 1997;39:119-28. patients. J Prosthet Dent 1983;49:204. 73. Oakley C, Epstein JB, Sherlock CH. Reactivation 59. Epstein JB, Chin EA, Jacobson JJ, et al. The rela- of oral herpes simplex virus. Implications for tionship among fluoride, cariogenic oral flora, clinical management of herpes simplex virus and salivary flow rate during radiation therapy. recurrence during radiotherapy. Oral Surg Oral Oral Surg Oral Med Oral Pathol Oral Radio1 Med Oral Pathol 1997;84:272-8. Endod 1998;86:286-92. Periodontal Disease and Periodontal Management in Patients with Cancer 20 3

74. Burns WH, Santos GW, Saral R, et al. Isolation and 79. Zaia JA, Forman SJ. Cytomegalovirus infection in characterization of resistant herpes simplex virus the bone marrow transplant recipient. Infect after acyclovir therapy. Lancet 1982;1:421-3. Dis Clinics N Am 1995;9:879-900. 75. Crumpacker CS, Schnipper LE, Marlowe SI, et al. 80. Scully C, Epstein J, Porter S, Cox M. Viruses and Resistance to anti-viral drugs of herpes simplex chronic disorders involving the human oral virus isolated from a patient treated with acy- mucosa. Oral Surg Oral Med Oral Pathol 1991; clovir. N Engl J Med 1982;306:343-6. 72: 5 37-44. 76. de Clerq E. In search of a selective antiviral chemo- 81. Schubert MM, Epstein JB, Lloid ME, Cooney E. therapy. Clin Microbial Rev 1997;10:674-93. Oral infection due to cytomegalovirus in 77. Wagstaff AJ, Bryson HM. Foscarnet. A reappraisal immunocompromised patients. J Oral Pathol of its antiviral activity, pharmacokinetic proper- Med 1993; 22:268-73. ties and therapeutic use in immunocompro- 82. Epstein JB, Sherlock CH, Wolber RA. Oral mani- mised patients with viral infections. Drugs festations of cytomegalovirus infection. Oral 1994;48:199-226. Surg Oral Med Oral Pathol 1993;75:443-5 1. CHAPTER13

PERIODONTALCONSIDERATIONS IN PATIENTS WITH BONE MARROW OR SOLIDORGAN TRANSPLANTS

Terry D. Rees, DDS, MSD

The science of organ and bone marrow transplan- KIDNEY TRANSPLANTATION tation has evolved over the past 30 to 40 years from last-ditch desperate efforts to briefly prolong Acute and Chronic Renal Failure life, or improve the quality of life, to a sophisticated treatment modality that is preferred in the Renal failure is a major complication of kidney dis- management of a variety of diseases.' In most ease and transplantations, and failure in both instances, the various diseases and disorders which native and transplanted kidneys most commonly lead to a need for transplantation have oral mani- occurs as a result of chronic renal disease. Progres- festations, which may cause the alert dental prac- sive end-stage renal disease may develop rapidly or titioner to refer the affected patient for medical may occur many years after the onset of the initi- evaluation and appropriate treatment, including ating condition. Essentially, renal failure occurs as transplantation. Improved prognosis following a result of the accumulation of circulating serum organ transplantation is the direct result of the proteins, which, in turn, induce endocytosis of development of superior methods for obtaining renal vascular epithelial cells and a nephrotoxic donor-patient tissue matches, transportation solu- effect due to the release of vasoactive and inflam- tions, and the effective use of immunosuppressant matory substances into the renal interstitium. drugs.2 Although transplantation procedures are Classic phases of failure include inflammation, often beneficial, they are not without complica- fibrosis, atrophy, and end-organ tions, which range from life-threatening infections Glomerulonephritis in its various forms was to rejection of the grafted organ. Safe and effective once the most common condition leading to dental therapy in these patients requires an under- chronic renal failure (CRF). However, due to more standing of the diseases that are best treated by success in noninvasive management of glomeru- transplantation, their complications, and the after lonephritis, diabetes mellitus is now the most com- effects of the transplantation procedure. In each mon cause of chronic failure, followed by pro- circumstance, careful dental protocols must be longed or progressive hyperten~ion.~-~ followed in order to provide this safe and effective Glomerulonephritis usually presents with care for patient^.^ Dental infections and manipu- manifestations of nephrotic syndrome, which may lation of oral tissues may subject immunosup- be acute or chronic in nature. This condition is pressed patients to infections, which can lead to characterized by massive edema, proteinuria, organ rejection, compromise of other body sys- hypoalbuminemia, and susceptibility to intercur- tems, or even death. This paper will review the rent infections. Posts trep tococcal glomeru- systemic conditions that may result in a need for lonephritis is associated with an inflammatory organ or bone marrow transplantation, discuss reaction appearing after infection with group A or systemic and oral complications associated with B hemolytic streptococci or with staphylococci. the diseases and their treatment, and provide a Nephritis has been associated with skin infections, protocol for the management of patients who are but its relationship to oral streptococcal bac- transplant recipients. teremias is unknown. 20 6 Periodontal Medicine

Other forms of postinfectious glomeru- Nephrotic syndrome may occur in association lonephritis may occur after a variety of bacterial, with systemic conditions such as amyloidosis, sys- viral, or parasitic infections. This type of nephritis temic lupus erythematosus, and diabetes mellitus may be induced by bacterial endocarditis or infect- and ranges in degree from lipoid nephrosis to renal ed ventriculoatrial shunts. The severity of nephritis failure requiring transplantation. Unfortunately, is related to the duration of infection before appro- the condition may recur in the transplanted kid- priate antibacterial therapy is initiated. Control of ney4 More rapid renal deterioration may occur the causative infection usually leads to the rapid when related to heroin abuse or acquired immun- resolution of glomerulonephritis, but irreversible odeficiency syndrome (AIDS). l2 Corticosteroid- renal failure can occur, especially if initiation of resistant patients with nephrotic syndrome may antimicrobial therapy has been delayed. It should require cyclosporine therapy before renal trans- be noted, however, that antimicrobial therapy itself plantation. Therefore, these individuals are prone may induce acute interstitial nephritis. to cyclosporine-induced gingival overgrowth, Membranoproliferative glomerulonephritis together with more serious drug side-effects.13-16 (hypocomplementemia) may occur due to inherit- Cyclosporine may induce toxic nephropathy both ed complement deficiencies or in conjunction with before and after kidney tran~plantation.~J~ other conditions such as systemic lupus erythe- Membranous nephropathy may occur idio- matosus, mixed cryoglobulinemia, systemic sclero- pathically or in association with the presence of sis, shunt infections, or bacterial endocarditis, all solid tumors, systemic lupus erythematosus, of which are associated with persistent immune hepatitis B, and occasionally hepatitis C infection, complex f~rmation.~Rapidly progressive glomeru- or with certain medications such as gold salts, lonephritis may induce a steady alteration of renal penicillamine, or amphotericin B. l3 Nephrotic function over a period of weeks or months, poten- patients may be particularly susceptible to drug- tially leading to renal failure. This condition may induced rhabdomyolysis.l7 also be associated with bacterial endocarditis or Acute renal failure may be associated with ele- shunt infection. vated blood urea nitrogen (BUN) and creatinine Goodpasture's syndrome features a specific concentrations. Acute failure may be induced by a pathologic entity associated with formation of anti- reduction in blood volume due to hemorrhage, bodies to glomerular epithelial basement membranes severe hypotension, advanced heart failure, or liver (GMB). Other forms of anti-GMB may be associat- disease. Drugs such as angiotensin-converting ed with pulmonary changes resulting from influenza, enzyme (ACE) inhibitors or ACE receptor abuse of tobacco or illicit drugs, or other conditions inhibitors may sustain renal hypotension. Inges- that permit circulating antibody complexes access tion of nonsteroidal anti-inflammatory drugs to lung al~eoli.~>~'Anti-GMB diseases usually (NSAIDs) may produce similar effects.l8 Renal progress to renal failure within I year of onset. failure can occur as a complication of severe Fibrillary glomerulonephritis has recently been ischemia or hypovolemia or that of a major surgi- described as an idiopathic disorder which features cal procedure such as cardiac surgery and may also pathognomonic fibril deposition in the glomeruli, be induced by sepsis or by obstructive biliary cir- which may induce nephrotic effects. At present, rhosis. Acute renal tubular necrosis is generally there is no known treatment for this disorder. reversible, but hemodialysis may be required. 19,20 Immunoglobulin A (16) nephropathy (Berg- Chronic renal failure is a bilateral, progressive er's disease) is usually idiopathic but may occur in deterioration of functioning nephrons and is often association with other diseases such as hepatic cir- insidious in progression. Acute and chronic renal rhosis. The condition usually leads to reversible failure can alter the hnction of virtually every acute renal failure, but some patients experience organ system of the body.8 The uremic syndrome life-threatening renal failure, sometimes over a peri- occurs in part due to the accumulation of BUN od of 20 or more yeas4 IgA disease often recurs in and other metabolic waste products normally patients undergoing kidney transplantation, excreted by the kidneys. The condition features although resultant graft rejection is rare." azotemia, impaired ability to concentrate urine, Hereditary nephritis (Alport's syndrome) polyuria, hypokalemia, hypocalcemia, hyperphos- may be accompanied by hepatic impairment. phatemia, and metabolic acidosis in its late stages. The condition is often progressive, especially in It may be accompanied by hypertension, pericardi- men, leading to end-stage renal failure over a tis, congestive heart failure, coronary artery dis- period of years. ease, multiple neuropathies, metabolic encephalo- Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 207 pathy, osteopenia or osteoporosis, and bleeding patients receiving dialysis or renal transplantation, disorders due to anemia. 18,21 due in part to the administration of immunosup- Abnormal hemostasis occurs as a result of pro- pressant drugs. longed bleeding time, decreased activity of the platelet receptor complex, abnormal platelet aggre- Oral Features of Renal Failure gation and adhesiveness, and impaired prothrombin consumption. Central nervous system disturbances Renal failure induces many abnormalities in the oral may first manifest as inability to concentrate, cavity. An increase in salivary calculus formation has drowsiness, insomnia, memory lapses, and errors in been described, probably due to elevated serum cal- judgment. If untreated, the condition becomes asso- cium-phosphate levels. Conversely, caries incidence ciated with hiccups, cramps, muscle twitching, may be reduced, possibly due to plaque inhibition asterixis, stupor, seizures, and coma.8’22-24 related to increased levels of salivary urea.28 Uremic Gastrointestinal abnormalities include anorex- stomatitis occurs in two forms (I) the erythemopul- ia, nausea and vomiting, as well as uremic fetor, taceous type, which features dry, burning, erythema- which is the uriniferous breath odor resulting from tous, and painful oral tissues that may be covered breakdown of the urea in saliva to ammonia. This with a thick gray exudate; and (2) the ulcerative condition may also be associated with a metallic form, which is characterized by mucosal ulcerations. taste sensation. Mucosal ulcerations may occur at Xerostomia may be the most common oral manifes- any level of the gastrointestinal tract. tation and occurs due to altered salivary production, Endocrine-metabolic disturbances include with or without parotid enlargement or infectious altered parathyroid function, glucose intolerance, parotitis. Oral dryness may be compounded by nasal and insulin metabolism disorders. Dermatologic congestion resulting from insidious nasal bleeding, disorders may include the pallor of anemia, ecchy- which, in turn, initiates mouth breathing. Insidious moses and hematomas due to defective hemostasis, oral bleeding may induce gingival hemorrhage and calcium deposition in soft tissues, pruritus and hematoma formation in the presence of slight trau- excoriations related to secondary hyperparathy- ma. Enamel hypoplasia and brownish discoloration roidism, and/or dehydration. In some circum- of the teeth may occur in children, and pulpal nar- stances, the combination of anemia and hemato- rowing has been described. Infections may be quite logic dysfunction leads to development of a sallow, fiequent with candidal overgrowth being common, yellow cast to the skin or to slate-gray-to-bronze although bacterial, viral, and other hngd infections discoloration associated with hemochromatosis. In may also occur. Increased esophageal reflux has been severe uremia, the concentration of urea in sweat described among dialysis patients, with resultant and saliva may be sufficient to induce a deposition dental erosion and oral dis~omfort.~~-~~>~~>~~ of a fine white powder (uremic frost) on the skin Secondary hyperparathyroidism may induce and mucosa as the result of e~aporation.~~~’~~~~~~~~~fine granular metastatic calcifications in the con- Renal osteodystrophy occurs in renal failure nective tissues of the oral cavity, which may initiate due to disordered calcium and phosphorus metab- mucosal swelling, pain, and ulceration. Radi- olism and altered vitamin D absorption and metab- ographic evidence of hyperparathyroidism may olism. The result is a secondary hyperparathy- include loss of lamina dura around the teeth. This roidism induced by renal retention of phosphorus, is not a universal finding and may occur more often which causes a compensatory release of calcium in the anterior dentiti~n.~~>~~A reduced radiodensi- from bone in an effort to maintain the calcium- ty of the bones of the jaws may occur in association phosphorus homeostasis. Skeletal changes include with osteopenia. This can result in a “ground glass” altered bone remodeling, osteopenia, osteomalacia radiographic osseous appearance, which may be and osteoporosis, osteitis fibrosa cystica, osteoscle- associated with an increased possibility of sponta- rosis, and central giant cell tumors (the brown neous fractures of the jaws in extreme cases. Extrac- tumor of hyperparathyroidism). 5,8,21-23,26,27 tion sockets tend to retain the lamina dura and scle- Individuals with renal failure exhibit increased rotic radiopacities have been reported. Small susceptibility to infection due to altered leukocyte, unilocular or multilocular cystic lesions of the jaws monocyte, and lymphocyte function. The systemic may denote pseudocyst cavities or giant cell tumors conditions associated with end-stage renal disease (brown tumor). These lesions may induce loosen- (hyperglycemia, protein malnutrition, serum and ing of teeth, jaw enlargement, and localized oral tissue hyperosmolarity) further impair infection pain. Spontaneous gingival hemorrhage, ulcera- susceptibility. This susceptibility may continue in tions, and petechial lesions are common.21-23,27,28 20 8 Periodontal Medicine

Increased mobility of teeth is a common find- make this technique efficient, the anastomosis ing in osteopenic patients, even in the absence of should be in place for 6 to 8 weeks before use to periodontal pockets. Individuals with osteopenia enable vessels to mature and enlarge. Conse- experience increased tooth loss and more advanced quently, this site is rarely used in the event imme- periodontal disease. This may be reversed in diate dialysis should be necessary to treat acute women by estrogen therapy or by use of bispho- renal failure. In such circumstances, a double nate~.~'-~~Periodontal inflammation is very com- lumen catheter is inserted in the femoral, internal mon among patients with renal failure, and oppor- jugular, or subclavian vein. The dialysis equip- tunistic infections with or without blood seeding is ment enables blood flow through a filtering a constant hazard.25>35>36Extraction of loose teeth membrane, resulting in the cleansing of the should be avoided because of delays in wound dialysate solutions. In some circumstances, the healing. In most instances, mobile teeth can be membrane may activate complement via the alter- maintained with splinting.2'-23.25.27,37 nate pathway or generate interleukin- I (IL- I), which can induce hypotension and P2-microglob- Dialysis ulin accumulation. These effects may be minimized by use of biocompatible membrane mate- Hemodialysis may be employed in the management rials. Despite this, dialysis membranes may acti- of reversible or irreversible renal failure. Unfortu- vate the clotting mechanism within the dialysis nately, dialysis may also adversely affect renal hnc- system itself. Intersystem clotting is controlled by tion due to decreased urine output, induction of administration of he~arin.~~ hypotension, or complement activation.3839 Indications for hemodialysis include uremia, A variety of drugs commonly used in dentistry hyperkalemia, volume overload, acidosis, uremic may induce acute renal failure through tubular pericarditis, and other features of uremic syn- necrosis. These drugs include aminoglycoside drome. Hypotension is the major complication of antibiotics, acyclovir, sulfonamides, and aceta- hemodialysis, usually occurring as the result of min~phen.'~The severity of the nephrotoxic effect excessive filtration and volume depletion. The con- may relate to dosing frequency and plasma levels dition is far more likely when vasoconstrictive achieved, especially in patients with concurrent mechanisms are impaired as a result of medications renal i~chemia.~'The presence of sepsis or liver dis- or of autonomic neuropathy such as that found in ease, particularly severe obstructive jaundice, may diabetics. Chronic anemia may also result due to enhance drug-induced nephrotoxicity. factors such as decreased erythropoietin produc- Accumulation of uric acid from gout or other tion, iron deficiency, folate deficiency, or hemoly- diseases may also induce acute or chronic renal dis- sis related to the dialysis process.39 ease and failure. Chronic urate nephrotoxicity is Long-term hemodialysis patients may mani- rare today but occasionally results from deposition fest musculoskeletal changes such as carpal tunnel of sodium urate crystals in the kidney medullary syndrome, arthropathies, or amyloidosis, with or inter~titium.~'Fanconi-like syndromes are possible without increased tissue levels of P2-microglobu- when tetracyclines or other specific drugs are used lim7 Encephalopathy may occur toward the end of in patients with pre-existing nephrosis. dialysis and may persist even after completion of Hemodialysis is initiated when a failing kid- the therapeutic regime. Symptoms include subtle ney cannot successfully excrete waste products, changes in personality, reduced short-term memo- regulate acid-base balance, or maintain sodium ry, slurred speech, and myoclonic spasms of the homeostasis. In this procedure, solutes such as face, arms, legs, and trunk.39 excessive urea or potassium are filtered out of the Therapeutic outcomes of hemodialysis have blood, and excessive extracellular fluid is removed. remained constant over the past few years, with a The procedure is usually performed every 2 to 3 mortality rate of approximately 20 to 25%. Com- days and requires 3 to 5 hours per session.21Side plications include cardiovascular disease (stroke, effects include severe hypotension, cramping, nau- myocardial infarction) and infections. A variety of sea, and vomiting.42 infections occur due to protein malnutrition and Vascular access is necessary to perform blood inability to produce antibodies. As a consequence, purification by dialysis. Today, this is most fre- hemodialysis patients are at increased risk for quently accomplished by the creation of an arte- infectious endocarditis and endoarteritis at the riovenous fistula, often by anastomosis of the shunt site. The patient's quality of life is impaired radial artery and cephalic vein of the arm.39,43To by frequent dialysis that must be performed and Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 209 the amount of time required to complete the ther- seronegative for VZV or HBV should receive vacci- apy although hemodialysis can be performed at nation prior to transplantation, although anti-CMV home, after a reliable family member has been antibodies do not always confer pr~tection?~>~~ trained to conduct the procedure. Graft rejection is mediated by both humoral Peritonea1 dialysis is performed by introducing and cellular mechanisms. Acute rejection may dialysate solution into the peritoneal cavity. The occur if the recipient patient has cytotoxic anti- procedure may be continuous (continuous ambula- bodies to donor blood group or HLA antigens. tory peritoneal dialysis) or periodic (cyclic ambula- Chronic humoral rejection progresses more slowly tory peritoneal dialysis). It is often the treatment of but inexorably leads to graft loss. choice in acute renal failure, obviates the need for Cardiovascular disease is one of the leading heparin, and minimizes marked changes in blood causes of morbidity and mortality in organ recipi- pressure, especially the hypotension associated with ents and may include congestive heart failure, conventional dialysis. In this technique, the dialysis severe hypertension, or cardiac arrythmias. An solution is infused into the abdominal cavity and increased incidence of infective endocarditis may drained after sufficient time for collection of toxic occur even in patients without known cardiac val- waste products and excess fluids. Often three to five var le~ions.~l>~~Risk factors include pretransplant exchanges are performed daily but the procedure cardiovascular disease, diabetes mellitus, elevated can be performed at home. The primary complica- serum lipids, hypertension, tobacco or drug abuse, tions are infection of the exit port within the and allograft dysfunction. Patients who have catheter or infection in the peritoneal cavity. Other undergone coronary artery angioplasty or bypass disadvantages include protein loss and glucose surgery are at increased risk of re-sten~sis.~~Hyper- absorption into the bloodstream and this procedure tension is very common after renal transplantation, also interferes with patient quality of life.44 most often due to the direct nephrotoxic effect of Most peritoneal inhsion infections are caused cyclosporine or possibly tacrolimus. Hypertension by gram-positive microorganisms such as Stupbylo- may lead to chronic graft rejection due to reduced coccus epiderrnitis and Stupbylococcus uureus. How- renal function or renal artery ~tenosis.~~ ever, peritonitis may also be induced by gram-neg- Infection is a constant hazard and most often ative anaerobic organisms including putative peri- occurs immediately following transplantation. Sur- odontal pathogens and by hngi.27>28>44 gical wound infection, blood transfusions before or during organ transplantation (especially hepatitis Renal Transplantation C transmission), dialysis-related sepsis, urinary tract infection, and aspiration pneumonia infec- Renal transplantation offers the best opportunity tions are most common. The greatest risk of post- for resumption of normal daily activities and hll transplant infection occurs within the first 6 rehabilitation in end-stage renal disease (ESRD) months, when immunosuppressive therapy is at its although graft rejection and infection remain seri- peak.37Delayed infections most often occur due to ous problems. Both living and cadaver organs can viral (HSV, CMV, EBV), hngal (Cundidd ulbi- be used; however, the best results occur when cuns) or other opportunistic organism^.^'^^ donors and recipients share compatible AB0 Other common post-transplant complications blood groups and HLA antigens. No matching of include hyperlipidemia, which may be influenced Rh factor is required. Transplantation from identi- by hyperinsulinemia or by the use of drugs such as cal twins offers the greatest opportunity for suc- cyclosporine or diuretics. Hyperparathyroidism may cess, and immunosuppressant drugs are usually not persist after renal transplantation and may require required with hlly compatible donor-receptors. initiation of dialysis. Metabolic derangement, Improvements in immunosuppressant proto- hyperkalemia, hypomagnesemia, hyperuricemia, cols have resulted in reduced graft rejection even in and post-transfusion diabetes mellitus (PTDM) are poorly matched donor-receptors. Unfortunately, additional risks. The last may be associated with immunosuppressant drugs also suppress host administration of corticosteroids, but cyclosporine defenses against bacterial, viral, and hngal infec- and tacrolimus can also be diabetogenic due to tion~?~When possible, pregraft antibody titers increased insulin resistance, decreased insulin secre- against varicella mster virus (VZV), cytomegalo- tion, or other mechanisms. Anemia and leukopenia virus (CMV), hepatitis B (HBV), and the human are associated with poor renal hnction and defi- immunodeficiency virus (HIV) should be obtained ciency in the renal production of erythropoeitin, prior to tran~plantation.~~Receptor patients who are which is essential to red blood cell development. 2 1 O Periodontal Medicine

Liver disease is a common complication fol- for organ transplant patients in combination with lowing renal transplantation. This may be drug- antihypertensive drugs such as the calcium channel induced (cyclosporine, azathioprine) or due to blocking agent, nifedipine, also associated with gin- viral hepatitis. gival overgrowth. 57,9497 Recent reports indicate Immunosuppression therapy is usually provid- that nifedipine-induced gingival overgrowth can be ed by various combinations of glucocorticoids, aza- reversed by using alternative calcium channel thioprine, cyclosporine, tacrolimus, monoclonal blocking drugs such as amlodipine or isradip- antibody OKT 3, or antilymphocyte globulin. ine.98>99Other calcium channel blockers, however, Appropriate cyclosporine or tacrolimus serum lev- may induce increased plasma levels of cyclosporine els are essential to prevent graft rejection although while nifedipine does not. This may explain the fre- higher serum levels are associated with more severe quent use of nifedipine in postrenal transplant adverse side effects. Serum levels can be uninten- patient^.^ Treatment for drug-induced gingival tionally increased by simultaneous intake of drugs overgrowth includes establishment of effective oral such as erythromycin, oral contraceptives, and hygiene and discontinuance or reduction in dosage some calcium channel blockers. of the causative drug, when possible. Unfortunate- Rifampin, phenobarbital, phenytoin, and ly, surgical removal of enlarged gingivae is often other anticonvulsant drugs may decrease cyclo- necessary to facilitate patient oral hygiene measures. sporine levels, and aminoglycoside antibodies New immunosuppressant drugs (sirolimus may promote cyclosporine nephrotoxicity. Thus, and mycophenolate mofetil) are now available as the prescription of any drug for patients receiv- cyclosporine substitutes, when appropriate. These ing cyclosporine should be preceded by medical agents appear to induce fewer side effects, and no consultation. 18,48 gingival overgrowth has been reported to date. Cyclosporine is an excellent immunosuppressant drug, which is often prescribed following organ Dental Management transplantation because it selectively suppresses cell- mediated immunity. Complications of the drug No firm protocols have been established for dental include nephrotoxicity, renal vasculopathy, hyper- management of recipients of solid organ transplants. tension, chronic renal interstitial fibrosis (which is Periodontal disease was recently reported in 100% of also common in heart transplantation), neurotoxic- 45 renal dialysis patients studied, suggesting that ity, gingival overgrowth, and increased susceptibility most patients scheduled for renal dialysis or trans- to malignancies, including B cell lymphoma, squa- plantation may have oral infections which could mous cell carcinoma of the skin, lip or oral mucosa, prove life-threatening.loo However, application of or Kaposi's sarcoma.23,35,52-86Malignancy may be common treatment principles should facilitate safe transmitted from the donor or it may develop de and effective periodontal therapy. Dental and peri- novo po~t-transplantation$~>~~-'~and oral malig- odontal management of patients with ESRD must nancies have been reported within sites of be carellly coordinated with the patient's physician. cyclosporine-induced gingival overgr~wth.~~.~~The dentist should participate in treatment planning Cyclosporine-induced perioral dermatitis has been and provide necessary pretreatment for patients described and features red papules, pustules, and scheduled for elective dialysis or organ transplanta- scaling of the chin, upper lip, and nasolabial tion. Under ideal circumstances, all potential oral Oral hairy leukoplakia may occur in HIV-neg- foci of infection should be eliminated prior to trans- ative individuals taking cyclosporine, and gingival plant placement.37~50J01J02Teeth that are beyond overgrowth is a common occurrence. This may be repair and those that are suspect should be extracted especially prevalent in patients with pregraft peri- although endodontic therapy may be appropriate in odontitis .9 l ,92 Nephro toxicity and neurotoxicity selected circumstances. Patients should be instructed may be more severe in patients immunosuppressed in effective oral physiotherapy, and the use of anti- with tacrolimus although gingival enlargement has septic mouthrinses such as chlorhexidine may be not been identified in association with this appropriate. 18,28,37~103~104 Individuals who receive Recent evidence indicates that the presence or organ transplantation on an emergency basis and absence of pretransplant gingival hyperplasia may who have existing dental infection should be given influence the incidence and severity of drug- antibiotics before and after the transplantation until induced gingival ~vergrowth.~~The true incidence dental treatment can be accomplished. of cyclosporine-induced gingival enlargement is The potential for oral and systemic infections is difficult to determine since the drug is often used quite high after transplantation because of the use of Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 2 1 1 immunosuppressive drug regimens. These drugs on the alternate day. Higher levels of corticosteroids may include cyclosporine, tacrolimus, corticos- will protect the patient from adrenal deficiency and teroids, azathioprine, antilymphocyte globulin, or shock. Further protection against adrenal crisis may combinations of these. Most organ transplant recip- be attained by following a stress reduction protocol ients are maintained on immunosuppressant drugs consisting of morning appointments, maintenance for life to attenuate graft reje~tion.~.~'Immunosup- of a nonthreatening treatment environment, use of pressant drugs may mask early manifestations of oral conscious sedation, attainment of profound local infection, including periodontal disease.18,23 Patients anesthesia, and prescription of safe and effective are especially susceptible to urinary tract infections postoperative analgesics. Some authorities recom- with Escbericbiu coli. Most vascular access site infec- mend doubling the usual steroid dose the day tions occur from S. uureus. Occasionally, however, before, on the day of, and for 2 days following a the oral cavity is the source of gram-negative enter- stresshl dental procedure. As an alternative, the coccal infections (Pseudornonus, Proteus, KikbsieZh), dentist must be prepared to administer intravenous fungal infections (Cundidd, Aspergillus, Mucor), or corticosteroid supplementation in the event of an viral infections (herpes simplex, Epstein-Barr, adrenal crisis.23>25>37 cytomegalovirus, and others), all of which can result Dental treatment should be conservative and in life-threatening systemic sepsis.37 Oral lesions noninvasive when possible, especially during the suggestive of infection should be evaluated by cyto- first 3 months after tran~plantation.~~When an logic examination, culture, and/or biopsy, when invasive periodontal or surgical procedure is indicated. '05-'07 planned, prophylactic antibiotic coverage should Medical complications associated with renal be considered, especially if a dialysis shunt or fistu- dialysis or transplantation must be clearly identi- la is present. 18,23,27,28,37 Generally, the recommen- fied by obtaining a thorough medical and dental dations of the American Heart Association for the history, by evaluation of vital signs, by use of prevention of bacterial endocarditis are considered appropriate laboratory screening tests, and by sufficient.'08~'09 Infective endocarditis (IE) may medical consultation. occur in dialysis patients with no evidence of pre- Drugs often used in dental practice may be vious cardiac valvar damage.28Therefore, the den- retained in blood plasma for prolonged periods of tal practitioner should remain alert for signs and time due to diminished renal function in ESRD symptoms of IE, which include fever of unknown patients. Therapeutic administration of these drugs origin, malaise, unexplained elevation of white may require adjustment of dosage or lengthening blood cells, and others.'" of intervals between administration. The prudent Chlorhexidine rinses prior to soft tissue manip- practitioner should consult the patient's physician ulation may reduce the occurrence of orally prior to the use of any drugs.'8,28Local anesthetics induced bacteremia~.'~~J~~J 'O Several authorities are metabolized in the liver and therefore usually have noted, however, that there are no controlled safe for ESRD patients. Acetaminophen and studies that establish the beneficial effect of topical codeine may be appropriate for postoperative anal- or systemic prophylactic antibiotic therapy in organ gesia, but aspirin and other NSAIDs should be transplant patients.2J"J'2 They note that antibiot- avoided. Antibiotics such as aminoglycosides, ic suppression of normal bacterial flora may render tetracyclines, and polypeptides (bacitracin and the patient more susceptible to enterococcal, hn- polymyxin) are nephrotoxic. Potassium penicillins gal, or other opportunistic systemic infections. should not be prescribed because of their high lev- Care must be taken to avoid trauma to the els of potassium salts.27 arteriovenous site in patients who are receiving Patients with ESRD should be observed for hemodialysis either before or after renal transplan- signs and symptoms associated with long-term glu- tation. The arm with an anastomosis site should cocorticosteroid therapy. These include excessive not be used for injection of intramuscular or intra- weight gain, moon facies, buffalo hump, abdominal venous medications, and the access site should not striae, acne, and mental depression, or psychosis. l8 be used as a portal for injection^.^^,^^ Blood pres- Stressful dental procedures may require cortico- sure recordings should not be obtained from the steroid supplementation. Recent evidence, however, involved arm, and the arm should not be placed in suggests that the administration of low-dose corti- a cramped po~ition.~~,~~ costeroids (prednisone, 5 to 10 mg administered The presence of a hemodialysis access site every other day) is not likely to induce an adrenal places the patient at increased risk for endarteritis crisis, especially if dental procedures are performed induced by manipulation of periodontal tissues. 2 12 Periodontal Medicine

Peritonea1 dialysis patients are subject to retrograde association with risk factors such as household staphylococcal or streptococcal infection, but there exposure, sexual contact, or multiple sex partners. is only a low risk of orally-induced bacteremia ini- Transmission of HCV has declined as a result of tiating this infe~tion.~~>~~ screening tests, which identify the virus in blood Excessive and prolonged bleeding may occur in and blood products prior to ESRD in conjunction with dialysis or following In most cases, acute viral liver infections are transplantation. This may be compounded in transient although a small percentage of infected patients receiving hemodialysis because heparin is individuals will follow a fulminant course leading usually administered during the dialysis process to to hepatic coma or death. The most significant prevent clotting, and warfarin compounds aftermath of acute hepatic viral infection is chron- (Coumadin) may be used for management of relat- ic hepatic deficiency, which may lead to end-stage ed medical complications. Patients with ESRD may hepatic disease (ESHD) or development of hepat- have reduced platelet counts and hnction due to ic malignancy. uremia, further increasing bleeding potential.28 For Chronic hepatitis is generally described as these reasons, any necessary dental procedure likely hepatic inflammation that lasts longer than 6 to induce bleeding should be performed following months. It is most commonly caused by autoim- medical consultation, usually on the day after dial- mune hepatitis and chronic viral hepatitis.'l9~l2O ysis to allow normal clotting, and to permit partial Alternatively, the condition may be drug induced or healing prior to the next dialysis ~ession.~~>~~Surgi- initiated by genetic susceptibility (Wilson's disease), cal flaps should be avoided when possible, and primary biliary cirrhosis, or primary sclerosing appropriate surgical techniques should be per- cholangitis. On occasion, clinical features are formed (atraumatic surgery, adequate wound clo- absent, but elevated serum aminotransferase levels sure with sutures, application of postsurgical pres- may be noted. Common clinical features include sure with or without topical clotting agents such as fatigue, malaise, abdominal pain, and possibly jaun- gelfoam, topical thrombin, oxidized regenerated dice. The condition may lead to liver failure, and the cellulose or synthetic collagen.)18,21,25,27,28~1 13p1 l5 patient may eventually require organ transplanta- Screening laboratory tests should be obtained prior tion. Other causes of ESHD include primary hepa- to invasive procedures, including a complete blood tocellular carcinoma without metastasis, alcoholic count with platelets, a partial thromboplastin time, liver disease, acetaminophen overdose, overdose of and a prothrombin time. Drugs such as I-deamino- other drugs, or toxin-induced hepatitis. 'l7,l2l 8-D-arginine vasopressin (DDAVP) or conjugated Severe recurrent HBV infection can develop in estrogen may be prescribed by the patient's physi- patients suffering from chronic hepatitis B, and cian to hrther control hemorrhage during neces- recurrent viremia invariably occurs in individuals sary oral surgical procedure^.^^.^^ who undergo transplantation due to chronic hepatitis C. 122~123In addition to recurrent hepatitis, Liver Diseases this often leads to liver fibrosis or cirrhosis. Recent evidence suggests that HBV is sequestered in extra- Acute hepatitis may be caused by a variety of viruses, hepatic tissues, especially bone marrow. This may drugs, or toxins. In most circumstances, recovery explain why recurrent HBV occurs. 12* occurs over time, but hepatitis B virus (HBV) Liver cirrhosis is the sequela of a wide variety infections may lead to chronic liver disease in 5 to of chronic progressive hepatic diseases that lead to 10% of adults and 80 to 90% of children. Chron- scarring and fatty infiltration of liver tissues and ic liver disease also develops in 70 to 90% of indi- disruption of normal liver architecture and func- viduals infected with hepatitis C virus (HCV). tion. To date, no clinical features have been recog- Infection with HBV has been markedly reduced in nized that invariably signify liver cirrhosis. Clini- the developed countries due to immunization cal indicators, however, include palmar erythema, against the virus, appropriate health care for infect- spider nevi, gynecomastia, testicular atrophy, ed individuals, and establishment of universal pre- splenomegaly, ascites, esophageal varices, and xan- cautions against disease transmission among health thelasmia, and the condition may ultimately lead care workers. Hepatitis C virus is primarily trans- to hepatic encephalopathy or the hepatorenal syn- mitted by parenteral means (blood transhsion, Skin bronzing is common in vari- intravenous drug abuse, or occupational exposure ous types of hepatic diseases but most frequently to blood or blood products). In some circum- occurs in specific forms of cirrhosis (alcoholic, pri- stances, HCV may be community acquired in mary biliary, or hemochromatosis). 123 Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 2 13

Liver Transplantation thereafter.128 Cyclosporine and tacrolimus are both metabo- Liver transplantation has become the standard of lized in the liver and therefore drug interactions care for virtually all forms of ESHD. Absolute con- may occur. Ketoconazole may increase circulating traindications for transplantation include seroposi- levels of these immunosuppressant drugs while tivity for HIV, extrahepatic malignancy, metastatic phenytoin reduces serum levels due to enzyme- hepatic malignancy, active sepsis, advanced car- induced enhanced metabolism. Hyperuricemia diopulmonary disease, and active alcoholism or 116,117,121,123,125,126 often occurs after liver transplantation, and treat- substance abuse. ment may be difficult because allopurinol alters To avoid the need for long-term hemodialysis, azathioprine metabolism, and NSAIDs may patients who suffer from severe renal disease may adversely influence renal function. require a combined liver-kidney transplant Despite these potential complications, the 5- although individuals with severe neurologic or car- year survival rate for liver transplantation continues diopulmonary disease cannot withstand the stress to improve. That average is currently above 80%.125 of transplantation surgery. Increased vascular peripheral resistance may induce transient myocardial dysfunction even in individuals free of pre- Dental Management existing cardiovascular disease. Prior to liver transplantation, the primary goal of Postoperative management after liver trans- dental intervention is to eliminate oral sepsis plantation includes the use of immunosuppressant which could potentially lead to systemic infection drugs (corticosteroids, azathioprine, cyclosporine, and possible transplant rejection or compromise. tacrolimus, or others) to help prevent organ rejec- There are many consequences of ESHD, however, tion. Both cyclosporine and tacrolimus can induce which must be considered when developing a den- nephrotoxicity, hepatotoxicity, neurotoxicity, and tal treatment plan for such patients. For example, diabetes mellitus. Hirsutism and gingival over- the ability of the liver to metabolize drugs may be growth are not associated with tacrolimus. Patients impaired. Drugs commonly used in dentistry, such may continue to suffer from pregraft systemic dis- as acetaminophen, narcotics, local anesthetics, orders such as severe cardiopulmonary disease or benzodiazepam, barbiturates, and antibiotics (ery- renal dysfunction. 127 thromycin, ampicillin), are metabolized in the Complications of hepatic transplantation liver, and these agents should be used with caution. include nonhnction or compromised hnction of Alternative drugs should be considered, and mini- the implanted liver (5 to lO%), and graft rejection mal required dosages should be administered fol- or infection. Candidiasis and aspergillosis infec- lowing consultation with a physician. tions have a high morbidity rate because they often Bleeding disorders are very common in occur in critically ill patients or those who require patients with ESHD. This may result from a extremely high dosages of immunosuppressant decrease in coagulation factors produced by the drugs. Viral, mycobacterial, parasitic, and bacterial liver or from thrombocytopenia due to bone mar- (Nocardid, Legionella, Listerid) infections become row suppression or hypersplenism. Increased clot more evident a few months following transplanta- fibrolysis may also occur. Patients with ESHD tion, and infection with CMV is almost universal should be screened prior to invasive dental proce- in this patient group. Immunosuppressive therapy dures by obtaining appropriate blood tests, includ- has resulted in a marked decrease in the prevalence ing a complete blood count, bleeding time, proof irreversible graft rejection, especially if high thrombin time, and partial thromboplastin time. trough levels of cyclosporine or azathioprine are Prothrombin times are important in evaluating the sustained. Recurrent autoimmune hepatitis has hnction of the clotting factors manufactured in been reported when immunosuppressant therapy the 1i~er.l~~In recent years, an international refer- is reduced. ence thromboplastin (IRT) has been developed to Osteoporosis is common in individuals with facilitate standardized prothrombin results in all chronic cholestatic liver disease, even following medical laboratorie~.~~J~~J~~-~~~Corrected normal liver transplantation. Recent evidence suggests that prothrombin time has been established with an increased bone density and elimination of vertebral international normalized ratio (INR) of approxi- fractures occurs when administration of intra- mately I .O, although patients receiving anticoagu- venous bisphonates is initiated 3 months before lant medications may be maintained at INR levels transplantation and maintained for 9 months ranging from 1.2 to 4.0.131J32Patients with an 2 14 Periodontal Medicine

INR value of 3.5 or lower can usually be managed with ESHD or those with liver transplants. Sup- successfully for invasive dental procedures without pression of oral bacteria may promote sepsis from lowering the INR level, provided appropriate local opportunistic organisms such as Cundidd uZ6i- hemos tatic measures are taken.9' l3O>l3 ' '34,'35, '37 cuns."' In any case, any oral sepsis has the potential The use of oral rinses containing tranexamic acid to induce life-threatening systemic septicemia. Con- may be sufficient to control hemorrhage in minor sequently, afflicted patients must be informed of the surgical procedures in patients with an INR of 4.0 significance of good oral health to their survival. or less. However, extensive surgical procedures in They must be instructed in effective oral hygiene the same patients may require additional hemosta- procedures, and frequent recall intervals of 2 to 3 tic measure^.'^^,'^^ In ESHD patients, however, all months should be established. These principles hemorrhagic factors should be taken into consider- apply both before and after liver transplantation. ation and those individuals with altered platelet In most instances, successhl organ transplan- levels (below 50,000) or INR values higher than tation reduces the dental treatment risks to those 3.5 may need vitamin K supplementation, blood risks described previously in patients taking transfusion, or infusion of fresh frozen plasma or immunosuppressive drugs. It should be anticipated packed platelets. In all cases, selection and applica- that solid-organ transplant patients will require tion of proper surgical techniques should be used these drugs indefinitely. as described previously. Abnormal protein metabolism associated with Pancreatic Transplantation hepatic failure may result in toxic levels of serum ammonia. This substance may induce asterixis, Pancreas transplantation is occasionally used in the hepatic encephalopathy, coma, or death. The dental treatment of type 1 diabetes mellitus. The organ is clinician must remain alert for signs or symptoms of often obtained in conjunction with kidney trans- these conditions. These may include personality plantation from the same donor. Postoperative changes, mood alterations, conhsion and/or even- complications often occur, and the need for long- tual tonic or clonic muscle activity. Altered protein term immunosuppression adversely affects treat- metabolism may also interfere with normal wound ment outcomes. healing. Excessive postoperative bleeding following Pancreatic transplantation may not reverse oral procedures may induce swallowing of blood pre-existent diabetic microangiopathies, nephropa- and thus a possible increase in serum ammonia lev- thy, or retinopathy but may halt or reverse diabet- els. The patient who has undergone nonsurgical or ic neuropathy. Under selected circumstances, the surgical therapy should not be dismissed until clot procedure may be beneficial, especially in diabetic stabilization has been achieved.' '5~138 patients who require renal hemodialysis or kidney Ascites is the accumulation of fluid in the peri- transplantation. 140 toned cavity, secondary to liver failure or portal hypertension. Bacterial peritonitis is potentially Lung Transplantation life threatening in patients with ascites and may be initiated by transient bacteremia induced by Lung transplantation may be performed unilateral- manipulation of oral soft tissues. Consequently, ly, bilaterally, or as a joint heart-lung transplanta- prophylactic antibiotic coverage is indicated for tion. Treatment outcomes are not yet as successful dental procedures likely to induce significant as those reported for renal and hepatic transplants bleeding. ''2~138 The antibiotic regimen recom- although they range between 50 and 70%. Indica- mended by the American Heart Association for tions include emphysema, idiopathic pulmonary prophylaxis against bacterial endocarditis is proba- fibrosis, primary pulmonary hypertension, cystic bly sufficient although some authorities recom- fibrosis, and other rare disorders. mend broad-spectrum antibiotics or metronida- Availability of donor lungs is scarce, and zole in conjunction with amoxicillin to provide therefore the selection of recipient candidates is protection against a broader range of bacteria. restricted. Active tobacco smokers or those who With the exception of patients with ascites, the inhale or smoke illicit drugs are not accepted, and issue of whether or not to administer prophylactic no other systemic diseases should be present antibiotics to patients with liver disease continues to which may result in end-organ damage. 'OJ~' be contr~versial.~J''J~~J~~ No controlled studies are Potential recipients who have significant coronary available to suggest that bacteremias induced by artery disease, renal insufficiency, hepatic diseases, dental procedures affect the prognosis for patients osteoporosis, or significant neurologic impairment Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 2 15 are also excluded. Patients with a history of previ- heart size, AB0 blood type matching, negative ous malignancy, chronic systemic illnesses (dia- lymphocyte cross-match, and avoidance of trans- betes mellitus and others), or chronic unresolved plantation from a CMV-positive donor to a CMV- infections may also be precluded from receiving negative recipient. As a result, prevention of organ lung transplantation. 142 rejection while avoiding the adverse effects of Heart-lung transplants may be indicated for immunosuppressive drugs is essential for successful irreparable congenital cardiac defects or simultane- transplantation. ous advanced heart and lung disease. Cystic fibrosis Transplantation may be indicated for any usually requires bilateral lung transplantation while patient with end-stage heart disease and a prognosis unilateral organ transplants are performed when for survival of 2 years or less. It is also indicated for indicated for more localized pulmonary diseases. patients with severely limited quality of life follow- Post-transplant complications include acute ing other appropriate medical or surgical therapy. graft rejection, usually occurring within the first 3 Candidates may include those with congestive heart months after placement. Bronchiolitis obliterans failure, coronary artery disease (including angina occurs in at least half of all patients receiving lung pectoris and myocardial infarction), patients with transplants and is the primary cause of chronic hypertrophic cardiomyopathy, severe valvar defects, transplant rejection. 143~144Airway stenosis may also or intractable ventricular tachyarrhythmias.149~150 adversely affect treatment outcomes. As in all other Exclusion criteria include individuals with solid-organ transplants, infection is a major cause active virulent infections, those with recent pul- of mortality. This is especially true for recipients of monary infarction, severe diabetes mellitus with lung transplants because the lungs are highly vul- end-organ damage, irreversible pulmonary hyper- nerable to direct contact with infectious microor- tension, active peptic ulcerations, recent or current ganisms as well as to hematologic infection. Most malignancy, or cerebrovascular disease, those with infections are bacterial (St~p~yZococcus>,viral (CMV) , active alcohol or substance abuse, or severe chron- or fungal (Aspergillus). The immunosuppressive ic obstructive pulmonary disease.150 complications previously described for other solid- Complications are common among post-car- organ transplants are common. These include diac transplant recipients. Early complications may nephrotoxicity, hypertension, hyperlipidemia, neu- include acute graft rejection, right side heart failure rotoxicity, osteoporosis, and lymphoproliferative and bacterial, viral, or protozial infection. Late disorders. Recurrence of underlying diseases such as complications occur relative to chronic transplant sarcoidosis, lymphangioleiomyomatosis, and inter- rejection and lifelong administration of immuno- stitial pneumonitis have been rep~rted.’~~J~~ suppressive drugs . Dental protocols have not been established for Chronic rejection elicits fibrointimal hyper- management of post-lung transplant patients, but plasia which may be aggravated by CMV infection. putative periodontal pathogenic microorganisms Successful therapeutic outcomes may allow have been implicated in lower respiratory infec- approximately 70% restoration of maximal cardiac tions. 146 Therefore, establishment of periodontal output during resting and exercise stages. The health and elimination of any oral sepsis are imper- transplanted heart commonly remains denervated ative. 146-148 General protocols for patients using resulting in some alterations in cardiac hnction. lol immunosuppressive drugs are also applicable. Angina rarely occurs during subsequent post-transplant coronary artery disease, resulting in “silent” Heart Transplantation myocardial infarction or sudden death. Less serious symptoms of immunosuppression include hyper- Cardiac transplantation is limited to patients most trichosis, impotence in men, and painful menstru- likely to survive the procedure and resume normal ation in women. In general, women experience a life hnctions. As a result, transplants are limited to significantly higher degree of symptomatic side individuals who have not suffered from other end- effects although cyclosporine-related gingival stage organ damage, those who do not have signif- enlargement is frequent in both sexes.151 icant systemic infections (HIV seropositivity), and those without advanced systemic diseases such as Dental Management diabetes mellitus or collagen vascular disease. Tissue cross-matching between the donor and Dental management of heart transplant patients is recipient is difficult due to a shortage of sufficient consistent with that previously described. Howev- donors. Consequently, organ selection is based on er, strong evidence suggests a positive correlation 2 16 Periodontal Medicine between the presence of severe periodontitis and multiple myeloma, neuroblastoma, some solid risk of myocardial infarction. 152-159 Therefore, tumors, and various forms of anemia.76J75-181In achievement of periodontal health may be essential this procedure, autologous stem cells or bone mar- for successful management of recipient patients. row from a donor is inhsed into a recipient who As discussed above, the use of immunosuppres- may or may not have received chemoradiation ther- sant agents alters host response while simultaneous- apy designed to eliminate the host marrow cells. ly suppressing the inflammatory response." ,54~160-163 Usually, BMT grafts are obtained from a histo- Although prolonged corticosteroid therapy may compatible donor, and syngeneic graft material may lead to osteoporosis and other abnormalities in bone be taken from an identical twin. On some occasions, and periodontal fibrous tissue, available evidence the patient's own marrow cells may be harvested and suggests that destructive periodontitis is no more reimplanted following chemotherapy. It is difficult common among patients treated with cortico- to obtain true histocompatibility in allogeneic graft steroids than the general population. Such patients procedures. Therefore, allogeneic engraftment usu- may, however, be more susceptible to primary her- ally initiates graft-versus-host disease (GVHD), in petic or other viral or hngal infections. which the transplanted marrow cells recognize the Immunosuppression may affect bone marrow new host as foreign and attempt reje~tion."~-"~ function. The resulting thrombocytopenia, ane- Chemotherapy and total body irradiation may mia, and neutropenia may lead to oral hemorrhage be used to destroy malignant marrow cells prior to and severe bacterial, viral, fungal, or mixed infec- engraftment although chemotherapy alone is cur- tions. The risk of infection is directly proportional rently preferred in many oncology centers. Chemo- to the degree and duration of the drug-induced radiation therapy is usually conducted I to 2 weeks leukopenia and anemia.54J6"167 prior to BMT.183>184After inhsion of donor cells, Cyclosporine-induced gingival enlargement stem cells, or bone marrow, the patient is isolated resembles other drug-induced gingival overgrowth, for 4 to 6 weeks to minimize the risk of infection both clinically and histologically.The labial surfaces while marrow cells are revitalized and host defenses of anterior teeth are most frequently aected and re-established.76, 179, '82, ' 85-187 Immunosuppressant the overgrowth usually begins within 3 months of drugs and granulocyte colony growth factors start of treatment. The reaction may be preceded by (GCGF) are started at the time of engraftment, and plaque-related inflammati~n.~~J~~Effective plaque pancytopenia exists until the absolute neutrophil control and removal of local irritants, with or with- count exceeds 500 cell~/mm~.'~~-'~~ out the use of antimicrobial mouthrinses, may Patients who undergo BMT are at high risk for diminish the severity of cyclosporine-induced gin- development of opportunistic viral, hngal, and bac- gival enlargement,103J04J69-172but oral hygiene terial infections, including putative periodontal measures alone do not totally suppress gingival pathogens.191-204 Children may suffer from develop- overgrowth.35 ,66,82 mental abnormalitie~.~~~-~~~Epstein-Barr virus has Prophylactic antibiotic therapy should be con- been reported to induce hairy leukoplakia in HIV- sidered for periodontal or oral surgical procedures negative BMT Recipients of BMT may required during the first 6 months of recuperation also be susceptible to necrotizing ulcerative gingivi- following heart transplantation. If the recipient tis, necrotizing stomatitis, and possibly necrotizing patient achieves maximal restoration of cardiac ulcerative periodontitis. '06 Lesions of this type dur- function, preventive antibiotics for dental therapy ing marrow suppression are best treated with gentle may not be required unless a requirement for a dkbridement, chlorhexidine, or povidine-iodine high maintenance level of immunosuppression is mouthrinses, removal of necrotic osseous and soft present.28J'2 The medical complications of organ tissue, and antibiotic therapy administered after transplantation, however, may put recipient consultation with the oncologist.49J69-'72J95~211-213 patients at risk of orally acquired systemic sepsis. Graft-versus-host disease is a multisystem, Close coordination between the patient's physician potentially life-threatening phenomenon, in which and dentist is essential; and, continuance of excel- the engrafted marrow reacts against the tissues of lent oral health is req~ired.'~~J~~ the host. 185,214 A similar condition may occasionally be induced by blood transf~sion.~'~-~'~UP to Bone Marrow Transplantation 70% of BMT patients may be affected with acute GVHD within the first 30 days after engraft- Bone marrow transplantation (BMT) is currently ment.218-220Affected tissues include the liver, lungs, used in the treatment of leukemia, lymphoma, gastrointestinal tract, exocrine glands, skin, and Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 2 17 mucosa.218Acute GVHD may induce painhl, ery- prim and sulfamethoxazole may be recommended thematous or ulcerative oral mucosal lesions. by the patient’s oncologist. 119,237-240 Lesions which persist for more than I month are considered chronic although GVHD may appear de novo months or years after eng~-aftrnent.~’~>~~lREFERENCES Chronic GVHD may present with oral features suggestive of lichen planus, systemic lupus erythe- 1. Perlroth MG. The role of organ transplantation in matosus, scleroderma, or Sjogren’s medical therapy. In: Rubenstein E, Federman Diagnosis is based on clinical features and biopsy DD, editors. Scientific American medicine. New findings suggestive of the mucocutaneous condi- York: Scientific American Medicine, Inc.; 1986. tions described above.225Oral signs may range from 2. Glassman Wong C, Gish R A review of liver mild mucosal erythema to severe mucositis, desqua- transplantation for the dentist and guidelines mative gingivitis, xerostomia, and infection^.^^^-^^^ for dental management. Spec Care Dent 1993; Chemoradiation therapy-induced xerostomia may 13:74-80. subside over time after cessation of treatment. 3. Sakurai K, Drinkwater D, Sutherland DE, et al. While present, however, it may promote dental Dental treatment considerations for the pre- caries and mucositis.218On occasion, unusual oral and post-organ transplant patient. J Calif Dent side effects may occur, including minor salivary Assoc 1995;23:61-6. gland retention phenomena, verrucous xanthomas, 4. Coggins CH, Rennke HG, Rose BD. Glomeru- and atypical pyogenic granulomas.184,226,227,229,230 lonephritis and the nephrotic syndrome. In: Cyclosporine or tacrolimus are usually pre- Dale DC, Federman DD, editors. Scientific scribed for the prevention and treatment of GVHD American medicine. New York: Scientific Amer- although successful treatment of chronic oral ican Medicine, Inc.; 1995. lesions with psoralen plus ultraviolet A (PUVA) has 5. Remuzzi G, Bertani T. Pathophysiology of progres- recently been reported.231It is desirable to maintain sive nephropathies. New Engl J Med 1998;339: immunosuppression with the minimal quantity of 1448-56. drug necessary, but in the event of persistent 6. Appel GB. Preventing or slowing the progression of GVHD, the dosage may be increased. diabetic nephropathy. BUMC Proc 1999;12: Periodontal management prior to BMT is 3-6. consistent with the protocols described above. 7. Fenves AZ, Stone MJ, Johnson KB. Systemic pri- When possible, maximal oral health should be mary amyloidosis in chronic hemodialysis. achieved prior to engraftment. However, brushing BUMC Proc 1999;12:614. and flossing are usually discontinued immediately 8. Lazarus JM, Brenner BM. Chronic renal failure. following chemoradiation and re-initiated only In: Harrison’s Principles of internal medicine, after white blood cell counts exceed 2000/mm3.188 14th ed. New York: McGraw-Hill Co.; 1998. In the interim, oral cleansing is performed using p. 1513-20. cotton swabs, gauze sponges, soft sponge sticks, 9. Donohoe JF. Scleroderma and the kidney. Kidney and chlorhexidine rinses. 103,232 After partial recov- Int 1992;41:462-77. ery, patients are managed as described for other 10. Cruz R, Davis M, O’Neil H, et al. Pulmonary recipients of organ transplants. Oral GVHD is manifestations of inhaled street drugs. Heart usually controlled by meticulous oral hygiene, fre- Lung 1998;27:297-305. quent dental recall visits, and use of topical or sys- 11. Bachman U, Biava C, Amend W, et al. The clinical temic corticosteroids, antifungals, and antivi- course of IgA nephropathy and Henoch-Schon- ral~.~~~>~~~Mucositis may be soothed by rinsing lein purpura following renal transplantation. with lukewarm saline or 5% sodium bicarbonate Transplantation 1986;42:511-5. solution to elevate salivary pH. Other soothing 12. Rees TD. Oral effects of drug abuse. Curr Rev Oral mouthrinses containing kaolin, diphenhydramine, Biol Med 1992;3:163-84. and topical anesthetics have been recommended 13. Butler WT, Bennett JE, ALling DW, et al. Nephro- for comfort .234-237 toxicity of amphotericin B: early and late effects in Treatment of oral infections with antibiotic 8 1 patients. Ann Intern Med 1964;61 : 175-87. combinations are often indicated to prevent gram- 14. Lee MR. Dopamine and the kidney: ten years on. negative bacillary septicemia when oral or peri- Clin Sci 1993;83:357-75. odontal tissues must be manipulated during mar- 15. Olsen NV, Hansen JM, Ladefoged SD, et al. Renal row suppression therapy. Agents such as trimetho- tubular resorption of sodium and water during 2 18 Periodontal Medicine

infusion of low-dose doparnine in normal men. 31. Grossi SG. Effect of estrogen supplementation on Clin Sci 1990;78:503-7. periodontal disease. Comp Cont Ed Dent 1998; 16. Zager RA. Gentarnicin effects on renal ischemial (Suppl)22:S30-6. reperfusion injury. Circ Res 1992;70:20-8. 32. Jeffcoat MK. Osteoporosis: a possible modifjring 17. Black RM. Acute renal failure. In: Dale DC, Fed- factor in oral bone loss. Ann Periodontol 1998; erman DD, editors. Scientific American medi- 3:3 12-2 1. cine. New York: Scientific American Medicine, 33. Reddy MS, Weatherford TW 111, Smith CA, et al. Inc.; 1995. Alendronate treatment of naturally-occurring 18. Naylor GD, Fredericks MR. Pharmacologic con- periodontitis in beagle dogs. J Periodontol 1995; siderations in the dental management of the 66:2 11-7. patient with disorders of the renal system. Dent 34. Reeves HL, Francis RM, Manas DM, et al. Intra- Clin N Am 1996;40:665-83. venous bisphosphonate prevents symptomatic 19. Better OS, Stein JH. Early management of shock osteoporotic vertebral collapse in patients after and prophylaxis of acute renal failure in trau- liver transplantation. Liver Transplant Surg matic rhabdomyolysis. N Engl J Med 1990;322: 1998;4:404-9. 825-9. 35. Seymour RA, Thomason JM, Nolan A. Oral lesions 20. Zager RA, Garnelin LM. Pathogenetic mechanisms in organ transplant patients. J Oral Pathol Med in experimental hemoglobinuric acute renal 1997;26:297-304. injury. Am J Physiol 1989;256:F455-66. 36. Yamalik N, Avcikurt UF, Caglayan F, Eratalay K. 21. Ferguson GA, Whyman RA. Dental management The importance of oral foci of infection in renal of people with renal disease and renal trans- transplantation. Aust Dent J 1993;38:108-13. plants. N Z Dent J 1998;94:125-30. 37. Naylor GD, Hall EH, Terezhalmy GT. The patient 22. Bookatz BN. Management of oral problems related with chronic renal failure who is undergoing to kidney disease and dialysis. In: McDonald dialysis or renal transplantation: another consid- RD, Hurt WC, Gilmore HW, Middleton RA, eration for antimicrobial prophylaxis. Oral Surg editors. Current therapy in dentistry. Vol. 7. St. Oral Med Oral Pathol 1988;65:116-21. Louis: C.V. Mosby Co.; 1980. p. 31-6. 38. Alfrey AC. Phosphate, aluminum and other ele- 23. Cohen SG. Renal disease. In: Lynch MA, Bright- ments in chronic renal disease. In: Schrier RW, man VJ, Greenberg MS, editors. Burket’s oral Gottschalk CW, editors. Diseases of the kidney, medicine, 9th ed. Philadelphia: J.B. Lippincott 5th ed. Boston: Little, Brown and Co.; 1991. Co.; 1994. p. 487-509. p. 3153. 24. Pierce TB, Razzuk MA, Razzuk LM, Hoover SJ. A 39. Tolkoff-Rubin NE. Dialysis and transplantation. comprehensive review of the physiology of In: Dale DC, Federman DD, editors. Scientific hemostasis and antithrombotic agents. BUMC American medicine. New York: Scientific Amer- Proc 1999;12:39-50. ican Medicine, Inc. 1996. 25. Eigner TL, Jastak JT, Bennett WM. Achieving oral 40. Gotch FA, Sargent JA. A mechanistic analysis of health in patients with renal failure and renal the National Cooperative Dialysis Study. Kid- transplants. J Am Dent Assoc 1986;113:612-6. ney Int 198528:526-34. 26. Wactawski-Wende J, Grossi SG, Trevisan M, et al. 41. Beck LH. Requiem for gouty nephropathy. Kidney The role of osteopenia in oral bone loss and peri- Int 1986;30:280-7. odontal disease. J Periodontol 1996;67:1076-84. 42. Schulman G, Hakim RM. Complications of 27. Ziccardi VB, Saini J, Demas PN, Braun TW. Man- hemodialysis. In: Jacobson H, Shaker K, Klahr S, agement of the oral and maxillofacial surgery editors. Principles and practice of nephrology, patient with end-stage renal disease. J Oral 2nd ed. St. Louis: C.V. Mosby Co.; 1995. p. 673. Maxillofac Surg 1992;50:1207-12. 43. Brescia MJ, Cimino JE, Appel K, Harwich BJ. 28. DeRossi SS, Glick M. Dental considerations for the Chronic hemodialysis using venipuncture and patient with renal disease receiving hemodialysis. surgically created arteriovenous fistula. N Engl J J Am Dent Assoc 1996;127:211-9. Med 1966;275:1089-92. 29. Glick M. Dental considerations for the patient 44. Carpenter CB, Lazarus JM. Dialysis and transplanta- with renal disease receiving hemodialysis. J Am tion in the treatment of renal failure. In: Fauci AS, Dent Assoc 1996;127:211-9. Braunwald E, Wilson JO, et al, editors. Harrison’s 30. Bando K, Nitta H, Matsubara M, Ishikawa I. Bone Principles of internal medicine, 14th ed. New mineral density in periodontally healthy and York: McGraw-Hill Co.; 1998. p. 1520-9. edentulous postmenopausal women. Ann Peri- 45. Ruskin JD, Wood W, Bailey MR, et al. Compara- odontol 1998;3:322-7. tive trial of oral clotrimazole and nystatin for Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 2 19

oropharyngeal candidiasis prophylaxis in ortho- 59. Brambilla L, Boneschi V, Fossati S, et al. Vinorel- topic liver transplant patients. Oral Surg Oral bine therapy for Kaposi’s sarcoma in a kidney Med Oral Pathol 1992;74:567-71. transplant patient. Dermatology 1997; 194: 46. Schubert MM, Epstein JB, Lloyd ME, Cooney E. 28 1-3. Oral infections due to cytomegalovirus in 60. Bunney MH, Benton EC, Barr BB, et al. The immunocompromised patients. J Oral Pathol prevalence of skin disorders in renal allograft Med 1993;22:268-73. recipients receiving cyclosporine A compared 47. Whitley RJ, Blum MR, Barton N, de Miranda E with those receiving azathioprine. Nephrol Pharmacokinetics of acyclovir in humans fol- Dialysis Transplant 19 9 0; 5 :379-82. lowing intravenous administration. A model for 61. Eslamboltchi F, Rees TD, Iacopino AM. Cyclospor- the development of parenteral antivirals. Am J ine A-induced gingival enlargement. A compre- Med 1982;73(Suppl 1A):165-71. hensive review. Quintessence Int 1999 [In press]. 48. McCauley J. Medical complications. In: Shapiro R, 62. Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Aggres- Simmons RL, Starzl TE, editors. Complications sive squamous cell carcinomas in organ transplant of renal transplantation. Stamford, CT: Apple- recipients. Transplant Proc 199527:1767-8. ton & Lange; 1997. p. 299-313. 63. Glover MT, Deeks JJ, Raftery MJ, et al. Immuno- 49. Finberg R, Fingeroth J. Infections in transplant suppression and risk of non-melanoma skin recipients. In: Fauci AS, Braunwald E, Wilson cancer in renal transplant recipients [letter]. JO, et al, editors. Harrison’s Principles of internal Lancet 1997;349:39 8. medicine, 14th ed. New York: McGraw-Hill 64. Green C, Hawk JL. Cutaneous malignancy related Co.; 1998. p. 840-6. to cyclosporine A therapy. Clin Exp Dermatol 50. Kusne S, Manez R. Infectious complications. In: 1993;1830-1. Shapiro R, Simmons RL, Starzl TE, editors. 65. Gruber SA, Gillingham K, Sothern RB, et al. De Complications of renal transplantation. Stam- novo cancer in cyclosporine-treated and non- ford, CT: Appleton & Lange; 1997. p. 3 15-32. cyclosporine-treated adult primary renal allo- 51. Muzyka BC, Glick M. A review of oral fungal graft recipients. Clin Transplant 1994;8:388-95. infections and appropriate therapy. J Am Dent 66. Hallmon WW, Rossmann JA. The role of drugs in Assoc 1995;126:63-72. the pathogenesis of gingival overgrowth. A col- 52. Aebischer MC, Zala LB, Braathen LR Kaposi’s sar- lective review of current concepts. Periodontol coma as manifestation of immunosuppression 2000 1999 [In press]. in organ transplant recipients. Dermatology 67. Halmos 0, Inturri Galligioni A, et al. Two cases 1997;195:91-2. of Kaposi’s sarcoma in renal and liver transplant 53. al-Sulaiman MH, Mousa DH, Dhar JM, al-Gad- recipients treated with interferon. Clin Trans- er A. Does regressed post-transplantation plant 1996;10:374-8. Kaposi’s sarcoma recur following reintroduction of immunosuppression? Am J Nephrol 1992; 68. Hepburn DJ, Divakar D, Bailey RR, Macdonald 12:384-6. KJ. Cutaneous manifestations of renal trans- 54. Bakr MA, Sobh M, el-Agroudy A, et al. Study of plantation in a New Zealand population. N Z malignancy among Egyptian kidney transplant Med J 1994;107:497-9. recipients. Transplant Proc 1997;29:3067-70. 69. Hiesse C, Kriaa F, Rieu et al. Incidence and type 55. Bencini PL, Marchesi L, Cainelli T, Crosti C. of malignancies occurring after renal transplan- Kaposi’s sarcoma in kidney transplant recipients tation in conventionally and cyclosporine-treat- treated with cyclosporine. Br J Dermatol 1988; ed recipients: analysis of a 20-year period in 118:709-14. 1600 patients. Transplant Proc 1995;27:9724 56. Bencini PL, Montagnino G, Sala F, et al. Cutaneous 70. Hiesse C, Larue JR, Kriaa F, et al. Incidence and lesions in 67 cyclosporine-treated renal transplant type of malignancies occurring after renal trans- recipients. Dermatologica 1986;172:24-30. plantation in conventionally and in 57. Blohme I, Larko 0. No difference in skin cancer cyclosporine-treated recipients: single-center incidence with or without cyclosporine. A 5- analysis of a 20-year period in 1600 patients. year perspective. Transplant Proc 1992;24:313. Transplant Proc 1995;27:2450-1. 58. Bocchi EA, Higuchi ML, Vieira ML, et al. Higher 71. Jordan ML. Malignancy after renal transplantation. incidence of malignant neoplasms after heart In: Shapiro R, Simmons RL, Starzl TE, editors. transplantation for treatment of chronic Chagas’ Complications of renal transplantation. Stam- heart disease. J Heart Lung Transplant 1998;17: ford, CT: Appleton & Lange; 1997. p. 353-82. 339-405. 72. London NJ, Farmery SM, Will EJ, et al. Risk of 220 Periodontal Medicine

neoplasia in renal transplant patients. Lancet 87.Jonas S, Rayes N, Neumann U, et al. De novo malig- 1995;346:403-6. nancies after liver transplantation using 73. Margiotta V, Florena AM, Giuliana G. Primary tacrolimus-based protocols or cyclosporine- angiosarcoma of the alveolar mucosa in a based quadruple immunosuppression with an haemodialysis patient: case report and discus- interleukin-2 receptor antibody or antihymo- sion. J Oral Pathol Med 1994;23:429-3 1. cyte globulin. Cancer 1997;6:1141-50. 74. Margolius I, Stein M, Spencer D, Bezwoda WR. 88.Lipkowitz GS, Madden RL. Transmission of Kaposi’s sarcoma in renal transplant recipients. Kaposi’s sarcoma by solid organ donation. Experience at Johannesburg Hospital, 1966- Transplant Sci 1994;4:9-11. 1989. S African Med J 1994;84:16-7. 89.Sheil AG, Disney N,Mathew TH, Amiss N. De 75. Masuhara M, Ogasawara H, Katyal SL, et al. Cyclo- novo malignancy emerges as a major cause of sporine stimulates hepatocyte proliferation and morbidity and late failure in renal transplanta- accelerates development of hepatocellular carcino- tion. Transplant Proc 1993;25:1383-4. mas in rats. Carcinogenesis 1993;14: 1579-84. 90.Varga E, Tyldesley WR. Carcinoma arising in 76. Maxymiw WG, Wood RE. The role of dentistry in cyclosporine-induced gingival hyperplasia. Br patients undergoing bone marrow transplanta- Dent J 1991;171:26-7. tion. Br Dent J 1989;167:229-34. 91.Patton LL, Ship JA. Treatment of patients with 77. Maxymiw WG, Wood RE, Lee L. Primary, multi- bleeding disorders. Dent Clin North Am 1994; focal, non-Hodgkin’s lymphoma of the jaws 38:465-82. presenting as periodontal disease in a renal 92.Varga E, Lennon M, Mair L. Pre-transplant gingival transplant patient. Int J Oral Maxillofac Surg hyperplasia predicts severe cyclosporine- 1991;20:69-70. induced gingival overgrowth in renal transplant patient. J Clin Periodontol 1998;25:225-30. 78. Merot Y, Miescher PA, Balsiger F, et al. Cutaneous malignant melanomas occurring under cyclo- 93.Adams CK, Famili E A study of the effects of FK506 sporine A therapy: a report of two cases. Br J on gingival tissues. Transplant Proc Dermatol 1990;2:237-9. 1991;23:3 193-4. 94.Nery E, Edson R Prevalence of nifedipine-induced 79. Montagnino G, Bencini PL, Tarantino A, et al. gingival hyperplasia. J Periodontol 1995;66: Clinical features and course of Kaposi’s sarcoma 572-8. in kidney transplant patients: report of 13 cases. 95.Ryman K, Pharm D, Gurk-Turner C. Pharmacology Am J Nephrol 1994;14: 121-6. notes-calcium channel blocker review. BUMC 80. Ozen S, Saatci U, Karaduman A, et al. Kaposi’s sar- Proc 1999;12:34-6. coma in a paediatric renal transplant recipient. 96.Thomason JM, Seymour RA, Ellis JS, et al. Deter- Nephrol Dialysis Transplant 1996;1 1: 1162-3. minants of gingival overgrowth severity in organ 8 1. Penn I. Cancers in cyclosporine-treated vs azathio- transplant patients. An examination of the role prine-treated patients. Transplant Proc 1996;28: of HLA phenotype. J Clin Periodontol 1996; 876-8. 23:628-34. 82. Rees TD. Drugs and oral disorders. Periodontol 97.Wilson RF, More1 A, Smith D, et al. Contribution of 2000 1998;18:21-36. individual drugs to gingival overgrowth in adult 83. Regev E, Zeltser R, Lustmann J. Lip carcinoma in and juvenile renal transplant patients treated renal allografi recipient with long-term immuno- with multiple therapy. J Clin Periodontol suppressive therapy. Oral Surg Oral Med Oral 1998;25:457-64. Pathol 1992;73:4124. 98.Jorgensen MG. Prevalence of amlodipine-related gin- 84. Sabeel A, Qunibi W. Recurrent Kaposi’s sarcoma in gival hyperplasia. J Periodontol 199368:676-8. a renal transplant recipient maintained on min- 99.Westbrook Bednarczyk EM, Carlson M, et al. imum doses of immunosuppression [letter]. Regression of nifedipine-induced gingival Neph Dialysis Transplant 1998;13:1609-10. hyperplasia following switch to a same class cal- 85. Thomas DW, Seddon SV, Shepherd JE Systemic cium channel blocker, isradipine. J Periodontol immunosuppression and oral malignancy: a 1997;68: 645-5 0. report of a case and review of the literature. Br J 100. Naugle K, Darby ML, Bauman DB, et al. The oral Oral Maxillofac Surg 1993;3 1:39 1-3. heath status of individuals on renal dialysis. Ann 86. Veness MS. Cardiac transplant-related cutaneous Periodontol 1998;3:197-205. malignancies in an Australian recipient: 101. Rees TD, Rose LF. Periodontal management of immunosuppression, friend or foe? Clin Oncol patients with cardiovascular diseases. J Peri- 1998;10: 194-7. odontol 1996;67:627-35. Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 22 1

102. Slots J. Casual or causal relationship between peri- 117. Keeffe EB. Acute hepatitis. In: Dale DC, Federman odontal infection and non-oral disease: [guest DD, editors. Scientific American medicine. New editorial] J Dent Res 1998;77:1764-5. York: Scientific American Medicine, Inc.; 1998. 103. Ciancio SG. Expanded and future uses of mouth- 118. Lodi G, Porter SR, Scully C. Hepatitis C virus rinses. J Arn Dent Assoc 1994;125: 29s-32s. infection: review and implications for the den- 104. Ciancio SG, Bartz NW, Lauciello FR. tist. Oral Surg Oral Med Oral Pathol Oral Radi- Cyclosporine-induced gingival hyperplasia and 01 Endod 1998;86:8-22. chlorhexidine-a case report. Int J Periodont 119. Semba SE, Mealey BL, Hallmon Ww. Dentistry Restor Dent 1991;11:241-5. and the cancer patient. Part 2. Oral health man- 105. MacPhail LA, Hilton JF, Heinic GS, Greenspan D. agement of the chemotherapy patient. Comp Direct immunofluoresencevs. culture for detect- Cont Educ Dent 1994;15:1378-88. ing HSV in oral ulcers: a comparison. J Am Dent 120. Sempoux C, Horsmans Y, Lerut J, et al. Acute lob- Assoc 1995;126:74-8. ular hepatitis as the first manifestation of recur- 106. Rees TD. Periodontal considerations in the man- rent autoimmune hepatitis after orthotopic liver agement of the cancer patient. J Periodontol transplantation. Liver 1997;17:3 11-5. 1997;68:791-801. 121. Keeffe EB. Cirrhosis of the liver. In: Dale DC, 107. Samaranayake Le MacFarlane Tw, Lamey PJ, Federman DD, editors. Scientific American Ferguson MM. A comparison of oral rinse and medicine. New York: Scientific American Med- imprint sampling techniques for the detection icine, Inc.; 1998. of yeast, coliform and Stapbylococcus aureus car- 122. Belli LS, Silini E, Alberti A, et al. Hepatitis C virus riage in the oral cavity. J Oral Pathol 1986; genotypes, hepatitis and hepatitis C virus recur- 15386-8. rence after liver transplantation. Liver Trans- 108. Dajani AS, Taubert KA, Wilson W, et al. Preven- plant Surg 1996;2:200-5. tion of bacterial endocarditis. J Am Med Assoc 123. Podolsky DK, Isselbacher KJ. Major complica- 1997;277: 1794-80 1, Circulation 1997;96: tions of cirrhosis. In: Fauci AS, Braunwald E, 358-66. Wilson JO, et al, editors. Harrison’s Principles of 109. Lamas W. A study of transient bacteremia fol- internal medicine, 14th ed. New York: lowing an intraoral soft tissue biopsy [MS The- McGraw-Hill Co.; 1998. p. 1710-25. sis]. Baylor College of Dentistry; 1998. 124. Ilan Y, Galun E, Nagler A, et al. Sanctuary of 110. Rutkauskas JS, Davis JW. Effects of chlorhexidine hepatitis B virus in bone marrow cells of during immunosuppressive chemotherapy. A patients undergoing liver transplantation. Liver preliminary report. Oral Surg Oral Med Oral Transplant Surg 1996;2:206-10. Pathol 1993;76:441-8. 125. Dienstag J. Liver transplantation. In: Fauci AS, 111. Douglas LR, Douglass JB, Sieck JO, Smith PJ. Braunwald E, Wilson JO, et al, editors. Harrison’s Oral management of the patient with end-stage Principles of internal medicine, ed. New liver disease and the liver transplant patient. 14th Oral Surg Oral Med Oral Pathol Oral Radio1 York: McGraw-Hill Co.; 1998. p. 1721-5. Endod 1998;86:55-64. 126. Isselbacher KJ, Podolsky DK. Infiltrative and meta- 112. Little JW, Rhodus NL. Dental treatment of the bolic diseases affecting the liver. In: Fauci AS, liver transplant patient. Oral Surg Oral Med Braunwald E, Wilson JO, et al, editors. Harrison’s Oral Pathol 1992;73:419-26. Principles of internal medicine, 14th ed. New 113. Mulligan R, Weitzel KG. Pretreatment manage- York: McGraw-Hill Co.; 1998. p. 1717-20. ment of the patient receiving anticoagulant 127. Sampathkumar E Lerman A, Kim BY, et al. Post- drugs. J Am Dent Assoc 1988;117:479-83. liver transplantation myocardial dysfunction. 114. Okamoto GU, Duperon DF. Bleeding control Liver Transplant Surg 1998;4:399-403. after extractions in a patient with aplastic ane- 128. Ludwig J, Hashimoto E, Porayko MK, Therneau mia during bone marrow transplantation: report TM. Failed allografts and causes of death after of case. ASDC J Dent Child 1989;56:50-5. orthotopic liver transplantation from 1985 to 115. Rossmann JA, Rees TD. The use of hemostatic 1995: decreasing prevalence of irreversible agents in dentistry. Postgrad Dent 1996;3(3): hepatic allograft rejection. Liver Transplant Surg 3-12. 1996;2:185-9 1. 116. Keeffe EB. Chronic hepatitis. In: Dale DC, Feder- 129. Bussey HI, Force RW, Bianco TM, Leonard AD. man DD, editors. Scientific American medi- Reliance of prothrombin time ratios causes sig- cine. New York: Scientific American Medicine, nificant errors in anticoagulation therapy. Arch Inc.; 1998. Intern Med 1992;152:278-82. 222 Periodontal Medicine

130. Carr MM, Mason RB. Dental management of in lung transplant recipients. J Heart Lung anticoagulated patients. J Can Dent Assoc Transplant 1996; 15:888-94. 1992;58:838-44. 144. Sundaresan S, Trulock EC Mohanakumar T, et al. 131. DeClerck D, Vinckier F, Vermylen J. Influence of Prevalence and outcome of bronchiolitis obliter- anticoagulation on blood loss following dental ans syndrome after lung transplantation. Wash- extractions. J Dent Res 1992;71:387-90. ington University Lung Transplant Group. Ann 132. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anti- Thorac Surg 1995;60:1341-6. coagulants. Mechanism of action, clinical effec- 145. Maurer JR, Tewari S. Nonpulmonary medical tiveness, and optimal therapeutic range. Chest complications in the intermediate and long- 1992;102(Suppl4):312~-326s. term survivor [review]. Clin Chest Med 1997; 133. International Committee for Standardization in 18:367-82. Haematology and International Committee on 146. Scannapieco FA, Mylotte JM. Relationships Thrombosis and Haemostasis. ICSH/ICTH between periodontal disease and bacterial pneu- recommendations for reporting prothrombin monia. J Periodontol 1996;67:11 14-22. time in oral anticoagulant control. J Clin Pathol 147. Hayes C, Sparrow D, Cohen M, et al. The associ- 19 8 5;3 8 :1 3 3-4. ation between alveolar bone loss and pulmonary 134. Lippert S, Gutschik E. Views of cardiac-valve function: the VA dental longitudinal study. Ann prosthesis patients and their dentists on antico- Periodontol 1998;3:257-61. agulation therapy. Scand J Dent Res 1994;102: 148. Limeback H. Implications of oral infections on 168-71. systemic diseases in the institutionalized elderly 135. Martinowitz U, Mazar AL,Taicher S, et al. Dental with a special focus on pneumonia. Ann Peri- extraction for patients on oral anticoagulant odontol 1998;3:262-75. therapy. Oral Surg Oral Med Oral Pathol 149. Bourke JC Loaiza A, Parry G, et al. Role of ortho- 1990;70:274-7. topic heart transplantation in the management 136. Purcell CAH. Dental management of the antico- of patients with recurrent ventricular tach- agulated patient. N 2 Dent J 1997;93:87-92. yarrhythmias following myocardial infarction. Heart 1998;80:473-8. 137. Ramstrom G, Sindet-Pedersen S, Hall G, et al. Prevention of postsurgical bleeding in oral 150. Schroeder JS. Cardiac transplantation. In: Fauci AS, Braunwald E, Wilson JO, et al, editors. Harrison’s surgery using tranexamic acid without dose Principles of internal medicine, 14th ed. New modification of oral anticoagulants. J Oral Max- York: McGraw-Hill Co.; 1998. p. 1298-300. illofac Surg 139351 : 12 1 1-6. 15 1. Moons De Geest S, Abraham I, et al. Symptom 138. Rakocz M, Mazar A, Varon D, et al. Dental extrac- experience associated with maintenance tions in patients with bleeding disorders. Oral immunosuppression after heart transplantation: Surg Oral Med Oral Pathol 1993;75:280-2. patients’ appraisal of side effects. Heart Lung 139. Cutler LS. Evaluation and management of the 19 9 8 ;27:3 15-2 5. dental patient with a history of hepatitis, jaun- 152. Beck JD, Offenbacher S, Williams R, et al. Peri- dice, or liver disease. J Conn State Dent Assoc odontitis: a risk factor for coronary heart dis- 1985; 59~115-7. ease? Ann Periodontol 1998;3:127-4 1. 140. Carithers RL, Perkins JD. Liver and pancreas 153. Herzberg MC, Meyer MW. Dental plaque, transplantation. In: Dale DC, Federman DD, platelets, and cardiovascular diseases. Ann Peri- editors. Scientific American medicine. New odontol 1998;3:15 1-60. York: Scientific American Medicine, Inc.; 1998. 154. Herzberg MC, Meyer Mw. Effects of oral flora on 141. Caiffa WT, Vlahov D, Graham NMH. Drug platelets: possible consequences in cardiovascu- smoking, Pneumocystis carinii pneumonia, and lar disease. J Periodontol 1996;67:1138-42. immunosuppression increase risk of bacterial 155. Joshipura KJ, Douglas CW, Willett WC. Possible pneumonia in HIV-seropositive injection drug explanations for the tooth loss and cardiovascu- users. Arn J Respir Crit Care Med 1994;150: lar disease relationship. Ann Periodontol 1493-8. 1998;3:175-83. 142. Maurer JR Lung transplantation. In: Fauci AS, 156. Kinane DF. Periodontal diseases’ contribution to Braunwald E, Wilson JO, et al, editors. Harrison’s cardiovascular disease: an overview of potential Principles of internal medicine, 14th ed. New mechanisms. Ann Periodontol 1998;3:142-50. York: McGraw-Hill Co.; 1998. p. 1491-3. 157. Lowe GDO. Etiopathogenesis of cardiovascular 143. Hohlfeld J, Niedermeyer J, Hamm H, et al. Sea- disease: hemostasis, thrombosis, and vascular sonal onset of bronchiolitis obliterans syndrome medicine. Ann Periodontol 1998;3:121-6. Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 223

158. Mealey BL. Influence of periodontal infections on 172. Fleming E Dental management of the pediatric systemic health. Periodontol 2000 1999 [In oncology patient. Curr Opin Dent 199 1; 1: press]. 577-82. 159. Page RC. The pathobiology of periodontal diseases 173. Montgomery MT, Redding SW, LeMaistre CE The may affect systemic diseases: inversion of a par- incidence of oral herpes simplex virus infection in adigm. Ann Periodontol 1998;3:108-20. patients undergoing cancer chemotherapy. Oral 160. Bader G, Lejeune S, Messner M. Reduction of Surg Oral Med Oral Pathol 1986;61:238-42. cyclosporine-induced gingival overgrowth fol- 174. Poland J. Prevention and treatment of oral com- lowing a change to tacrolimus. A case history plications in the cancer patient. Oncology involving a liver transplant patient. J Periodon- 19915: 45-50,52,57,6 1-2. to1 1998;69:729-32. 175. Attal M, Harousseau JL, Stoppa AM, et al. A 161. Baldwin L, Henderson A, Hickman E Effect of prospective, randomized trial of autologous bone postoperative low-dose dopamine on renal func- marrow transplantation and chemotherapy in tion after elective major vascular surgery. Ann multiple myeloma. N Engl J Med 1996;335: Intern Med 1994;120:744-7. 9 1-7. 162. Mattsson T, Arvidson K, Heimdahl A, et al. Alter- 176. Berkowitz RJ, Strandjord S, Jones et al. Stoma- ations in test acuity associated with allogeneic tologic complications of bone marrow trans- bone marrow transplantation. J Oral Pathol plantation in a pediatric population. Pediatric Med 1992;21:33-7. Dent 1987;9:105-1 0. 163. Niehaus CS, Meiller TF, Peterson DE, Overholser 177. Cooper B. New concepts in management of acute CD. Oral complications in children during can- leukemia. BUMC Proc 1990;3:31-3. cer therapy. Cancer Nurs 1987;10: 15-20. 178. Devine SM, Larson RA. Acute leukemia in adults: 164. Bressman E, Decter JA, Chasens AI, Sackler RS. recent developments in diagnosis and treat- Acute myeloblastic leukemia with oral manifes- ment. CA Cancer J Clin 1994;44:326-52. tations. Report of a case. Oral Surg Oral Med 179. Greenberg MS, Garfunkel A. Hematologic disease. Oral Pathol 1982;54:401-3. In: Lynch MA, Brightman VJ, Greenbert MS, 165. Brown AT, Shupe JA, Sims RE, et al. In vitro effect of editors. Burket’s Oral medicine 9th ed. Philadel- chlorhexidine and amikacin on oral gram-negative phia: J.B. Lippincott Co.; 1994. p. 510-8. bacilli from bone marrow transplant recipients. 180. Lazarchik DA, Filler SJ, Winkler ME Dental eval- Oral Surg Oral Med Oral Path01 1990;70:715-9. uation in bone marrow transplantation. Gen 166. Brown AT, Sims RE, Raybould et al. Oral TC Dent 1995;43: 369-71. gram-negative bacilli in bone marrow transplant 181. Vose JM, Kennedy BC, Bierman PJ, et al. Long- patients given chlorhexidine rinses. J Dent Res term sequelae of autologous bone marrow or 1989;68:1 199-204. peripheral stem cell transplantation for lym- 167. Peters E, Monopoli M, Woo SB, Sonis S. Assess- phoid malignancies. Cancer 1992;69:784-9. ment of the need for treatment of postendodon- 182. Armitage JO. Bone marrow transplantation. In: tic asymptomatic periapical radiolucencies in Fauci AS, Braunwald E, Wilson JO, et al, edi- bone marrow transplant recipients. Oral Surg tors. Harrison’s Principles of internal medicine, Oral Med Oral Pathol 1993;76:45-8. ed. New York: McGraw-Hill Co.; 1998. 168. Bartold PM. Cyclosporine and gingival over- 14th growth. J Oral Pathol 1988;16:463-8. p. 724-30. 169. Ferretti GA, Ash RC, Brown AT, et al. Chlorhexi- 183. Collins RH, Miller GW, Fay JW. Autologous bone dine for prophylaxis against oral infections and marrow transplantation: a review. BUMC Proc associated complications in patients receiving 1991;4:3-12. bone marrow transplants. J Arn Dent Assoc 184. Rhodus NL, Little JW. Dental management of the 1987;1 14:461-7. bone marrow transplant patient. Comp Cont 170. Ferretti GA, Hansen IA, Whittenburg K, et al. Educ Dent 1992;13:1042-50. Therapeutic use of chlorhexidine in bone mar- 185. Dahllof G, Heimdahl A, ModCer T, et al. Oral row transplant patients: case studies. Oral Surg mucous membrane lesions in children treated Oral Med Oral Pathol 1987;63:683-7. with bone marrow transplantation. Scand J 171. Flaitz CM, Hammond HL. The immunoperoxi- Dent Res 1989;97:268-77. dase method for the rapid diagnosis of intraoral 186. Set0 BG, Kim M, Wolinsky L, et al. Oral mucosi- herpes simplex virus infection in patients receiv- tis in patients undergoing bone marrow trans- ing bone marrow transplants. Spec Care Dent plantation. Oral Surg Oral Med Oral Pathol 1988;8:82-5. 1985;60:493-507. 224 Periodontal Medicine

187. Wescott WB. Dental management of patients being analysis of factors associated with infection. Oral treated for oral cancer. CDA J 1985;13:42-7. Surg Oral Med Oral Pathol 1990;70:286-93. 188. American Dental Association. Patients receiving 201. Schuchter LM, Wingard JR, Piantadosi S, et al. cancer chemotherapy. Chicago: American Den- Herpes zoster infection after autologous bone tal Association; 1989. marrow transplantation. Blood 1989;74:1424-7. 189. Birek C, Patterson B, Maximiw WC, Minden 202. Shearer BH, Hay KD. Hard and soft tissue oral MD. EBV and HSV infections in a patient who changes following bone marrow transplanta- had undergone bone marrow transplantation: tion. N 2 Dent J 1987;83:1034. oral manifestations and diagnosis by in situ 203. Thurmond JM, Brown AT, Sims RE, et al. Oral nucleic acid hybridization. Oral Surg Oral Med Candidd albicans in bone marrow transplant Oral Pathol 1989;68:612-7. patients given chlorhexidine rinses: occurrence 190. Childers NK, Stinnett EA, Wheeler et al. Oral and susceptibilities to the agent. Oral Surg Oral complications in children with cancer. Oral Med Oral Pathol 1991;72:291-5. Surg Oral Med Oral Pathol 1993;75:41-7. 204. Wade JC, Newton B, McLaren C, et al. Intra- 191. Barasch A, Mosier KM, D’Ambrosio JA, et al. venous acyclovir to treat mucocutaneous herpes Postextraction osteomyelitis in a bone marrow simplex virus infection after marrow transplan- transplant recipient. Oral Surg Oral Med Oral tation: a double blind study. Ann Intern Med Pathol 1993;75:391-6. 1982;96:265-9. 192. Barrett Ac Schifter M. Antibiotic strategy in oro- 205. Dahllof G, Barr M, Bolme et al. Disturbances in facial/head and neck infections in severe neu- dental development after total body irradiation tropenia. Oral Surg Oral Med Oral Pathol in bone marrow transplant recipients. Oral Surg 1994;77:350-5. Oral Med Oral Pathol 1988;65:414. 193. Cutler LS. Evaluation and management of the den- 206. Dahllof G, Forsberg CM, RingdCn 0, et al. Facial tal patient with cancer. I. Complications associat- growth and morphology in long-term survivors ed with chemotherapy or bone marrow transplan- after bone marrow transplantation. Eur J tation. J Conn State Dent Assoc 1987;61:236-8. Orthod 1989; 11 :33240. 194. Epstein JB, Sherlock CH, Page JL, et al. Clinical 207. Dahllof G, Krekmanova L, Kopp S, et al. Cran- study of herpes simplex virus infection in iomandibular dysfunction in children treated leukemia. Oral Surg Oral Med Oral Pathol with total-body irradiation and bone marrow 1990;70: 38-43. transplantation. Acta Odontol Scand 199452: 195. Kolbinson DA, Schubert MM, Flournoy N, Tru- 39-105. elove EL. Early oral changes following bone 208. Dahllof G, ModCer T, Bolme et al. Oral health marrow transplantation. Oral Surg Oral Med in children treated with bone marrow transplan- Oral Pathol 1988;66:130-8. tation: a one-year follow-up. ASDC J Dent 196. Mattsson T, Heimdahl A, Dahllof G, et al. Oral Child 1988;55:196-200. and nutritional status in allogeneic marrow 209. Dahllof G, Rozell B, Forsberg CM, Borgstrom B. recipients treated with T-cell depletion or Histologic changes in dental morphology cyclosporine combined with methotrexate to induced by high dose chemotherapy and total prevent graft-versus-host disease. Oral Surg body irradiation. Oral Surg Oral Med Oral Oral Med Oral Pathol 1992;74:34-40. Pathol 1994;77:56-60. 197. Nikoskelainen J. Oral infections related to radia- 210. Epstein JB, Sherlock CH, Wolber RA. Hairy tion and immunosuppressive therapy. J Clin leukoplakia after bone marrow transplantation. Periodontol 1990;17:504-7. Oral Surg Oral Med Oral Pathol 1993;75: 198. Peterson DE, Minah GE, Overholser CD, et al. 690-5. Microbiology of acute periodontal infection in 211. Ellegaard B, Bergmann OJ, Ellegaard J. Effect of myelosuppressed cancer patients. J Clin Oncol plaque removal on patients with acute leukemia. 1987;5:1461-8. J Oral Pathol Med 1989;18:54-8. 199. Redding SW, Montgomery MT. Acyclovir pro- 212. Epstein JB, Vickars L, Spinelli J, Reece D. Effka- phylaxis for oral herpes simplex virus infection cy of chlorhexidine and nystatin rinses in pre- in patients with bone marrow transplants. Oral vention of oral complications in leukemia and Surg Oral Med Oral Pathol 1989;67:680-3. bone marrow transplantation. Oral Surg Oral 200. Schubert MM, Peterson DE, Flournoy N, et al. Oral Med Oral Pathol 1992;73:682-9. and pharyngeal herpes simplex virus infection 213. Raether D, Walker PO, Bostrum B, Weisdorf D. after allogeneic bone marrow transplantation: Effectiveness of oral chlorhexidine for reducing Periodontal Considerations in Patients with Bone Marrow or Solid Organ Transplants 22 5

stomatitis in a pediatric bone marrow transplant body irradiation on salivary gland function and population. Pediatr Dent 1989; 11:37-42. caries-associated oral microflora in bone mar- 214. Eggleston TI, Ziccardi VB, Lumerman H. Graft- row transplant patients. Oral Surg Oral Med versus-host disease: case report and discussion. Oral Pathol 1992;73:670-6. Oral Surg Oral Med Oral Pathol Oral Radiol 229. Wandera A, Walker PO. Bilateral pyogenic granu- Endod 1998;86:692-6. loma of the tongue in graft-versus-host disease: 215. LeVeque FG. An unusual presentation of chronic report of a case. ASDC J Dent Child 1994;61: graft-versus-host disease in an unrelated bone 401-3. marrow transplantation. Oral Surg Oral Med 230. Lee L, Miller PA, Maxymiw WG, et al. Intraoral Oral Pathol 1990;69:5814. pyogenic granuloma after allogeneic bone mar- 216. Williams MC, Lee GT. Childhood leukemia and row transplant. Report of three cases. Oral Surg dental considerations. J Clin Pediatr Dent Oral Med Oral Pathol 1994;78:607-10. 199 1;15:160-4. 231. Redding SW, Callander NS, Haveman CW, 2 17. Williamson LM. Transfusion associated graft ver- Leonard DL. Treatment of oral chronic graft- sus host disease and its prevention [editorial]. versus-host disease with PWA therapy: case Heart 1998;80:21 1-2. report and literature review. Oral Surg Oral Med 218. Curtis JW Jr, Caughman GB. An apparent unusu- Oral Pathol Oral Radiol Endod 1998;86:183-7. al relationship between rampant caries and graft- 232. Lefkoff MA, Beck FM, Horton JE. The effective- versus-host disease. Oral Surg Oral Med Oral ness of a disposable tooth cleansing device on Pathol 1994;78:267-72. plaque. J Periodontol 1995;66:218-21. 219. Heimdahl A, Johnson G, Danielsson KH, et al. 233. Wingard JR, Niehaus CS, Peterson DE, et al. Oral Oral condition of patients with leukemia and mucositis after bone marrow transplantation. A severe aplastic anemia. Follow-up one year after marker of treatment toxicity and predictor of bone marrow transplantation. Oral Surg Oral hepatic veno-occlusive disease. Oral Surg Oral Med Oral Pathol 1985;60:498-504. Med Oral Pathol 199 1;72:4 19-24. 220. Woo S-B, Lee SJ, Schubert MM. Graft-vs-host dis- 234. Borowski B, Benhamou E, Pico JL, et al. Preven- ease. Crit Rev Oral Biol Med 1997;8:201-16. tion of oral mucositis in patients treated with 22 1. LeVeque FG, Ratanatharathorn V, Danielsson high-dose chemotherapy and bone marrow KH, et al. Oral cytomegalovirus infection in an transplantation: a randomized controlled trial unrelated bone marrow transplantation with comparing two protocols of dental care. Eur J possible mediation by graft-versus-host disease Cancer B Oral Oncol 1994;30B:93-7. and the use of cyclosporine A. Oral Surg Oral 235. Fay JT, O’Neal R. Dental responsibility for the Med Oral Pathol 1994;77:248-53. medically compromised patient. J Oral Med 222. Barrett AI? Graft-versus-host disease. A clinico- 1984;39:148-56. pathologic review. Ann Dent 1987;46:7-11. 236. National Institutes of Health. National Institutes 223. Heimdahl A, Mattsson T, Dahllof G, et al. The of Health consensus development conference oral cavity as a port of entry for early infections statement: oral complications of cancer thera- in patients treated with bone marrow transplan- pies: diagnosis, prevention, and treatment. J Am tation. Oral Surg Oral Med Oral Pathol Dent Assoc 1989;119:179-83. 1989;68:711-6. 237. Rosenberg SW. Oral care of chemotherapy 224. Hiroki A, Nakamura S, Shinohara M, Oka M. patients. Dent Clin N Am 1990;34:239-50. Significance of oral examination in chronic 238. Car1 W. Managing the oral manifestations of can- graft-versus-host disease. J Oral Pathol Med cer therapy. Part 11. Chemotherapy Comp Cont 1994;23: 209-15. Educ Dent 1988;9:376-86. 225. Johnson ML, Farmer ER Graft-versus-host reac- 239. Cheatham BD, Henry RJ. A dental complication tions in dermatology. J Am Acad Dermatol involving Pseudomonas during chemotherapy 1998;38:369-92. for acute lymphoblastic leukemia. J Clin Pediatr 226. Allen CM, Kapoor N. Verruciform xanthoma in a Dent 1994;18:215-7. bone marrow transplant recipient. Oral Surg 240. O’Sullivan EA, Duggal MS, Bailey CC, et al. Oral Med Oral Pathol 1993;75:591-4. Changes in the oral microflora during cytotoxic 227. Barrett AJ? Gingival lesions in leukemia. A classi- chemotherapy in children being treated for fication. J Periodontol 1984;55:585-8. acute leukemia. Oral Surg Oral Med Oral Path01 228. Jones LR, Toth BB, Keene HJ. Effects of total 1993;76:16 1-8. CHAPTER14

BLEEDINGDISORDERS

Spencer W. Redding, DDS, MEd Car1 W. Haveman, DDS, MS

The tissues of the oral cavity are supported by a Adjacent vessels are also involved in this vaso- rich and varied blood supply. Therefore, it is com- constriction process. Blood flow to the area is mon for abnormalities of the hemostatic system to slowed, resulting in a reduction of blood loss fol- present with manifestations in the oral cavity. Mul- lowing injury. 1,2 tiple oral manipulations including periodontal The platelet phase is also initiated after trauma surgery, scaling and root planing, extractions, and to blood vessels and results in the circulating biopsies require an intact coagulation system for platelets attaching to the site of injury in a process normal hemostasis. Patients with gingivitis and termed “platelet adhesion.” Other substances that periodontal disease are particularly vulnerable to contribute to this process of platelet adhesion bleeding disorders because of the increased vascu- include subendothelial collagen, platelet receptors, larity associated with inflammation. Certainly, sur- fibronectin, thrombospondin, and Factor VIII von gical procedures in these patients subject them to Willebrand‘s. Platelet adhesion initiates a process bleeding problems; however, spontaneous bleeding whereby more circulating platelets clump to the can also occur in sites of significant tissue inflam- initial group of platelets. This process, termed mation. Therefore, it is necessary for the periodon- “platelet aggregation,” requires substances both tist to have a good working knowledge of the internal and external to the functioning platelet. hemostatic mechanism and be prepared to manage These substances include thromboxane A2, locally and, when necessary, systemically patients adenosinediphosphate (ADP), and thrombin. The with diseases of hemostasis. This chapter will dis- platelet phase is extremely critical in stopping cuss the most common causes of oral bleeding and bleeding from small vessels as these small platelet will include material on the appropriate manage- plugs formed in this process can occlude vessels up ment of these patients. to 50 microns in The coagulation phase is the final and most involved of the three phases. It, too, is initiated by NORMAL HEMOSTASIS the process of vascular injury and results in multiple blood proteins or factors being activated. The evaluation and treatment of patients with These factors then activate other factors in a bleeding disorders or of patients who present with process that is termed the “coagulation cascade.” abnormal bleeding require a basic understanding Thrombin is formed as a result of this cascade, of the normal physiology of hemostasis. This and fibrin is formed from the combination of process is quite complex, involving numerous thrombin and fibrinogen. Fibrin is the substance blood and tissue products, but all activity can be that makes up the stabilized clot at the end of the divided into three phases: the vascular phase, the coagulation process. Prothrombin is converted to platelet phase, and the coagulation phase. These thrombin by activated Factor X which results three phases must work together to achieve ade- from two different pathways. The intrinsic path- quate clot formation. way involves components contained within the The vascular phase is initiated immediately blood itself and includes factors XII, XI, IX, and following injury to a blood vessel. Mediation by VIII. The extrinsic pathway is activated by sub- the autonomic nervous system results in direct stances that are external to the blood, called tissue vasoconstriction in the area of the injured vessel. thromboplastins and includes factor VII. Integri- 22 8 Periodontal Medicine ty of both pathways is necessary for normal clot lating factors and plasmin are inactivated by pro- formation. After a clot is formed and stabilized, it teins and removed from the circulation by the is broken down over a period of time. This reticuloendothelial system. This process limits process, called “fibrinolysis,” is initiated even clot formation and lysis to the site of the injury. while the clot is being formed. A substance from Figure 14-1 provides a systematic representation the blood vessel endothelium, called tissue plas- of the multiple processes and how they interre- minogen activator (TPA), stimulates the release late for normal hemostasis. Even though the of plasmin, which dissolves the clot. Both circu- three phases of hemostasis are described here as

Platelet Adhesion

- Initial Release1 Reaction Vasoconstriction ADP

Platelet AggregationI A Vascular Platelet Phase Phase Serotonin Increased Release Reaction -ADP Phospholipids

First HemostaticI Plug (platelet plug)

, Phospholipids + Factor XI1 + Factor XI I Complex 1 Prekallikrein i Factor IX 4 Phospholipids-Act. Factor XI1 - Plasminogen F%ospholipid>Act. Factor XI Complex I KallikreinI - Ca++ Plasmin I I Act. Factor IX + Factor Vlll + Phospholipids+ Ca++ 1 Coagulation Phase Factor X

Extr Prothrombin

t t

Tissue Thromboplastin Thrombin

Fibrinogen - Fib& Figure 14-1. Phases of Normal Hemostasis. With permission from Montgomery MT, Redding SW, editors. Oral-facial emergencies. Chicago: Federation of Special Care Organizations in Dentistry; 1994. Bleeding Disorders 22 9 separate processes for ease of understanding, it is ly as a complication of HIV infection. In adults, still imperative to realize that there is multiple ITP is a chronic disease that waxes and wanes. interrelation of these three phases. For example, However, in children, the disease has an acute and phospholipids released from the platelet phase usually self-limiting course. It frequently follows are necessary for the normal activation of factors minor viral infections. The onset of bleeding prob- in the coagulation phase, and thrombin is lems in patients with ITP may be either insidious required for the smooth functioning of platelet or abrupt. These patients present with a reduced aggregation. All three phases and their interrela- platelet count and easy bleeding. Treatment for tion are necessary for normal clot formation. ITP usually includes prednisone therapy. Splenec- tomy is performed in patients who fail to respond after 2 to 3 weeks. Another treatment available for BLEEDING DISORDERS ITP is intravenous immune gl~bulin.”~ Thrombotic thrombocytopenic purpura is a Vascular Disorders relatively rare form of thrombocytopenia, which results in a decreased platelet number and para- Any disruption in the three phases of hemostasis or doxically widespread platelet thrombi that form in in their interaction can result in a significant bleed- the microcirculation. Some cases involve infec- ing disorder. 1,2 Vascular disorders other than from tious, genetic or immunologic etiologies, but the trauma are relatively rare. However, the possibility cause in most cases is unknown. Major clinical of abnormal and prolonged bleeding must be con- manifestations include thrombocytopenia which sidered in a person whose hemostatic system is may result in severe bleeding, microangiopathic normal but in whom a large vessel has been inad- hemolytic anemia, neurologic signs and symptoms vertently traumatized leading to copious bleeding. including headache, disorientation, seizures, coma, Vascular wall abnormalities do occur and include and focal neurologic signs, renal abnormalities hereditary hemorrhagic telangiectasia and certain including proteinuria and hematuria, and fever. In deficiency diseases. Hereditary hemorrhagic addition to thrombocytopenia, diagnosis of this telangiectasia is an autosomal-dominant inherited disease can be made by looking for microscopic disorder characterized by multiple small vascular clots in vessels from a gingival biopsy. Unlike ITP, malformations found on epithelia1 surfaces (Figure the prognosis for TTP is poor, with up to 50% 14-2). When traumatized, these lesions may bleed. mortality. Therapy has been highly unpredictable. Treatment focuses on topical control of the hem- Initially, prednisone therapy is started, followed by orrhage. Steroid therapy may reduce the incidence plasmaphoresis with plasma exchange or infusion of bleeding. of fresh frozen plasma. Second-line treatments may Long-term systemic steroid use can induce vascular friability. Also, elderly individuals may manifest senile purpura as a result of a loss of protective fat from the cutaneous vascular bed. Many healthy women, especially in the older age group, will complain of easy bruising2

Platelet Disorders

Platelet disorders can be divided into primary and secondary forms. Primary diseases include idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), and thrombasthenia. Idiopathic thrombocytopenic purpura presents as a chronic disease characterized by autoimmune platelet destruction. Over 50% of all cases of Figure 14-2. Photograph of vascular lesions on fingers asso- ITP are without known cause, but ultimately it is ciated with hereditary hemorrhagic telangiectasia. With per- determined that many patients have underlying mission from Montgomery MT, Redding SW, editors. Oral- autoimmune diseases such as systemic lupus ery- facial emergencies. Chicago: Federation of Special Care thematosus. It has also been recognized increasing- Organizations in Dentistry; 1994. 230 Periodontal Medicine include heparin, aspirin, vincristine, and splenec- ondary to liver or kidney failure. Hypersplenism as tomy. Platelet transfusions are contraindicated a result of portal hypertension secondary to alco- since they may exacerbate the thrombotic compo- holic cirrhosis results in increased splenic sequestra- nent.4’5 tion and a drop in platelet count. Nonsteroidal Primary functional platelet abnormalities are anti-inflammatory drugs, such as aspirin and rare. Thrombasthenia, or Glanzmann’s thrombas- ibuprofen, block the conversion of arachidonic acid thenia, is an unusual autosomal recessive disease, to thromboxane. Thromboxane accelerates the which shows platelet abnormalities characterized platelets’ release of ADP, which is needed for by a structural loss of platelet membrane sub- platelet aggregation; therefore, blocking the forma- stances. Platelet count and morphology are normal tion of thromboxane will reduce the release of ADP in this disorder. Treatment of thrombasthenia is and impair platelet aggregation. Nonsteroidal anti- often not necessary. However, any platelet-inhibit- inflammatory drugs thus prolong the bleeding ing drugs, including aspirin, should be avoided. time. It is important to note that aspirin’s effect will Treatment for severe bleeding involves transfusion be exerted on the platelet for its entire lifespan. of normal platelet^.^.^ However, the effect of drugs such as ibuprofen is Secondary causes of platelet abnormalities, only for the duration of drug therapy4.’ especially thrombocytopenia, are much more common than primary abnormalities. Any process or Coagulation Disorders condition that either depresses bone marrow function or increases platelet destruction may produce Hemophilias thrombocytopenia. Causes of these abnormalities Three disorders account for more than 95% of include antineoplastic chemotherapy, severe liver congenital disorders of blood coagulation. These and renal disease, and nonsteroidal anti-inflamma- include the two sex-linked disorders, hemophilia A tory drugs. Antineoplastic chemotherapy is toxic to or factor VIII deficiency and hemophilia B or fac- normal bone marrow function; thus, megakary- tor IX deficiency, and the autosomal von Wille- ocyte production is decreased, resulting in lowered brand disease. platelet counts (Figure 14-3). Patients with severe Hemophilia A is caused by a deficiency of fac- end-stage liver disease and severe end-stage kidney tor VIII. The diagnosis of hemophilia A is often disease present with both qualitative and quantita- made from observance of clinical bleeding and a tive platelet defects. Platelet function is affected by prolonged partial thromboplastin time (PTT) and continuous ingestion of high amounts of ethanol in then an abnormal factor VIII assay. Hemarthrosis is chronic alcoholics and by circulating toxins sec- the most characteristic disabling hemorrhage in these patients. Multiple hemarthroses tend to lead to joint swelling and ultimately joint collapse, with marked limitation or complete loss of motion. The disease is characterized by clinical bleeding, which is classified as severe, moderate, or mild, depending on the frequency of hemorrhage and the severity. The severitiis usually related to-the plasma level of factor VIII. Severely affected individuals tend to have two or three bleeding episodes per month which may be profuse unless treated (Figure 14-4). Mod- erately affected individuals tend to bleed five to six times per year and may have prolonged periods of free bleeding. Mildly affected individuals may rarely bleed at all, except with significant trauma or surgical stress. Generally, severe hemophiliacs have less than 1% of normal factor VIII, moderate hemophiliacs have between 1 and 5%, and mild hemophiliacs have between 5 and 30%. Inhibitors to fac- Figure 14-3. Photograph of hematoma of buccal mucosa in tor VIII develop in up to of patients treated a patient who is severely thrombocytopenic from cancer 20% chemotherapy. With permission from Montgomery MT, with factor VIII. The presence of inhibitors may Redding SW, editors. Oral-facial emergencies. Chicago: Fed- make it very difficult to treat patients who have eration of Special Care Organizations in Dentistry; 1994. bleeds or to provide prophylaxis to patients who are Bleeding Disorders 23 1 being treated surgically. Inhibitors can often be sup- I11 disease, factor VIII levels are below 10% of nor- pressed but if they are high, patients may not mal, and both vWf and vWf:Ag are absent. Type I11 respond to any replacement therapy, makmg clinical is the most severe of the von Willebrand types clin- bleeding truly life threatening.8,9J0 ically and may involve bleeding into joints and soft Hemophilia B-factor IX deficiency or tissue.8>l2 Christmas disease-also results in an increased Factor XI disease, or hemophilia C, is an inher- PTT and a reduced factor IX assay. Types and ited autosomal recessive disease and is usually found complications of hemorrhages in hemophilia B are in individuals of Jewish ancestry. In these patients, similar to those in hemophilia A. As in factor VIII PTT is prolonged and diagnosis is made with a fac- disease, level of factor IX is indicative of severity of tor XI assay. Most patients are asymptomatic disease, and disease is also described as mild, mod- throughout their lives and are diagnosed following erate, or severe.8J1 postoperative bleeding. Bleeding after tooth extrac- Von Willebrand disease is probably the most tion is a common first presenting ~ymptom.~J~ commonly diagnosed inherited bleeding disorder Management of patients with inherited in adults because its manifestations are less severe coagulation disorders will be discussed under than factor VIII or factor IX disease and often “Treatment .” would not have been previously diagnosed. It is an autosomal disease (autosomal dominant in the Anticoagulation most common forms but autosomal recessive in the The number of patients receiving anticoagulation, most severe form) and is characterized by reduced especially with Coumadin (warfarin sodium), has levels of factor VIII along with qualitative platelet increased dramatically in recent years. These abnormalities. There are several different molecules patients include those with prosthetic heart valves, related to factor VIII that are important in the chronic atrial fibrillation, or a past history of deep understanding of von Willebrand disease. These vein thrombosis, transient ischemic attacks, or include factor VIII (VIII), factor VIII von Wille- stroke. Coumadin anticoagulation is an effective brand’s (vWf), and factor VIII von Willebrand and convenient therapy because it can be given antigen (vWf:Ag). Factor VIII von Willebrand’s cir- orally. Coumadin acts by inhibiting the vitamin-K- culates in plasma as a complex with factor VIII. It dependent carboxylation of factors 11, VII, IX, and acts as a carrier for factor VIII and helps promote X (the so-called vitamin-K-dependent factors). adhesion of the platelets to the subendothelium and Carboxylation of these factors is needed because to one another. Therefore, in addition to its role in without this activation, these factors are left out of coagulation, vWf plays a significant part in prima- the coagulation process. As will be explained later ry hemostasis or the platelet phase. Therefore, von Willebrand disease will be marked by an increased PTT and a prolonged bleeding time. Von Wille- brand disease is divided into three different types, on the basis of the presence of different levels of factor VIII, vWf, and vWf:Ag. (The blood levels of these molecules can vary over time in the same patient. Therefore, testing patients may be needed on more than one occasion to make an accurate diagnosis.) Type I is the most common form of the disease, where patients have reduced levels of all three of the above molecules. Type I1 variants are marked by differing combinations of normal and reduced levels of these molecules. Bleeding in types I and I1 is usually much less severe than with severe factor VIII disease. Bleeding from mucous membranes, including from the nasal, intestinal and uterine mucosa, is common as is bruising following Figure 14-4. Photograph of liver clot after tooth extraction minor trauma. Bleeding typically follows minor in a patient with hemophilia A. With permission from injury or surgery. Therefore, this disease may be Montgomery MT, Redding SW, editors. Oral-facial emer- first diagnosed in an adult who has had a minor gencies. Chicago: Federation of Special Care Organizations surgical procedure such as dental surgery. In type in Dentistry; 1994. 232 Periodontal Medicine under the section on treatment, Coumadin antico- plantation becomes the only viable therapy. Table agulation is evaluated by prothrombin time (PT) 14-1 provides a quick reference for the appropriate and international normalized ratio (INR). With characteristics of bleeding disorders. the increasing number of patients on Coumadin anticoagulation, the potential complication of abnormal bleeding is significant. Patients respond PATIENT EVALUATION differently to the same dose of Coumadin and must be monitored routinely to ensure that their History PT and INR are within the appropriate range. Patients on Coumadin who present to emergency The most important factor in identifying patients rooms with abnormal intraoral bleeding secondary with potential defects in hemostasis is patient his- to an extraction or chronic periodontal disease are tory. Patients should be asked, through question- among the most difficult of patients to manage. naires and interviews, about any past abnormal Patients often do not understand the potential side bleeding. Any patient that presents with abnormal effects of the drugs they are taking. Therefore, bleeding should be investigated further to try to Coumadin anticoagulation problems should be determine any past history or any incident that is considered in any patient that reports with abnor- suspicious. Table 14-2 is a group of appropriate mal bleeding.’>’J* questions to ask the patient who presents with Heparin anticoagulation is commonly used in abnormal bleeding. ’ the inpatient setting. Heparin acts by accelerating antithrombin 111, which inhibits coagulation fac- Lab0rat0 ry Evaluation tors throughout the cascade in both the intrinsic and extrinsic pathways. Heparin is administered Four screening laboratory tests are commonly used subcutaneously or intravenously and is monitored to evaluate patients with suspicion of abnormal by PTT.’ hemostasis: PT, PTT, the platelet count, and bleeding time. Liver Disease Prothrombin time and partial thromboplastin The liver is the site of production of fibrinogen, time are commonly ordered together and both factors 11, VII, VIII, IX, X, XI, and XI1 as well as evaluate the coagulation phase of hemostasis. Pro- antithrombin 111. Severe liver disease may result in thrombin time evaluates the extrinsic pathway and reduced synthesis of any or all of these factors. Dis- is commonly elevated in patients taking Coumadin eases such as alcoholic cirrhosis, chronic hepatitis anticoagulant medication. Platelet phospholipid is (especially hepatitis C), and others can result in a added to the patient’s blood, and the time is significant decrease in these clotting factors. These recorded until clotting occurs. Prothrombin time diseases will be marked by an increase in PT and has been standardized in the United States by use PTT. The vitamin-K-dependent factors (11, VII, of INR, which will be discussed in more detail IX, and X) are the most sensitive to liver disease under “Treatment.” The normal value for PT is and may be the only abnormalities in mild early usually I I to 14 seconds and is compared with a hepatic disease. Conversely, factors V and VIII are standard control. Partial thromboplastin time the most resistant to hepatocellular disease and are assesses the intrinsic pathway and is elevated with only decreased in fulminant hepatitis and severe hemophilia A, B, C, and von Willebrand disease. liver failure. Therefore, a decreased level of factor Tissue phospholipid is added to the patient’s VIII is an ominous sign.’.’ blood, and time is recorded until clotting occurs. Hemorrhage in patients with severe liver disease The normal range for this test is between 25 and can be overwhelming. Bleeding can occur sponta- 35 seconds, and the results are also reported in neously from mucous membranes, skin, and other comparison with a standard control. As mentioned sites. Complications of chronic liver disease, such as earlier, patients who are taking heparin anticoagu- varices and gastritis, may become life threatening lation are often evaluated with PTT.1>2 when complicated by abnormalities of hemostasis. The platelet count evaluates the platelet phase Because of coagulation defects and platelet abnor- of coagulation and indicates the number of malities, patients with severe liver disease can be the platelets present. It does not evaluate qualitative most difficult to manage with regard to bleeding platelet defects but only quantitative ones. Often, associated with surgical procedures. In patients with a platelet evaluation will be included with a com- the most severe end-stage liver disease, liver trans- plete blood count (CBC) but not a specific platelet Bleeding Disorders 233

TABLE 14- I. Characteristics of Bleeding Disorders

Dysfinction Sipand Symptoms Laboratory Zsts Phtelets Coaguhtion Gingival Disorders Number Function Intrinsic Extrinsic Petecbiae Eccbymosis Epistmis Bleeding Hernartbrosis BT PC PT PTT Platelets ITP TTP Thrombasthenia NSAIDsIAspirin Secondary TP

Coagulation Hemophilia A Hemophilia B Coumadin Heparin

Coagulation and Platelets von Willebrand disease - + + - + + + + - +-- + Alcoholism + + + - + + + + - ++-+

ITP = idiopathic thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura; NSAIDs = nonsteroidal anti- inflammatory drugs; TP = thrombocytopenic purpura; BT = bleeding time; PC = platelet count; PT = prothrombin time; PTT = partial thromboplastin time; + = affected by disorder; - = not affected by disorder With permission from Montgomery MT, Redding SW. Oral-facial emergencies. Chicago: Federation of Special Care Organiza- tions in Dentistry; 1994.

count. Therefore, this may need to be ordered sep- dicting clinically significant bleeding. l5 However, arately from the CBC. The normal platelet count it remains the only screening test for disorders of is between 150,000 and 400,000/mm3.1>2 platelet function and vascular disorders. The bleeding time test evaluates the platelet If patients present with a history of abnormal phase of hemostasis and also the vascular phase. bleeding, and the screening tests described above This test evaluates the platelet’s ability to clot small are abnormal, more specific tests need to be vessels up to 50 microns in diameter. Therefore, ordered to make the diagnosis of the bleeding when it is combined with the platelet count, ques- problem. An abnormal PTT or PT may lead to a tions concerning the platelet phase of hemostasis further evaluation of levels of coagulation factors can be answered. This test is performed by making using specific factor assays to determine which a standardized incision, I mm deep and 9 mm factor is responsible. The normal range of indi- long, on the flexor surface of the forearm, distal to vidual factor assays is between 50 to 150% of a blood pressure cuff on the arm inflated to 40 mm normal and the most commonly ordered factor is of mercury. Because of the standardization of this factor VIII. 1,2 test, only smaller vessels are affected. These inci- Patients who develop inhibitors to factor VIII sions are blotted every 30 seconds until no blood is are evaluated by the Bethesda assay with the absorbed. The normal range of the bleeding time is Bethesda Unit (BU) being the standard unit of 3 to 9 minutes, and bleeding is normally stopped measurement. Patients with inhibitors are divided after 20 minutes if it persists. Bleeding times into low responders (those who will always have between 9 and 20 minutes would be prolonged, inhibitor levels of less than 20 BU) and high though functional. Beyond 20 minutes, the responders (those who will have an inhibitor level platelet phase of hemostasis would be considered of greater than 20 BU at least once). Low respon- In recent years, some authors have ders make up 25% of inhibitor patients, with high questioned the value of the bleeding time in pre- responders making up 75%.1° 234 Periodontal Medicine

suggestive of the condition. The first indication of TABLE 14-2. Hemostasis Questionnaire the problem may be prolonged bleeding following 1. Have any of the following members of your family a dental procedure. During any episode of pro- ever had a problem with prolonged or unusual longed bleeding, local measures are the first line of bleeding: parents, brothers and sisters, children, defense to control hemorrhage. These local mea- grandparents, great grandparents? sures include pressure, topical agents, and stents. l 2. Have you ever had marked bleeding for up to 24 hours after a surgical procedure (ie, tooth extrac- Pressure tion or tonsillectomy)? 3. Have you ever required a blood transfusion after Prior to attempting any local measures, it is critical surgery? to visualize the source of the bleeding in a clear 4. Women: Do you feel that you have abnormal field with a good intraoral light source. Once the bleeding during menstruation? source and severity of the bleeding have been iden- 5. Do you get bruises larger than the size of a quarter tified, firm manual pressure should be applied with for which you cannot remember the injury? a moist gauze sponge pack for a minimum of 5 6. Do you experience numerous and severe nose minutes. It is imperative that the pressure be bleeds for up to several hours? applied to the actual bleeding site and that the size 7. Do your gums often bleed not related to trauma or of the gauze pack correspond to the size of the brushing? bleeding site. Proper pressure is essential to con- 8. Are you taking any blood thinner (anticoagulant)? trolling abnormal bleeding. Slowing of the blood 9. Have you taken any medication, such as pills, flow greatly enhances the process of platelet aggre- powders, or liquids, in the last week? gation and the formation of a platelet plug. Placing 10. Have you had or do you have any liver disease sutures across wound margins or across extraction such as hepatitis or alcoholic cirrhosis? sites may assist in maintaining hemostasis by stabi- With permission from Montgomery MT, Redding SW. Oral- lizing and providing pressure to the tissue respon- facial emergencies. Chicago: Federation of Special Care sible for the bleeding. If the bleeding is controlled Organizations in Dentistry; 1994. with pressure, it is advisable to observe the patient for an additional 5 to 10 minutes to confirm hemostasis. Patients should be given both verbal TREATMENT and written postoperative instructions concerning prevention of recurrent bleeding. They should also Prevention of untoward bleeding is the best form be supplied with extra gauze packs and instructed of “treatment.” Obtaining a good history is the on the proper placement and use of the packs. best single screening procedure to identifi- a patient with a bleeding or clotting disorder. Com- Topical Agents prehensive extraoral and intraoral examinations are likewise important in discovering clinical signs of Clinicians who treat patients with bleeding disor- an occult bleeding or clotting disorder. No surgical ders need to have sufficient local hemostatic agents procedures should be performed on a patient sus- available to treat the anticipated bleeding and be pected of having a coagulation disorder. Such prepared to deal with any unexpected complica- patients should be referred to a physician for tions. When local pressure is inadequate to control screening laboratory tests and final diagnosis. bleeding, topical hemostatic agents should be When a patient is known to have a bleeding or employed to augment the pressure. Oxidized cellu- clotting disorder, it is essential that their hematol- lose (OxyceP, SurgiceP) is one such agent. Its ogist be consulted concerning appropriate medical mechanism of action is unclear; however, it physi- management prior to performing any procedures cally absorbs blood and promotes clot formation. that could result in bleeding. When periodontal It should be applied dry and loosely placed, not surgical procedures are anticipated, the surgeon packed, into the bleeding site and held in place must take into consideration the fact that the with sterile gauze for 1 to 8 minutes. It is an mucoperiosteal flaps on the lingual aspect of the absorbable hemostatic agent available as a woven mandible may open up fascia1 planes into which fabric that resorbs in 7 to 14 days. It is also bacte- blood can accumulate and endanger the airway. ricidal in vitro against a variety of both gram-posi- A person with an occult coagulation disorder tive and gram-negative organisms. It should be may not have any subjective or objective findings noted that according to some authors the acidic Bleeding Disorders 235 nature of oxidized cellulose agents may result in Another useful topical agent is thrombin postoperative pain. l6 (Thrombogen@),supplied as a sterile powder. The Another routinely used topical agent is powder also contains calcium chloride and comes absorbable gelatin sponge (Gelfoam@). It is a water- with a vial of isotonic saline for use as a diluent. insoluble, porous, pliable sponge material prepared Thrombin requires no intermediate physiologic from purified pig skin. Its hemostatic action occurs agent for its action. It converts the fibrinogen of because it absorbs the blood and provides an the blood directly into fibrin. Its failure to clot increased area for clot formation. It can be applied blood occurs in the rare case where the primary dry or moistened with normal saline and it should clotting defect is due to the absence of fibrinogen be pressed into place with finger pressure and held itself. The speed with which topical thrombin clots for 1 to 2 minutes. It is absorbed within 6 weeks. blood depends upon its concentration. The desired Gelatin sponge does not possess bacteriostatic strength for dental applications is 100 to 1000 properties and has been reported to act as a nidus U/mL. It is useful wherever any oozing from small for infection and therefore should not be used in vessels is accessible. It can be applied topically the presence of infection. If it is used in an infected either in its powder form or diluted in isotonic extraction site, impregnating it with tetracycline saline or sterile water after the bleeding surface has powder may be beneficial. been sponged or blotted free of blood. It must Additional topical agents consist of absorbable never be injected or otherwise allowed to enter purified bovine collagen. Hemostatic activity is an large blood vessels. Wiping or suctioning the treat- inherent property of collagen. When it comes into ed surface should be avoided in order that the clot contact with blood, platelets aggregate in large remain securely in place. numbers on the collagen and release coagulation Thrombin may also be used in conjunction factors enabling the formation of fibrin. Several with Gelfoam@ or the Colla@ products either in physical forms of purified bovine collagen are avail- the powder or liquid form. When used as a pow- able. One such product is Avitene@, which is a der, the Gelfoam@ or Colla@ product should be microfibrillar collagen available as an off-white, moistened with sterile saline or water and then flufti; finely fibrous, water-insoluble material with touched to the powder to pick up a light coating of a highly open structure. It can be applied directly to the particles. When used in the diluted form, the the bleeding surface with dry cotton forceps, then Gelfoam@or Colla@product should be saturated pressed and held in place with a sterile sponge. As with the thrombin solution. With either method, soon as it comes into contact with blood, it attracts the combination is then applied to the bleeding platelets, which triggers hrther platelet aggregation area and held in place for about 15 seconds with a and initiates the formation of a platelet plug. It is sterile Q-tip or a small gauze sponge. Thrombin absorbed in 4 to 6 weeks. should not be used with oxidized cellulose since its Other absorbable purified bovine collagen prod- acidity will render the topical thrombin ineffective. ucts available specifically for dental surgery are Col- Suturing with a resorbable material may also be laTape@, CollaCote@, and CollaPlug@. These are very beneficial to controlling hemorrhage. Primary soft, white, pliable, nonfriable sponges. They retain closure should be achieved, if possible. Even without their structural integrity even when wet and their primary closure, sutures place slight pressure on the application to wounds is easily controlled. They are tissue and may assist in keeping topical agents in highly absorbent, holding blood or solution that is place, especially when placed as a figure-of-eight many times their own weight. The sponge structure suture across an extraction site into which Gelfoam@ provides a three-dimensional matrix for additional or a CollaPlug@has been placed. Another local mea- strength of the blood clot. A piece of CollaTape@or sure to aid in controlling hemostasis is the injection CollaCote@ large enough to cover the bleeding of a local anesthetic with a vasoconstrictor such as wound surface should be held in place for 2 to 5 lidocaine 2% with I: 100,000 or 1:50,000 epineph- minutes and subsequently can be removed or left in rine. However, caution must be exercised while place. If desired, a periodontal packing can be used using this technique as bleeding may resume when to hold it in place. A CollaPlug@is bullet shaped and the effects of the vasoconstrictor end. designed to be placed into an extraction site. It can Custom-fabricated acrylic or plastic stents or be held in place with gentle pressure using a sterile latex mouthguard appliances may also prove help- Q-tip. These products should not be used on infect- hl in controlling hemorrhage and in preventing ed wounds. They are, however, very valuable for the mechanical displacement of the clot.' Care is controlling persistent bleeding from tooth sockets. required during stent construction to avoid exces- 236 Periodontal Medicine sive pressure on soft tissues, which could result in and a half to three times the control value to pre- necrosis. An acrylic or plastic stent can be used to vent thrombosis. The ratio of the patient's PT to a retain CollaTape@ or SurgiceP in place over a laboratory control PT is termed the prothrombin palatal wound, such as a free gingival or connective time ratio or (PTR). Because of the variations in tissue graft donor site, while at the same time pro- dose response in individual patients during the viding protection of the wound from trauma. course of anticoagulant therapy, their dosage must When the patient has a known bleeding diathesis, be monitored closely to prevent overdosing or a prefabricated soft latex mouthguard type of underdosing. In the 1970s, it was found that there appliance may be used to apply a topical agent. were wide differences in the PTR from one labora- Avitene@may be delivered in this type of appliance tory to another. These differences occurred because when generalized bleeding from the gum tissue or of the variation in sensitivity of the thromboplas- gingival sulcus is anticipated. Such an appliance tin reagents the laboratories used to perform PT. can also be used to hold CollaTape@in place on This meant that some patients were being antico- bleeding sites. These appliances combine the light agulated to a greater extent than others and were pressure from the appliance with the hemostatic prone to having more significant bleeding compli- effects of the topical agents. They should be worn cations. Because of these variations, the World until hemostasis has been maintained for several Health Organization recommended that the PTR hours and subsequently only if needed; however, be standardized using the International Normal- they require cleaning at least once each day because ized Ratio (INR) that is based on the sensitivity of they can promote sepsis. different thromboplastin reagents (International The choice of a topical agent is somewhat Sensitivity Index [ISI]). The INR=PTRIS'results in dependent upon the type of bleeding abnormality. the INR being essentially the same, regardless of SurgiceP, Gelfoam@, and thrombin are usefd in which thromboplastin reagent a laboratory uses. l7 most patients with persistent bleeding whereas the Clinical research supports using the INR over the absorbable collagen products are more effective for PTR and it is currently recommended that the those patients who have a platelet dysfunction or INR be used to monitor the level of anticoagula- deficiency. It should be noted that many patients are tion. Table 14-4 gives the recommended therapeu- on aspirin anticoagulation therapy, especially those tic range for oral anticoagulation therapy using having suffered a heart attack or stroke. Aspirin INR values.18>19 therapy alone is not usually associated with serious Patients receiving oral anticoagulation therapy prolonged oral bleeding. In the vast majority of may present challenging management situations. cases, a bleeding tendency from aspirin therapy can The American Medical Association and the Amer- be controlled with the local measures cited. If a top- ican Dental Association previously recommended ical agent is necessary, one of the collagen products a PT of between 1.5 and 2.5 times the control PT should be chosen. A listing of the above topical before performing a surgical procedure. Presently, agents, a source for procurement, and the approxi- the literature is undecided on the acceptable INR mate cost for each can be found in Table 14-3. level to perform extractions. Values between 1.5 and 4.0 have been re~ommended.l~>~'There is Anticoagulants concern that reduction or elimination of anticoagulant therapy places the patient at an unacceptable Anticoagulants are needed to prevent thrombosis risk of thromboembolism. In assessing risk, clini- and embolism. By far the most widely used is war- cians need to weigh the probability of embolism farin sodium (Coumadin) . A consultation with the occurring if anticoagulant therapy is reduced. Sub- patient's physician is essential in the dental man- therapeutic anticoagulation levels in patients with agement of patients on anticoagulant therapy. a mechanical valve prosthesis entails a significant Information needed from the physician includes risk of valve thrombosis. l9 Withdrawal of anticoag- verification of the information obtained from the ulant therapy is not needed for most patients to patient, recent dose modifications, planned dura- safely undergo most dental procedures. Dental tion of anticoagulant therapy, and current labora- treatment planning dividing full arch procedures tory values. Since the early 1940s, prothrombin into multiple smaller procedures, using infiltra- time (PT) developed by Quick has been the pri- tion, periodontal ligament, or intraosseous injec- mary means of monitoring the level of oral antico- tions in place of block anesthesia, when practical, agulation control. Hematologists have recom- and using local hemostatic measures can signifi- mended that the level of anticoagulation be one cantly reduce the risk to the patient by avoiding Bleeding Disorders 237

TABLE I 4-3. Topical and Antifibrinolytic Hemostatic Agents Agent Source Approximate Cost (US dolhrs) SurgiceP Johnson and Johnson Medical Inc. $133.00/box of 12 Arlington, TX 76004-3 130 (0.5 x 2.0 inch) (800-255-2500) Gelfoam@ Pharmacia & Upjohn $23.00/Jar (15 Squares) Kalamazoo, MI 49001 (800-253-8600) Avitene@ Med Chem Products Inc. $43.00/0.5 gram pack Subsidiary of C.R. Bard Inc. Woburn, MA 01801 (800-45 1-4716) CollaPlug@ Calcitek\ Sulzer Medica $ 63.OO/package of 10 CollaTape@ 2320 Faraday Avenue $llO.OO/package of 10 CollaCote@ Carlsbad, CA 92008 $71.OO/package of 10 (800-854-7019) Thrombogen@ Johnson and Johnson Medical Inc. $46.00/box (10,000 units) Arlington, TX 76004-3 130 (800-255-2500) hicar@ Immunex $ 345.00/480 mL bottle 5 1 University Street Seattle, WA 98101 (800-334-6273) Cyclokapron@ Pharmacia & Upjohn $225 .OO/10 ampules Kalamazoo, MI 49001 (1OmL/ 100 mg/mL) (800-442-4348)

anticoagulation therapy modification. Table 14-5 it on the day of surgery. The INR should always be gives our recommendations with regard to dental checked on the morning of the surgery to ensure it treatment and degree of anticoagulation as mea- is within an acceptable range. For patients at high sured by INR values. risk of thromboembolism, an alternative approach A variety of medications can affect anticoagu- is to discontinue Coumadin and introduce heparin lant therapy (Table 14-6). Salicylates and nons- to achieve a PTT of 1.5 to 2.0 times the control, teroidal anti-inflammatory drugs should be avoided midway between injections. Heparin prevents the entirely in patients on anticoagulant therapy. Even conversion of prothrombin to thrombin. It has a acetaminophen should be used with caution. A short half-life of approximately 90 minutes but its recent study found a highly significant dose- duration of action is dose dependent.22 It should response relationship between acetaminophen and be discontinued for 4 to 6 hours before surgery and Coumadin’s effect. For patients who reported taking resumed 12 to 24 hours after surgery. Coumadin is at least four 325-mg tablets per day for longer than resumed on the day of surgery and is continued I week, the odds of having an INR greater than 6.0 were increased tenfold compared with those taking no acetaminophen.2’Although some antibiotics can TABLE 14-4. Recommended Therapeutic adversely affect Coumadin therapy, antibiotic pro- Ranges Using IN R Values 18* I 9*20 phylaxis against infective endocarditis is unlikely to Indication INR Range affect the patient’s anticoagulation status.l9 Patients in whom the risk of thromboem- Prophylaxis of venous thrombosis 2.0 to 3.0 bolism is less of a problem and who need to have Treatment of venous thrombosis 2.0 to 3.0 their INR values lowered can be managed by dis- Prevention of systemic embolism 2.0 to 3.0 continuation of their Coumadin dose approxi- Treatment of pulmonary embolism 2.0 to 3.0 mately 48 hours prior to the surgery and restarting Mechanical prosthetic heart valves 2.5 to 3.5 238 Periodontal Medicine until the INR returns to an optimal range. This coagulation carry significant risks and should be method usually requires hospitalization and is very carried out by the patient's hematologist. The type expensive. Because heparin can only be adminis- of replacement therapy employed will depend tered parenterally, it is unlikely that patients on upon the type and severity of factor deficiency. heparin therapy will be encountered in other than Mild hemophilia A (5 to 25% factor VIII), hemo- a hospital-based dental practice. philia B or von Willebrand disease (type 1) can Of note are the new low-molecular-weight usually be managed with local measures alone heparins (LMWHs), including ardeparin dal- (topical agents plus antifibrinolytic agents, dis- teparin, and enoxaparin, which represent an impor- cussed in the next section). In addition to local tant therapeutic advance in the treatment of measures, moderate hemophilia A (I to 5% factor patients with venous thromboembolism. They have VIII) or moderate von Willebrand disease (type 11) a lower incidence of heparin-induced thrombocy- may be managed with desmopressin 1-deamino-8- topenia, greater bioavailability, longer half-life, and D-arginine vasopressin (DDAVP). a more predictable anticoagulant response com- Desmopressin is a synthetic analog of vaso- pared with standard he~arin.~~Because of these pressin which causes an increased release of benefits, these drugs can be used subcutaneously endogenous factor VIII and vWf levels by approx- (patient administered), without laboratory moni- imately fourfold. This mimics replacement therapy toring, to treat select patients with venous throm- with blood products. Desmopressin can be given boembolism in the outpatient setting. Periodontists via nasal spray, subcutaneous injection, or IV inh- may encounter medically compromised patients in sion. A dose of 0.3 to 0.5 pg/kg intravenously pro- their practices. Because of the predictable anticoag- duces peak factor levels at 30 to 60 minutes, which ulant response to these drugs, the medical manage- tapers to baseline at 24 hours. It is also available for ment of these patients to prevent potential bleeding subcutaneous or intranasal use. The optimal problems should be less complicated compared intranasal dose is 300 pg for adults and 150 pg for with patients on Coumadin therapy. Low-molecu- children. After intranasal or subcutaneous admin- lar-weight heparins are given once or twice daily. If istration, factor levels peak at 60 to 90 minutes. currently used for venous thromboembolism, it The above doses can be repeated at 12-hour inter- would appear reasonable to discontinue the dose vals up to three or four times. Common side effects prior to any dental surgery and then have the are facial flushing and headache. In addition, it is a patient resume the next scheduled dose. This potent antidiuretic and causes the release of the should be confirmed with the patient's physician. plasminogen activator. Because of the latter effect, adjunctive use of topical tranexamic acid (dis- Factor Enhancement cussed in the next section) is beneficial. It should be noted that DDAVP does not usually shorten Patients with inherited coagulation defects may the bleeding time in patients with severe von require factor replacement to prevent postoperative Willebrand factor deficiency (type 111) or dysfunc- bleeding complications. Therapies to promote tional von Willebrand factor (type I1 variant).

TABLE 14-5. Managing Patients as Related to Their INR INR Vdlue Recommenddtions Concerning Invasive E-eatment" 4.0 or greater No surgical treatment until the INR is reduced. 3.5-4.0 Emergency minor surgical procedures only, simple extraction, incision and drainage. Avoid block anesthesia injections; use local measures for hemostasis. 3.0-3.4 Minor surgical procedures, simple extraction, gingivoplasty; block anesthesia not recommended; use local measures for hemostasis. 2.5-2.9 Multiple extractions, single bony impaction, quadrant periodontal flap surgery or scaling and root planing; avoid block anesthesia, if possible, and use local measures for hemostasis. 1.5-2.4 Full-mouth extractions, multiple bony impactions, gingivectomy, multiple quadrant flap surgery; avoid block anesthesia, if possible, and use local measures for hemostasis.

*Local factors such as periodontitis/gingival inflammation or medications the patient is taking can increase the severity of bleeding. Risk assessment must include all applicable factors. Bleeding Disorders 239

TABLE 14-6. Medications Affecting Coumadin the rap^'^*'^*^^ Potentiating effect Acetaminophen (underappreciated), cephalosporins, chloral hydrate, cimetidine, ciprofloxacin, corticosteroids, diflunisal, erythromycin, fluconazole, fluoroquinolones, indomethacin, ketoconazole, metronidazole, nonsteriodal anti-inflammatory drugs, penicillins, propoxyphene, salicylates, tetracyclines, trimethoprim/sulfamethoxazole. Opposing effect Ascorbic acid, barbiturates, carbamazepine, dicloxacillin, nafcillin, penicillin.

Severe factor deficiencies usually require con- dose of 50 unidkg of factor IX complex intra- centrated forms of replacement therapy such as venously followed by 20 unidkg every 12 to 24 factor VIII concentrate or cryoprecipitate for hours. Factor IX has a half-life of up to 2 days. hemophilia A and some forms of von Willebrand Factor XI deficiency (hemophilia C) can be disease (types I1 and 111) and factor K complex for successfully managed using fresh frozen plasma hemophilia B. For severe hemophilia A (1% or less and local hemostatic measures. The periodontal factor VIII), the therapeutic goal for replacement is surgeon must be aware that factor replacement 50% of normal. A normal factor VIII level is one products are very expensive and may carry the risk unit of factor VIII per one milliliter of blood. To of transmission of infectious diseases. It is impera- avoid possible hematomas leading to airway tive that they be used appropriately and only when obstruction, block injections should not be needed. Patients requiring these products are best employed unless at least a 30% level can be managed by a hematologist. achieved.24The formula for determining the quantity of replacement factor needed is the desired fac- Antifi brinolysis tor VIII level minus the patient's factor VIII level times the plasma volume (approximately 4 I mWkg In addition to the use of local measures and of body weight).' For example, a patient with 2% increasing coagulation action, maintenance of clot of normal factor VIII has 0.02 units/mL. If the stability following formation is critical to prevent patient weighs 70 kg, the patient has a plasma vol- rebleeding. This can be accomplished via antifibri- ume of approximately 2870 mL. In order to raise nolysis agents such as Amicar (epsilon-aminocaproic the patient's factor VIII level to 30%, the patient acid [EACA]) and Cyclokapron (tranexamic acid). should receive approximately 804 units of factor These antifibrinolytics are usehl in patients with a VIII ([0.30to 0.021 x 2870). Factor VIII has an 8 broad range of bleeding disorders especially when to 12-hour half-life unless the patient has devel- the bleeding involves mucosal sites. Both these oped antibodies to it (5 to 20% of patients). It agents block the binding of plasminogen to fibrin should be given 10 to 30 minutes prior to surgery. and its activation and transformation to plasmin. All necessary surgery should be performed at one sit- This results in increased clot stability. Tranexamic ting to minimize the number of times replacement acid is about 10 times more potent than amino- therapy is needed. Patients with inhibitors to factor caproic acid and has a longer half-life. The half-life VIII can be treated with increased doses of factor of EACA is 4 hours, and it may be given as a tablet concentrate if their inhibitor level is low (below 20 or an elixir. The elixir is preferred for oral bleeding BU). With high inhibitor levels, prothrombin com- because of potential topical effects (plasmin is plex concentrates (contains factors 11, VII, K, and found on the oral mucosa and in saliva). The rec- X) may be used, but the response is highly variable. ommended oral dose of aminocaproic acid is 50 to This product is thought to bypass the factor VIII 60 mg/kg every 4 hours.25However, systemic treat- inhibitor. Unfortunately, some patients with high ment with antifibrinolytic agents is prohibited in inhibitor levels will not respond to any form of patients using anticoagulant medication because of replacement therapy. All efforts must be made to the risk of thromboembolism. prevent bleeding episodes in these patients. 'O Tranexamic acid is preferred over aminocaproic In patients with hemophilia B, a moderate fac- acid as a topical agent. The use of tranexamic acid tor IX deficiency can be managed with local mea- in conjunction with other local measures will sig- sures alone or in combination with fresh frozen nificantly decrease postoperative bleeding in plasma. For patients with severe hemophilia B, the patients with hemophilia or those who are on anti- therapeutic goal for factor IX replacement is 25% coagulation therapy. '6,25,26 Saliva has fibrinolytic of normal. This can be attained by giving an initial qualities, which may contribute to postoperative 240 Periodontal Medicine bleeding in the oral cavity. The topical use of accomplished in a hospital environment. Platelet tranexamic acid appears to neutralize the fibri- transhsions also carry the risk of infectious diseases. nolytic effects of saliva and stabilize the fibrin structure. It has proven effectiveness in eliminating postoperative complications in patients on antico- CONCLUSION agulation therapy who have undergone surgical procedures without lowering their anticoagulant Dental management of patients with a bleeding or therapy.16,26 Additionally, topical antifibrinolytic clotting diathesis should be accomplished in con- therapy does not increase the risk of thromboem- sultation with the patient’s physician. Most bolism. A I- to 2-minute preoperative rinse with patients with mild to moderate bleeding or clot- 10 cc of a solution diluted to 50 mg/mL of tranex- ting problems can be safely treated in the dental amic acid, followed by identical rinses four times office using local measures, provided there is prop- per day for 4 to 7 days, is usually effective. Its con- er planning, preparation, and a judicious surgical centration in saliva remains high enough to sup- technique. Hospitalization is reserved for those press fibrinolysis for several hours after use. Extrac- patients with severe defects. Aspirin and other tion sites can also be irrigated with the solution nonsteroidal anti-inflammatory agents used as during surgery, and postoperative bleeding sites postoperative analgesics should be avoided or used can be treated by pressing with gauze soaked in only with extreme caution in these patients. Mild tranexamic acid. The Colla@products, Gelfoam@ narcotics such as codeine or hydrocodone and and SurgiceP can also be soaked in the agent prior acetaminophen are safer analgesics. Additional to use. A listing of the above antifibrinolytic hemostatic agents and recombinant products are agents, a source for procurement, and the approx- being investigated as to their effectiveness. imate cost for each can be found in Table 14-3. Early human clinical trials involving interleukin- I I, recombinant human thrombopoietin, PIate1 et Transfusions or polyethylene glycol conjugated recombinant human megakaryocyte growth and development Postoperative bleeding in patients with mild to factor have shown promise in increasing platelet moderate thrombocytopenia usually can be man- production in bone marrow suppressed patients.27 aged with local measures alone. However, in addi- Recombinant factor VIII, factor IX and activated tion to local measures, platelet transhsion must be factor VII are available (Factor VII only in Europe) considered for severely thrombocytopenic patients and are being studied. Clinical studies of recombi- (c 20,000 platelets/mm3). Regional block anesthet- nant von Willebrand factor are also due to begin.25 ic injections should be avoided when the platelet Fibrin tissue adhesives (fibrin sealants) have count is c 30,000/mm3. The goal for these patients also been used clinically with good success.28These is to raise their platelet count to at least 50,000 sealants mimic the last phase of blood clotting by platelets/mm3 prior to a surgical procedure. This means of the conversion of fibrinogen to fibrin. should be increased to 75,000 platelets/mm3 for They consist of two components; (I) fibrinogen multiple extractions, multiple quadrants of peri- and plasma proteins, and (2) thrombin and calcium odontal surgery, or a bony impaction. Platelet trans- chloride. When the two components are mixed, hsions are usually performed in a hospital setting. thrombin converts fibrinogen into fibrin, and the One unit of platelets will raise the average patient’s mixture solidifies. These topical agents have not count by 10,000 platelets/mm3 unless the patient been recommended because objective data on their has platelet antibodies. At least 30% of transhsions efficacy and safety are limited.25Undoubtedly, with result in complications, and the incidence of all these new agents, there will be continued efforts patients developing antibodies to platelets after to advance the clinical management and treatment repeated transhsions is approximately 75%; there- of patients with bleeding and clotting disorders. fore, they should be given judiciously. They are usually given six units at a time at a cost of approximately US $300. Platelet transhsions should be REFERENCES done about 30 minutes prior to the surgical procedure because platelets are rapidly sequestered. If the 1. Redding SW. Oral bleeding. In: Montgomery MT, patient has antibodies to platelets, a continuous Redding SW, editors. Oral-facial emergencies. transhsion of platelets will probably be required Chicago: Federation of Special Care Organiza- during the surgical procedure. This can only be tions in Dentistry; 1994.p. 103. Bleeding Disorders 24 1

2. Olive JA. Disorders of hemostasis. In Tullman MJ, 14. Furie B. Oral anticoagulant therapy. In: Hoffman Redding SW, editors. Systemic disease in dental R, Benj EJ, Shattil SJ, et al, editors. Hematology treatment. New York: Appleton Century Crofts; basic principles and practice. 2nd ed. New York: 1982.p. 195. Churchill Livingstone; 1995.p. 1795. 3. Bussel J, Cines D. Immune thrombocytopenic pur- 15. De Rossi SS, Glick M. Bleeding time: an unreliable pura, neonatal alloimmune thrombocytopenia, predictor of clinical hemostasis. J Oral Maxillo- and post-transfusion purpura. In: Hoffman R, fac Surg 1996;54:1119-20. Benj EJ, Shattil SJ, et al., editors. Hematology 16. Gaspar R, Brenner B, Ardekian L, et al. Use of basic principles and practice. 2nd ed. New York: tranexamic acid mouthwash to prevent postop- Churchill Livingstone; 1995.p. 1849. erative bleeding in oral surgery patients on oral 4. Schafer A. Thrombocytopenia and disorders of anticoagulant medication. Quintessence Int platelet function. In: Stein JH, editor. Internal 1997; 18: 375-9. medicine. 5th ed. Philadelphia: CV Mosby Co.; 17. Meehan S, Schmidt MC, Mitchell PF. The interna- 1998.p.6 10. tional normalized ratio as a measure of antico- 5. Moake JL. Thrombotic thrombocytopenic purpura agulation: significance for the management of and the hemolytic uremic syndrome. In: Hoff- the dental outpatient. Special Care in Dentistry man R, Benj EJ, Shattil SJ, et al., editors. Hema- 1997;17(3) ~94-6. tology basic principles and practice. 2nd ed. 18. Hirsh J, Dalen DE, Deykin D, Poller L. Oral anti- New York: Churchill Livingstone; 1995.p.1879. coagulant mechanism of action, clinical effec- 6. Bennett JS. Hereditary disorders of platelet func- tiveness, and optimal therapeutic range. Chest tion. In: Hoffman R, Benj EJ, Shattil SJ, et al, 1992;102(Suppl):3 12s-26s. editors. Hematology basic principles and prac- 19. Herman W, Konzelman J Jr, Sutley S. Current per- tice. 2nd ed. New York: Churchill Livingstone; spectives on dental patients receiving coumadin 1995.p. 1909. anticoagulant therapy. J Arn Dent Assoc 1997; 7. George JN, Shattil SJ. Acquired disorders of 128:327-35. platelet function. In: Hoffman R, Benj EJ, Shat- 20. Beirne OR, Koehler JR Surgical management of til SJ, et al, editors. Hematology basic principles patients on warfarin sodium. J Oral Maxillofac and practice. 2nd ed. New York: Churchill Liv- Surg 1996;54:1115-8. ingstone; 1995.p. 1926. 21. Hylek EM, Heiman H, Skates SJ, et al. Aceta- 8. White G. Disorders of blood coagulation. In: Stein minophen and other risk factors for excessive JH, editor. Internal medicine, 5th ed. Philadel- warfarin anticoagulation. J Arn Med Assoc 1998; phia: CV Mosby Co.; 1998.p.617. 279:657-62. 9. Brettler DB, Kraus EM, Levine PH. Clinical aspects 22. Gage Tw,Pickett FA. Dental drug reference. 4th of and therapy for hemophilia. In: Hoffman R, ed. Philadelphia: CV Mosby Co., 1999.p.700. Benj EJ, Shattil SJ, et al, editors. Hematology 23. Litin SC, Heit JA, Mees KA. Use of low-molecular- basic principles and practice. 2nd ed. New York: weight heparin in the treatment of venous throm- Churchill Livingstone; 1995.p.1648. boembolic disease: answers to frequently asked 10. Redding SW, Stiegler ICE. Dental management of questions. Mayo Clin Proc 1998;73:545-5 1. the classic hemophiliac with inhibitors. Oral 24. Scully C, Cawson RA. Medical problems in den- Surg Oral Med Oral Pathol 1983:56 (1);145-8. tistry. 4th ed. Oxford, England: Buttenvorth- 11. Roberts HR, Gray TF. Clinical aspects of and ther- Heinemann; 1998.p.82. apy for hemophilia B. In: Hoffman R, Benj EJ, 25. Mannucci PM. Hemostatic drugs. N Engl J Med Shattil SJ, et al, editors. Hematology basic prin- 1998;339(4):245-53. ciples and practice. 2nd ed. New York: 26. Brandrowshy T, Vorono A, Borris T, Marcantoni Churchill Livingstone; 1995.p. 1678. H. Arnoxicillin-related postextraction bleeding 12. White GC, Montgomery RR. Clinical aspects of in an anticoagulated patient with tranexamic and therapy for von Willebrand disease. In: Hoff- acid rinses. Oral Surg Oral Med Oral Pathol man R, Benj EJ, Shattil SJ, et al, editors. Hema- Oral Radiol Endod 1996;82:610-2. tology basic principles and practice. 2nd ed. New 27. Kaushansky K. Thrombopoietin. N Engl J Med York: Churchill Livingstone; 1995.p. 1725. 1998;339(11):746-54. 13. Roberts HR, Gray TF. Factor XI and other clotting 28. Bodner L, Weinstein JM, Baumgarten AK. Effka- factor deficiencies. In: Hoffman R, Benj EJ, cy of fibrin sealant in patients on various levels Shattil SJ, et al, editors. Hematology basic prin- of oral anticoagulant undergoing oral surgery. ciples and practice. 2nd ed. New York: Churchill Oral Surg Oral Med Oral Pathol Oral Radiol Livingstone; 1995.p.1691. Endod 1998;86(4):4214. CHAPTER15

PHARMACOTHERAPY

Sebastian G. Ciancio, DDS

Drugs were first used to treat disease when Paul An ideal antibiotic should: (1) be selective and Ehrlich treated syphilis with salvarsan, an organic effective against microoganisms without injuring chemical. Much later, in 1936, sulfonamides were the host; (2) destroy microorganisms (bactericidal introduced for treating infections and antibiotics action) rather than retard their growth (bacterio- became clinically available in I 94 1. Since then, static action); (3)not become ineffective as a result numerous antibiotics have become available and of bacterial resistance; (4) not be inactivated by new antibiotics are constantly being evaluated. enzymes, plasma proteins, or body fluids; (5) Antimicrobial agents either suppress the quickly reach bactericidal levels throughout the growth of microorganisms or destroy them. They body and be maintained for long periods; and (6) are divided into three categories: antibiotics, anti- have minimal adverse effects. septics, and sulfonamides. In dentistry, antibiotics Depending on the antibiotic, several mecha- and antiseptics are most frequently used. nisms of action are possible. They include: (I) Pharmacotherapeutic agents of value as inhibition of bacterial cell wall synthesis, (2) alter- adjuncts to periodontal therapy can be classified ation of bacterial cell membrane permeability, (3) into agents which are useful for their antimicrobial alteration of bacterial synthesis of cellular compo- properties and those which are usehl for their abil- nents, and (4) inhibition of bacterial cell metabo- ity to improve “host resistance.” In the former cat- lism. egory are antibiotics and antiseptics, and in the lat- Certain basic terms and concepts are impor- ter category are anticollagenase and antiprosta- tant in understanding the pharmacology of antibi- glandin agents. otics; they are described below. A sub-antimicrobial dose of doxycyline hyclate has recently become available for use an as adjunct Resistance to mechanical methods of periodontal therapy. This agent arrests the progress of periodontal disease and Microorganisms are sometimes resistant or unaf- results in probing depth reduction and attachment fected by an antibiotic. Resistance can be natural, gain.’ It produces its effect by reducing the release that is, present before contact with drug, or and activity of matrix metalloproteinases such as acquired and develop during exposure to the drug. collagenase and gelatinase by polymorphonuclear The development of acquired resistance is genetic, leukocytes. These effects occur without the side with a change in the microorganism’s DNA, and is effects associated with systemic antibiotic therapy, inherited by each subsequent generation. Once including the development of bacterial resistance. resistance develops to an antibiotic, it persists, and a new antibiotic must be found that will destroy the resistant strain. ANTIBIOTICS Microorganisms resistant to a particular drug frequently are resistant to other chemically related Antibiotics, which are chemical substances origi- antimicrobial agents. This is referred to as cross- nally produced by microorganisms, either retard resistance. Occasionally, cross-resistance can also the growth of microorganisms or result in their occur between two chemically dissimilar drugs. death. Now, some antibiotics are chemically Antibiotic resistance usually implies inactiva- synthesized. tion of the antibiotic by bacterial enzymes and 244 Periodontal Medicine development by the bacteria of alternative meta- Type of Action bolic pathways-unaffected by the antibiotic, or by biochemical alterations in the bacteria that prevent Antibiotics are either bacteriostatic or bactericidd2 the uptake or binding of the antibiotic. Bacteriostatic antibiotics inhibit the growth and Antibiotic effectiveness can be reduced by multiplication of microorganisms while bactericidal inadequate therapy. For example, if a drug is given antibiotics kill microorganisms. While bacteriostatic at a late stage of a disease, it may not control the antibiotics alter the metabolic pathways or synthesis large number of microorganisms that are present. of cellular components in microorganisms, bacteri- At other times, no clinical improvement may cidal drugs interfere with the synthesis or hnction be seen even when the microorganisms are sensi- of either the cell wall, cell membrane, or both. tive to the antibiotic, which may result from too When two bactericidal antibiotics are given low a dose of antibiotic. This has an additional together, they may exert a greater effect than when danger in that low doses only destroy the weaker each is given alone. This is called “antibiotic syner- microorganisms and allow the stronger to survive, gism.” Sometimes, however, when a bacteriostatic multiply, and possibly become drug resistant. The and a bactericidal antibiotic are given together, antibiotic thus serves to permit the growth of less their effectiveness is negated or reduced. This is susceptible microorganisms without the competi- called “antibiotic antagonism.” In the majority of tion of the more susceptible bacteria that have dental infections, combination therapy is not usu- been destroyed by the antibiotic. This phenome- ally necessary. However, in the prophylaxis of non is called “selective pressure.” The process of patients with a history of rheumatic fever, combi- selecting increasingly less susceptible or resistant nation therapy for antibiotic synergism is some- microorganisms occurs in a stepwise manner. times indicated. Therefore, it is imperative that an antibiotic concentration be reached at the site of the infection to Inhibition of Oral Contraceptive kill these microorganisms. This can also occur if Effectiveness drug therapy is not long enough. In view of this, it is important that patients take all the medica- Occasionally, contraceptive failures without obvi- tion prescribed to them for the duration pre- ous cause are reported, and some evidence suggests scribed. Too often, patients prematurely stop tak- that these events are related to the concurrent use ing an antibiotic because they “feel better.” Lastly, of certain other drugs, including antibiotics. antibiotics can be ineffective if they do not reach It has been suggested that with the trend therapeutic levels at the site of the infection, or if toward lower steroid dosages in oral contraceptive they are antagonized by their interaction with preparations, there is increased frequency of drug other drugs. interactions that cause lowered efficacy of oral contraceptives. Spectrum of Activity Ampicillin and other penicillins were the antibiotics most frequently listed as having the This term refers to the different types of microor- potential to inhibit contraceptives; tetracycyline, ganisms affected by an antibiotic. An antibiotic although listed less frequently, was also implicated may affect only a few species of microorganisms in several cases. In some cases, a combination of and have a limited spectrum of activity or affect a penicillin and a tetracycline was taken.3 wide variety and have a broad spectrum of activity. Contraceptives belong to the steroid class of Broad-spectrum antibiotics are only necessary if an drugs. Steroid levels in the body are dependent on infection is caused by a variety of microorganisms. metabolic action by bacteria in the gastrointestinal Often, an infection caused by one microorganism (GI) tract. By suppressing the bacterial flora, will even respond more readily to a limited-spec- antibiotics diminish their ability to maintain the trum antibiotic that is directed toward that required levels of the contraceptive drug in the GI microorganism. tract. This, in turn, results in less availability of the Antibiotic therapy may suppress one group of drug for absorption. Consequently, plasma con- microorganisms while permitting the growth of centrations of the steroid are abnormally low, and another group of bacteria that are normally present it is cleared more rapidly from the body than under but do not cause disease. In large numbers, they normal circumstances. can produce a superimposed infection, referred to If a patient taking an oral contraceptive is in as a “superinfection.” need of antibiotic therapy as part of dental treat- Pharmacotherapy 245 ment, the patient should be cautioned about drug been reported with products containing iron, mag- interaction and advised to use alternative methods of nesium, and aluminum. Therefore, patients should contraception until cessation of antibiotic therapy. be told to refrain from foods containing these for It should be noted that the clinical importance at least I1/2 hours prior to or following administra- of this drug interaction is currently being question of the medication by the oral route. tioned, and ongoing studies may prove it not to be Mechanism of action. Tetracyclines are bacte- a significant clinical concern. riostatic drugs that retard the growth of susceptible bacteria by inhibiting protein synthesis. Since they Antibiotics Used in Periodontics all have the same mechanism of action, resistance to one implies resistance to all tetracyclines. The most common antibiotics used in periodon- Tetracyclines can block the antibacterial effect tics are listed in Table 15-1. They are listed accord- of penicillin. Penicillin is most effective on multi- ing to frequency of use, with the most commonly plying, growing bacteria while tetracyclines exert used listed first. Dosages vary according to the their effect by slowing down the rate of bacterial drug used. However, with oral administration, the growth and multiplication. Therefore, concomitant initial dose should be double the subsequent doses administration of these drugs is contraindicated. so that high blood levels are rapidly obtained. Dosage and Forms. The oral forms include Although systemic antibiotics appear to offer tablets, chewable wafers, capsules, liquids, and oint- only minimal long-term benefit as pharmacothera- ments. The adult dosage for tetracycline, oxytetra- py for adult periodontitis, a number of studies cycline, and chlortetracycline is 250 to 500 mg have suggested that they are beneficial in rapidly given four times per day. The adult dosage for advancing periodontitis, localized juvenile peri- demeclocyline and methacycline is 150 mg four odontitis, and refractory periodontitis. times per day, that for doxycycline 100 mg daily, and minocycline 100 mg twice daily. Tetracyclines Spectrum of Activity. Tetrayclines are broad- Tetracyclines are the most widely prescribed adjunc- spectrum antibiotics that are effective against a tive agents for periodontal therapy.* Tetracyclines number of oral gram-negative and gram-positive are broad-spectrum antibiotics that were initially cocci and bacilli. They are also effective against a obtained from soil microorganisms. few viruses, Treponemu, Mycophsmu, Cbhmydiu, Types of Tetracyclines. Seven basic types of and Rickettsiu. Minocycline may be effective against tetracyclines are currently in use. They are similar staphylococci that are not susceptible to other chemically and therefore possess similar antibacte- tetracyclines. rial spectra and have cross-hypersensitivity. When Metabolism. These drugs are usually admin- resistance or hypersensitivity occurs to one tetracy- istered orally since injections are painful. Peak plas- cline, it will also occur to all in the group. Tetracy- ma levels are attained slowly, so the daily recom- clines are summarized in Table 15-2. mended dose is doubled the first day of therapy. The first tetracyclines developed were chlorte- These antibiotics pass into most body fluids and tracycline, oxytetracycline, tetracycline, and deme- tissues. They can also pass through the placenta clocycline. The next group of tetracyclines devel- and occur in low doses in breast milk. However, no oped were doxycycline, methacycline, and minocy- adverse effects on the newborn have been reported cline. All these agents have a similar spectrum of activity. However, minocycline appears to be the most effective in the treatment of meningococcal TABLE 15- I. Antibiotics of Frequent Use in infections. The newer tetracyclines can be admin- Periodontal Therapy istered in smaller doses since they are more rapidly Action absorbed and more slowly excreted. From Table 15-2, it can be noted that most of the tetracyclines Antibiotic Bacteriostatic Bactericiddl are affected by metal ions but doxycycline and Tetracyclines J minocycline are affected to a lesser extent. This Metronidazole J interaction has also been observed with dairy prod- Arnoxicillin J ucts and antacids because of their calcium content. Clindamycin* J Tetracyclines bind to the calcium in the GI tract Cephalosporins J and cannot be absorbed, so minimal therapeutic benefits can be expected. A similar interaction has *depending on dose, may be bacteriostatic or bactericidal 246 Periodontal Medicine

Table I 5-2. Various Tetracyclines Generic Name Trade Name Route ofAdministration Affected by Metal Ions Chlortetracycline HCl Aueromycin Demeclocycline HCl Declomycin Doxycycline and salts Vibramycin Methacycline HCl Rondomycin

Minocycline HCl Minocin, Vectrin Oxytetracycline and salts Terramycin PO, IM, Iv Tetracycline and salts Achromycin V, Cyclopar, Panmycin, PO, IM, IV Robitet, SK-Tetracycline, Tetracyn, Sumycin, Tetrex

PO = per OS (by mouth); IV = intravenous; IM = intramuscular when the child receives low doses in the mother’s clines. Unfortunately, there is no diagnostic labo- milk. These antibiotics also pass into the gingival ratory test for allergy to tetracycline. crevicular fluid and are therefore in intimate con- Regarding teratogenesis, the effects of tetra- tact with the plaque in the gingival crevice. They cyclines on the formation of fetal hands and have an affinity for and are found in higher con- limbs is not established. Other side effects associ- centrations in rapidly growing and metabolizing ated with tetracycline therapy are rare and include tissue such as liver, tumors, bone, and teeth. lymphoepithelioma and simulated systemic lupus Tetracyclines are excreted mainly by the kid- erythematosus. neys and can be recovered from the urine in their Tetracycline Discoloration of Permanent unchanged form. Treatment with tetracyclines can Teeth. It has been reported that long-term therapy also adversely alter the normal oral and intestinal with minocycline (as used for patients with acne) flora, resulting in GI problems, such as diarrhea. may discolor adult teeth and gingival tissue (Figure Some patients have also developed monilial infec- 15-1). tions of the GI tract, oral cavity, and vagina due to In reviewing the cases of discoloration of adult alteration of the flora. teeth, no pattern of discoloration could be found Adverse Effects. The side effects associated that was common to all. The tooth discoloration, a with tetracycline therapy are varied. A number of gray color, was present at the incisal edge in some side effects have been related to the use of outdat- cases, the midtooth surfaces in some, and the gin- ed tetracyclines, and side effects also are more com- gival third in other^.^>^ Minocycline used for long mon in pregnant patients (in addition to the fetal periods has also been reported to cause a yellow tooth-staining problem). These side effects and pigmentation of the skull. Similarly, black discol- toxicities are summarized in Table 15-3. As this oration of the thyroid has been ~bserved.~ table indicates, these drugs are contraindicated in Permanent tooth-staining can be caused all women in the childbearing age group. In these when tetracycline or fluoride is administered dur- women, the risks involved in therapy are too high ing the time when teeth are developing in utero to justify their therapeutic value for dental usage. or after birth. If the drug is given during the time In one animal study, tetracyclines were found when the development of the crowns is being deposited in damaged areas of the heart, particu- completed and they are calcifying, the crowns as larly regions containing calcified deposits. well as the roots will be stained. However, in all Whether these agents are contraindicated in cases studied, the patients (who ranged in age humans with a history of a cardiac infarct is ques- from 18 to 29 years) were over the age of tooth tionable. Further investigations to clarify this are formation, with the exception of the younger needed; however, no additional studies since 1962 patients, whose third molar roots could have been have been reported relative to this effort. Although forming at the time of therapy. It should be noted the incidence of allergy is low, allergy to one tetra- that since tetracyclines become incorporated into cycline usually means allergy to all other tetracy- dentin, this is a permanent discoloration that can Pharmacotherapy 247

TABLE I 5-3. Side Effects and Toxicities of Tetracyclines Blood urea Elevation of blood urea nitrogen occurs mainly in patients taking diuretics or presenting nitrogen initially with a high blood urea nitrogen. Nausea, vomiting, and their sequelae are associated with this rise Bone Possible retardation of growth and development-may be transient Gastrointestinal Overgrowth with monilial microorganisms has been reported on a number of occasions in tract conjunction with tetracycline therapy. However, some articles question this statement. Alteration in absorption of vitamin K may occur, leading to inadequate formation of prothrombin and subsequent bleeding problems Liver Lethal hepatic toxicity has been reported in conjunction with use in pregnancy and in the nonpregnant state in the presence of renal dysfunction, shock, and sepsis. Abnormal liver function tests have been reported (due to high dose in the presence of renal dysfunction) Renal Azotemia. Also, renal disorders have been reported following administration during pregnancy. A Fanconi-type syndrome has been associated with the use of outdated or degraded tetracycline. Nephrogenic diabetes insipidus has been reported in conjunction with administration of demeclocycline Skin Photosensitivity (especially with demeclocycline), rash, onycholysis. Seldom seen with chlortetracycline, minocycline, and tetracycline Teeth Permanent discoloration and dysgenesis in the offspring due to administration of tetracycline during the last half of pregnancy or the first 6 years of life. Question of discoloration of permanent teeth under study Teratogenesis These agents may be potential teratogens and result in malformed hands and limbs. Do not use in females of childbearing age range who have missed one or more menstrual periods only be corrected by covering the tooth with enhanced bone formation and possibly reattach- restorative materials. Varied reports have appeared ment. In addition, animal studies have suggested in the dental literature suggesting that tetracy- beneficial effects of antibiotics in terms of early cline-discolored teeth may be partially bleached crestal bone repair and reversal of a unique peri- with long-term concentrated solutions of hydro- odontal syndrome in the rice rat. They are valuable gen peroxide sometimes preceded by acid-etching in that they not only kill oral pathogens but also and followed by the application of heat. These diminish the pathogenic potential of these findings are not well documented but deserve fur- microorganisms. Since plaque is dynamic, a bacte- ther investigation. riostatic drug would retard the growth of certain Indications. Nondentul Conditions. Since their microbial components of plaque. Therefore, by introduction in 1948, tetracyclines have been wide- reducing these pathogens before and following ly used, particularly in the treatment of acne. This therapy, an enhanced response can be expected. widespread use has led to antibiotic resistance. A This hypothesis is supported by studies in our lab- number of gram-negative bacilli now carry factors conferring resistance to tetracyclines and to other drugs, thus decreasing their effectiveness. Several species of Escherichiu coli, beta hemolytic streptococci, Streptococcus pneumoniue, Neisseriu go n o rrhoeue, so me Bucteroides, Shigellu, and Stuph~lococcusuureus are resistant to tetracyclines. Since there is evidence that resistance develops in direct proportion to usage, the prevalence of these resistant strains may increase in the future. However, tetracyclines remain the drugs of choice for a variety of rarely occurring nondental infections. Dentul Conditions. Clinical studies on humans indicate that use of tetracyclines results in Figure 15-1. Minocycline discoloration of adult teeth. 24 8 Periodontal Medicine oratories and elsewhere that have shown the pres- anaerobic gram-negative bacteremias and, in com- ence of tetracyclines in gingival crevicular fluid fol- bination with other antibiotics (primarily peni- lowing oral administration. Studies comparing cillin), in treating severe odontogenic infections. tetracycline HCl and minocycline HCl have shown Although supportive data are weak, metron- that the minocycline concentration in gingival idazole has been shown to be of benefit in treating crevicular fluid is higher than that of tetracycline severe adult periodontitis when the major outcome HCL8 Therefore, these antibiotics become an inte- evaluated is avoidance of surgery.16J7 It has also gral part of the crevicular environment and may been reported to be of value in treating refractory further exert an effect on plaque and gingival periodontitis, with or without combining with health. They have also been shown to be present in other antibiotics such as ciprofloxacin, amoxicillin saliva, the level of concentration far below that or doxycycline. Although not effective against found in serum. A. uctinomycetemcomituns,both metronidazole and Although the value of tetracyclines in the its hydroxymetabolite act synergistically with treatment of adult periodontitis is questionable, amoxicillin. Metronidazole affects most anaerobes their value is established in the treatment of gener- and amoxicillin most facultative and aerobic bacte- alized and localized juvenile period~ntitis,~-'' ria, which makes this combination useful to treat refractory peri~dontitis,'~-'*and rapidly progres- many mixed periodontal infections. The recom- sive periodontitis. l5 mended dosage for metronidazole is 250 to 500 mg tid for 7 to 10 days.18 Metronidazole Metronidazole (Flagyl, Metryl) is a unique Amoxicillin antimicrobial agent in that it is effective against Penicillin, the first antibiotic used in humans, was anaerobic bacteria and parasites but has little or derived from a number of molds. Although the no effect on facultative and aerobic organisms. It effect of this derivative from the mold Penicillium was initially developed in 1959 as an antitricho- notutum was discovered as early as 1928 by Sir monal drug. Alexander Fleming in London, United Kingdom, Spectrum of Action. Metronidazole is most therapeutic trials did not take place until 1941. active against obligate anaerobic gram-negative This delay mainly resulted from lack of sufficient bacilli (Bucteroides sp, Fusobucterium sp, Clostridi- quantities of the drug for a clinical trial. Difficul- um sp) and certain anaerobic protozoa1 parasites ties in penicillin production occurred because (Tricbomonus, Giurdiu, Entumoebu). It is the only broth cultures of Penicillium could not be pro- antimicrobial agent that consistently exhibits bac- duced rapidly. tericidal activity against B. fiugilis. It is also effec- Amoxicillin is sometimes called a broad-spec- tive against obligate anaerobic cocci (Peptococcus trum penicillin and is a derivative of ampicillin. sp, Peptostreptococcus sp). It has minimal efficacy For periodontal therapy, it is often combined with against Actinobucillus uctinomycetemcomituns. clavulanate, which inhibits p-lactamases produced While metronidazole has no in vitro activity by some bacteria. It is highly acid stable, and pre- against aerobes, it has been shown to be effective in dictable blood levels can be attained following oral the treatment of mixed infections. The theory is administration. Over 90% of the dose adminis- that susceptible bacteria convert metronidazole to tered is absorbed. metabolites that are effective against the aerobic Amoxicillin is a bactericidal drug that inhibits organisms in a mixed infection. However, despite the synthesis of bacterial cell walls. The deficient cell the effectiveness of the drug against mixed infec- walls thus created do not protect bacteria against tions, clinical data supporting its use as the sole high osmotic pressure. Fluids enter the cell causing agent are lacking; therefore, the drug is often used swelling, membrane disruption, and subsequent cell in combination with other microbial agents in the death. The action of the drug also depends on its treatment of periodontal infections. ability to reach and bind penicillin-binding proteins Contraindications. Its main adverse effect is located in the bacterial cytoplasmic membranes. its interaction with alcoholic beverages, which can Because penicillin acts during the synthesis of cell result in severe nausea and vomiting, metallic taste, walls, it is most effective against multiplying bacte- gastric discomfort, and diarrhea. ria. The administration of a bacteriostatic drug in Indications. In dentistry, metronidazole has conjunction with penicillin therapy could therefore been used in the treatment of acute necrotizing render the penicillin less effective by slowing down ulcerative gingivitis (ANUG), and postextraction the bacterial growth rate. Pharmacotherapy 249

Metabolism. Penicillin can be administered mechanism of action of clindamycin is similar to orally or parenterally. Since absorption following that of erythromycin and identical to that of chlo- oral administration is influenced by the presence of ramphenicol. These drugs bind to a specific sub- food in the stomach, more predictable blood levels unit of the bacterial ribosomes, thereby inhibiting can be obtained if the drug is taken on an empty their protein synthesis. stomach. However, the absorption of amoxicillin Spectrum of Activity. Its antibacterial spec- from the gastrointestinal tract is not affected by the trum is similar to that of erythromycin. Because of presence of food and therefore is more predictable its ability to penetrate bone, however, it is particu- following oral administration. Alternatively, pre- larly usehl in treating periodontal disease when dictable blood levels are also possible when the bacterial invasion of tissue is suspected. drug is given parenterally. Levels in the crevicular fluid usually are above Once absorbed, penicillin is widely distributed the minimum inhibitory concentration for peri- throughout the body, and is found in low levels in odontal pathogens.21 It is almost completely the saliva and gingival crevicular fluid. It does not absorbed from the GI tract and is excreted in cross the blood-brain barrier in normal persons, but urine, feces, and bile, with the biliary route being in meningitis it does pass through and may be clin- the most important. Following oral administra- ically effective. Penicillin is rapidly eliminated from tion, levels in bone are similar to levels in serum. the plasma by the kidneys; it can cross the placenta Adverse Effects. The main adverse effect of and be found in cord blood and amniotic fluid. clindamycin is diarrhea and gastric upset if taken Penicillins are excreted in breast milk in low on an empty stomach. Therefore, it should be concentrations. Although significant problems in taken with food. Ulcerative colitis has been report- humans have not been documented, a risk-benefit ed but the frequency of its occurrence is less than analysis must be done since the drug may lead to that seen with ampicillin or the cephalosporins. sensitization, diarrhea, and candidiasis in nursing When colitis occurs, it is best treated with metron- mothers. idazole (250 mg qid) or vancomycin (500 mg qid). Adverse Effects. Penicillin toxicity is extreme- Since colitis can be fatal, patients must be closely ly low, and except for allergic reactions, it is one of monitored for this condition. the safest drugs known. However, intrathecal injec- Indications. Clindamycin has been shown to tion or topical application during surgery on the be of value in the treatment of refractory peri- brain has resulted in convulsive reactions. odontitis, either alone or in combination with Patients hypersensitive to one penicillin most amoxicillin/clavulanate (Augmentin) .22-26 The likely are hypersensitive to all other penicillins. usual dosage is 150 mg tid or qid for 7 to 10 days. Also, those with a history of hypersensitivity to cephalosporins, griseofulvin, or penicillamine may Miscellaneous Antibiotics show a similar response to penicillins. Spiramycin. Spiramycin is active against Indications. Some studies have suggested that gram-positive organisms and is excreted in high amoxicillin is of value in combination with concentrations in saliva. It is used as an adjunct to metronidazole (see “Metronidazole”) for treatment periodontal treatment in Canada and Europe but of localized juvenile periodontitis. In addition, as is not available in the United States. amoxicillin/clavulanate (Augmentin), in doses of This drug has minimal adverse effects. Some 250 to 500 mg tid, it may be of value in treating studies have suggested its benefit in adult peri- refractory periodontitis. 19,20 odontitis but data are not c~nvincing.~~-~~ Ciprofloxacin. Ciprofloxacin is categorized as Clindamycin a fluoroquinolone and was initially developed to Lincomycin, the predecessor to clindamycin, was treat urinary tract infections. Studies of its value in discovered in 1962 in soil samples from Lincoln, periodontal therapy are limited, with a possible Nebraska. Although lincomycin is no longer pre- benefit reported in refractory ca~es.~O’~lIn combi- scribed because of significant adverse effects, its nation with metronidazole, it is effective against derivative, clindamycin, is still available since it has A. uctinomycetemcornit~ns.~~The dosage is 500 mg fewer adverse effects and its antibacterial action is bid for 8 to 10 days. more effective than that of lincomycin. Adverse effects include gastrointestinal upset, Mechanism of Action. This antibiotic oral candidiasis, headache, restlessness, insomnia, inhibits bacterial protein synthesis and is usually hypersensitivity, hyperpigmentation, and photo- bacteriostatic but is bactericidal in high doses. The sensitivity. 25 0 Periodontal Medicine

Anti biotic-Associated Treatment Pseudomembranous Colitis Treatment depends on the severity of the disease. If it is mild (as it is in most cases), the most impor- Pseudomembranous colitis is a severe diarrheal distant therapeutic decision is to discontinue the ease that can result from virtually any orally or par- antibiotic (if possible and appropriate) and to enterally administered antibiotic used in dentistry rehydrate the patient and replace lost electrolytes. (Table 15-4), but is most commonly associated In many patients, this approach usually results in a with ampicillin, cephalosporins, and clindamycin. rapid, complete resolution of symptoms with no The true incidence of this disease from antibi- hrther necessary diagnostic tests (endoscopy, or otic use in dentistry is unknown because definitive examination of stool to detect C. dzficile entero- diagnosis is based on endoscopic examination of toxin) or treatment regimens. The medication of the bowel, and this is rarely performed on patients choice is orally administered vancomycin or suffering from diarrhea. However, there are a num- metronidazole. It is important to note that under ber of signs and symptoms associated with this dis- no circumstances should antidiarrheal agents that ease that should suggest to the dentist that a decrease GI motility be used. They have been patient might be suffering from antibiotic-associat- implicated in worsening the symptoms and out- ed pseudomembranous colitis. The majority of come of the disease. patients present with fever, leukocytosis, abundant Most patients with pseudomembranous colitis watery diarrhea, and a crampy abdominal pain recover without specific therapy, but the mortality beginning on the fourth to ninth day of antibiotic rate in seriously ill patients can approach 30%. therapy. It is important to note, however, that as Because pseudomembranous colitis is associated many as 40% of these patients do not manifest with antibiotics that are commonly used in den- signs or symptoms until 2 to 10 weeks following tistry, the practitioner should be aware of this the conclusion of antimicrobial therapy. potentially serious adverse reaction. Patients should contact their dentist immediately if diarrhea occurs Etiology during or after antibiotic therapy because prompt Current data suggest that in the majority of cases treatment can produce a rapid symptomatic the disease is confined to the colon and is caused response with essentially 100% recovery. by a toxin produced by Clostridium dzficile that is widely distributed in the environment and is a nor- Antibiotic Combinations mal inhabitant of the GI tract in approximately in Periodontal Therapy 3% of the population. The postulation is that administration of antibiotics alters the normal GI An approach using a combination of antibiotics in flora, thereby creating an environment more favor- periodontal therapy has recently been studied by var- able to the growth of C. dzficile and/or the pro- ious investigators. Van Winkelhoff and colleagues33 duction and release of its enterotoxin. There is no reported on the concomitant use of metronidazole microbial invasion of the intestinal mucosa, but and amoxicillin in the treatment of A. uctino- rather the toxin most likely interacts with the cells mycetemcomituns-associated periodontitis. Their lining the lower GI tract, causing cell necrosis and results concluded that this regimen was able to sup- decreased water and electrolyte absorption, and press A. uctinomycetemcomituns (also Porpbyromonus producing a significant diarrhea. gingivulis) from being detected from the periodontal pocket for over I year. Kornman and colleagues3* have reported some value in the adjunctive systemic TABLE 15-4. Antibiotics Commonly use of metronidmle in combination with amoxi- Used in Dentistry that Are Associated with cillin or amoxicillidclavulanate (Augmentin) in the Pseudomembranous Colitis treatment of patients with refractory periodontitis. Also, Aitken and colleagues35 indicated that Most Common Less Frequent Rare prevention of recurrent periodontitis with metron- Ampicillin Amoxicillin Aminoglycosides Idazole may be enhanced by previous treatment with doxycycline. The serial use of doxycycline and Cephalosporins Cloxacillin Metronidazole metronidazole has also been shown to be of value Clindamycin Erythromycin Tetracyclines in reducing periodontal pathogens.36 Penicillin G A more recent study was designed to compare Penicillin K the effect of short-term systemic administration of Pharmacotherapy 25 1 a sequential antibiotic treatment therapy using measurements, there was a trend toward reductions Augmentin and doxycycline with that of a short- in the doxycycline group, which was better than term systemically administered doxycycline alone that in the Augmentin/doxycycline group. in the treatment of periodontitis caused by A. uctinomycetemcomitunsand I? gingivulis.37 Doxy- cycline was included in this regimen for both its LOCALLY DELIVERED MEDICATIONS antibacterial and anticollagenolytic proper tie^.^^ In a 25-week study, patients were randomly Irrigation represents one of the earliest forms of placed in one of two treatment groups: one group local delivery of a medication. A major limitation (five patients) was to receive doxycycline (200 mg of irrigation is the short duration of application of the first day, then 100 mg each day thereafter for a the medication. However, agents with significant IO-day period); the second group (six patients) substantivity or strong antibacterial properties may received a combination of Augmentin (500 mg tid show some benefit, particularly in the treatment of for 5 days) and doxycycline (200 mg the first day, gingivitis. then 100 mg each day for a total of 5 days). Each Water and a variety of chemical agents have patient received one session (approximately I to 2 been shown to be effective as irrigants in reducing hours) of local therapy via root planing for one half gingivitis. Additionally, subgingival irrigation with of the mouth; the other half mouth received no a variety of antimicrobial agents has been shown to local therapy. No attempt was made to alter the reduce a number of microorganisms associated patient’s oral hygiene regimen. with the pathogenesis of periodontal disease. Fur- Clinical and microbiologic measurements ther short-term studies have suggested some reduc- were recorded at 0, 4, 12, and 25 weeks as follows: tion of pocket depth; however, long-term studies gingival index,39 plaque index?’ probing depth in this area are needed. It is also noteworthy that and attachment level by using a manual (William’s) irrigants, whether supra- or subgingivally deliv- probe and a controlled-force probe (Interprobe) at ered, have been shown to be safe whether applied eight selected sites in each patient (four sites root at home or in the office, and have been well planed and another four without root planing), received by patients. and bleeding upon probing/suppuration. Some representative studies on powered irriga- The results of the study are summarized as tion will be reviewed in this section. follows : The doxycycline/Augmentin groups produced Irrigation with Antimicrobial Agents significant reduction in probing pocket depth (PPD) at 4, 12, and 25 weeks (1.1, 1.3, and 1.1 A study in the Journal of Period~ntology~~evaluated mm, respectively). The doxycycline group pro- the effect of in-office irrigation with PerioPik@ duced a significant reduction in probing depths (Teledyne Water Pik) followed by at-home subgin- only at 4 and 12 weeks (both times 0.8 mm) and a gival irrigation with a Pik Pocket@(Teledyne Water significant gain of 0.8 mm in probing attachment Pik) tip and a Water Pik Oral Irrigator@(Teledyne level at the same periods; and the doxycycline/Aug- Water Pik). The in-office and at-home irrigant mentin group in conjunction with root planing used was Listerine@(Warner Lambert Company). produced the most sustained reduction in probing Included in this study were 50 patients with depth and gain in attachment level. adult periodontitis and at least four bilateral sites A lower percentage of bleeding sites was noted with probing depths between 4 and 5 mm, which in the doxycycline/Augmentin group than in the bled upon probing. Following baseline examina- doxycycline group. All sites at 4, 12, and 25 weeks tions, the patients received a half-mouth scaling and in both groups showed no signs of suppuration, prophylaxis and hll-mouth subgingival irrigation with the exception of one site in the doxycycline with either the antimicrobial mouthrinse or control group at week 25. solution professionally delivered. The subjects con- It should be noted that the reductions in prob- tinued the irrigation at home once daily for 42 days ing depths and gains in attachment levels reported with their assigned rinse delivered via a subgingival were relative to their own baselines and not to each delivery system. All sites within the mouth were other. When the groups were compared with each scored at baseline and at day 42 for supragingival other, no intergroup differences were found. plaque, bleeding on probing, and redness. For the Although there were no significant reductions four selected periodontitis sites, probing depth and in the gingival or plaque indexes or the microbial attachment level were measured at baseline and on 2 5 2 Periodontal Medicine day 42; additionally, supragingival plaque and gin- supragingival irrigation with water can be expected gival redness were scored on days 7 and 2 I. Subgin- to have a therapeutic effect in most patients with gival plaque samples for microbiologic analysis were periodontal disease (Figure 15-2). In a 6-month harvested from the selected periodontal sites at base- assessment of patients with gingivitis who per- line and on days 7, 21, and 42. The samples were formed daily supragingival irrigation with water, analyzed for Porpbyromonus gingivulis, Prevotelh gingival inflammation was shown to be significant- intermediu, Fusobucterium sp, Cupnocytopbugu sp, ly reduced. The therapeutic effects of supragingival Streptococcus sunguis, Porpbyromonus loescbeii, and irrigation with water corresponded to the effect of Zeponemu denticoh. Microbiologically, irrigation twice-daily rinsing with 0.12% chlorhexidine glu- with the antimicrobial mouthrinse resulted in statis- conate solution. However, in this study, supragin- tically significant reductions compared with control gival irrigation with water influenced neither the in periodontal pathogens, including black pigment- supragingival plaque mass nor the composition of ing species, which persisted at 42 days. Clinically, the subgingival mi~roflora.~~Thus, it appears pos- subgingival irrigation with the antimicrobial sible that supragingival irrigation reduced gingival mouthrinse produced a significant reduction in inflammation without altering the supra- and sub- supragingival plaque (p c .OOI), bleeding on prob- gingival mass. Although the mechanism responsi- ing (p = .019), and redness (p = .017) compared ble for this is not exactly known, it can be assumed with the control, whether or not a prophylaxis was that through irrigation there is a dilution or performed. There were no significant differences removal of bacterial toxins, which leads to an between the active and control groups in either improvement of gingival health. Also, it has been probing depth or attachment level (p > .OS). shown that irrigation changes the morphology of The authors concluded that subgingival deliv- bacteria so that, although present, they appear as ery of an antimicrobial agent with a powered oral cells with ruptured membranes.44 irrigation device can play a potential role in the Following scaling and root planing, daily management of chronic periodontitis by virtue of supragingival irrigation with water for 4 weeks its significant effects on the subgingival periodon- leads to an improvement in gingival health that topathic microflora and supragingival plaque and persists for I to 3 months.45 A 6-month study in gingivitis. the Journal ofPeriodontoloay evaluated the effect of In another study at the University of Min- daily water irrigation in 155 patients receiving nesota, 74 patients were divided into irrigation and maintenance periodontal treatment. The study nonirrigation groups.42 Following a periodontal demonstrated that adjunctive supragingival irriga- recall visit, the PerioPik@was used in the office to tion with water can provide meaningful clinical irrigate all gingival crevices with I .64% stannous outcomes for patients with periodontitis who are fluoride. Subjects were then given a powered pul- being treated in the maintenance phase of peri- sating irrigator with a subgingival delivery tip (the odontal therapy.46They also found that irrigation Pik Pocket@) for daily irrigation at home with with water was significantly better (p c .OS) than 200 mL of an iodine-containing solution (tetrahy- zinc sulfate irrigation for all parameters measured. drazine hydroperiodide) for 8 weeks. In the irriga- The effect of supragingival irrigation on the tion group, statistically significant reductions in subgingival microflora appears to depend on the gingivitis were found compared with the control pocket depth. Supragingival irrigation with water group and reductions in gingival bleeding com- has been shown, in pockets of 5 mm and more, to pared with baseline. These reductions are notewor- reduce periodontal pathogenic bacteria, particular- thy since the control group was instructed in ly I;' intermediu, spirochetes, and motile rods. twice-daily brushing and once daily flossing, fol- Further, following supragingival scaling alone, lowing their recall visit. This study also demon- supragingival irrigation with 0.02% stannous fluo- strated the safety of at-home subgingival irrigation ride solution as an irrigant resulted in a significant using the subgingival tip as well as a high degree of improvement of gingival health, compared with acceptability as shown by an 89% compliance rate. supragingival irrigation with

Su pragingival Irrigation Irrigation with Anti-inflammatory Drugs

Since patients with gingivitis and/or periodontitis Nonsteroidal anti-inflammatory drugs (NSAIDs), rarely demonstrate optimal oral hygiene even when such as acetylsalicylic acid, flurbiprofen, naproxen, given oral hygiene information and instruction, and others, offer the possibility of limiting the Pharmacotherapy 2 5 3 destructive side effects of the immune responses that occur in periodontal disease. However, the therapeutic effect of irrigation with various concentrations of acetylsalicylic acid solution has not been found to be significantly better than irrigation with at er.^^,^^ Further studies with more effective anti-inflammatory agents are needed since they are readily absorbed through oral tissues and may offer beneficial effects on the periodontium. The various irrigants reviewed are summarized in Table 15-5.

Irrigation around Implants

Powered irrigation has also been shown to be of Figure 15-2. Powered irrigation device with both supra- benefit to improve gingival health around and subgingival applicator tips. implants. A 3-month study was conducted in 24 men and women between the ages of 35 and 75 requirements for treating periodontal disease years to evaluate the effect of irrigation with 0.06% include a means for targeting an antimicrobial chlorhexidine (PerioGarda) using a powered oral agent to sites of infection and for sustaining its irrigator (Water Pika) with a special subgingival localized concentration at effective levels for suffi- irrigating tip (Pik Pocket Subgingival Tipa), com- cient lengths of time that, at the same time, evoke pared with rinsing with 0.12% chlorhexidine glu- minimal or no side effects (Table 15-6). conate once daily.” The results of this study showed that irrigation with 0.06% chlorhexidine was significantly better Tetracycline-Containing Fibers (Actkite@) than rinsing with 0.12% chlorhexidine for mea- The first local delivery product available in the sures of plaque and health (MGI and PI, p < .OS) United States and one which has been extensively and that the reduction in BI, although not statisti- studied is an ethylenehinyl acetate copolymer cally significant, was almost twice as large as that fiber, diameter 0.5 mm, containing tetracycline, seen in the rinsing group (62% versus 33%). Also, 12.7 mg/9 inches (Actisitem tetracycline fiber; the chlorhexidine-associated stain score was signif- manufactured by Alza Corporation, Palo Alto, CA, icantly lower in the irrigation group compared with and distributed by Procter and Gamble Co., the control (p = .04). Further, it was found that the Cincinnati, OH) (Figure 15-3). When packed into presence of calculus showed a 22% increase in the a periodontal pocket, it is well tolerated by oral tis- rinsing group in contrast to a 42% decrease in the sues, and for 10 days it sustains tetracycline con- irrigation group. centrations exceeding 1300 pg/mL, well beyond The results of this study show that powered irrigation with a chemotherapeutic agent such as chlorhexidine is supportive of the health of tissues around implants and minimizes calculus and stain TABLE 15-5. lrrigants Showing Benefits as associated with the use of chlorhexidine. Adjuncts to Periodontal Therapy Concentration Amount Application (W (mL) Per Day LOCAL DELIVERY OF ANTIBIOTICS Water N/A 500 1 The limitations of systemic therapy have prompt- Chlorhexidine 0.06 200 1 ed research for the development of alternative digluconate delivery systems. Recently, advances in delivery solution technology have resulted in the controlled release Stannous fluoride 0.02 500 1 of drugs, usually systemically, for certain medical solution conditions. The oral cavity offers another relative- Listerine@ Undiluted 100 1 ly accessible disease site for localized therapy. The Iodine 0.38 200 1 2 5 4 Periodontal Medicine

TABLE I 5-6. Desirable Characteristics improvement in probing depth reduction and clinical attachment level gain of over and bleed- for Locally Delivered Antimicrobials for 60% ing on probing reductions over scaling and root Periodontal Therapy planing alone at 6 months after therapy5’ Reaches site of disease (base of pocket) Among the tested putative periodontal Achieves adequate drug concentrations pathogens, no change in antibiotic resistance to Maintains sufficient duration of treatment tetracycline has been found following tetracycline Effective against periodontal pathogens fiber the rap^.^' Disadvantages of the fiber include Clinically effective as an adjunctive therapy the length of time required for placement (I 0 min- Safe for teeth and soft tissues utes or more per tooth), the considerable learning Minimal adverse side effects curve required to gain proficiency at placement, No bacterial resistance and the need for a second appointment 10 days Easy application after placement for removal of the fiber. Also, Biodegradable placement of fibers around 12 or more teeth has resulted in oral candidiasis. Another study suggested that rinsing with the 32 to 64 pg/mL required to inhibit the growth 0.12% chlorhexidine (Peridexa, Zila Pharmaceuti- of pathogens isolated from periodontal pocket^.^'.^^ cals, Inc., Phoenix, AZ) following fiber placement In contrast, crevicular fluid concentrations of only had a synergistic effect, enhancing the reduction of 4 to 8 pg/mL are reported following systemic tetra- bacterial pathogen^.^' It is possible that at-home cycline administration, 250 mg four times daily for irrigation with an antimicrobial agent following 10 days (total oral dose, 10 g).53Thus, controlled fiber removal could prolong this synergistic effect. site-specific tetracycline delivery can achieve an Evaluation of the effect of tetracycline fibers on antibacterial effect at approximately one-thou- root surfaces, using fluorescent light and scanning sandth of the dose administered systemically. electron rnicro~copy,~~showed superficial penetra- Studies demonstrate that the tetracycline tion of tetracycline, with minor penetration into fibers, applied with or without scaling and root the dental tubules, and a few areas of demineralized planing, reduce probing depth, bleeding on prob- root surface. Scanning electron microscopic obser- ing, and periodontal pathogens and provide gains vations made in this study also revealed reductions in clinical attachment level. Such effects are signif- in the subgingival microbial flora on the root sur- icantly better than those attained with scaling and faces of teeth treated with the fibers versus the con- root planing alone or with placebo fibers. In a 2- trol specimens. Many of the residual microbes month study, compared with scaling and root observed in the fiber-treated teeth appeared nonvi- planing, the fibers used alone have provided over a able, in contrast to the residual microbes found on 60% greater improvement in probing depth and the root-planed and control specimens. clinical attachment level than scaling alone.54The fibers used in conjunction with scaling and root Subgingival Delivery of Doxycycline planing have also provided a statistically significant (At ri d ox@)

Atridoxa (manufactured by Atrix Laboratories, Fort Collins, CO; licensed for marketing by Block Drug, Inc., Jersey City, NJ) is a gel system that incorporates the antibiotic doxycycline (I 0%) in a syringeable gel system (Figure 15-4). A 9-month multicenter study in 180 patients was designed to study the effects of subgingivally placed doxycycline compared with subgingival placement of the vehicle and a herbal agent (sanguinaria). Patients with initial probing depth of > 5 mm in selected sites were included in this study.59 The patients were instructed in oral hygiene and randomly assigned to one of three groups: vehicle control, 5% sanguinaria in the vehicle control, and Figure 15-3. Actisit@ fiber being placed. 10% doxycycline in the vehicle control. No scaling Pharmacotherapy 25 5 or root planing was performed in any of the groups, Wayne, NJ, and SunStar, Osaka, Japan) is available and there was no untreated group. Therefore, the in a number of countries for use as an adjunct to study's objective was to evaluate the effect of the subgingival dkbridement. This system is a syringe- various agents, compared with the vehicle when able gel suspension delivery formulation. used as a monotherapy. In a four-center, double-blind, randomized Treatment with doxycycline was more effective trial, patients with periodontal pockets at least 5 than the other treatments at all time periods with mm deep were selected, and either 2% minocy- the exception of the 3-month clinical attachment cline gel or vehicle was applied once every 2 weeks level value. Also, on evaluation of the effect based four times. 62 Treatment followed initial su bgingival on initial probing depth, the differential effect in dkbridement in both treatment groups. Microbio- the doxycycline group in comparison with the logic assessments were made at baseline and at other two groups was greater as pretreatment prob- weeks 2, 4, 6, and 12, with clinical assessments at ing depth increased. For the doxycycline group, the baseline and weeks 4 and 12. A total of 103 reduction in clinical attachment level at 9 months patients were treated and 90 were evaluable for showed a gain of 0.4 mm compared with vehicle efficacy, of which 48 had been treated with control, the reduction in probing depth was 0.6 minocycline gel and 42 with vehicle. mm greater than vehicle control, and the reduction A total of 343 teeth (976 sites) were included of bleeding on probing was 0.2 units greater than in the minocycline group with 299 teeth (810 vehicle control. The differences were small but sites) in the control group. The microbiologic they were statistically significant. Although resis- analysis in this study focused on three relevant tance was not evaluated in this study, the local plaque species: I! gingivulis, I! intermediu and A. application of doxycycline has previously been uctinomycetem co mituns. reported to have shown transient increases in resis- Reductions in I! gingivulis and I! intermediu at tance in oral microbes and no overgrowth of for- weeks 2, 4, 6, and 12 and at weeks 6 and 12 for eign pathogens." A. uctinomycetemco mituns were statistically signifi- Data from two multicenter clinical trials have cant. These results demonstrated the advantages of also been reported, each studying 41 I patients supplementing standard subgingival dkbridement with moderate to severe periodontitis.'l At base- with minocycline gel application. line, patients were randomized to one of four treat- The three primary clinical efficacy variables in ment groups: doxycycline, vehicle control, oral this study were probing depth, clinical attachment hygiene only, and scaling and root planing. Sites level, and bleeding index. There was a trend with probing depth 2 5 mm that bled on probing toward clinical improvement in both treatment were treated at baseline and then again with the groups for all three measures, and the reduction in same treatment at 4 months. Clinical assessments probing depth was significantly greater with were made at months 1, 2, 4, 5, 6, 8, and 9 by minocycline gel. measuring clinical attachment level, probing When sites with probing depth of at least 7 mm depth, and bleeding on probing. All treatment and significant bleeding at baseline were consid- groups in both studies showed clinical improve- ered, the improvements were greater than with 5 ments from baseline over the 9-month period. The results for all parameters measured were significantly better in the doxycycline group compared with the vehicle-control and oral-hygiene-only groups. Compared with scaling and root planing, the effects of doxycycline on clinical attachment level gain and probing depth reduction were equivalent. This product has been approved by the FDA for sale in the United States.

Subgingival Delivery System for Mi nocycli ne (Dentamycin@,Perio C line@)

A subgingival delivery system of 2% (w/w) minocycline hydrochloride (Dentamycina, Perio Clinem';Cyanamid International, Lederle Division, Figure 15-4. Atridox@being placed into a pocket. 25 6 Periodontal Medicine mm pockets. The improvements with minocycline were effective in reducing probing depth and bleed- were statistically significantly better than the vehi- ing on probing over the 6-month period. At the end cle-control group. of the follow-up period, the mean reduction in In a 3-month study, 2% minocycline was also probing depth was 1.3 mm after gel treatment and evaluated in 30 patients.63 Patients received oral I .5 mm after subgingival scaling. Bleeding on prob- hygiene education and root planing with local anes- ing was reduced by 35% and 42%, respectively. No thesia. Active or placebo gel was placed subgingi- significant differences between the two treatments vally at planed sites in each subject according to a were detected. Dark-field microscopy showed a shift double-blind protocol, immediately after instru- toward a seemingly more healthy microflora for mentation and 2 and 4 weeks later. A periodontal both treatment modalities; this effect persisted examination was made with a constant force probe throughout the 6-month period. before instrumentation and 6 and 12 weeks later. A large multicenter study of 206 subjects Two subjects failed to complete the study; their investigated two applications of this gel in two ran- pairs were therefore not included in the analysis. domly selected quadrants versus two quadrants of Results were tested with an analysis of covariance. scaling.67As in the study described above, probing The differences between the groups in mean prob- depths were reduced by I .2 mm in the gel and I .5 ing depth did not reach statistical significance at mm in the scaling group. At 6 months, the differ- any visit, but mean clinical attachment levels were ences between treatments were statistically but not different in favor of the minocycline group (p c .OS) clinically significant. Also, bleeding on probing at both reassessments. There was also a difference in was reduced by 88% in both treatment groups. the number of sites that bled after deep probing at 12 weeks, favoring the minocycline group (p c .OS). This trial showed that adjunctive minocycline gel LOCAL DELIVERY OF provided a more advantageous outcome for non- AN ANTISEPTIC AGENT surgical periodontal treatment in terms of clinical attachment level and bleeding on probing. This Chlorhexidine Delivery System product is not available in the United States. (Pe rioC h i p") A topical medication (ElyzoP; Dumex, Copenhagen, Denmark) containing an oil-based The PerioChip@(manuhctured by Perio Products metronidazole 25% dental gel (glyceryl mono- Ltd., Jerusalem, Israel; distributed by Astra USA, oleate and sesame oil) has been tested in a number Inc., Westborough, MA) is a small chip (4.0 x 5.0 x of studies.64 It is applied in viscous consistency to 0.35 mm) composed of a biodegradable hydrolyzed the pocket, where it is liquidized by the body heat gelatin matrix, cross-linked with glutaraldehyde and and then on contact with water hardens again, also containing glycerin and water, which has been forming crystals. As a precursor, the preparation incorporated into a chip containing 2.5 mg contains metronidazole-benzoate, which is con- chlorhexidine gluconate (Figure 15-5). It is rounded verted into the active substance by esterases in the at one end and inserts easily, in less than a minute, crevicular fluid. Two 25% gel applications at a 1- into periodontal pockets that are 5 mm or greater in week interval have been used in clinical studies.65 depth. The PerioChip@releases chlorhexidine and Studies of the metronidazole gel have shown it maintains drug concentrations in the gingival crevic- to be equivalent to scaling and root planing but have ular fluid greater than 100 pg/mL for at least 7 not shown adjunctive benefits in conjunction with concentrations well above the tolerance of scaling and root planing. For example, a recent 6- most oral bacteria.69 Because the PerioChip@biode- month study in 30 patients showed the following grades in 7 to 10 days, a second appointment for results." The treatment consisted of two applica- removal is not needed. tions of the dental gel in two randomly selected Two multicenter, randomized, double-blind, quadrants (on days O and 7)as well as simultaneous parallel-group, controlled clinical trials of the Perio- subgingival scaling of the remaining quadrants. Oral Chip@were conducted in the United States with a hygiene instructions were given on day 21. The total of 447 patients in 10 cent er^.^' In these stud- average probing depth and the average frequency of ies, patients received a supragingival prophylaxis bleeding on probing were calculated for all sites with for up to I hour, followed by scaling and root plan- an initial probing depth of 5 mm or more; this was ing for I hour. Chips were placed in target sites continued at each examination, using the same sites. with a probing depth 5 to 8 mm at baseline that The statistical analysis showed that both treatments bled on probing and again at 3 and 6 months if the Pharmacotherapy 257 probing depth remained 5 mm or greater. Sites in quadrant. Clinical measurements, including prob- control-group subjects received either a placebo ing depth, clinical attachment level, and bleeding chip (inactive) plus scaling and root planing or on probing, as well as gingivitis, plaque, and stain- scaling and root planing alone. Sites in test-group ing indices, were recorded at baseline and at I, 3, subjects received either a chlorhexidine chip and 6 months. At the 3-month visit, a full-mouth (active) plus scaling and root planing or scaling supragingival prophylaxis was undertaken accord- and root planing alone (to maintain the study ing to clinical needs, and a chlorhexidine chip was blind). Examinations were performed at baseline inserted into each test pocket with a remaining and at 3, 6, and 9 months. depth of 5 to 8 mm. At 9 months, significant decreases were The average probing depth reduction in the observed in probing depth from baseline favoring scaling and root planing plus PerioChipa-treated the active chip compared with controls (chlorhexi- sites was significantly greater than in the sites dine chip plus scaling and root planing, -0.95 k receiving scaling and root planing alone, at both 3 0.05 mm; placebo chip plus scaling and root plan- and 6 months, with a mean difference of 0.42 mm ing, -0.69 k 0.05 mm [p =.001]; scaling and root (p < .Ol) at 6 months. Improvement in clinical planing alone -0.65 k 0.05 mm [p =.OOOOl]). The attachment levels at the treated sites was greater proportion of pocket sites with a probing depth than at sites that received scaling and root planing reduction of 2 mm or more was increased in the alone although the difference was statistically sig- chlorhexidine chip group (30%), compared with nificant at the 6th-month visit only (p < .OS). An scaling and root planing alone (16%), a difference analysis of patients with initial probing depths of 7 which was statistically significant on a per-patient to 8 mm (n = 56) revealed an even greater basis (p < .OOOl). Improvements favoring the improvement in both probing depth and attach- chlorhexidine chip compared with controls were ment level in those pockets adjunctively treated also observed for clinical attachment levels at 9 with PerioChipa compared with scaling and root months, improvements which were significant planing alone, at both 3 and 6 months, suggesting when the data were pooled (p < .OS). Bleeding on that the deeper the initial probing depth, the probing was reduced in the active chip group com- greater is the clinical improvement. The mean dif- pared with both controls, differences which were ferences between test and control sites at 6 months significant in one of the two studies (p < .OS) and for these deeper pockets were 0.71 mm and 0.56 also when the data were pooled (p =.012). These mm for probing depth and clinical attachment lev- data indicate that the biodegradable chlorhexidine els, respectively. chip, when used as an adjunct to scaling and root Relative to bleeding on probing, the scaling planing, significantly reduces probing depth and and root planing plus PerioChipa sites showed con- maintains clinical attachment levels when com- sistently less bleeding on probing than control sites pared with scaling and root planing alone. with a significant difference (p < .OS) between the Another study was reported that evaluated the treatment groups occurring at the 3-month exami- results of a 6-month clinical trial using the Perio- nation. The test quadrants showed a significant Chipa." The study was a randomized, blinded, decrease (p < .OS) in gingival index when compared controlled, split-mouth, multicenter study con- with control quadrants at 3 and 6 months. ducted with I18 patients in three study centers outside the United States. Patients, aged 30 to 65 years, with moderate periodontitis and in good general health were studied. Patients received a full-mouth scaling and root planing. The subgingival instrumentation was performed after baseline measurements were recorded. The two quadrants of the maxillary arch were randomized to the two treatment arms-scaling and root planing alone (control quadrant) or scaling and root planing plus PerioChipa (test quadrant). All remaining maxillary pockets with a probing depth between 5 and 8 mm at the baseline visit were entered into the study. The PerioChipa was inserted into each pocket measuring 5 to 8 mm in the designated Figure 15-5. PerioChip@ compared to tip of a pencil. 2 5 8 Periodontal Medicine

No signs of staining were noted in any of the antibacterial effects since the dose of 20 mg twice above three studies as a result of the chlorhexidine daily is too low to affect bacteria. As a result, resis- chip treatment as measured by a stain index. tance to this medication cannot develop. Adverse effects were minimal with a few patients Four double-blind clinical multicenter studies who complained of slight pain and swelling in the in over 650 patients have demonstrated that Perio- first 24 hours after chip placement. staP improves the effectiveness of professional periodontal care and slows the progression of the disease process. HOST MODULATION The results of the first three studies showed that PeriostaP resulted in approximately a 50% The US Food and Drug Administration recently improvement in clinical attachment level (CAL) in granted marketing approval for PeriostaP for the pockets with probing depths of 4 to 6 mm and a adjunctive treatment of periodontitis. PeriostaP, 34% improvement in pockets with probing depths available as a 20 mg capsule of doxycycline hyclate, 2 7 mm. It was also noted that attachment loss was is prescribed for use by patients twice daily. The prevented in sites with normal probing depths (0 to mechanism of action is by suppression of the activ- 3 mm) while the placebo groups lost 0.13 mm at ity of collagenase, particularly that produced by 12 months (p = .05).71>72 polymorphonuclear leukocytes. The role of colla- The improvement in pocket depth generally genase in the pathogenesis of periodontal disease is paralleled the improvement in CAL after treatment illustrated in Figure 15-6. Although this drug is in for 12 months. Tooth sites with a baseline pocket the antibiotic family, it does not produce any probing depth (PPD) of 4 to 6 mm improved by

Figure 15-6. Collagenase and the pathogenesis of periodontal disease. Pharmacotherapy 25 9 over 50%. Sites with a baseline probing depth 2 7 receiving Periostat@ and SRP compared with mm, improved by Periostat@by 45%. patients receiving SRP and placebo (p < .OOl). A mean reduction of 0.96 mm was observed after 9 lncidences of Rapid Progression months of treatment with Periostat@whereas treatment with SRP and placebo resulted in a mean Attachment loss of 3 mm or more occurring dur- reduction of 0.71 mm (p < .OOl) representing a ing the first 6 months of the three 12-month stud- benefit of over 30%. Likewise, PPD at more severe ies that required interventions by scaling and root sites (PPD 2 7 mm at baseline) improved signifi- planing (SRP) occurred in 52 tooth sites in a total cantly after 3 (p < .OOl), 6 (p < .OOl), and 9 months of 9 patients receiving placebo versus 14 tooth sites (p < .OI) of treatment with Periostat@ compared in a total of 9 patients in the l?eriostat@-treatment with SRP and placebo treatment. A mean reduction group. Thus, there was a 73% reduction in the of 1.68 mm was seen after 9 months of treatment incidence of rapid progression of periodontitis with Periostat@whereas SRP and placebo treatment associated with Periostat@ and scaling treatment. resulted in a mean reduction of 1.21 mm (p < .OI), Furthermore, in patients with incidences of rapid representing a benefit of almost 40%. progression who received SRP treatment at 6 Results of safety studies showed the use of months, CAL improved by 2.16 mm after treatment Periostat@ 20 mg bid, either with or without with Periostat@plus SRP for an additional 6 months. mechanical therapy (SRP), did not exert an In comparison, in patients who received placebo plus antimicrobial effect on the periodontal microflora SRP at 6 months, CAL improved by only 0.78 mm and did not result in a detrimental shift in the nor- after an additional 6 months (p = .005). mal flora and the colonization or overgrowth of the periodontal pocket by bacteria resistant to doxycy- Adjunct to Scaling and Root Planing cline, tetracycline, minocycline, amoxicillin, erythromycin, or clindamycin. In addition, there was A fourth study was conducted over a %month no evidence of any tendency toward the acquisi- period in 190 patients who had at least two sites in tion of multiantibiotic re~istance.~*>~~ each of two quadrants with CAL and PPD Although no product is available at this time, between 5 mm and 9 mm.73The study design was host modulation by inhibition of prostaglandins similar to the first three studies with the exception may be of value in the hture treatment of peri- that Periostat@was evaluated as an adjunct to sub- odontal disease. The drugs of interest in this catego- gingival SRP. All data were analyzed by appropriate ry are the nonsteroidal anti-inflammatory agents.76 statistics as in the previous studies but also included a per-patient analysis of variance (ANOVA). Agents for Oral Fungal Infections The results of this study showed that there was a consistent improvement of CAL of approximately Oral fungal infections can be expected to increase 20% (1.03 mm versus 0.86) in patients with a with an aging population; with increasing age, Cundidd ulbicuns, the agent responsible for these probing depth of 4 to 6 mm (p < .OS) and approximately 30% (1.55 vs 1.17) in those with probing infections, flourishes due to a decrease in salivary flow that may be physiologic, psychological, or depths of 2 7 mm (p < .OS). It is also noteworthy medication induced. that sites with a probing depth of 4 to 6 mm at baseline showed statistically significant improve- Fungal infections may occur as a side effect of ments in CAL after 3, 6, and 9 months of treat- antibiotic therapy or during chronic medication with tranquilizers, sedatives, and anticholinergic ment with Periostat@and SRP (p < .OS) compared with treatment with SRP and placebo. drugs. If these infections occur in patients wearing hll or partial dentures, therapy includes not only Similarly, for sites with a probing depth 2 7 mm medicating the patients but also having them soak at baseline, treatment with Periostat@significantly augmented the efficacy of SRP compared with SRP their prosthesis in the medication for the duration and placebo. Statistically significant improvements of the oral therapy. In some cases, the acrylic por- in CAL with Periostat@were observed after 3 months tions of the appliances must be remade since fungi may be present in its pores. Some common anti- (p < .Ol), and after 6 and 9 months (p < .OS). Reductions in PPD were similar to those seen hngal agents are reviewed below. for gains in CAL. For sites with a baseline PPD of Nystatin 4 to 6 mm, a statistically significant reduction was Nystatin (eg, Mycostatin) was discovered in 1954 demonstrated after 3, 6, and 9 months in patients and is an excellent antibiotic for the treatment of 260 Periodontal Medicine fungal infections. It is most useful in the treatment Dosage and Dosage Forms. It is available in of both oral and vaginal moniliasis (thrush, can- tablet form in 200 mg doses and also as an oint- didiasis). This drug binds to the covering mem- ment. For oral candidiasis, the usual dose is 200 brane of susceptible fungi, altering the permeabili- mg daily for I O days. ty of the cell membrane and leading to cell death. It is both fungistatic and fungicidal. Miconazole (Monistat) Metabolism. This drug can be given orally This drug is classified as an imidazole and has the but is poorly absorbed from the gastrointestinal same mechanism of action as ketoconazole. Howev- tract, and large amounts are found in feces. Also, er, it is used mainly as an antihngal vaginal prepa- it is not absorbed from the skin and mucous ration and as a skin medication applied topically. membranes and is therefore not given parenteral- Its main side effects are irritation, burning, or ly. It exerts its main effect via the topical route in maceration. It is considered safe for use in preg- most cases. nancy because absorption is less than I% when Adverse Effects. Adverse effects are rare and applied topically. Studies relative to its use in den- include nausea, vomiting, and diarrhea following tistry are minimal. oral administration. However, no adverse effects have been reported via the topical route. Hypersensitivity Clotrimazole (Lotrimin, Mycelex) reactions have not occurred, nor has resistance. It This drug is chemically similar to miconazole. It is also appears to be safe for use during pregnancy. available as a topical and systemic agent and is used Dosage and Dosage Forms. This antibiotic is more widely in Europe than in this country. Since available as a tablet or liquid for oral or vaginal use it is more toxic than the other antifungal agents, it and as an ointment and cream for topical and vagi- should be used when the others have not been suc- nal use. Since it is not absorbed when swallowed, it cessful topically. has a topical effect in the gastrointestinal tract. For Adverse Effects. Its main side effects after oral candidiasis, a rinse of 400,000 to 600,000 topical use are the same as those of miconazole. units daily is usually effective. For vaginal condi- Also, after topical or systemic use, it may cause hal- tions, a dose of 100,000 to 200,000 units daily for lucinations, gastrointestinal disturbances, and 2 weeks is indicated. abnormal liver function. Since abnormal liver hnction has occurred in 15% of patients using the Ketoconazole troche, periodic liver function tests are indicated if Ketoconazole (Nizoral) is classified as an imida- therapy exceeds 2 weeks. zole, and its oral administration is approved for the Dosage and Dosage Forms. A 10-mg troche is treatment of systemic hngal infections. It is also available for oral topical use every 3 hours. Studies useful for the treatment of oral and vaginal can- have shown that if the troche is allowed to dissolve didiasis (thrush). in the mouth for 30 minutes, therapeutic levels can Mechanism of Action. Ketoconazole inter- be found in saliva for up to 3 hours. Apparently, feres with the synthesis of chemicals needed to this is due to release of the drug from sites in the form the plasma membrane of fungi, resulting in oral mucosa to which it binds. Since the amount disorganization of the membrane. absorbed systemically by this route has not been Metabolism. Its absorption from the gas- determined, signs of adverse reactions associated trointestinal tract is better than that of nystatin. It with systemic administration must be monitored. is metabolized in the liver, and only small amounts Its safety in pregnancy has not been determined. are found in urine and feces. Since data for its use in pregnancy are lacking, it is not recommended Mouthrinses and Dentifrices for pregnant women. The presence of the drug in Mouthrinses and dentifrices have been shown to breast milk has been recognized. be of value mainly in the reduction of plaque and Adverse Effects. The most common adverse gingivitis. Some of these agents have been shown effects are nausea and pruritus. Headache, dizzi- to have a significant effect in the reduction of gin- ness, gastrointestinal problems, nervousness, and givitis, and they have received the American Den- liver dysfunction occur less often. Gynecomastia tal Association (ADA) Seal of Acceptance. has been reported in 10% of men treated with Listerine Antiseptic@, Cool Mint Listerine@, ketoconazole. Since this medication has some liver FreshBurst Listerine@, chlorhexidine gluconate toxicity, if it is used for more than 2 weeks, liver (Peridex@),and two generic equivalents of Lister- function tests should be performed. ine Antiseptic@and triclosan have been granted the Pharmacotherapy 26 1

ADA Seal of Acceptance. These antimicrobial its retention (substantivity) onto hard and soft oral mouthrinses provide a standard of comparison for surfaces. This formula, found in Colgate Total@,has all other available products. been cleared by the U.S. Food and Drug Adminis- The phenolic compound Listerine@ showed a tration (FDA) for sale in the United States and is reduction of 20 to 34% in plaque and a reduction of also ADA accepted. Formulas without the co-poly- 28 to 44% in gingivitis in two 6-month studies and mer are not cleared for sale by the FDA. Therefore, one 9-month The bis-biguanide chlorhex- formulations by Unilever and Procter & Gamble are idine (0.12%) has also proven effective in the reduc- only available outside the United States. tion of both plaque and gingivitis.80Chlorhexidine, The clearance given by the FDA was based on however, has been associated with staining of teeth, data from two pivotal studies conducted in approx- altered taste, and increased levels of calculus forma- imately 600 patients. Both studies were conducted tion and is available by prescription only. A hrther at independent research centers and followed a sim- consideration is that a patient should rinse and/or ilar Both these long-term clinical irrigate with this preparation at least 30 minutes after studies provided statistically significant differences brushing because of a decrease in efficacy due to an (p c .Ol) in gingivitis in favor of the 0.3% triclosan interaction with the positively charged sodium lauryl and 2.0% PVM/MAO co-polymer dentifrice (in a sulfate, the detergent component of dentifrices.81 sodium fluoride/silica base). The reduction in gin- Similarly, the negatively charged fluoride ion may givitis averaged 24.3%. The Gingivitis Severity interact with chlorhexidine and also greatly reduce its Index showed an average reduction of 60.6%. efficacy. This cationic nature, however, is the basis for These two pivotal studies provided statistically sig- the substantivity of chlorhexidine. This property nificant differences (p c .OI) in supragingival allows chlorhexidine to bind to negatively charged plaque accumulation in favor of the 0.3% triclosan ions and proteins of the mucous membranes and and 2.0% PVM/MA co-polymer dentifrice (in a teeth, and to maintain that contact for some time.82 0.243% sodium fluoride/silica base) as compared There are several other antimicrobial with a placebo dentifrice (in a 0.243% sodium flu- mouthrinses available that have not yet received oride/silica base). The Quigley-Hein Plaque Index the ADA Seal of Acceptance. The quaternary efficacy results showed an average efficacy score of ammonium compounds such as CepacoP, Scope@, 15%. The Plaque Severity Index results averaged a and New Viadent@ have some degree of substan- 19% reduction. tivity but less than that of ~hlorhexidine.~~ Seven other studies showed a reduction in gin- Sanguinaria, an herbal extract, has not been givitis for the Colgate Total@formulation, ranging shown to produce significant reductions in plaque from 19.7 to 81.5%, with an average reduction of and gingivitis in 6-month studies. The recent addi- 25.3%. The reduction in Gingivitis Severity was tion of zinc chloride to the dentifrice and 56%. Reductions in plaque in these studies ranged mouthrinse formulations, however, has helped to from 12.7 to 58.9%, with an average reduction of produce a significant reduction in both plaque and 30.2%. The average reduction in Plaque Severity gingiviti~.~~In the United States, the sanguinaria was 54.9%.95-101 products are available as original formula in In all the studies carried out (in a total of over Viadent@ mouthrinse and toothpaste. To date, 1,400 patients), no extrinsic staining was observed, however, the ADA Seal of Acceptance has not been there were no serious adverse effects associated awarded to the Viadent@products. with the triclosan containing dentifrice (Colgate Plax@, a popular prebrushing rinse, has not Total@), and there were no complaints of taste been shown to reduce plaque and gingivitis exten- alterations or unpleasant taste. Additionally, reduc- sively enough to receive the ADA Seal of Accep- tions in calculus averaging 35% have been report- tance. Clinical studies regarding the efficacy of ed in studies with durations ranging between 3 and Plax@have yielded equivocal res~lts.~~-~~ 6 months.lo2 A recent study evaluated the effect of a denti- Triclo San frice containing triclosan/co-polymer on the Triclosan (2,4,4'-Trichloro-2' - hydroxydiphenyl microflora and clinical signs characteristic of recur- ether) is a new antiplaque/antigingivitis agent avail- rent adult periodontiti~."~Sixty patients (mean able in dentifrices marketed throughout the world. age of 55 years) previously treated for advanced The addition of a co-polymer (polyvinylmethyl- periodontal disease were included in this 36- ether maleic acid [PVM/MA]) has been shown to month study. During a 3- to 5-year period follow- improve the effectiveness of triclosan by enhancing ing active therapy, the patients had been enrolled 262 Periodontal Medicine in a supportive periodontal therapy program and deep pockets increused with an average of 2%. For were on a 3-month recall interval. All patients who CAL, the mean value increased between the base- were enrolled had, at various intervals during the line and the 36th-month. In the test group, the preceding 3 to 5 years, exhibited signs of recurrent mean additional CAL loss amounted to 0. I I mm periodontitis, such as deepened pockets and addi- (12 months), 0.14 mm (24 months), and 0.18 tional loss of attachment (> 2 mm) and alveolar mm (36 months). The corresponding additional bone. All subjects presented with moderate gin- loss in the control group was 0.22 mm (12 givitis and exhibited lesions characterized by prob- months), 0.35 mm (24 months), and 0.52 mm ing pocket depth of > 5 mm in eight sites (at least (36 months). The additional loss in probing two in each quadrant), and loss of interproximal attachment that occurred between baseline and alveolar bone (> 40% of original height), as seen in the 24th- and 36th-month examinations was sig- radiographs. Standardized radiographs were taken nificantly higher in the control group than in the at baseline and 36 months. In a subset of 40 test group (p c .05 andp c .O1, respectively). In all patients, the deepest pocket site in each quadrant three intervals (0 to 12 months; 12 to 24 months; (ie, four sites per subject) was selected, and samples 24 to 36 months), the test group exhibited fewer of the subgingival bacteria were taken. The test sites with additional attachment loss than did the group included 30 individuals who used a denti- control group. Thus, between baseline and the frice containing triclosan/co-polymer/fluoride, 12th month, in the test group, there were 48 loser that is, 0.3% triclosan, 2% co-polymer, and 1100 sites compared with 67 sites in the controls. The ppm F from 0.243% sodium fluoride. The control corresponding numbers for period 2 (12 to 24 group also included 30 subjects who used a denti- months) were 37 and 59, and for period 3 (24 to frice identical to the one used in the test group but 36 months) were 72 and 197. without the triclosan/co-polymer content. No pro- The microflora analysis showed that the total fessional subgingival therapy was delivered viable count (TVC) of bacteria decreased in both between the baseline and the 36th-month exami- groups between the baseline examination and the nations. The subjects were recalled every 3 months. re-examination after 36 months. In the control Re-examinations were performed after 6, 12, 24, group, the TVC value was reduced from 15 x I O6 and 36 months of the trial. to 12 x 106 (not significant). In the test group, The clinical results of this study showed that for the corresponding reduction was more pro- bleeding on probing (BOP), in both groups between nounced (from 17 x 106 to 9 x 106) and statisti- the baseline and the 36th-month examination, there cally significant (p c .OS). It was also noted that was a small but insignificant decrease in the number for periodontal pathogens, the reductions were of BOP-positive sites (test group 4% and control greater in the triclosan/co-polymer group than in group 8%). For probing depth, in the test group, the the control group. PPD value gradually decreused between examina- The results of this study suggest that use of a tions. The mean reductions in PPD between baseline triclosan/co-polymer dentifrice reduced the fre- and the 6th-, 12th-, 24th-, and 36th-month exami- quency of deep periodontal pockets and the num- nations were 0.02 mm, 0.05 mm, 0.03 mm, and ber of sites that exhibited additional probing 0.14 mm, respectively. In the control group, the attachment and bone loss. This finding may be mean PPD gradually increused, and the correspond- related to the fact that a number of studies have ing mean PPD increases at the 6th-, 12th-, 24th-, shown that supragingival plaque reduction has a and 36th-month examinations were 0.03 mm, 0.10 strong influence on the quantity and quality of the mm, 0.17 mm, and 0.19 mm, respectively. The dif- subgingival microflora. lo4~lo5It has been shown ference in PPD change (mean 0.33 mm) between that thorough removal of supragingival plaque the test and control groups during the 36th-month results in a reduction in the TVC of subgingival interval was statistically significant (p c .OI). It was microflora and in the number of periodontal also noted that in the test group the frequency of sites pathogens in shallow (c 3 mm) as well as moder- with shallow pockets (c 3 mm) increused between ately deep pockets (4 to 6 mm).106J07 baseline and 36 months (from 57 to 61%), the Triclosan is marketed in Europe as a mouth- medium deep pockets (4 to 5 mm) decreused horn 3 I rinse (Plax@)as well. The European formula differs to 27% while the percentage of sites with deep pock- from the U.S. formula because of the inclusion of ets (6 mm) remained unchanged (12%). In the con- triclosan. This triclosan-containing mouthrinse trol group, the frequency of shallow pockets has been shown to significantly reduce plaque and decreused with an average of 2% while sites with gingivitis with minimal side effects. Pharmacotherapy 263

EFFECTS OF MEDICATIONS troches, and oral solutions and are kept in the mouth for extended periods, they may place patients The Periodo n t iu m at a significant risk for caries. Antacid tablets also contain large amounts of sugar and, in the older Medications can have both beneficial and adverse adult, may result in increased caries of root surfaces. effects on periodontal tissues. Some of these effects The readily fermentable carbohydrates in thick liq- are discussed below. uid preparations may add significantly to alteration In terms of their relationship to tissues, medica- of plaque pH and composition. Although the risk of tions should be categorized on the basis of the fol- caries has been shown to increase with the use of lowing: alteration of methods in behavior and oral these medications,lo9 their effects on the periodon- hygiene, alteration of plaque composition, alteration tal pathogens has not been evaluated. of salivary pH, effect on salivary flow, effect on gin- Sugars, metabolized by bacteria to acid end- gival tissues, effect on alveolar bone, and effect on products, lower salivary pH as well as the pH with- gingival crevicular fluid. Some effects of medications in an adherent bacteria-rich plaque that is relative- may increase the risk of dental diseases while some ly unavailable to salivary buffering. This lowered others may actually decrease the risk. pH near the tooth surface can cause ionic dissolu- tion from the hydroxyapatite crystals, increase sur- Behavioral Alteration of Oral Hygiene Practice face roughness, and enhance the plaque’s ability to Patients who are on medications that have a be more adherent and to initiate caries. It has been depressant effect on the central nervous system, shown that human plaque pH decreased signifi- such as sedatives, tranquilizers, narcotic analgesics, cantly after administration of liquid iron supple- antimetabolites, and antihypertensives, may mentsl10 and cough syrups.”’ become careless about their oral hygiene practices; A controlled clinical study of patients on chron- therefore, they have a tendency toward increased ic doses of medication reported a significant increase plaque formation. The basis for the change in a in both dental caries and gingivitis in a population patient’s attitude or behavior must be understood, of children taking liquid or chewable medications and an oral hygiene program must be designed on continuously for a minimum of 6 months.l12 the basis of these changes. The alteration of plaque composition and Two of the top 20 prescription drugs in the plaque retention to tooth surfaces may have peri- United States act directly as mood-altering drugs; odontal implications that must be considered in alprazolam (Xanax) and fluoxetine (Prozac) may patients with excess plaque. make patients more amenable to improving their oral hygiene.lo8However, since drowsiness is a side Salivary Flow effect of these medications, motivation may still be a problem. Two other drugs that alter moods as a Adequate salivary flow is critical to the maintenance side effect of their antihypertensive action, of the health of oral soft tissues.l13 It has been sug- enalapril maleate (Vasotec) and captopril (Capoten), gested that “mouthbreathers” have modified plaque may make patients less amenable to following oral accumulations and associated soft-tissue changes. A hygiene procedures. number of medications that decrease salivary flow (xerostomia) mimic mouthbreathing. l4 For exam- Plaque Composition and Salivary pH ple, a study at our research center evaluated the Plaque composition and pH as well as salivary pH effect of anticholinergic agents on plaque and oral may be altered by the dosage of medications. Over- health in patients who had gastrointestinal ulcers the-counter (OTC) medications and liquid pharma- and were receiving such medications.l15 It was ceutical preparations are used daily by some people. found that these patients had a tendency to accu- Although the active ingredients in these medicines mulate more plaque after dental prophylaxis and are sometimes necessary for improvement or main- oral hygiene instructions and had a slower rate of tenance of health, some inactive ingredients pose resolution of gingivitis following scaling and root hidden dangers. For example, many liquid or chew- planing. In this short-term study, it was found that able pharmaceutical preparations for children are a statistically significant reduction occurred in the made palatable by the addition of sucrose, glucose, control patients in all clinical measures of gingival or fructose as sweeteners. Sugars are the sweetening health other than pocket depth, but no significant agents in orally administered antifungal prepara- reductions were observed in the medicated patients. tions. Since these medications come as lozenges, Agents that produce xerostomia include antihyper- 264 Periodontal Medicine tensives, narcotic analgesics, some tranquilizers, givitis, it may result in a decreased risk factor for quinolones, antimetabolites, antihistamines, seda- bone loss found in periodontitis. tives, and even vitamin D in large doses.'" In addi- Gingival enlargement has also been associated tion to the effect of xerostomia on oral soft tissues, with a number of calcium channel blockers, root surface caries may be more prevalent in those including nifedipine (Procardia) , verapamil taking such medications. '17 (Calan), diltiazem (Cardizem), and isradipine Long-term tranquilizing agents, especially the (DynaCirc). Gingival enlargement is seen in 5 to phenothiazines and meprobamate, have been report- 20% of patients taking these medications. ed to produce xerostomia and, in some situations, an A proposed mechanism of action relates overgrowth of C ulbicuns in the oral rnicroflora.'l8 inflammatory factors within the gingival tissue to Patients on long-term phenothiazines have also gingival enlargement. It has been shown that the shown a tendency to developing less calculus. histology in a nifedipine patient resembled an inflammatory-type hyperplasia similar to that Gingival Tissue described for phenytoin, in which numerous inflammatory cells replaced collagen in connective A number of medications may cause gingival tissue.'26 This paper supports the concept that enlargement. Phenytoin (Dilantin) was the first alteration of the intracellular calcium level in gin- drug reported to produce this effect with the inci- gival cells by nifedipine in combination with dence ranging between 3 and 62% (mean 50%). A appropriate local inflammatory factors is impor- number of investigations have suggested a causal tant in eliciting gingival enlargement. relationship between inflammation and gingival It has also been shown that if nifedipine could hyperplasia, the implication being that this hyper- not be discontinued, gingival enlargement did not plasia could be minimized or prevented if gingival recur after gingivectomy when thorough plaque inflammation were eliminated.' l9>l2O It is possible control was carried out, again supporting earlier that, if patients are placed on a strict program of oral reported findings of the role of inflammation and hygiene within 10 days of the initiation of therapy plaque. 127 with medications promoting gingival enlargement, Gingival enlargement has also been reported its occurrence can be minimized.121J22 with cyclosporine, with an incidence of approxi- Although the occurrence of gingival enlarge- mately 25%.128There are a number of similarities ment due to phenytoin has been clearly established, between the clinical and histopathologic changes its cellular and molecular mechanisms of action for seen in cyclosporine- and phenytoin-induced gin- this effect are unclear. A recent study suggests that gival enlargement. Also, both drugs are known to phenytoin augmented the expression of the gene have an effect on the immune system, including for platelet-derived growth factor-B (PDGF-B) .123 the induction of lymphoid hyperplasias and lym- In this study, the authors also showed that gingival phomas. For these patients, meticulous plaque macrophages exposed to phenytoin secrete control, as a preventive measure upon initiation of increased amounts of PDGF. This may increase not and throughout cyclosporine therapy and as a cor- only the proliferation of gingival cells but also alve- rective procedure after completion of therapy, may olar bone cells. A recent report suggests that pheny- be of value as in the case of patients on phenytoin toin has the ability to stimulate bone cell prolifera- therapy.'29J30 Also, it has been postulated that tion and differentiation and may mature osteoblas- cyclosporine alters fibroblastic activity. The role of tic activities to stimulate bone formation.12* If so, plaque in this process has not been clearly estab- this may explain the authors' clinical impression of lished, and conflicting results have been reported. minimal bone loss in patients with phenytoin- induced gingival hyperplasia. The effect on PDGF Alveo Iar Bone may also explain an early report in which a patient being medicated with phenytoin underwent ortho- In addition to their antibacterial effects, tetracy- dontic tooth movement; and with no special rapid clines are now known to inhibit pathologically movement planned, the teeth moved in half the excessive host-derived matrix metalloproteinase time with no adverse effects on bone or shortening activity during periodontal and other diseases. The of the r00ts.l~~In this case, phenytoin may have discovery of the anticollagenolytic properties of the favored bone remodeling. It is possible that tetracyclines was made using an animal model of although phenytoin produces an increased risk fac- both pathologically excessive collagenase activity in tor for gingival enlargement and the associated gin- gingival tissues and periodontal breakdown. 131~132 Pharmacotherapy 265

A recent study showed that treating germ-free and one might expect less plaque to be present in pathogen-reduced rats, inoculated with Porpby- these patients. However, in contrast, an earlier romonus gingivulis, by the oral administration of a study reported that, although GCF flow nonantimicrobial dose of a tetracycline (as dis- decreased with topical steroid application of flu- cussed earlier in this chapter) or a chemically mod- ocinonide (Sulindac) , a systemic nonsteroidal ified nonantimicrobial tetracycline significantly anti-inflammatory drug, this had no plaque- inhibited periodontal bone 10ss.l~~ reducing effect. 140 Noting that the same amount Although the mechanisms of this drug effect are of plaque was present in both groups of patients, not yet clear, tetracyclines can also directly inhibit they concluded that GCF flow may not have an osteoclast-mediated bone resorption and the pro- effect on plaque accumulation. duction of collagenase and ge1atina~e.l~~It is not yet known whether this therapeutic effect reflects a Change in Crevicular Fluid Content direct inhibition of bone resorption longitudinally, Since GCF is in intimate contact with plaque, the inhibition of episodes of bone resorption in its alterations in its content and pH deserve investiga- early stages, or the proanabolic effects on bone for- tion. Do anti-inflammatory and other systemic mation. These issues as well as others such as the drugs change the pH and composition of this temporal relationship of matrix metalloproteinase fluid? Are the changes significant to plaque accu- (collagenase, gelatinase) induction and bone loss mulation and metabolism? It has been demonstrat- should be addressed in fbture studies. ed that glucose is present in GCF in levels higher Antibiotics have also been shown to be of than those found in ~a1iva.l~~An unanswered ques- value in arresting bone loss in special types of peri- tion is, “Does this level change when oral hypo- odontal disease, such as rapidly advancing peri- glycemics or insulin are administered?” Soluble odontitis, localized juvenile periodontitis, and gold salts decrease the number of inflammatory refractory periodontitis, with the mechanism of cells in gingival tissues;142since metals like gold action related to the drugs antimicrobial effects.135 have antibacterial properties, can their administra- Nonsteroidal anti-inflammatory drugs tion improve periodontal health? (NSAIDs) may reduce bone loss in both animal and human models, with a variety of agents show- Antibiotic Resistance ing some effect.136 Epidemiologic studies of the Since antibiotics have been extensively discussed in periodontium of patients receiving NSAIDs on a this chapter, consideration must be given to the long-term basis for arthritis suggested that they development of resistance to them. Resistance to had less alveolar bone loss than a similar popula- mouthrinse and dentifrice ingredients or to locally tion not receiving these medi~ati0ns.l~~The mech- delivered medications has not been demonstrated anism of action of these agents appears to be relat- with one exception. S. sunguis resistance to chlor- ed to their effect on prostaglandins. hexidine has been reported after 2 years of use of the drug. However, the clinical significance of this Gingival Crevicular Fluid finding is unclear at this time since oral disease has not been associated with S. sunguis, although bac- An increase in gingival crevicular fluid (GCF) flow terial endocarditis has been caused by this microbe. may be responsible for more rapid plaque forma- However, resistance to systemically adminis- tion. With the increasing severity of gingivitis, the tered antibiotics is increasing, and a brief review of GCF flow also increases, which may contribute to this topic follows. an increased amount of ~1aque.l~~This relation- Penicillin was first discovered in 1896 by a ship was first observed when more plaque was seen French medical student, but at the time the dis- to have formed as the gingivitis became more covery was not evaluated for its true meaning. In severe. A possible mechanism may be that GCF 1928, it was rediscovered by Fleming, a Scottish has higher levels of calcium, which may act as a physician. However, penicillin was not mass pro- binding agent favoring bacterial aggregation and duced by drug companies until 1943. Shortly after precipitation of salivary proteins. 139 Also, it has the introduction of penicillin, Stupbylococcus uureus been noted that plaque wettability increases with resistance to it developed, sending manufacturers disease and that this factor may be affected by rushing to produce forms of penicillin that could GCF. Following this reasoning, since anti- overcome this resistance. inflammatory drugs decrease gingival inflamma- The development of antibiotic resistance has tion, if an associated decrease in GCF occurs, been dramatic. In 1967, the resistance of Streptococ- 266 Periodontal Medicine cus pneumoniue and Neisseriu gonorrhoeue was docu- homes) and increased use of medications (for mented. In 1983, another penicillin-resistant bac- immunocompromised patients, transplantation terium, Enterococcus fecrisu, developed in hospital patients, and patients on cancer chemotherapy), settings. Between 1979 and 1987, only 0.02% of which make people more prone to infection. Addi- pneumococcal strains infecting a large number of tionally, the aging of our population is an added patients surveyed by the Centers for Disease Con- risk factor for infection. trol and Prevention (CDC) were penicillin resistant. The CDC survey included 13 hospitals in 12 states in the United States.143Today, 6.6% of pneumococ- ANTIBIOTICS IN POULTRY cal strains are resistant.14 In 1992, 13,300 hospital AND OTHER MEATS patients in the United States died of bacterial infec- Although the FDA limits the amount of antibiotic tions that were resistant to antibiotic treatment. residue in meats, the question arises as to whether Although antibiotics themselves do not directly these foods are a source of low-dose antibiotics, cause resistance, they do create situations that subsequently resulting in resistance. The FDA is allow an existing variant strain of bacteria to flour- also evaluating whether bacterial resistance to ish. This results in the development of resistance to quinolone antibiotics can emerge in animals the antibiotic. A patient can develop a drug-resis- slaughtered for food and consequently cause distant infection either by contracting a resistant ease in humans. Although thorough cooking great- microorganism before treatment or by having a ly reduces the likelihood of antibiotic-resistant bac- resistant microbe emerge in the body in the course teria surviving in meat and infecting a human, the of antibiotic treatment. Drug-resistant infections possibility remains. There have been sporadic not only increase the risk of death but are also reports of pathogens resistant to drugs other than often associated with prolonged hospital stays and fluoroquinolones surviving in cooked meat and even medical complications. These infections infecting a human. For example, in 1983, 18 peo- could necessitate removing part of a ravaged lung, ple in four midwestern states suffered multidrug- or replacing a damaged heart valve. resistant Sulmonelh food poisoning after eating In another example of the natural development beef from cows fed antibiotics. Eleven of the peo- of resistance, erythromycin attacks ribosomes with- ple were hospitalized and one died. in a cell, enabling it to make proteins. Resistant bacteria have slightly altered ribosomes to which the antibiotic cannot bind. The ribosomal route is also ANTIBIOTIC RESISTANCE how bacteria become resistant to other antibiotics AND HUMAN USE such as tetracycline, streptomycin, and gentamicin. Antibiotic resistance can occur in three ways: A study of the development of antibiotic resistance spontaneous mutations of a bacterium’s own in humans shows that the increase in antibiotic genetic material (DNA), acquisition of DNA from resistance parallels the increase in antibiotic use. another bacterium through transformation, and This study examined a large group of cancer acquisition via plasmid transmission. Though bac- patients given fluoroquinolones to prevent infec- terial antibiotic resistance is a natural process, as tion. The patients’ white blood cell counts were very outlined above, other factors also contribute to the low as a result of their cancer treatment, leaving problem (eg, increased infection transmission cou- them open to infection. Between 1983 and 1993, pled with inappropriate antibiotic use). the percentage of such patients receiving antibiotics Today, more people are contracting infections. rose from 1.4 to 45%. During these years, Sinusitis among adults is on the rise, as are ear researchers isolated Escbericbiu coli annually from infections in children. Nearly 6 million antibiotic the patients and tested the microbes for resistance to prescriptions for sinusitis were written in 1985 and five types of fluoroquinolones. Between 1983 and nearly 13 million in 1992. For middle-ear infec- 1990, all 92 E. coli strains tested were easily killed by tions, the numbers of prescriptions are 15 million the antibiotics. But from 1991 to 1993, I I of the 40 in 1985, and 23.6 million in 1992. tested strains (28%) were resistant to all five drugs. Clearcut reasons for the dramatic rise in infec- Resistance is also occurring to vancomycin, which tions are not available; however, suggested causes has been the “last resort” antibiotic for many infec- include an increase in communal living situations tions, including Stupbylococcus. Vancomycin-resis- (day-care centers for children and adults, senior tant enterococci were first reported in England and citizen centers, homeless shelters, and nursing France in 1987, and appeared in one New York City Pharmacotherapy 267 hospital in 1989. By 1991,38 hospitals in the Unit- 10. Kornman KS, Robertson PB. Clinical and micro- ed States reported the pathogen. By 1993, 14% of biological evaluation of therapy for juvenile patients with enterococci infections in intensive-care periodontitis. J Periodontol 1985;56:443-6. units in some hospitals had vancomycin-resistant 11. Lindhe J, Liljenberg B. Treatment of localized juve- strains, a 20-fold increase from 1987. In 1992, a nile periodontitis. Results after 5 years. J Clin British laboratory observed the transfer of a van- Periodontol 1984;11:399-410. comycin-resistant gene from Enterococcus to Stupby- 12. Papli R, Lewis JM. Refractory chronic periodonti- Zococcus uureus in the laboratory. The fear now is that tis: effect of oral tetracycline hydrochloride and if vancomycin-resistant enterococci can transfer root planing. Aust Dent J 1989;34:60-8. their resistance, anti-Stuphylococcus antibiotics will 13. Kornman KS, Karl E. The effect of long-term low- no longer be of value. dose tetracycline therapy on the subgingival In view of the rapid rise in antibiotic resistance microflora in refractory adult periodontitis. J in recent years, all dental prescriptions for antibi- Periodontol 1982; 5 3: 604-1 0. otics should be accompanied by careful instruc- 14. Shapiro A. Healing potential of periodontal tions to the patient regarding proper dosage and osseous defects treated by scaling and root plan- taking the full prescription. All antibiotics should ing. J Dent Que 1990;27:587-92. be prescribed in situations where their value is well 15. Preus H. Treatment of rapidly destructive peri- established so that unnecessary prescribing against odontitis in Papillon-Lefevre syndrome. Labora- “normal” bacteria does not occur. These simple tory and clinical observations. J Clin Periodon- safeguards can help us all win the battle against to1 1988;15:639-43. resistant strains. 16. Loesche WH, Schmidt E, Smith BA, et al. Effects of metronidazole on periodontal treatment needs. J Periodontol 1991;62:247-57. REFERENCES 17. Loesche WJ, Giordano JR, Hujoel Pc et al. 1. Ciancio SG. FDA Approves periostat marketing. Metronidazole in periodontitis: reduced need for Biol Ther Dent 1998; 14:21-2. surgery. J Clin Periodontol 1992;19: 103-12. 2. Ciancio SG, Bourgault PC. Clinical pharmacology 18. Loesche WJ, Giordano JR Metronidazole in peri- for dental professionals. 3rd ed. St. Louis (MO): odontitis V: debridement should precede med- C.V. Mosby Co.; 1989. p.58. ication. Compendium Cont Educ Dent 1994; 3. Barnett ML. Inhibition of oral contraceptive effec- 251198-2001. tiveness by concurrent antibiotic administra- 19. van Winkelhoff AJ, de Graaff J. Microbiology in tion. J Periodontol 1985;56(1):18-21. the management of destructive periodontal dis- 4. Preus HR, Lassen J, Aass AM, Christersson LA. ease. J Clin Periodontol 1991;18:411-20. Prevention of transmission of resistant bacteria 20. Collins JG, Offenbacher S, Arnold RR. Effects of a between periodontal sites during subgingival combination therapy to eliminate Porpbyromonas application of antibiotics. J Clin Periodontol gingivalis in refractory periodontitis. J Periodon- 1993;20:299-303. to1 1993;64:998-1007. 5. Poliak SC, DiGiovanna JJ, Gross EG, et al. 21. Walker CB, Gordon JM, Cornwall HA, et al. Gin- Minocycline-associated tooth discoloration in gival crevicular fluid levels of clindamycin com- young adults. JAMA 1985;254:2930-2. pared with its minimal inhibitory concentra- 6. Salman RA, Salman DG, Glickman RS, et al. tions for periodontal bacteria. Antimicrob Minocycline-induced pigmentation of the oral Agents Chemo 1981; 19:867-7 1. cavity. J Oral Med 198540:154-7. 22. Walker CB, Gordon JM, Magnusson I, Clark WB. 7. Attwood HD, Dennett X. A black thyroid and A role for antibiotics in the treatment of refractory minocycline treatment. Br Med J 1976;2: periodontitis. J Periodontol 1993;64:772-8 1. 1109-10. 23. Magnusson I, Clark WB, Low SB, et al. Effect of 8. Ciancio SG, Slots J, Reynolds HS, et al. The effect non-surgical periodontal therapy combined of short-term administration of minocycline with adjunctive antibiotics in subjects with HCl on gingival inflammation and subgingival “refractory” periodontal disease: I. Clinical microflora. J Periodontol 1982;9:557-61. results. J Clin Periodontol 1989;16:647-53. 9. Hayes C, Antczak Bouckoms A, Burdick E. Quali- 24. Magnusson I, Marks RG, Clark WB, et al. Clinical, ty assessment and meta-analysis of systemic microbiological and immunological characteris- tetracycline use in chronic adult periodontitis. J tics of subjects with “refractory”periodontal dis- Clin Periodontol 1992;19: 164-8. ease. J Clin Periodontol 1991;18:291-9. 268 Periodontal Medicine

25. Magnusson I, Low SB, McArthur W, et al. Treat- Tetracyclines inhibit tissue collagenase activity. A ment of subjects with refractory periodontal dis- new mechanism in the treatment of periodontal ease. J Clin Periodontol 1994;21:628-37. disease. J Periodontal Res 1984;19:651-5. 26. Walker C, Gordon J. The effect of clindamycin on 39. Loe H, Silness PJ. Periodontal disease in pregnancy. the microbiota associated with refractory peri- I. Prevalence and severity. Acta Odontol Scand odontitis. J Periodontol 1990;61:692-8. 195321~533-5 1. 27. Quee TC, Clark C, Lautar-Lemay C, et al. The role 40. Silness PJ, Loe H. Periodontal disease in pregnan- of adjunctive Rodogyl therapy in the treatment cy. 11. Correlation between oral hygiene and of advanced periodontal disease. A longitudinal periodontal condition. Acta Odontol Scand clinical and microbiologic study. J Periodontol 1964;22:121-35. 19 87;5 8 :5 94-60 1. 41. Fine JB, Harper DS, Gordon JM, et al. Short-term 28. Quee TC, Al-Joburi W, Lautar-Lemay C, et al. microbiological and clinical effects of subgingi- Comparison of spiramycin and tetracycline used val irrigation with an antimicrobial mouthrinse. adjunctively in the treatment of advanced peri- J Periodontol 1994;65:30-6. odontitis. J Antimicrob Chemother 1988;22 42. Wolff LF, Bakdash MB, Pihlstrom B1, et al. The effect (Suppl B): 171-7. of professional and home subgingival irrigation 29. Bain CA, Beagrie GS, Bourgoin J, et al. The effects with antimicrobial agents on gingivitis and early of spiramycin and/or scaling on advanced peri- periodontitis. J Dent Hygiene 1989;63:222-6. odontitis in humans. J Can Dent Assoc 1994; 43. Flemmig TF, Newman MG, Doherty FM, et al. 60:209- 17. Supragingival irrigation with 0.06% chlorhexi- 30. Slots J, Rams TE. Rational use of antibiotics. J Calif dine in naturally occurring gingivitis. I. 6 month Dent Assoc 1990;18:21-3. clinical observations. J Periodontol 1990;61: 31. Slots J, Feik D, Rams TE. In vitro antimicrobial 112-7. sensitivity of enteric rods and pseudomonads 44. Cobb CM, Rodgers RL, Killoy WJ. Ultrastructur- from advanced adult periodontitis. Oral Micro- a1 examination of human periodontal pockets bial Immunol 1990;5:298-301. following the use of an oral irrigation device in 32. Pavicic M, van Winkelhoff A, de Graaff J. Synergis- vivo. J Periodontol 1988; 59:155-9. tic effects between amoxicillin, metronidazole, 45. Aziz-Gandour IA, Newman HN. The effects of a and the hydroxymetabolite of metronidazole simplified oral hygiene regimen plus supragingi- against Actinobacillus actinomycetemcomitans. val irrigation with chlorhexidine or metronida- Antimicrob Agents Chemother 199 1;35:961-6. zole on chronic inflammatory periodontal dis- 33. van Winkelhoff AJ, Rodenberg Jc Goene RJ, et al. ease. J Clin Periodontol 1986;13:228-36. Metronidazole plus amoxicillin in the treatment 46. Newman MG, Cattabriga M, Etienne D, et al. of Actinobacillus actinomycetemcomitans-associ- Effectiveness of adjunctive irrigation in early ated periodontitis. J Clin Periodontol 1989;16: periodontitis-multicenter evaluation. J Perio- 128-31. dontol 1994;65:224-9. 34. Kornman KS, Newman MG, Flemmig TF, et al. 47. Boyd RL, Leggott Quinn R, et al. Effect of self- Treatment of refractory periodontitis with metro- administered daily irrigation with 0.02% SnFz nidazole plus amoxicillin or Augmentin (Abstract on periodontal disease activity. J Clin Periodon- 403). J Dent Res 1989;68(Spec Issue):917. to1 1985;12:420-31. 35. Aitken S, Birek Kulkarni GV, et al. Serial doxy- 48. Drisko C, Forgas L, Killoy WJ. Subgingival irriga- cycline and metronidazole in prevention of tion with effervescent buffered aspirin solution recurrent periodontitis in high-risk patients. J in gingivitis and periodontitis (Abstract 1257). J Periodontol 1992;63:97-102. Dent Res 1994;73. 36. Birek D, Kulkarni GV, Lee WK, et al. Effect of ser- 49. Flemmig TF, Funkenhauser 2, Epp B, et al. ial doxycycline/metronidazole on recurrent peri- Adjunctive supragingival irrigation in periodon- odontitis pathogens (Abstract 864). J Dent Res titis treatment (Abstract 554). J Dent Res 1989;68(Spec Issue):373. 1992;72 (Spec Issue):584. 37. Matisko Mw, Bissada NF. Short-term sequential 50. Felo A, Shibly 0, Ciancio SG, et al. Effects of sub- administration of amoxicillin/clavulanate potas- gingival chlorhexidine irrigation on peri- sium and doxycycline in the treatment of recur- implant maintenance. Am J Dent 1997;lO: rent/progressive periodontitis. J Periodontol 107-10. 1993;64:553-8. 51. Tonetti M, Cugini AM, Goodson JM. Zero order 38. Golub LM, Ramamurthy N, McNamara TF, et al. delivery with periodontal placement of tetracy- Pharmacotherapy 269

cline loaded ethylene vinyl acetate fibers. J Peri- randomized controlled-trial of a 2% minocycline odontal Res 1990;25:243-7 gel as an adjunct to non-surgical periodontal 52. Walker CB, Gordon JM, McQuilkin SJ, et al. treatment, using a design with multiple matching Tetracycline: levels achievable in gingival crevice criteria. J Clin Periodontol 1997;24:249-53. fluid and in vitro effect on subgingival organ- 64. Ainamo J, Lie T, Ellingsen BH, et al. Clinical isms. Part 11. Susceptibilities of periodontal bac- responses to subgingival application of a teria. J Periodontol 1981;52:613-6. metronidazole 25% gel compared to the effect 53. Gordon JM, Walker CB, Murphy CJ, et al. Tetra- of subgingival scaling in adult periodontitis. J cycline: levels achievable in gingival crevice fluid Clin Periodontol 1992;19 (Part II):723-9. and in vitro effect on subgingival organisms. 65. Klinge B, Attstrom R, Karring T, et al. Three regi- Part I. Concentrations in crevicular fluid after mens of topical metronidazole compared with repeated doses. J Periodontol 1981;52:609-12. subgingival scaling on periodontal pathology in 54. Goodson JM, Cugini MA, Kent RL, et al. Multi- adults. J Clin Periodontol 1992;19 (Part 11): center evaluation of tetracycline fiber therapy: 708-14. 11. Clinical response. J Periodontal Res 199 1;26: 66. Stelzel M, Flores-de-Jacoby L. Topical metronida- 371-9. zole application compared with subgingival seal- 55. Newman MG, Kornman KS, Doherty FM. A 6- ing. A clinical and microbiological study on month multi-center evaluation of adjunctive recall patients. J Clin Periodontol 1996;23: tetracycline fiber therapy used in conjunction 24-9. with scaling and root planing in maintenance 67. Ainamo J, Lie T, Ellingsen BH, et al. Clinical patients: clinical results. J Periodontol 1994;65: responses to subgingival application of a 685-9 1. metronidazole 25% gel compared to the effect 56. Goodson JM, Tanner A. Antibiotic resistance of of subgingival scaling in adult periodontitis. J the subgingival microbiota following local tetra- Clin Periodontol 1992;19(Part I):723-9. cycline therapy. Oral Microbiol Immunol 1992; 68. Soskolne WA, Heasman PA, Stabholz A, et al. Sus- 7: 113-7. tained local delivery of chlorhexidine in the 57. Niederman R, Holborow D, Tonetti M, et al. Rein- treatment of periodontitis: a multi-center study. fection of periodontal sites following tetracy- J Periodontol 1997; 68:32-8. cline fiber therapy (Abstract 1345). J Dent Res 69. Briner WW, Kayrouz GA, Chanak MX. Compara- 1990;69:277. tive antimicrobial effectiveness of a substantive 58. Morrison SL, Cobb CM, Kazakos GM, Killoy WJ. (0.12% chlorhexidine) and a nonsubstantive Root surface characteristics associated with sub- (phenolic) mouthrinse in vivo and in vitro. Com- gingival placement of monolithic tetracycline- pend Contin Educ Dent 1994;15: 1 158-68. impregnated fibers. J Periodontol 1992;63: 70. Jeffcoat M, Bray KS, Ciancio SG, et al. Adjunctive 137-43. use of a subgingival controlled-release chlorhex- 59. Polson AM, Garrett S, Stoller NH, et al. Multi- idine chip reduces probing depth and improves center comparative evaluation of subgingivally attachment level compared with scaling and delivered sanguinarine and doxycycline in the root planing alone. J Periodontol (In press). treatment of periodontitis. 11. Clinical results. J 71. Caton J, Bleiden T, Adams D, et al. Subantimicro- Periodontol 1997;68:1 19-26. bial doxycycline therapy for periodontitis 60. Larsen T. Occurrence of doxycycline-resistant bac- (Abstract). J Dent Res 1997;76:1307. teria in the oral cavity after local administration 72. Ciancio SG, Adams D, Blieden T, et al. Suban- of doxycycline in patients with periodontal dis- timicrobial dose doxycycline: a new adjunctive ease. Scand J Infect Dis 1991;23:89-95. therapy for adult periodontitis. Presented at the 6 1. Garrett S, Adams D, Bandt C, et al. Two multicen- Annual Meeting of The American Academy of ter clinical trials of subgingival doxycycline in Periodontology, Boston, MA, September 1998. the treatment of periodontitis (Abstract 1113). J 73. Caton JG, Ciancio SG, Crout RJ, et al. Post-treat- Dent Res 1997;76:153. ment effects of adjunctive sub-antimicrobial 62. Van Steenberghe D, Bercy Kohl J. Subgingival dose doxycycline therapy. J Periodontology minocycline hydrochloride ointment in moder- 1999 [Submitted]. ate to severe chronic adult periodontitis: a ran- 74. Walker C, Thomas J. The effect of subantimicro- domized, double-blind, vehicle-controlled, mul- bial doses of doxycycline on the microbial flora ticenter study. J Periodontol 1993;64:63744. and antibiotic resistance in patients with adult 63. Graca MA, Watts TLC Wilson RF, Palmer RM. A periodontitis. Presented at The American Acad- 270 Periodontal Medicine

emy of Periodontology Meeting, Boston, MA, 90.Rustogi KN, Petrone DM, Singh SM, et al. Clinical September, 1998. study of a pre-brush rinse and a triclosan/co- 75. Crout R, Adams D, Blieden T, et al. Safety of doxy- polymer mouthrinse: effect on plaque forma- cycline hyclate 20 mg BID in patients with tion. Arn J Dent 1990;3:S67-9. adult periodontitis. Presented at The American 91.Cronin MJ, Kohut BE. A two-phase clinical efficacy Academy of Periodontology Meeting, Boston, study of Plax pre-brushing rinse. J Clin Dent MA, September, 1998. 1991;3:19-21. 76. Howell TH, Williams RC. Non-steroidal anti- 92.Chung L, Smith SR, Joyston-Bechal S. The effect of inflammatory drugs as inhibitors of periodontal using a prebrushing mouthwash (Plax) on oral disease progression. Crit Rev Oral Biol Med hygiene in man. J Clin Periodontol 1992;19: 1993;4:177-96. 679-82. 77. Lamster IB, Alfano MC, Seiger MC, et al. The 93.Mankodi S, Walker C, Conforti N, et al. Clinical effect of Listerine antiseptic on reduction of effect of a triclosan-containing dentifrice on existing plaque and gingivitis. Clin Prev Dent plaque and gingivitis: a six-month study. Clin 19835:12-6. Prevent Dent 1992;14:4-10. 78. Gordon JM, Lamster IB, Seiger MC. Efficacy of 94.Bolden TE, Zambon JJ, Sowinski J, et al. The clini- Listerine antiseptic in inhibiting the develop- cal effect of a dentifrice containing triclosan and ment of plaque and gingivitis. J Clin Periodon- a co-polymer in a sodium fluoride/silica base on to1 1985;12:697-704. plaque formation and gingivitis: a six-month 79. DePaola LG, Overholser CD, Meiller TF, et al. clinical study. J Clin Dent 1992;4:125-31. Chemotherapeutic inhibition of supragingival 95.Garcia-Godoy F, Garcia-Godoy K, DeVizio W, et al. dental plaque and gingivitis development. J Effect of a triclosadco-polymer/fluoride denti- Clin Periodont 1989:16:311-5. frice on plaque formation and gingivitis: a 7- 80. Loe H, Schiott CR The effect of mouthrinses and month clinical study. Am J Dent 1990;3:S15-26. topical application of chlorhexidine on the 96.Cubells AB, Dalmau L, Petrone ME, et al. The effect development of dental plaque and gingivitis in of a triclosan/co-polymer/fluoride dentifrice on man. J Periodontal Res 1970;5:79-83. plaque formation and gingivitis: a six-month 81. Barkvoll Rolla G, Svendsen AK. Interaction clinical study. J Clin Dent 1991;2:63-9. between chlorhexidine digluconate and sodium 97.Deasy MJ, Singh SM, Rustogi KN, et al. Effect of a lauryl sulfate in vivo. J Clin Periodontol 1989; dentifrice containing triclosan and a co-polymer 16:593-5. on plaque formation and gingivitis. Clin Pre- 82. Mandel ID. Chemotherapeutic agents for control- vent Dent 199 1; 13: 12-9. ling plaque and gingivitis. J Clin Periodontol 98.Denepitiya JL, Fine D, Singh SM, et al. Effect upon 198 8; 15 :488-9 8. plaque formation and gingivitis of a triclosanl 83. Davies RM. Rinses to control plaque and gingivi- co-polymer/fluoride dentifrice: a 6-month clini- tis. Int Dent J 1992;42(Suppl):276-80. cal study. Am J Dent 1992;5:307-31. 84. Wennstrom J, Lindhe J. Some effects of a san- 99.Palomo F, Wantland L, Sanchez A, et al. The effect

guinarine-containing mouthrinse on developing of three commerciallvJ available dentifrices con- plaque and gingivitis. J Clin Periodontol 1985; taining triclosan on supragingival plaque forma- 12: 8 67-72. tion and gingivitis: a six-month clinical study. 85. O’Mahony G, O’Mullane DM. Evaluation of Plax Int Dent J 1994;44 (Suppl 1):S75-81. pre-brushing rinse in reducing dental plaque 100. Triratana T, Tuongratanaphan S, Kraivaphan et (Abstract). J Dent Res 1990;69:246. al. The effect on established plaque formation 86. Patters MR, Shiloah J. A method for evaluating the and gingivitis of a triclosan/co-polymer/fluoride effect of a pre-brushing rinse in reducing dental dentifrice: a six-month clinical study. J Dent plaque [Abstract]. J Dent Res 199 1;70:323. Assoc Thailand 1993;43:19-28. 87.Singh SM. Efficacy of Plax pre-brushing rinse in 101. Lindhe J, Rosling B, Socransky SS, Volpe AR. The reducing dental plaque. Am J Dent 1990;3:15-6. effect of a triclosan containing dentifrice on 88.Freitas Bastos L, Collaert B, Attstrom R Plaque established plaque and gingivitis. J Clin Peri- removing efficacy of the pre-brushing rinse Plax odontol 5327-34. [Abstract]. J Dent Res 1991;70:768. 102. Ciancio SG. Calculus reduction of a triclosanl 89.Balanyk T, Sharma N, Galustians J. Antiplaque effi- co-polymer/fluoride dentifrice. Biol Ther Dent cacy of Plax pre-brushing rinse: plaque mass/ 1997;13. area analysis [Abstract]. J Dent Res 1991;70:374. 103. Rosling B, Wannfors B, Volpe AR, et al. The use Pharmacotherapy 27 1

of a triclosan/co-polymer dentifrice may retard 121. Ciancio SG, Yaffe SJ, Catz CC. Gingival hyper- the progression of periodontitis. J Clin Peri- plasia and diphenylhydantoin. J Periodontol odontol 1997;24:873-80. 1972; 43:411-14. 104. Smulow JB, Turesky SS, Hill RG. The effect of 122. Hall WB. Prevention of dilantin hyperplasia: a pre- supragingival plaque removal on anaerobic bac- liminary report. Bull Acad Gen Dent 1969;20. teria in deep periodontal pockets. J Am Dent 123. Dill RE, Miller EK, Weil T, et al. Phenytoin Assoc 1983;107:737-42. increases gene expression for platelet-derived 105. Hellstrom MK, Ramberg Krok L, Lindhe J. The growth factor B chain in macrophages and effect of supragingival plaque control on the monocytes. J Periodontol 1993;64:169-73. subgingival microflora in human periodontitis. 124. Nakade 0, Baylink DJ, Lau K-Hw. Phenytoin at J Clin Periodontol 1996;23:934-40. micromolar concentration is an osteogenic 106. Dahlen G, Lindhe J, Sat0 K, et al. The effect of agent for human-mandibular-derived bone cells supragingival plaque control on the subgingival in vitro. J Dent Res 1995;74(1):331-7. microbiota in subjects with periodontal disease. 125. Cunat JJ, Ciancio SG. Diphenylhydantoin sodi- J Clin Periodontol 1992;195302-9. um: gingival hyperplasia and orthodontic treat- 107. McNabb H, Mombelli A, Lang NE Supragingival ment. Angle Orthod 1969;3:192-5. cleaning three times a week: the microbiological 126. Nishikawa SJH, Tada H, Hamasaki A, et al. effects in moderately deep pockets. J Clin Peri- Nifedipine-induced gingival hyperplasia: a clin- odontol 1992;19:348-56. ical and in vitro study. J Periodontal Res 1991; 108. Wynn U. The top 20 medications prescribed in 52: 3 0-5. 1993. General Dentistry. 1995; March-April: 127. Nuki K, Cooper SH. The role of inflammation in 114-9. the pathogenesis of gingival enlargement during 109. Bosco JA, Pearson RE. Sugar content of selected the administration of diphenylhydantoin sodi- liquid medicinals. Diabetes 1973;22:776-8. um in cats. J Periodontal Res 1972;78:102-10 110. Lokken Birkeland JM, Sannes E. pH changes in 128. Stone C, Eshenaur A, Hassell T. Gingival enlarge- dental plaque caused by sweetened, iron-con- ment in cyclosporine treated multiple sclerosis taining liquid medicine. Scand J Dent Res patients. J Dent Res 1989;68:285-9. 1975;83:279-83. 129. Seymour RA, Smith DG. The effect of a plaque 111. Imfeld TH. Kariogene hustenspezialitaten. control program on the incidence and severity Schweiz Mschr Zahnheilk 1977;87:774-7. of cyclosporine induced gingival changes. J Clin 112. Roberts IF, Roberts GJ. Relation between medi- Periodontol 1991;18: 107-10. cines sweetened with sucrose and dental disease. 130. Ciancio SG, Bartz Nw, Lauciello FR Cyclo- Br Med J 1979;2:14-6. sporine-induced gingival hyperplasia and 113. Ship JA, Fox PC, Baum BJ. How much saliva is chlorhexidine: a case report. Int J Periodont enough? ‘Normal’ function defined. JADA Restor Dent 1991; 3:241-5. 199 1;122:63-69. 131. Golub LM, Lee HM, Lehrer G, et al. Minocycline 114. Sreebny LM, Schwartz SS. A reference guide to drugs reduces gingival collagenolytic activity during and dry mouth. Gerodontology 1986;5:75-99. diabetes: preliminary observations and a pro- 115. Ogle RE, Ciancio SG. The effect of anticholinergic agents on the periodontium. J Periodontol posed new mechanism of action. J Periodontal 1971;42:280-2. Res 19 83; 18: 5 16-26. 116. The United States Pharmacopeia, 21st revision. 132. Golub LM, McNamara TF, D’Angelo G, et al. A Rockville, MD: United States Pharmacopeial non-antimicrobial chemically-modified tetracy- Convention, Inc.; 1984. cline inhibits mammalian collagenase activity. J 117. Beck R, Kohout FJ, Hunt RJ, et al. Root caries: Dent Res 1987;66:13104. physical, medical and psychosocial correlates in 133. Golub LM, Evans RT, McNamara TF, et al. A an elderly population. Gerodontics 1986;3: non-antimicrobial tetracycline inhibits gingival 242-7. matrix metalloproteinases and bone loss in Por- 118. Accepted dental therapeutics. 39th edition. Chica- pbyromonas gingivalis-induced periodontitis in go: American Dental Association; 1982. rats. Ann N Y Acad Sci 1994;732:96-110. 119. Ziskin DE, Stowe LR, Zegarelli EV. Dilantin hyper- 134. Delaisse JM, Eeckhout Y, Neff L, et al. (Pro) col- plastic gingivitis. Am J Orthod 1941;27:350. lagenase (matrix metalloproteinase- 1) is present 120. Baden E. Sodium dilantin gingival hyperplasia in rodent osteoclasts and in the underlying bone and conservative treatment: a case report. J resorbing compartment. J Cell Sci (HNK) Dent Med 1950;5:46. 1993;106: 1071-82. 272 Periodontal Medicine

135. Ciancio SG, Genco RJ. The use of antibiotics in 140. Vogel RI, Copper SA, Schneider LG, Goteiner D. periodontal disease. Int J Periodont Restor Dent The effects of topical steroidal and systemic 1990;17:479-93. nonsteroidal anti-inflammatory drugs on exper- 136. Williams RC, Jeffcoat MK, Howell TH, et al. imental gingivitis in man. J Periodontol 1984; Altering the course of human alveolar bone loss 55:247-51. with the non-steroidal anti-inflammatory drug 141. Hara K, Loe H. Carbohydrate components of the flurbiprofen. J Periodontol 1989;60:485-90. gingival exudate. J Periodont Res 1969;4:202 137. Feldman RS, Szeto B, Chauncey HH, Goldhaber -7. I? Non-steroidal anti-inflammatory drugs in the 142. Freeman E, Novak MJ, Polson AM. Effects of gold reduction of human alveolar bone loss. J Clin salts on experimental periodontitis. 111. Ultra- Periodontol 1983;10:131-6. structural observations. IADR Program Abstracts; 138. Saxton CA. Scanning electron microscope study 1984. of the formation of dental plaque. Caries Res 143. Lewis R. The rise of antibiotic-resistant infections. 1973;7:102-19. FDA Consumer 1995;9:11-5. 139. Hillman DG, Hull PS. The influence of experi- 144. Breiman RF, Butler JC, Tenover FC, et al. Emer- mental gingivitis on plaque formation. J Clin gence of drug-resistant pneumococcal infections Periodontol 1976;4:56-6 1. in the United States. JAMA 1994;271:1831-5. CHAPTER16

MEDICOLEGALISSUES

Edwin J. Zinman, DDS, JD

The dental practitioner has the responsibility to below the standard of care merely because they provide patients with treatment that meets the cur- render below statistically average care. Nor do fifty rent standards of care. In managing patients with percent of practitioners statistically automatically significant systemic conditions or patients whose comply with the standard of care merely because periodontal disease may adversely affect systemic they render care above the statistical average. health, thorough examination and review of rele- The standard of care represents what a reason- vant medical history are paramount. This chapter ably prudent practitioner should do under the reviews important medicolegal issues involving all same or similar circumstances. It is no defense or those that are primarily involved in providing excuse for a negligent practitioner that other negli- health care: the patient, the physician, and the gent practitioners (even a majority) follow similar dental practitioner. negligent practices, or that only a minority of practitioners follow the reasonably prudent approach.

STANDARD OF CARE NEGLIGENT CUSTOM Two essential ingredients comprise the standard of care. First, the practitioner must possess that A negligent custom, even if practiced by the major- degree of skill and learning ordinarily possessed by ity of practitioners, violates the standard of care. By prudent practitioners. Second, the practitioner lay analogy, jaywalking, seatbelt avoidance, speed- must exercise or use the requisite skill and learning ing, inattention due to car phone use, and going in a reasonably prudent manner.’ through stop signs are often tolerated traffic viola- In recent years, legal standards of care have tions, except in a court of law, if injury results from been influenced by the various specialty organiza- such customarily negligent practices. tions that establish parameters of care. Such para- Examples of negligent dental practice customs meters are peer reviewed, based upon existing sci- include (I) failing to monitor dental unit water- entific literature, and periodically updated. A rea- lines for bacterial counts to assure compliance with sonably prudent practitioner usually adheres to the American Dental Association’s recommended such guidelines. Some organizations include a standards of 200 CFU/mL or potable water of 500 caveat that parameters of care are not to be equat- CFU;3 (2) routinely performing endodontics with- ed with the legal standard of care.2 Nevertheless, an out a rubber dam;* (3) failing to record pathologic expert witness may reasonably rely upon these periodontal probe measurement^;^ (4)prescription parameters in offering expert opinion. Therefore, periodontics for abutment teeth only while ignor- as a practical matter, a specialty organization’s para- ing periodontal disease elsewhere in the mouth;6 meters of care are usually consonant with prudent (5) blindly adhering to managed-care guideline practice, which is also termed “due care.” restraints which delay, or deny, necessary care and The standard of care is not average care but constrain specialty referral^;^ (6) unnecessary radi- rather represents the minimum standards of a rea- ation exposure with D-speed film, rather than E- sonably prudent practitioner. Although most prac- speed film as well as use of short round collimators, titioners adhere to the standard of care, the medi- rather than long-cone rectangular collimators, for an or statistically average practitioner does not intraoral radi~graphy;~.’(7) using a glass-bead or exclusively dictate the standard of care. Fifty per- chemiclave sterilizer for terminal sterilization of cent of practitioners do not automatically practice instruments;” and (8) employing cold chemical 274 Periodontal Medicine solution sterilization without adhering to the man- ple, a referring general dentist who prescribes only ufacturer’s recommendations for development limited periodontal therapy for a patient who time, temperature, and dilution. requires comprehensive therapy may be liable if the specialist acquiesces and both the referring dentist and periodontist fail to diagnose and adequately DUTY TO REFERTO SPECIALIST treat all of the patient’s periodontal disease. The referring dentist’s chart should reflect a While a dental license provides a dentist with the reasonable attempt to determine if the referred right to perform all dental procedures, few gener- patient consulted the specialist and obtained rec- alists actually possess the knowledge, training, and ommended treatment. The chart should also note skill to perform every procedure within the requi- reminders to the patient about the need to follow site standard of care. Possession of a dental license through with the referral and the consequences of does not alone prove competency or prudence. For not doing so. This may be accomplished when the instance, general practice physicians usually lack patient returns for a visit to the referring dentist’s sufficient training to perform open heart or sophis- office. The prudent referring practitioner should ticated brain surgery. Likewise, general dentists check with the patient to ensure that the patient’s often lack training to perform mandibular fracture appointment with the specialist has been kept. reduction, or periodontal regenerative surgery such Noncompliance, with either consultation or treat- as membrane grafting or bone augmentation. ment, should be recorded. A general dentist has the duty to refer a patient to a specialist in situations where other reasonable general dentists would make a referral under similar UPDATING SKILLS AND LEARNING circumstances.l2 If specialist training and experience are specifically required, the general dentist would The standard of care requires that dentists possess be considered negligent for attempting to diagnose the necessary level of skill and learning ordinarily or treat and will be held to the specialist’s standard possessed by prudent practitioners. Most profes- of care12 (ie, what the reasonable and prudent spe- sional negligence suits involve failure by an other- cialist would have done in similar circumstances). wise qualified practitioner to muintuin the requi- A specialist’s treatment failure may be justified site skill and learning. Experience alone is insuffi- as an inherent treatment risk. By contrast, in the cient to comply with the standard of care. Dentists case of the general dentist, who does not have ade- with many years of experience who only repeat quate training and therefore should not have each year the skills and learning present in their attempted sophisticated therapy, such failure is first year of practice are likely perpetuating outdat- considered a negligently caused avoidable risk. ed methods. Lack of availability of specialists in a certain local- A prudent practitioner constantly replaces ity does not justifv failure to refer when a referral is outdated methods with improved and advanced indicated. It is the patient’s choice whether or not therapies. It is estimated that following graduation, to travel to a distant specialist. scientific advances surpass even the most up-to- The duty to refer is not limited to general den- date educational training provided only 5 years tists only. Specialists also routinely encounter clin- earlier.13 Accordingly, to comply with the standard ical conditions that are best treated by a more expe- of care, prudent practitioners should update cur- rienced specialist in their discipline or by specialists rent knowledge, skill, and learning by subscribing in another discipline. Competency includes not to scientific journals and attending continuing only knowledge and training but also sufficient education courses. experience and mastery. For sophisticated thera- The standard of care does not require that pies, the standard of care may require mastery even every practitioner adopt each and every new tech- to attempt the therapy. nology or device. A prudent practitioner would The referring dentist is not responsible for the not incorporate technologic advancements until treatment results obtained by the specialist, pro- they are scientifically proven with sufficient studies vided the specialist acted independently, without and are generally accepted in the scientific com- the referring dentist’s participation or control. munity. It is not necessary to be the first to adopt However, the referring dentist may be liable for the the latest technology; nor should a dentist be the specialist’s care, if he or she actively participated in last to adopt generally accepted, scientifically or controlled the specialist’s treatment. For exam- proven technologic advances. Medicolegal Issues 27 5

GOVERNMENTAL AGENCY regarded as significant by a reasonable person in STANDARDS VERSUS STANDARDS the patient’s position when deciding to accept or OF CARE reject a recommended procedure or treatment. The dentist is not bound to discuss the minor risks Merely because a device or drug has received gov- inherent in common procedures, when such pro- ernmental approval, the practitioner who uses, rec- cedures very seldom result in serious ill effects.15 ommends, or prescribes it is not necessarily insu- The prudent practitioner’s goal is to serve and lated from liability. Governmental health care protect the patient’s best interests to preserve agencies, such as the Food and Drug Administra- health. Consequently, a practitioner’s fiduciary tion (FDA), set their own minimum standards. obligation to his or her patient should not be sole- Such standards on occasion may still fall short of ly guided by the limitations set by the patient’s reasonably prudent practice. insurance carrier and by managed care guidelines; For instance, some newer, unapproved implant nor should the practitioner recommend only the devices may be better suited because of their size or most profitable procedure when reasonably conser- maneuverability than some older FDA-approved vative alternative therapies are an option as well. implant systems, particularly where there is risk of Honesty is the best policy, which is embodied injury to vital structures. Avoiding a permanent in the legal obligation of a practitioner to warn injury to a nerve may depend on whether the clin- patients of inherent, but reasonably unavoidable, ician used a contraindicated FDA-approved therapeutic risks. Before embarking on any proce- implant or an indicated but nonapproved implant. dure that involves the inherent risk of serious Similarly, manufacturers frequently defend a defec- injury or death, a practitioner must provide the tive product by underscoring compliance with patient with informed choices of the benefits, risks, industry or government standards. However, “com- and consequences of treatment as well as those of pliance with a legislative enactment or an adminis- nontreatment, and a similar analysis for reasonable trative regulation does not prevent a finding of neg- alternative therapies. A practitioner who fails to ligence where a reasonable (person) would take provide such information to aid informed consent additional precaution^."'^ of the patient may be judged negligent.16J7 Regulations by the FDA provide that a manu- In a failure-to-inform case, the dentist’s mis- facturer may change an approved drug label before conduct is nonfeasance (ie, nonperformance) approval if the change is intended to add or rather than misfeasance (ie, improper perfor- siringthen warnings OF instructions or delete false mance). In most states, failure to inform a patient or misleading claims for use or effectiveness. The of a material risk constitutes a legal cause for the FDA has the authority to take actions that avoid patient’s injury if a reasonably prudent patient, the use of false or misleading labels on drugs. The when fully informed of the material risks, would FDA’s Labeling and Nomenclature Committee have avoided the risk by not consenting to the pro- (LNC) was established to facilitate trademark posed therapy. Accordingly, informed consent is review for products, as well as the labeling of prod- tested objectively, ie, what would a reasonably pru- ucts that are brought before the FDA for approval. dent person in the patient’s position have decided The FDA does not perform its own drug test- if adequately informed of all significant perils?15 ing. Instead, the FDA relies on each manufacturer’s Whether a dentist’s failure to inform causes injury candor and integrity in submitting drug data both turns not on biomechanical principles, but rather before and after approval. Before being marketed, on human factors measuring reasonable risk avoid- prescription drugs must be proven safe and effec- ance when adequately informed. tive in double-blinded clinical studies authorized Merely because a dentist adequately informs a by the FDA (21 United States Code, section 321). patient of the material risks of a procedure does not necessarily relieve the dentist of liability if the INFORMED CONSENTVERSUS risk subsequently materializes. Informed consent is MISREPRESENTATION not an “affirmative defense” to negligent treatment.16J7That is, it is immaterial that the dentist The dentist has a duty to disclose all material infor- warned the patient of a material risk if the dentist mation to enable the patient to make an informed performs negligent treatment. Adequate informed decision regarding proposed procedures or treat- consent avoids liability only when treatment is per- ment. This would comprise information that the formed non-negligently, and a previously disclosed dentist knows or should know and would be material risk subsequently manifests. 276 Periodontal Medicine

If the practitioner intentionally misrepresents ment may adversely affect the patient’s general known therapeutic goals, limitations, or risks, the health. Discussions with the patient’s physician practitioner may be subject to a fraud claim for should be documented and confirmed by facsimile intentionally deceiving the patient. Fraudulent mis- or letter. representations may include intentional overstate- The dentist who blindly follows the physician’s ment of surgical success while minimizing risks, recommendation, even when it conflicts with his claiming another’s success as one’s own, or quoting own professional judgment, probably violates the national success statistics when the quoting practi- standard of reasonable care. Each independent tioner‘s own success rate is substantially lower.l8>l9 practitioner is ultimately responsible for treatment Negligent misrepresentations involve state- decisions and should not rely on unreasonable rec- ments that have no reasonable basis (eg, a state- ommendations that are contrary to established ment to a 30-year-old patient that her newly specialty parameters of care. When the treatment placed upper anterior crown should last a lifetime). decisions conflict with each other, allowing the Professional liability insurance carriers will patient to choose is permissible provided that both defend a suit which claims both negligence and the dentist’s and the physician’s treatment recom- fraud and will indemnify or reimburse the dentist mendations are reasonable. for negligent acts. However, carriers are usually prohibited from indemnifi-ing or reimbursing PERIODONTAL EXAMINATION intentional acts, such as fraud, as contrary to pub- AND RE-EVALUATION lic policy, since liability insurance is intended to cover only unintentional (ie, negligent) conduct The American Academy of Periodontology recom- (California Insurance Code section 533).20 The mends that its Parameters on Comprehensive Peri- practitioner is generally responsible for payment of odontal Examination (1995) be regarded as the any judgments for the portion arising from inten- “standard of care for periodontal examinations.” tional misdeeds such as fraud. Periodic re-evaluation following therapy is essential to assess stability or hrther breakdown. Both host resistance and local factors can affect REFUSAL TO TREAT long-term maintenance. If disease deterioration occurs, the patient must be reassessed for both host Dentists are not obligated to render treatment that resistance and local factors. A practitioner who fails is not in the patient’s best interest, regardless of the to properly re-evaluate the patient’s disease state patient’s requests. In other words, if the patient cannot appreciate whether or not the patient’s requests treatment which the dentist knows to be health is being adequately maintained and there- improper or contraindicated, the practitioner fore fails to make adequate diagnostic or therapeu- should not accede to a patient’s request for negligent tic decisions. The American Academy of Periodon- care.“ Rather, the dentist should rehse to treat. tology Professional Policy Statement on Periodon- A dentist is also not obligated to treat a patient tal Disease Detection states: “Following treatment, when there is professional disagreement. When the the patient must be carefully monitored by the dentist declines to begin or continue treatment, the periodontist and the dentist for recurrence of any patient should be advised in writing and provided diseases. Periodic periodontal examinations must with names and addresses of other dentists the be performed, and the records compared to post- patient could go to for treatment. A patient may be treatment recordings. This is essential in order to discharged after reasonable notice so long as the monitor the effectiveness of therapy during this dentist’s rehsal to continue treatment does not jeop- professional maintenance phase. This maintenance ardize the patient’s dental or physical health before phase is essential to ensure long-term periodontal the patient’s appointment with a new dentist. health and the retention of natural teeth.” A dentist’s rehsal to treat may not be based on If the patient is presently periodontally disease discriminating reasons for protected classes, such free, the statement also recommends the following as the disabled, or for racial reasons.21,22 long-term care parameters: “All patients must be screened for the presence of periodontal diseases on PHYSICIAN CONSULTATIONS a regular basis. When periodontal diseases are detected, a comprehensive charting record must be A dentist should consult the patient’s physician completed and effective treatment should be ren- whenever the proposed dental procedure or treat- dered promptly.” Medicolegal Issues 277

RISK FACTORS extraction for over 100 years.24Linkage of oral and systemic disease with anecdotal unscientific The standard of care requires practitioners to be research risks unnecessary treatment. For example, aware of risk factors and to diagnose the patient‘s risk attributing systemic illness to dental amalgam is susceptibility in order to control or eliminate the risk another example of misstated science since, except factor. Failure to do so or to counsel a patient regard- in the extremely rare instances of mercury allergies, ing such factors may render the practitioner liable. there is no proven connection between dental Risk factor testing is standard practice since amalgam, mercury vapors, and systemic disease.25 prevention of serious disease is the hallmark of modern medicine. A carehl medical history identi- Inherited Risk Factors: fies risk factors and the need for a follow-up inter- Genetic Predisposition view or testing. For example, although the cause of heart disease may be multifactorial (including diet, A patient’s genetic composition is unchangeable. blood pressure, stress, and myriad other factors), a However, knowledge of genetic predisposition may physician must identifi; counsel, and appropriately affect treatment decisions and prognosis. Perio- refer for risk factor reduction, particularly when dontal disease occurs only in susceptible individuals. failure to do so may have fatal complications or Therefore, knowledge of the unchangeable elements cause serious injury. One well-known example of disease susceptibility help the practitioner in involves the relationship between cholesterol level determining which factors of host resistance to dis- and heart disease. Elevated cholesterol levels have a ease are changeable and which are unchangeable. risk ratio of 2.4.23Physician identification, counsel- According to one study, IL-I -genotype-posi- ing, and public awareness have resulted in changed tive patients have a 6.8-fold increased risk for severe diets and increased exercise to lower cholesterol lev- periodontal disease.23 Awareness of the genetic els and thereby reduce the cholesterol risk factor. marker for periodontal disease may allow the prac- This same medical model is increasingly being titioner to be aware of susceptibility to severe peri- applied to dentistry, in general, and periodontics, in odontal disease. Earlier onset and more rapid pro- particular. Many risk factors can be identified and gression of periodontal pathology are postulated communicated to patients, and their elimination but, to date, it is known only that IL-1-positive can be incorporated into periodontal therapy. Peri- subjects have been shown to be at greater risk for odontal disease risk factors may include (1) inherit- severe periodontitis in cross-sectional studies. Lon- ed risk factors (genetic predisposition), (2) systemic gitudinal data to show greater disease progression in risk factors, such as metabolic diseases, (3) acquired genotype-positive subjects are being gathered. risk factors, such as diet or excessive smoking, and Therefore, a genetic risk factor assessment may help (4) local risk factors, such as plaque and calculus. the practitioner and patient choose treatment Most acquired and local risk factors can be modi- options and determine whether increased frequen- fied or eliminated after the dentist first assesses a cy of monitoring is warranted. Informed consent patient’s potential risk factors and provides or rec- reflects the patient’s choice after disclosure of mate- ommends appropriate counseling and/or therapy. rial therapeutic risks. The more informed both Statistical associations or risk factors identify at- patient and practitioner become in determining risk patients who exhibit increased susceptibility to disease prognosis and susceptibility, the more the initiation or progression of periodontitis. informed they become regarding the level of accept- Although the standard of care requires the prudent able risks each is willing to assume in treatment practitioner to both identify and minimize such risk planning. For instance, a practitioner may prudent- factors, whether the failure to do so actually caused ly advise a young genotype-positive patient that a or aggravated periodontitis may be difficult to prove maxillary molar with moderate to severe periodon- in a legal case. By analogy, not all smokers develop titis may have a relatively poor prognosis. If that lung cancer. Nor do all hypertensive patients molar required extensive restorative treatment, the inevitably suffer strokes or myocardial infarcts. patient might elect extraction and replacement with In the 18th century, Benjamin Rush, a Penn- a fured partial denture. Another usehl example of sylvania physician and signer of the Declaration of knowledge of genetic predisposition is a young Independence, reported that arthritis sufferers patient with root resorption secondary to ortho- found relief after their infected teeth were extract- dontics performed during the patient’s teen years. ed. This theory of foci of infection, now aban- The prognosis will be affected by whether this doned, promoted unnecessary and wholesale teeth patient will ever suffer periodontitis since the 278 Periodontal Medicine crown-root ratio is already diminished. Long-term loss. Postmenopausal patients may demonstrate studies extend up to only 15 years.26Thus, know- changed bone density following periodontal dis- ing whether a 25-year-old patient is likely to suffer ease e1iminatio1.1.~~Further longitudinal studies are loss of periodontal attachment after 15 years, at age required to explore the extent of the linkage 40, because of a genetic positive risk factor, would between periodontitis and osteoporosis. aid prognosis and evaluation. Genetic testing is an optional diagnostic aid. If Acquired Risk Factors improved technology can aid treatment decisions, it is the patient’s right to know of newer diagnostic Smoking technology in order to make an informed rehsal Smoking and other types of tobacco use are regard- decision or elect such testing. The PSYtest is based ed as one of the primary proven risk factors for on the research premise that 30% of the population periodontal disease. Physicians and dentists alike has an interleukin-I gene polymorphism causing are obligated to counsel patients to curtail or elim- such individuals to produce greater IL-I levels as a inate tobacco use because of the myriad associated host response to bacterial plaque.27Not all popula- health risks. Since tobacco is addictive, counseling tions have a similar prevalence of this IL-I genotype. patients as close to the onset of the smoking habit Genetic testing of a Chinese population group as possible is essential.33 revealed only 2% genopositive rather than the 30% Excessive smoking is an important considera- prevalence on which the PSTtest is premi~ed.~~.~~tion in periodontal disease management. The diffi- Genetic testing must be done with the hll culty in controlling this risk factor is due to the knowledge and consent of the patient since surrep- patient’s addiction, which limits a patient’s voli- titious genetic testing, even for experimental rea- tional control. Nevertheless, it is the practitioner’s sons, violates the patient’s constitutional privacy obligation to counsel the patient to discontinue rights, as well as the fourth amendment protection tobacco use and to alert the patient that continued against illegal ~earches.~’ presence of the risk factor may adversely affect treatment outcomes. Systemic Risk Factors Oral Hygiene Diabetes Patients with significant pathologic periodontal Diabetes is a recognized risk factor for periodontal pockets have demonstrated periodontal disease disease progression primarily when metabolic con- susceptibility and require constant periodontal trol if poor. Conversely, if the diabetes is con- maintenance procedures (PMP) at frequent (usual- trolled, diabetic patients are generally not at risk ly quarterly) intervals. Regular and frequent PMP for increased disease progression. can maintain the oral health of even patients with Findings that periodontal disease adversely less than adequate oral affects diabetic control suggest a two-way street between certain metabolic systemic diseases and Stress periodontal disease. Elimination or reduction of Stress has become an inescapable component of oral infection has resulted in improved metabolic daily life and a periodontal disease risk factor. control of diabetes.31If further studies substantiate However, only those patients who are unable to these present research studies, both the physician successfully cope with or overcome life’s stresses are and dentist may reduce the risk for diabetic com- at increased risk for periodontal disease.38Dentists plications by proper periodontal disease control. should consider heightened stress levels when Both the systemic condition and the localized assessing risk factors for periodontitis. periodontal disease must be controlled for optimal Most dentists, however, lack sufficient training health. Therefore, physicians and dentists need to to assess a patient’s stress level and/or ability for interact in the overall management of patients to stress management. A referral to a psychotherapist ensure that neither the periodontitis nor the diabetes for stress reduction may be appropriate for some spirals out of control and adversely affect each other. patients, for example, in the patient with refractory periodontal disease when disease progression Osteoporosis defies conventional local therapy management. A The linkage between periodontal disease and simple screening device (Figure 16-1), incorporat- osteoporosk may represent different aspects of the ed into the health history questionnaire, may assist bone loss process: oral bone loss and systemic bone the dentist in identifying a patient’s stress level. Medicolegal Issues 279

If the patient answers “No” to the coping skills Preterm Birth and “Yes” to counseling needs, the practitioner The relationship between periodontal disease and should consider referral to a trained Imofessional in preterm low-birth-weight (PLBW) babies deserves stress management. This will assist in the control of further study of the connecting links of this associ- periodontitis, particularly if it is refractory or subject ation chain. Preterm birth is frequently considered to frequent recurrence as determined at PMP visits. multifactorial since its causes are multiple and diverse. Risk factors include malnutrition, drug Cardiovascular Disease abuse, smoking, and lack of prenatal care. Recent Since cardiovascular disease is the leading cause of periodontal research preliminarily suggests severe death, any reduction in cardiac disease is of vital periodontal disease as a risk factor.45 health care concern. Preliminary research evidence Maternal infections predispose to preterm suggests a linkage between periodontal disease and labor, membrane rupture, and spontaneous birth of cardiovascular Whether a causal relation- low-birth-weight babies. Preliminary research with ship exists or there is a predisposed patient group a relatively small case-control study population at risk for both periodontal and cardiac disease assessed an added risk of more severe periodontal remains a further research challenge. disease associated with primiparous (first live birth) Current scientific studies seek to confirm the mothers and small preterm birth (SPB). Whether association between periodontitis and heart disease. this is a true interactive risk factor or an indepen- Links have been discovered between oral health and dent incident awaits future study of research groups systemic medical problems. However, the major with greater statistical power. Therefore, it is pre- issue is distinguishingU U a causal relationshbI from a mature to definitively link premature births and coincidental connection between oral and systemic periodontal disease; if proven, however, it would diseases of a patient susceptible to both diseases. mandate counseling pregnant women to control Evidence to date does not conclusively prove a periodontal disease to avoid the risk of SPB. cause-and-effect link between periodontal and car- Identifying a single risk factor and eliminating diovascular diseases. Rather, preliminary research it does not always reduce disease incidence. For suggests that periodontal disease may increase the instance, when measuring the effect of eliminating risk of cardiovascular disease.40However, scientifi- single risk factors, such as malnutrition and prena- cally, it is premature for a dentist to advise a patient tal care, on rates of premature birth when studied that periodontal disease will lead to a greater risk of in isolation, elimination of such single risk factors stroke and heart attack since the definite causative has not resulted in a decline in preterm birth.41 linkage requires research studies with greater statis- Thus, data from multiple trials of single risk fac- tical power. Nor can prudent practitioners state that tors have provided substantial evidence that con- periodontitis is frequently associated with cardiac trolling only one single factor failed to reduce disease since a definite causal link has not been con- preterm birth clusively established. Rather, periodontal disease Controlling preterm delivery and low birth may be one of many potential risk factors for car- weight has proven an often insurmountable obstet- diovascular disease. One plausible explanation of the association between cardiovascular and periodontal diseases may be that the same patient group susceptible to heart disease may also be susceptible to periodontal disease, rather than one disease triggering the other disease. Another unproven theory is that periodontal disease may represent an early manifestation of a broader systemic disease component which will continue to progress to the more serious cardiac disease unless the same contributing risk factors are controlled, such as smoking or excessive stress. Further research may determine whether periodontal disease is the prognostic precursor to cardiovascular disease or if periodontitis acts as an aggravating factor in cardiac disease management . Figure 16-1. A simple screening questionnaire. 2 8 0 Periodontal Medicine rical challenge since the 10% risk of SPB has not conformance with the AHA guidelines. changed in the past 40 years despite improved pre- Antibacterial mouthrinse products such as natal care.47On the other hand, neonatal medicine chlorhexidine have proven effective in decreasing has improved survival rates of premature births. the overall oral quantity of bacteria and reducing the Further research will establish whether periodonti- incidents of bacteremia associated with third molar tis disease severity is a marker for a risk factor, extractions as well as localized al~eolitis.4”~~Use of which can prognosticate a preterm delivery suscep- these mouthrinse products prior to surgery makes tibility. If proven, clinical periodontal parameters empirical sense and is endorsed by the British or periodontal gingival crevicular fluid testing may antimicrobial societies. However, antibacterial rinses prove to be valuable screening tests for SPB risk are not proven as an efficacious substitute for assessment. administration of systemic antibiotic prophylaxis where otherwise indicated for SBE-at-risk patients. Local Risk Factors Mechanical irrigation devices can cause bacteremias, especially in the presence of chronic or Bacterial plaque is regarded as the primary acute periodontal infective states associated with causative agent for periodontitis. Nonetheless, not poor oral hygiene. These devices have the potential all patients with heavy plaque deposits develop for introducing larger bacteria boluses than brush- severe periodontitis. Consequently, plaque is a risk ing or flossing and therefore are not generally rec- factor which only causes periodontal disease mani- ommended for at-risk SBE patients. festation in a susceptible host. The FDA removed fiom the market Fen (fenfluramine aka Pondimin), as well as the chemically related drug dexfenfluramine (aka Redux) after SUBACUTE BACTERIAL reports linked these medications to heart valve E NDOCARD IT1 S abnormalities. The benefit of suppressing appetite did not outweigh the risk of valvular heart defects The mouth is a well-known reservoir of more associated with the altered metabolism of serotonin species of organisms than any other area of the related to these drugs and their off-label prescription. body. Many cases of subacute bacterial endocarditis Both the AHA and the American College of (SBE) have no known causative precipitating event. Cardiology (ACC) now recommend that patients However, no studies have shown that procedures who have taken these drugs should undergo a such as brushing and flossing can create a bacterial stethoscope examination for heart valvular defects inoculum of sufficient size to establish infective and a follow-up examination in 6 to 8 months. seeding of existing endocardial vegetations. It is Patients with symptoms of shortness of breath, therefore scientifically unsound and unproven to chest pain, or heart murmurs should have an recommend that patients at risk for SBE cease or echocardiographic examination. Asymptomatic curtail daily oral hygiene procedures to avoid pre- patients may have echocardiography depending cipitating bacteremias. On the other hand, both the upon the physician’s clinical judgment. American Dental Association (ADA) and the Although the incidence of valvular heart American Heart Association (AHA) strongly rec- defects appears to be a hnction of the length of ommend that SBE-susceptible patients maintain time that the patient takes the medication, the impeccable oral hygiene. Elimination or control of standard of care obligates the dentist to obtain a periodontal pockets reduces the potential that large history of such diet drug usage. A medical consul- numbers of bacteria will invade the bloodstream tation is necessary (if not previously obtained) for and thus reduces the potential for periodontal all patients who have taken diet drugs, including pathogens to contribute to an SBE exacerbation. those that are not at risk for SBE. The AHA recommends that any dental procedure capable of producing “significant” bleeding has the potential of introducing oral bacteria into DRUG SIDE EFFECTS the bloodstream and, as such, requires prophylaxis with an appropriate antibiotic for at-risk SBE Prudent periodontics carefully weighs risks against patients.43The AHA notes in its recommendations benefits of any prescribed or performed therapy. that the clinician’s judgment may supersede a given Newer local delivery drugs enjoy the benefit of sus- recommendation. However, unless good cause tained local release of the drug over a period of exists for deviation, the standard of care requires days or weeks, rather than hours. Tetracycline Medicolegal Issues 28 1 fibers may be impractical in many instances for of adult periodontitis. Accordingly, the routine use routine clinical application because it is time con- of local delivery agents with scaling and root plan- suming to place and maintain the fibers in the ing is usually not justified and is presently an off- pocket during the recommended period of use. On label use. Local delivery agents are most often used the other hand, second generation delivery agents, as adjunctive therapy to conventional care for non- such as gels or chips, are both patient and dentist responding sites with moderate pocket depth or in friendly and less time consuming to apply. patients who have recurrent disease despite repeat- Packet inserts for local delivery drugs list con- ed scaling and root planing. Long-term studies are traindications, including allergies. The practitioner needed to veri+ the efficacy of combined therapy may be liable for failure to follow or advise patients even in these instances of these warnings on drug packet inserts. Liability Fiberoptic illumination, which provides in- may also result from failure to follow Physician creased visual access to the subgingival space, Desk Reference recommendations. However, these increases the effectiveness of calculus removal on failures alone do not establish violation of the stan- root surfaces. Complete removal of subgingival cal- dard of care unless an expert so testifies.51 culus is limited during root planing. Greater pock- For instance, the packet insert for Periostat et depths often result in increased residual calculus (doxycycline hyclate) capsules warns of tetracycline due to the increased area of root surface to be hypersensitivity and possible discoloration of per- scaled and the increased number of irregularities manent teeth if used during the latter half of preg- found on the root surface. Deep narrow pockets nancy, or up to age 8 years. Discoloration is more impede accessibility to root irregularities. common during long-term use, but may also occur Flap exposure surgery of root surfaces also during repeated short-term courses. greatly enhances the effectiveness of scaling and The manufacturer of doxycycline warns that root planing. In one study, an average of 20% of the drug may cause harm to the fetus. The manu- postsurgery surfaces had residual calculus.52Non- factureralso advises that “concurrent use of tetracy- surgical pocket distention procedures resulted in cline may render oral contraceptives less effective.” approximately 40% of the root surfaces having An increased risk of a wronghl life lawsuit (birth of residual calculus.57If flap exposure or pocket dis- unplanned child) may occur if the patient is pre- tension procedures were not used, 64% of the root scribed doxycycline but is not adequately advised of surfaces had residual calculus.57 any increased risk of unwanted pregnancy and the Pocket distention following tetracycline fiber oral contraceptive dosage is not adjusted or alterna- removal provides improved visual detection of resid- tive birth-control methods advised. ual calculus. Thus, a possible added advantage to the Since photosensitivity has also been associated use of the tetracycline fiber local delivery system is with the tetracyclines, patients taking these drugs, the increased visual access immediately following including doxycycline, should be cautioned regard- fiber removal, which aids root calculus removal. ing excessive exposure to direct sunlight or any No studies have addressed the use of local drug ultraviolet light. Tetracyclines have also been delivery in specific types of periodontal bony shown to depress plasma prothrombin activity. defects such as intrabony defects or class I1 furca- Thus, patients taking anticoagulant therapy may tions. Results from studies assessing local drug require a downward adjustment of their anticoag- delivery systems have not justified extending the ulan t dosage. time interval between supportive PMP visits by Although the doxycycline dosage in Periostat is substituting them with local delivery therapies. below the concentration required to inhibit peri- Local delivery agents should be used as thera- odontitis-associated microorganisms, the lower peutic adjunctive aids rather than as monotherapy. dosage does not eliminate contraindications, drug Contraindications for using local delivery drugs interactions, allergies, or potential teratogenic include using them as (I) a replacement for thor- effects. Since the dosage of these newer drugs is ough scaling and root planing, and (2) full-mouth lower than the dosage used to treat other infections, treatment rather than specific local sites. the development of resistant strains of microorgan- Efficacious therapies that benefit the patient’s isms is reduced. Other local delivery tetracycline health should be the practitioner’s first considera- drugs, such as minocycline, are in clinical trials and tion rather than the financial gain from it. There- should be marketed in the near hture. fore, a third-party insurance carrier‘s allowance of Mechanical instrumentation with scaling and insurance benefits for local delivery agents should root planing has proven effective in the treatment not compromise necessary therapy, nor decrease 282 Periodontal Medicine the frequency of the scaling and root planing pro- doubled or tripled still does not reach the 51% or cedures. Prudent practitioners are primarily oblig- higher proof threshold. It is difficult to prove that ated to treat the patient’s periodontal pockets a particular risk manifested in any one patient rather than comply with the insurance carrier’s dic- caused severe or worsened periodontitis. Thus, epi- tates, or financial pockets. demiologic data of increased risk in the general population does not prove individual causation. Accordingly, a practitioner who fails to recognize BURDEN OF PROOF or reduce the risk factors (thereby violating the standard of care) may yet avoid liability if the “Burden of proof” refers to one party’s obligation patient-plaintiff cannot prove by a preponderance to produce sufficient evidence to prove the fact or of the evidence that the nonrecognition or non- contention proffered. “A party has the burden of treatment of a particular risk factor caused or proof as to each fact, the existence or nonexistence aggravated the particular disease at issue. of which is essential to the claim for relief or If scientific evidence cannot establish the defense that he is asserting.” (California Evidence greater weight of evidence in a particular case, the Code section 500) plaintiff may not prevail since the plaintiff will In a civil case, the burden of proof must be have failed to provide the burden of proof neces- established by a preponderance of the evidence. sary to establish causation despite epidemiologic Preponderance implies the greater weight of the evidence of the increased disease incidence in the evidence, ie, a probability (versus a possibility) of general population. truth or an event that is more likely than not to Epidemiologic research does not establish have occurred or be true. Vague, inconclusive, or individual cause and effect but only suggests a uncertain evidence fails to meet the burden of potential relationship. Epidemiologic studies best proof and is considered conjectural or speculative. identifi- very powerful associations, such as in a A patient-plaintiff bringing a professional neg- cohort study in which large groups of people are ligence lawsuit generally bears the burden of prov- followed up for a long time. One research study ing by a preponderance, or greater weight, of the alone does not establish the gold standard of care. evidence the following elements: ( 1) negligence, The hallmark of science is experimental replication (2) causation, and (3) damages. A defendant-den- in other independent studies that proves the hypo- tist bears the burden of proving by a preponder- thetical or premised postulate. However, a multi- ance of the evidence any affirmative defense, such center study does not always ensure scientific accu- as lack of adequate oral hygiene, missed mainte- racy if a flawed research methodology is repeated at nance, or refused specialist referral. multiple cent er^.^^-^^ Stated otherwise, the patient-plaintiff must Defense attorneys are particularly skillful in prove by at least a 5 I% or greater likelihood that exploring other causes of diseases, which can be (1) the defendant-dentist violated the standard of multifactorial. Tobacco companies have, for many care, (2) that the defendant’s negligence caused or years, successfully defended lung cancer cases since aggravated the plaintiff‘s periodontitis, and (3) a particular patient’s etiology for lung cancer may injury or damages resulted. For example, the be explained by factors other than tobacco, such as patient-plaintiff may be able to prove that the den- environmental, work-related, or idiopathic causes. tist violated the standard of care by not informing Tobacco companies also argue that they should the patient of the potentially deleterious effects of not be held accountable for the well-publicized stress on the patient’s periodontal health. However, risks of cigarettes which was well-known for years if the patient-plaintiff cannot prove that stress and further argue that there is no fraud to attempt aggravated his periodontitis, the evidence may be to hide something already known, such as risks of speculative that in his individual case the particular using tobacco. risk factor (stress) was the causative culprit. Con- Similarly, defense counsel defending periodon- versely, if the defendant-dentist contended that the tal negligence actions have been able to establish patient-plaintiff was at fault because of his smok- that risk factors such as smoking, poor oral ing, the defendant bears the burden of proving the hygiene, stress, or systemic diseases caused or plaintiff‘s smoking aggravated his periodontitis. aggravated a patient’s periodontal disease, rather As only a minority of the population develop than the dentist-defendant’s negligence. Although severe pathologic periodontal pockets that cause earlier periodontal literature was equivocal on the premature tooth loss, a risk factor of only 15% role of tobacco and periodontal disease,59 recent Medicolegal Issues 2 8 3 literature has established tobacco’s role as one of child took cookies from the cookie jar, even the most significant risk factors.“ though the act was not seen. Although in some states advising the patient of Circumstantial evidence is legally accepted as the greater risk, such as death, absolves the practi- equally convincing as direct testimony.61It is pos- tioner from failing to advise of the lesser risk, other tulated that periodontal disease is episodic and states (eg, Minnesota) require the practitioner to consists of bursts of activities; however, rather than advise patients of virtually all risks, such as impo- showing linear progression,62 circumstantial evi- tence which is a long-term health risk secondary to dence may help establish a causative link with par- smoking (88 ALR 3rd 1008). A practitioner ticular risk factors if significant periodontal disease should also include long-term risk assessment as progression coincided with risk factors such as part of a patient’s comprehensive health care eval- periods of uncontrolled diabetes or excessive smok- uation or re-evaluation. Comprehensive care ing, and disease activity ceased when the diabetes should include not only diagnosis of existing dis- was controlled or the smoking eliminated. If the eases but also health care warnings of known risk periodontal disease worsened after another bout of factors as part of a preventive health care measure. uncontrolled diabetes or resumption of smoking, Periodontal disease represents a non-life-threaten- the circumstantial evidence link may reasonably be ing disease associated with smoking. established as corroborative evidence. After first consulting with the patient’s physi- Both the scientific community and the courts cian, the patient may be cautioned that the smok- accept circumstantial evidence as proof of a postu- ing is not only beginning to manifest as oral dis- late.“ For example, a classic periodontal study ease, which is one of many predictable diseases demonstrated that dental students developed gin- associated with smoking, but that continuation givitis with failure to maintain oral hygiene and can cause other more serious diseases as well since that the condition was reversed when oral hygiene the patient has already demonstrated weakened measures were restored.63 host resistance and disease susceptibility. Alerting A patient-plaintiff need not prove in a lawsuit the patient’s physician of oral evidence (eg, peri- that the practitioner’s negligence was the sole cause odontitis) of the patient’s host resistance beginning of the patient’s disease but, rather, that such negli- to break down may serve as an early warning that gence was a substantial factor in causing injury.64 other more serious systemic diseases may occur in For instance, an expert may testi+ that defective the future. Thus, a prudent practitioner should not restorations predispose to bacterial plaque accumu- only diagnose early warning signs of known dis- lation and resulting periodontal disease.65 If peri- eases but also consider alerting the patient to con- odontal disease is confined to the offending plaque sult with the patient’s physician to determine if the retentive restorations, rather than being generalized, current manifestations of less serious diseases por- such evidence constitutes circumstantial evidence tend the worsening of these diseases and the likely which supports the expert’s opinion that the defec- development of more serious diseases linked with tive plaque-accumulating restoration substantially the same risk factor. increased the risk for localized periodontal disease. This opinion is particularly apt if it is clear that the patient’s natural host resistance prevented periodon- CIRCUMSTANTIAL EVIDENCE tal disease elsewhere in the mouth where the patient had similar types of restorations that were not defec- Evidence is either direct or circumstantial. Direct tive. Such comparative evidence constitutes strong evidence proves a fact without the need for any circumstantial evidence that restorative deficiencies inferences. Circumstantial evidence, on the other caused the localized periodontal disease. hand, proves a fact or facts from which an infer- ence of the existence of another fact may be drawn. For example, the fact that a child was taking cook- RESEARCH EVIDENCE ies from the cookie jar can be established if the child was seen taking a cookie from the jar, which Scientific research is the basis for evidence-based is direct evidence. If, on the other hand, the only parameters of care. Traditionally, most dental clin- visual evidence is a half-empty cookie jar, a trail of ical decisions were based on the clinician’s experi- cookie crumbs to the child‘s bedroom, and an ence. In an evidence-based approach, however, all unhungry child at dinner that night, it is circum- scientific evidence is not accorded the same weight. stantial evidence which infers the fact that the The stronger the scientific supporting evidence, 284 Periodontal Medicine the stronger is the supporting recommendation." instance, the recent FDA approvals of local delivery An evidence-based approach places greater weight drugs were based on a 9-month study.69 The sup- on analytic methods that determine both statistical porting research studies to obtain FDA approval and clinical significance as well as measure both evaluated the therapeutic efficacy of local drug ther- risks and benefits. Scientific standards include (1) apy on chronic periodontal disease. Periodontal dis- double-blind, placebo-controlled clinical trial to ease progresses episodically over years, with periods reduce potential bias, and (2) longitudinal studies of remission or exacerbation. Yet, the FDA approved to evaluate the long-term effects of treatment alter- for marketing these local delivery drugs with a ing the natural history of a disease. study that lasted only three-quarters of a year. Under federal law, scientific evidence concern- The manuhcturer also made claims that pocket ing health care has to meet scientific standards of reduction and clinical attachment levels, when proof before being admitted into evidence for the combined with scaling and root planing, were jury's consideration. Four factors that must be eval- superior to or at least equalled scaling and root uated to determine if a scientific theory or tech- planing alone. Reading the study's research proto- nique is reliable are: col reveals that the so-called combined therapy group of the experimental drug, when combined whether it has been, or can be, tested; with scaling and root planing, only existed at base- whether it has been subjected to peer review or line. Thereafter, scaling and root planing were not publication; repeated at 3 months, 6 months, or at the conclusion its known or potential rate of error; and of the 9-month period studied. Patients with moder- whether it is generally accepted by the relevant ate periodontal disease consisting of 5- to 6-mm scientific c0mmunity.~7~~ pockets with bleeding on probing who were stud- Emerging and changing technologies offer ied in the research group should have been gener- great benefit to patient care but challenge the pru- ally maintained with periodontal procedures on a dent practitioner to carefully evaluate manufactur- quarterly basis. General practitioners would likely er-supported studies for biased interpretation or have performed subgingival dkbridement at (mini- inadequate research. Due to political pressures, mal) 6-month intervals. Consequently, the study governmental agencies have shortened the review evaluated what occurred in those that may be time as well as the review process for approval. regarded as poorly maintained patients, ie, who Manufacturers frequently argue that governmental were maintained solely on the locally delivered approval delays are due to governmental bureau- drug rather than with quarterly subgingival cracy rather than the adequacy of research data. dkbridement as is common practice. This is but However, it is important to realize that the pres- one of many examples where a prudent practition- sures to rush a new product to market may also er should carefully evaluate advertised conclusions bring about conclusions that have not stood the before blindly adopting them. test of time with long-term clinical studies. Drug manufacturers are liable if their sales per- Manufacturer-subsidized researchers use gov- sonnel promote an FDA-approved drug with mis- ernmental agency approval (such as FDA approval) leading statements, if the manufacturer is aware of in their claim for efficacy or superiority. Instead of such marketing abuses.70 The individual practi- blindly accepting all advertising claims, prudent tioner need not abide by FDA-approved uses only practitioners must independently assess the validi- and may prescribe a drug for uses unapproved by ty of the research claims as biased research or disin- the FDA but the practitioner who strays beyond genuous data create untrustworthy research con- the FDA-approved line risks engaging in experi- clusions and interpretations. mental medicine. Prescribing a drug for unap- Governmental approval has not always proven proved use may be based only on empirical anec- efficacious in the disclosure of risk assessment. The dotal evidence rather than controlled careful burden of assessing advertised claims has increas- research studies. ingly shifted to the prudent practitioner, who must Diet drugs, such as Pondimin and Redux, are carefully evaluate the foundation of research con- a case in point. Although the FDA approved each clusions of claimed product efficacy or superiority drug individually by specific labelled use, the FDA before wholesale adoption of new devices or thera- never approved the combination of fenfluramine pies and abandonment of the time-tested methods. and Phentermine for birth control. Consequently, Multicenter research studies do not always risks of heart valve damage, which would likely guarantee statistically valid research conclusions. For have manifested with long-term clinical testing in Medicolegal Issues 2 8 5 a research controlled environment with sufficient but controlled, trials, has resulted in improved pre- numbers of patients, were undetected before mass ventive measures, such as vaccines and disease prescription of the potentially dangerous drug screening, as well as more efficacious therapies. combination occurred.* In applying diagnostic algorithms, objective Long-term clinical trials with vast numbers of probability estimates should be grounded in data studied patients are often regarded as the ideal valid- from well-designed studies to minimize the effect of ity test group for clinical research. Different patient numerous biases that potentially cloud diagnostic population groups need to be evaluated to avoid analysis. Studies that compare patients with severe erroneous diagnoses. Nevertheless, such platinum- disease with normal, healthy volunteers, may over- standard protocols may be tarnished if control estimate the usehlness of diagnostic testing.72 groups are not matched with the studied groups Statistical validity is a critical issue to measure for similar variables. Data inaccuracy results when quality that explains a substantial variation in there is misclassification between subgroups, research results, including tentative or uncertain which may affect the research trial results. In order to have predictably valid results, elim- Case reports describe a single case with clear ination of heterogeneity between trial groups is benefits. The degree of benefit derived from the necessary. Discrepancies occur within clinical new treatment is often greater in single case reports research trial groups so that the concept of com- than in large cohort studies of patients entered into parison of similar homogeneous groups is often a a trial study. myth, considering the variable treatment responses To obtain FDA approval, two well-controlled of different persons, populations, and protocols. If clinical trials are needed. Before prudent practi- the different groups studied have different risks, a tioners accept evidence for a new drug therapy, fair comparison cannot be established. This may they must ensure that it is based on a high propor- explain the reason for inconsistent results among tion of double-blind, randomized, placebo-con- various studies. Although a greater number of trolled clinical trials rather than on empirical con- patients provides greater statistical power, size clusions. The standard-of-care, evidence-based alone does not compensate for research method- approach can then integrate scientific research into ologic flaws. As one research team concluded: clinical practice. When scientific evidence is dis- puted, the court can appoint its own independent Periodontal research often confuses lack of sig- expert or panel of experts. For instance, a federal nificance in a clinical trial designed for superi- judge in Alabama established a scientific panel to ority for equivalence between different thera- help the court evaluate evidence in 8,600 nation- pies. Acceptable mean differences in equiva- wide breast implant cases.73The scientific panel set lency trials should be determined based not up under the Federal Rules of Evidence concluded only on statistical considerations, but also on that there was “no evidence that silicone breast clinical relevance of the proposed differences. implants precipitate novel immune responses or Equivalency trial has some concepts that induce systemic inflammation.” The independent are very different from those in a superiority panel also criticized other studies as “methodolog- design. It can be difficult distinguishing ically inadequate,” including flawed comparison between the items that are similar between the subjects, “unorthodox data analyses,” and other two designs and those that are different. problems. Also, “inconsistent results in studies Equivalency designs require larger sample sizes purporting to evaluate the same immunologic than their superiority counterparts. parameters are common.”

Scientific research continues to guide the prudent practitioner through the ever burgeoning COMPARATIVE NEGLIGENCE world of science. The long history of randomized, The U.S. legal system is based in part on the maxim, “No one can take advantage of his own *A Texas class action against American Home Products, wrong.” (California Civil Code section 35 17) seller of the diet drugs fenfluramine and dexfenfluramine, seeks medical screening for all Texans who took Regardless of how negligent the practitioner may the drugs for 60 days or more at a cost of around $500 have been, a patient’s own negligence (termed con- for each test. Class action certification of a Washington tributory negligence) may partially offset, or elim- state case is expected soon. inate, any liability. 2 8 6 Periodontal Medicine

In those states that recognize pure comparative nocere,” meaning “First, do no harm.” This prin- negligence, the patient’s negligence, if any, is com- ciple remains the bedrock foundation on which pared with the practitioner’s negligence, and any modern medicine provides optimum patient care. recovery by the patient is offset by the proportion Dentists are ethically obligated to adhere to the of the patient’s negligence. For example, if the patient‘s best dental health interest. The Hippocratic patient is held to have been 25% negligent, any Oath principles are embodied in the following: recovery for the patient is reduced by 25%. In I understand and accept that myprimary other states, if the patient’s negligence exceeds 5 I% “. . . responsibility is to my patients, and I shall ded- of the total negligent conduct of both plaintiff and icate myself to render, to the best of my abili- defendant, the plaintiff-patient may be completely ty, the highest standard of oral health care and denied from any recovery. to maintain a relationship of respect and con- Comparative negligence should be distinguished from failure to mitigate (minimize) dam- fidence. Therefore, let all come to me safe in the knowledge that their total health and well- ages. Comparative negligence assumes that the patient contributed to the cause or aggravation of being are myfirst considerations. . . .” [empha- the injury by the offending practitioner. If, after sis added.] (ADA Dentist’s Pledge, 1991) the injury occurred, the patient fails to obtain rec- Dentists are legally obligated to protect and ommended treatment from subsequent practition- preserve the patient’s health interests as foremost ers, the patient is held responsible for failing to since the dentist-patient relationship is fiduciary. minimize hrther damages. For example, in a case In the new millennium, periodontics recognizes alleging failure to diagnose and treat periodontal the obligation to protect and preserve the patient’s disease, the patient’s failure to maintain adequate total health care. Dentists and physicians are now oral hygiene and attend recommended quarterly able to see more clearly in the light of evidence- periodontal maintenance procedure appointments based periodontics. This new insight illuminates while under the care of the defendant-practitioner the inter-relationship between oral and systemic may constitute comparative negligence. The health rather than the tunnel vision of earlier views patient’s failure to also do so under the care of a which separated the periodontium from the body’s subsequent practitioner may constitute a failure to general health system. mitigate or reduce further damages. Patients advised to curtail or quit smoking but who hi1 to do so may arguably be held to be com- REFERENCES paratively negligent. However, if the patient is advised to restrict smoking after he or she has 1. California Book of Approved Civil Jury Instruc- become addicted to smoking, the volitional element tions (BAJI), BAJI No. 6.00.1. 1999. is substantially reduced or eliminated since the suc- 2. California Dental Association Peer Review Manu- cess of smoking cessation programs fiequently does al, page 1 (1995). not exceed 6%.74Conversely, the reasonably prudent 3. American Dental Association Statement on Dental patient may argue that the majority of patients in a Unit Waterlines (1995). similar situation cannot overcome smoking addic- 4. Simpson vs. Davis, 219 Kansas 584, 549 P2d 950 tion. Accordingly, it is not the patient‘s fault but, (1976). rather, the cigarette mandicturer whose advertise- 5. American Academy of Periodontology. Parameters of ments led to the addictive incurable smoking habit Comprehensive Periodontal Examination (1995). before the patient realized the pernicious effects of 6. American Academy of Periodontology. Parameters of smoking. Smokers > age 25 years only constitute Comprehensive Periodontal Examination (1995). 5% of addicted smokers.83A practitioner‘s advice to 7. Jury Award (120 Million) Against HMO is Biggest quit smoking is likely given to an addicted patient. Ever. Pittsburgh Post Gazette; January 22, 1999. The frustratingly small success rates of smoking ces- p. A17. sation programs are therefore not surprising. 8. Brown R, Hadley JN, Chambers DW. An evaluation of ektaspeed film versus ultraspeed film for endodontic working length determination. J CONCLUSION End0 1988;24:(1):54-6. 9. Hadley J. Dental radiology quality of care: the den- The guiding principle of the ancient Hippocratic tist makes the difference. J Calif Dent Assoc Oath for medical practitioners is “primum non 199523(5): 17-20. Medicolegal Issues 2 8 7

10. Kolstead RA. How well does the chemiclave steril- 30. Norman-Bloodshaw vs. Lawrence Berkeley Labora- ize handpieces? JADA 1998;129(7):985-91. tory. 9th Cir. 135 F.3d 1260 (1998). 11. Burke FJI, Coulter WA, Cheung SW, Pallemk MS. 3 1. Aldridge JC Lester V, Watts TLC et al. Single-blind Autoclave performance and practitioner knowl- studies on the effects of improved periodontal edge of autoclave use. A survey of selected UK health on metabolic control in type 2 diabetes practices. Quintessence Intl 1998;29(4):231-8. mellitus. J Periodontol 1996;67:166-76. 12. California Book of Approved Civil Jury Instruc- 32. Cohen DW, Rose LF. The periodontal-medical risk tions (BAJI), BAJI Nos. 6.01, 6.04. 1999. relationship. Compendium 1998;19: 11-24. 13. Fry RJ, Grosovsky A, Hanawalt PC, et al. The 33. Severson HH, Andrews JH, Lichtenstein E, et al. impact of biology on risk assessment. Workshop Using the hygiene visit to deliver a tobacco ces- of the National Research Council’s Board on sation program: results of a randomized clinical Radiation Effects Research. July 21-22, 1997. trial. JADA 1998;129:993-9. Radiation Research 1998;150(6):695-705. 34. Ramjford SE Maintenance care and supportive 14. Carlin vs. Superior Court. 13 Cal. 4th 1004, 920 periodontal therapy. Quintessence Int 1993;24: P2d 1347, citing Restatement Second of Torts 465-71. section 402A (1996). 35. Haffajee AD, Socransky SS, Dzink JL, et al. Clini- 15. California Book of Approved Civil Jury Instruc- cal, microbiological and immunological features tions (BAJI), BAJI No. 6.11. 1999. of subjects with destructive periodontal diseases. 16. Sfikas PM. Informed consent and the law. JADA J Clin Periodontol 1988;15:240-6. 1998;129: 16134. 36. Grossi SG, Genco RJ, Machtel EE. Assessment of 17. Waller vs. Aggarwal. 116 Ohio App.3d 355, 688 risk for periodontal disease. 11: Risk indicators for N.E. 2d 274 (1996). alveolar bone loss. J Periodontol 1995;66:23-9. 18. Hales vs. Pittman 118 Ariz. 305, 576 P2d 493 37. Grossi SG, Zambon JJ, Jo AW. Assessment of risk (1978). for periodontal disease. I: Risk indicators for 19. Shelter vs. Rochelle. 2 Ariz. App. 370, 409 P2d 86 alveolar bone loss. J Periodontol 1994;65:260-7. (1965). 38. Moss ME, Beck JD, Kaplan BH, et al. Exploratory 20. Quan vs. Truck Insurance Exchange. 67 Cal. case-control analysis of psychosocial factors and App.4th 583, 79 Cal. Rptr.2d 134 (1998). adult periodontitis. J Periodontol 1996;67: 21. Abbott vs. Bragdon. (1st Cir) 118 S. Ct. 2196 1060-9. (1998). 39. Klokkevold PR Periodontal medicine: assessment of 22. State vs. Clausen. (Minn. Ct. App.) 491 N.W.2d 662 (1992). risk factors for disease. Calif Dent Assoc J 1999; 23. Newman M. Genetic, environmental and behav- 27:135. ioral influence on periodontal infections. Com- 40. Offenbacker S, Beck J. Periodontitis: a potential pendium 1998;19:25-31. risk factor for spontaneous preterm birth. Com- 24. Ehrmann EH. Focal infection: the endodontic pendium 1998;19:32. point of view. Oral Surg 1977;44:628. 41. Gibbs RS, Ronero R, Hiller SL, et al. A review of 25. Anonymous. Dental amalgam: update on safety premature birth and subclinical infection. Am J concerns. JADA 1998; 129(4):494-503. Obstet Gynecol 1992;166:1515. 26. Remington DN, Joondeph AJ. Long term evalua- 42. Iams J. Prevention of Preterm Birth. New Engl J tion of root resorption occurring during ortho- Med 1998;338(1):54-6. dontic treatment. Am J Orth Dent Fac Ortho P 43. Dajani AS, Taubert KA, Wilson W, et al. Preven- 1989;96:43-6. tion of bacterial endocarditis: recommendations 27. Kornman KS, Crane A, Wong H-Y, et al. The by the American Heart Association. JAMA interleukin-1 genotype as a severity factor in 1997;277:1794-1 801. adult periodontal disease. J Clin Periodontol 44. Larson PE. The effect of a chlorhexidine rinse on 1997;24:72. the incidence of alveolar osteitis following the 28. Piper S. Gary Armitage searches for new ways to surgical removal of impacted mandibular third diagnose and treat periodontal disease. UCSF molars. J Oral Maxillofac Surg 1991; 49:932-7. Oracal 1998;12:11. Armitage G. Submitted for 45. Ragno JR Jr, Szkutnkik AJ. Evaluation of 0.12% publication J. Perio. chlorhexidine rinse on the prevention of alveo- 29. Armitage G, Wu Y, Wang HY, et al. Low preva- lar osteitis. Oral Surg Oral Med Oral Pathol lence of a periodontitis associated interleukin 1 19 9 1;72: 524-6. composite genotype in individuals of Chinese 46. Bonine FI. Effect of chlorhexidine rinse on the heritage. J Periodontol 1999. [Forthcoming] incidence of dry socket in impacted mandibular 28 8 Periodontal Medicine

third molar extraction sites. Oral Surg Oral Med 59. Reilly J. Tobacco use assessment is a new vital sign Oral Pathol 199579:154. in dentistry. J Mass Dent SOC1997;46:25-32. 47. American Association of Oral and Maxillofacial 60. Page RC, Beck JD. Risk assessment for periodontal Surgeons. Report of a workshop on the man- diseases. Int Dent J 1997;47:61. agement of patients with third molar teeth. J 61. California Book of Approved Civil Jury Instruc- Oral Maxillofac Surg 1994;52:1102-12. tions (BAJI), BAJI No. 2.0. 48. Rechmann Seewald M, Strassburg M, Naumann 62. Williams RC. Periodontal disease: the emergence I? Incidence of bacteremia following extrac- of a new paradigm. Compendium 1998;19:4. tions-a double blind study on local disinfec- 63. Loe H, Theilade E, Jensen SB. Experimental gin- tion using chlorhexidine. Dtsch Zahnarztl A givitis in man. J Periodontol 1965;36:177. 1989;44:622-4. 64. California Book of Approved Civil Jury Instruc- 49. Rahn R, Schneider S, Diehl 0, et al. Preventing tions (BAJI), BAJI No. 3.76. post-treatment bacteremia: comparing topical 65. Peumans M, Van Meerbeek B, Lambrechts et al. povidone-iodine and chlorhexidine [comment]. The influence of direct composite additions for J Arn Dent Assoc 1995;126:1474. the correction of the tooth form and/or position 50. Albandar JM, Gjermo Preus HR. Chlorhexidine on periodontal health. A retrospective study. J use after two decades of over-the-counter avail- Periodontol 1998;69:422-7. ability. J Periodontol 1994;65:109. 66. Jeffcoat MK, McGuire M, Newman MG. Evi- 51. Morlino vs. Medical Ctr. of Orange County. 706 dence-based periodontal treatment. Highlights A.2d 721 (1998). from the 1996 World Workshop in Periodon- 52. Shen EC, Maddalozzo D, Robinson PJ, Geivelis tics. JADA 1997;128:713-24. M. Root planing following short term pocket 67. Daubert vs. Merrell Dow Pharmaceuticals, Inc. distension. J Periodontol 1997;68:632-5. 509 U.S. 579 (1993). 53. LeLorier J, Grkgoire G, Benhaddad A, et al. Dis- 68. Kumho Tire Co. vs. Carmichael. 119 S.Ct. 1167 crepancies between meta-analysis and subse- (1999). quent large randomized controlled trials. N 69. Jeffcoat MK, Bray KS, Ciancio SG. Adjunctive use Engl J Med 1997;337:53642. of a subgingival controlled-release chlorhexidine 54. Capelleri JC, Ioannidis Jc Schmid CH, et al. Large chip reduces probing depth and improves attach- trials vs. meta-analysis of smaller trials: how ment level compared with scaling and root plan- do their results compare? JAMA 1996;276: ing alone. J Periodontol 1998;69:989-97. 1332-8. 70. Toole vs. Richardson-Merrill Inc. 25 1 Cal. App.3d 55. Villar J, Carroli G, Belizan JM. Predictive ability of 689; 60 Cal.Rptr. 398 (1967). 21 Code of Fed- meta-analyses of randomised controlled trials. eral Regulations, section 80 1.4 (intended use Lancet 1995;345:772-6. may be shown by oral statements of manufac- 56. Ioannidis Jc Cappelleri JC, Sacks HS, Lau J. The turer’s representatives). relationship between study design, results and 71. Woods KL. Mega-trials and management of acute reporting of randomized clinical trials of HIV myocardial infarction. Lancet 1995;346:611-4. infection. Control Clin Trials 1997;18:43 1-44. 72. Ransohoff DF, Feinstein AR Problems of spectrum 57. Horowitz RI, Singer BH, Makuch RW, Viscoli and bias in evaluating the efficacy of diagnostic CM. Can treatment that is helpful on average tests. N Engl J Med 1978;299:926. be harmful to some patients? A study of the 73. Fewer implant cases seen on wake of scientific find- conflicting information needs of clinical inquiry ings. San Francisco Daily Journal 1998 Dec 2; and drug regulation. J Clin Epidemiol 1996;49: Sect. C:l. 395-400. 74. Severson HH, Andrews JH, Lichtenstein E, et al. 58. Monmaney T. AMA fires editor over publishing sex Using the hygiene visit to deliver a tobacco ces- survey. Los Angeles Times, p. A1 6 (16 January sation program: results of a randomized clinical 1999). trial. JADA 1998;129:993-9. INDEX

Acatalasia, 18 antagonism, 244 periodontal infection and, 78-79 Acetaminophen, acute renal failure cross-resistancey243 Ross response, 71 and, 208 in diabetics, 142 triggers, 78 Acidosis, 123 dosages, 245 Attachment apparatus, 4-6 hyperosmolar nonketotic, 125 infective endocarditis and, 67-69, Attachment loss, 15, 50 Acquired immune deficiency 214 in diabetes, 17 syndrome (AIDS), 17, 18, 64 irrigation with, 25 1-253 improving, 25 8 Acute myeloid leukemia, 18 liver disease and, 214 in myocardial infarction, 73 Acyclovir, acute renal failure and, 208 local delivery, 253-256, 281 in psychological disorders, 20 Adhesion receptors, 91 in meat, 266 Azathioprine, liver disease, and 210 Adult periodontitis, 2 1 , 45-49, nephrotoxic, 2 I I , 2 13 Azithromycin/clarithromycin,68 5 1-56 in neutropenia, 199 in HIV patients, 190-1 9 1 oral contraceptives and, 244-245 Baby-bottle tooth decay, 158 Advanced glycosylation end-products patient instruction, 266 Bacteremia, transient, 67 (AGES), 128-129, 133-134 in periodontal therapy, 250-25 1 risk, 68 Age, as risk factor, 14, 25, 132 post-transplant, 205-2 17 Bacteria as opportunists, 2 Agranulocytosis, 15, 18 during pregnancy, 160 Bacterial endocarditis, 280 Alendronate, 19, 179 reduced effectiveness, 244 Bacterial pneumonia, 83-86 Alpha-1 antitrypsin, 18, 2, 85 resistance, 243-244, 266 nosocomial, 83-84, 85, 86, 92 Alport’s syndrome, 206 risk, 67 prevention of, 92 Alprazolam, 153,262 selective pressure, 244 Bacteroidesforytbus, 73 Alveolar bone, 2, 5 spectrum, 244 heat-shock protein, 78 medications and, 264 superinfection, 244 pocket depth and, 24 Alveolar bone height, genetics and, 22 synergism, 244 as risk factor, 11, 23, 25 Alveolar bone loss topical oropharyngeal, 92 Basic multicellular unit (BMU), 167 in diabetes, 16 Anticoagulants, 23 6-23 8 Berger’s disease, 206 estrogen and, 176 contraindications for, 237 Biofilms, 2, 87 as predictor of stroke, 77 INR, 70 Bismuth line, 23 as risk factor for COPD, 90 oral, 42,70-71 Bleeding, 233-236 tobacco smoke and, 101, 176 Anticoagulated patients, 70-7 1 applying pressure, 234 Alveolar crestal heights, 74, 172 Anticoagulation, 23 1-232 fibrin sealants, 240 Alveolar mucosa, 2 antifibrinolysis, 239-240 post-extraction, 23 1-232 Alveolar process, 4-5 monitoring, 42, 70-7 1 on probing, 24 Alveolar ridge resorption, 18 severe factor deficiencies, 239 spontaneous, 232 American Heart Association (MA) Antineoplastic chemotherapy, 230 suturing, 235 recommendations, 68-69 Antioxidants, 72 topical agents, 234-236, 237 Aminoglycosides, acute renal failure Antiseptic rinses, 68, 251 treatment, 234 and, 208 Antiseptics, 256 Bleeding disorders, 229-24 1 Amoxicillin/penicillin, 68, 248-249 Antivirals, 200 Bleeding time, 41, 233 adverse effects, 249 Aphthous ulcers, 152 normal range, 41 in breast milk, 249 Arthralgias, 64 Blood urea nitrogen (BUN), 41 metronidazole with, 11, 250 Ascites, 214 normal range, 41 Amphotericin By92 Aspirin, 70-7 1 Bone loss, 54 Ampicillin, with contraceptives, 244 risk, 71 Bone marrow transplantation, Androgens, 168 Atheroma formation, 71, 78, 128, 134 196-200,216-217 Angiotensin-converting enzyme Atherosclerosis Bone mass, 169 (ACE) inhibitors, 206 atheroma formation, 78, 134 Bone metabolism, 167 Anorexia nervosa, 64, 65 in diabetes, 127 fluoride and, 177 Antacids, 153 genetic predisposition, 79 smoking and, 176 Antibiotics, 243-266. See also infections in, 71 Bone mineral density, 169 individual antibiotics mechanisms of, 72 estrogen and, 175 activity of, 245 patient management, 79 loss of, 18 290 Index

mandibular, 171-172, 175 Cleidocranial dysplasia, 2 I Dentoalveolar unit, 4 Bone remodeling, 167-1 69 Clindamycin 249, 68 Dentures, 199 imbalance, 171 Clonidine, I I I Depression, 20, 65 peak bone mass, 168-169, 178 Clot formation, 228 nicotine dependency and, 105 Bone resorption, 174 Clotrimazole (Lotrimin, Mycelex), 260 Dermal gangrene, 64 Bronchitis, 89 adverse effects, 260 Desmopressin, 238 Bronchopneumonia, 84 Coagulation cascade, 227-229 Diabetes mellitus, 121-150 Bruxism, as risk factor, 25 Coagulation disorders, 230-23 1 acidosis, 123 Bupropion HCl (Zyban), 110 Colgate Total, 26 1 autoantigens in, 123 contraindication for, I 10 Collagen, 128, 134-135 causes, 122 Burden of proof, 282-283 tetracycline and, 135 characteristics of, 123 Complete blood count (CBC), 38 classifications, 121-125 Calan, 23 Congenital chromosomal disorders, complications of, 125-1 29, 137 Calcitonin, 168 46 dental implants and, 136 Calcium, dietary, 19, 177, 178 Congenital neutropenia, as risk dental management, 140-1 45 as risk indicator, 15, 25 indicator, 15 diagnosis, 129 Calcium, serum, normal range, 41 Consultations, 276 diarrhea, 127 Calculus, as risk factor, 24 Contraceptives, oral, 161-1 62 emergencies, 144 Cancer, head and neck, 195-196 antibiotic interference, 162, gestational, 121, 125 oropharyngeal, 200 244-245 histocompatibility complex Candida albicans, 259 Coping, as risk indicator, 15, 20,25, antigens, 123 as risk factor, I I 174,278,279 insulin-dependent, 121 Candidiasis, oral, in HlV patients, 17 Coronary artery disease, 71 insulin therapy, 138-140 Capoten, 262 C-reactive protein, 78 “juvenile,” 123 Captopril, 262 in diabetics, 127 ketoacidosis, 123-1 25 Carbamazepine, 23 fibrinogen, 78 laboratory diagnosis, 130 Cardia valve prostheses, 64 incidence of, 75 macrovascular disease in, 125 Cardiac conditions and dental oral infections and, 73-76 management of, 136-145 treatment, 65 TDI as predictor, 74-75 markers for, 122 Cardiac valve prosthesis, target INR, Coronary atheromatosis, 73 medical history, 36 42 Cortical bone loss, 18 monitoring, 129 Cardiovascular diseases, 63-82 Corticosteroid resistance, 206 myocardial infarction in, 127 as risk factor, 279 Corticosteroids, post-transplant, 209 non-insulin-dependent, 121 CD4 cells, 17, 183, 186, 190 Cortisol, 122, 123, 142 obesity in, 124, 136 Cementum, 2-6 Cotinine, 15, 101 onset of, 123 Cephalexin/cefadroxil, 68 Coumadin oral agents used, 138 Cephalosporins, 68 action of, 70, 231-232, 236 oral complications, 130-135 Cerebral infarction, 76 medications affecting, 239 other types, 121 TDI in, 76 monitoring, 70 pathophysiology, 124 Cerebral ischemia, 76 vitamin K administration, 70 periodontal infection in, 135-1 36 ChCdiak-Higashi syndrome, 18 Craniofacial dysostosis, 2 I presentation, 129 Chemotherapy, 196-200 C-Reactive protein, 78 renal failure, 126 Cherubism, 20 Crohn’s disease, 18 as risk factor, 16-17, 25, 278 Cbkzmydia pneumoniae, heart disease Cryptitopes, 93 risk factors for, 124 and, 73 Cyclosporine therapy, 23, 206, 2 10 self-monitoring, 130 Chlorhexidine, 2 I0 Cytokines, 87 susceptibility to, 123 delivery system (PerioChip), bone cells and, 168 treatment, 131 256-258 in diabetes, 129, 134 type 1, 121, 122-124, 136-137 irrigation with, 253 production of, 12, 51-55, 91-92 type 2, 124-125, 131-132, plaque formation and, 199 protease cascade, 72 13 6- 137 Chlorhexidine gluconate, 68, 187 release of, 91 viral infections and, 123 nosocomial reduction, 93 in respiratory disease, 9 1-92 Dialysis, 64, 208-209 Chronic bronchitis, 84 Cytomegalovirus Diet Chronic obstructive pulmonary heart disease and, 73 osteoporosis and, 177 disease (COPD), 84-90 post-transplant, 200 during pregnancy, 158 Chronic renal failure, 206-297 as risk indicator, 15, 19 Ciprofloxacin, 249 Data analysis, 13, 14 Dihydropyridines, 23 Circular fibers, 3 Dentifrices, 260-26 1 Distress, as risk indicator, 15, 20, 25 Circumstantial evidence, 283 Dentin, G, 5 Dose response, 14 Clefts, 21 Dento-peristeal fibers, 4 Down syndrome, 18, 21, 46, 65 Index 291

Doxycycline, 254-255 Genetic paradigm, 6-8 Glucometer, 130, 131, 143 amoxicillin with, 25 1 Genetic polymorphisms, 22 Gluconeogenesis, 122 in diabetes, 17, 135, 136 Genetic susceptibility, 4849, 5 1 Glucose, blood, 41, 125 metronidazole with, 250 resistance, 48 normal range, 41 Periostat, 258, 281 test requirements, 59 Glyburide, 138 subgingival delivery (Atridox), 254 types of, 48 Glycemia, 122 Drug packet inserts, 281 Genetic testing, 59-61 Glycemic control, 17, 132 Drug side effects, 280 patient selection for, 60 bone loss and, 132 Due care, 273 potential benefit(s) of, 60 periodontal infection and, 135 Genetics, 45-62 Glycosylated hemoglobin (HbAlc), Eating disorders, 152 autosomal dominant disorders, 129-130 Ehlers-Danlos syndrome, 18, 2 1, 65, 46,47 normal values, 130,142 171 autosomal recessive disorders, 47 Glycosylation, 128 as risk indicator, 15 carriers, 47 Gold salts, 206 Emphysema, 84-85, 89 in clinical practice, 56-57 Goodpasture’s syndrome, 206 Enalapril maleate, 262 environmental factors and, 4749 Governmental agency standards, 275 End-stage renal disease, 205 ethics, 57-58 manufacture compliance with, 275 Endothelial injury, 72-73 heterozygotes, 47 Growth hormone, 168 Epidemiologic research, 282 homozygotes, 47 Epinephrine, 122, 123, 142 phenotype, 48 Hairy leukoplakia, oral, 2 10 Epithelial cells, 91 pleiotropism, 46, 47 in HlV patients, 17 Epstein-Barr virus, 17 polymorphisms, 48 Heart disease, 11 Erythema, 184-1 87 predisposition, 277-278 Heart-lung transplants, 2 15 Estrogen, 15, 152, 156, 175 utility of, 57 Heart surgery, 69 deficiency, 173, 174-175 variable expression, 46, 47 Heart transplantation, 2 15-2 17 and periodontal disease, 174, 175 Gingiva, 2 Heat-shock protein, 78 in skeletal development, 168, 174 blood supply of, 4 Helicobacterpylori, heart disease and, Estrogen replacement therapy, 174, enlargement, 264 73 175-1773 178 healthy, 4, 7 Hematocrit, 38 smoking and, 176 medications and, 263-264 normal range, 41 Extracellular matrix, 12, 72 Gingival banding, 186 Hemifacial hypertrophy, 2 1 Gingival bleeding, 196 Hemoglobin, 38 Failure-to-inform, 275 Gingival crevicular fluid, 264-266 normal range, 41 Fatigability, 64 antibiotic resistance, 265 Hemophilias, 230-23 1 Fcy receptor, 49, 51 change in content, 265 liver clot, 231 polymorphism, 22 cytokines in, 92 Hemophilus influenza Febrile infections, stroke and, 77 IL-1 in, 52, 53 and COPD, 85 Fenfluramine/phentermine, 65 medications and, 264-266 Hemostasis, 227-229 Fever, 64, 69 pneumonia and, 87 platelet phase, 227, 232 Fibrillary glomerulonephritis, 206 Gingival grafts, 69, 102 questionnaire, 234 Fibrinogen, as risk factor, 78 Gingival hyperplasia, 155 Heparin, 232, 237-238 Fibrinolysis, 228 pretransplant, 2 10 Hepatitis, 2 12 Fibronectin, 90 Gingival infiltration, 196, 197 Hereditary nephritis, 206 Fibrosis, 23 Gingival overgrowth, 22, 23, 210 Hippocratic Oath, 286 Fluoxetine, 153, 262 Gingival sulcus fluid, 3 Histocompatibility complex, 48, 49 Fragile X syndrome, 21 Gingival sulcus, 2-3, 90, 92 History-taking, 36-38 Fraud, 276 Gingival ulceration, 196 HIV periodontitis, 17 Fructosamine tests, 130 Gingivectomy, 69 HIV-gingivitis, 17, 184 Fungal infections, 259-262 Gingivitis, 3, 4, 56 Human immunodeficiency virus anti-fungal agents, 259 bleeding disorders and, 227 (HIV), 183-193 Furcation, 55, 102 in diabetes, 132 oral lesions in, 17, 184 HIV-associated, 184 resistance to, 48, 49 Gastroesophageal reflux disease in leukemia, 198 Human leukocyte antigen (HLA), 21, (GERD), 152-1 53 irrigation and, 251 21-22,48 Gender, as risk factor, 15, 25 Glimepiride, 138 Hypercholesterolemia, 47 Genetic counseling, 58 Glipizide, 138 Hyperglycemia, 122, 127 Genetic disorders, types of, 4647 Glomerulonephritis, 205 sustained, 129 Genetic factors, 20-22 Glucagon, 123 Hyperhomocystinemia, 72 orofacial abnormalities, 20-2 I injection, 144 Hyperimmunoglobulin-E recurrent Genetic information issues, 58, 59 Glucocorticoids, 168 infection syndrome, 18 292 Index

Hyperresponsiveness , 12 Irrigation, 25 1-253 female patients, 162 Hypertension, 72 forms, 39-40 stroke and, 77 Job‘s syndrome, 18 medications, 36 Hypertriglyceridemia, stroke and, 77 Juvenile periodontitis, 2 1, 24 social history, 37 Hypocomplementemia, 206 Medications and periodontium, Hypoglycemia, 122, 140, 144-145 Kaposi’s sarcoma, in AIDS patients, 262-263 emergency treatment of, 144 17 over-the-counter, 263 severe, 140 Kawasaki disease, 65 Medications, effects of, 22-23 signs of, 144 Ketoacidosis, 123-124 Membranoproliferative unawareness, 145 Ketoconmole, 2 13, 259-260 glomerulonephritis, 206 Hypophosphatasia, as risk indicator, adverse effects, 260 Membranous nephropathy, 206 15 Kidney transplantation, 205, Mendelian disorders, 4647 209-212 Menses, 152-1 53 IgG2, 16 Mercury line, 23 Immune response, 49 Laboratory studies, 38-42 Metals, heavy, 23 Immunocompromised patients, 200, normal ranges, 41 Metformin, 138, 143 205 Lead poisoning, 23 Methysergide, 65 Immunoglobulin A (IgA) Lesions, HIV-associated, 184-1 9 1 Metronidazole, 248 nephropathy, 206 Leukemia, 196-200 contraindications, 248 Immunosuppression, 64 latent herpes simplex in, 199-200 in neutropenic patients, 199 as risk factor, 190 Leukocyte adhesion deficiency, 18 subgingival delivery, 256 risks, 1 Liebman Sacks verrucae, 66 Miconazole (Monistat), 260 Infective endocarditis, 63-64 Linear gingival erythema, 184-1 87 adverse effects, 260 antibiotic administration, 67-69 in AIDS patients, 17 Microalbuminuria, 126 dental considerations, 67-69 Lipid Microflora, local, as risk factor, 23-25 prevention, 64, 68 accumulation of, 71 Minocycline, 255-256 Inflammatory bowel disease, 18 altered metabolism, 129 in diabetes, 135 Informed consent/misrepresentation, in diabetics, 129 Misfeasance, 275 275 Listerine, 25 1, 260 Misrepresentation, 275-276 Insulin, 137-1 40 Liver cirrhosis, 2 I2 Mitral regurgitation, 66 action of, 122 Liver disease, 2 12 Mitral valve prolapse, 47, 64, 65 control of glucose, 122 abnormal hemostasis in, 232 Molecular medicine, 6 production of, 122 bleeding disorders in, 2 13 Moniliasis, 259 secretion, 124, 137 hemmorrhage in, 232 Monocytes, 38 Insulin deficiency, I22 Liver transplant, 2 13-2 14 Mouthrinse, 260-262 Insulin infusion pump, 137, 138-139 complications of, 2 13 Mucositis, 18 Insulin-like growth factor (IGF), 129, dental management, 2 13-2 14 Multiple myeloma, 170 168 Low-density lipoproteins (LDL), Myalgias, 64 Insulin resistance, 124, 125 71-72 Myelodysplastic syndrome, 197 gestational diabetes and, 125 elevated, 133 Myocardial infarction, 73 infection and, 136 oxidation of, 128, 129 studies, 74 Insulin therapy, 137-1 40 Lung cancer, 99-100 Intensive care units, 87-89 Lung infection, 85-86 Necrotizing periodontal diseases, Inter-radicular fibers, 6 risk factors, 86 187-1 89 Interdental craters, 187 Lung, normal, 85 Necrotizing stomatis, 187, 189 Interleukin 1 (IL-1), 12, 45, 91 Lung transplantation, 2 14 Necrotizing ulcerative lesions in adult periodontitis, 5 1-55 Lymphocytes, 38 in AIDS patients, 17 bone cells and, 168 Necrotizing ulcerative gingivitis, in diabetes, 129 Macrophages, 7 1 19-20 genetic variations, 52-56 Malaise, 64 Necrotizing ulcerative periodontitis genetics of, 22, 51 Mandibulofacial dysostosis, 2 1 in HIV patients, 17 polymorphisms, 25, 52, 53 Marfan’s syndrome, 21, 47, 65, 171 Negligence, comparative, 285-286 production of, 53 Matrix metalloproteinases, 12, 5 1, Negligent custom, 273-274 response to treatment, 54-55 72, 134 Nephropathy, 125, 127 International normalized ratio (INR), Medical history, 36-38 Nephrosis, 208 42,70,213-214,236,237 allergies, 36 Nephrotic syndrome, 206 management using, 238 body systems, 37 Neuropathy, 125-1 26 International sensitivity index (ISI), dental history, 43 Neutropenia, 18, 199 42,236 diabetes, 36 Neutrophil disorders, 18, 21, 134 Intraligamental analgesia, 67 family history, 37 as risk indicators, 18,25 Index 293

Neutrophils, 38 treatment, 178-179 Pharmacogenomics, 57 Nicotine, 101 Oxidant stress, 133 Phenytoin (sodium action of, 103 5, 5-phenylhydantoin) , 22-23, 2 13, addiction, 104 Pancreatic transplantation, 2 14 263-264 cardiovascular system and, 104 Panic disorder, 65 side effects, 22, 263 effects on fibroblasts, 10 I Pantomographic index, 73 Physician Desk Reference, 28 1 nonpharmacologic agents, I I I Papillon-Lefevre syndrome, 18 Pierre-Robin syndrome, 2 1 replacement agents, 109 as risk indicator, 15 Pigmentation, 23 withdrawal, 104, 109 Partial thromboplastin time (PTT), Plaque, 56 Nicotine dependency, 103-1 14 42,232,237 accumulation, 45 Nicotine gum, 107, 109-1 10 normal range, 41 composition, 262-263 contraindications for, I 10 Patient evaluation, 35-38 during pregnancy, 155, 156, 157 with patch, I I I reasons for, 35 medications and, 262-263 Nicotine nasal spray, 110 Patient monitoring, 276 respiratory disease and, 87-89 contraindications for, I 10 Penicillin, 68. See also Amoxicillin as risk factor, 24, 280 Nicotine patches, 109 allergy, 68 types of, 4546 contraindications for, I 10 with contraceptives, 244 Plasminogen, 72 with gum, 111 resistance, 68 Plasminogen activator inhibitor, 155 Nifedipine (Procardia), 23 Periapical lesions, as risk factor, 25 Platelet count, 4 1 Night sweats, 64 Periapical pathosis, 199 Platelet disorders, 229-230 Nitrendipine, 23 PerioChip, 256-258 aspirin and, 230 Non-Hodgkin’s lymphoma, in AIDS Periodontal disease, 1-9, 279 Platelet dysfunction, 196 patients, 17 background factors, 14-15 Platelet transfusions, 240 Non-Mendelian disorders, 47 diabetes and, 132-136 Platelet-derived growth factor, 129, Nonfeasance, 275 etiology of, I I 133,263 Nonsteroidal anti-inflammatories, genetics of, 46, 49-62 Pneumonia, 83-89 206 glycemic control and, 135-136 prevention, 92-93 Nystatin, 259 heart disease and, 11 Pocket, 3, 6 pathogenesis of, 12 Polymyxin By92 Occlusion, as risk factor, 25 pre-existing, 24-2 5 Porpbyromonas gingivalis, 9, 73 Optimum treatment, 57 pregnancy and, 15 3-1 5 5 heat-shock protein, 78 Oral hygiene, and risk, 24 presentation, 46 as risk factor, 23, 25 Oral lichen planus, 186 risk assessment, 12-15, 60, 173, Povidone iodine, 68, 187 Oropharyngeal cancer, 7-8 283 Pregnancy, 153-1 6 1 risk factors for, 8 as risk factor for COPD, 90 antibiotics, 1GO, 162 Osler’s nodes, 64 second-hand smoke, 99 breast feeding, 161, 162 Osteoclasts, activation of, 12 smoking-associated, 100, I01 dental treatment, 158-1 6 1 Osteogenesis imperfecta, 20 stroke and, 76-78 diet, 158 Osteopenia, 167-1 82 systemic disease and, 1-9, 15-22 emergency treatments, 158-1 59 oral bone and, 171-173 untreated, 9 I fetal risk, 159,279 as risk factor, 18-19 Periodontal ligament, 2, 4, 5-6, 7 gingivitis, 153 as risk indicator, 15 Periodontitis, 45 immunoresponse, 155, 156 Osteoporosis, 169-1 82, 278 bleeding disorders and, 227 local anesthetics/analgesics, 160, causes, 171 diabetes and, 135-136 162 classification, 170 in diabetics, 132 management, 157-158 definition, 169 early-onset, 46, 49 medications, 159 diet, 177 etiology of, 56 nicotine replacement during, I 10 future research, 179 HIV associated, 184-19 1 nutrition, 157 genetics, 177 in leukemia, 198 perimylolysis, 157 high turnover, 174 measurement of, 13 plaque composition, 155, 156 involutional, 170 rapidly progressive, 190-1 9 1 prenatal fluoride, 158 in liver disease, 213 recurrence of, 12 preterm low-birth-weight births, pathophysiology, 17 1 stroke and, 77,78 156-1573 279 and periodontal disease, 172-1 79 Periodontium, 2-6 radiography, 15 9 postmenopausd, 170 diabetic influence on, 133-1 35 sedatives, 160, 162 as risk indicator, 15, 25 medications and, 262-263 supine hypotensive syndrome, 158 as risk factor, 18-19 smoking and, 100 Pregnancy tumors, 154-1 55, 157, risk factors for, 173 Peritonitis, 209 158 secondary, 170 Peroxetine, 153 Preleukemic syndrome, 18 smoking and, 175-177 Petechiae, oral, 64 Premenstrual syndrome, 153 294 Index

Principal fibers, 4 Selective digestive decontamination, Thrombocytopenia, 229-230 Probing, 24 92-93 Thromboembolism, risk, 237 improving depths, 258 Serotonin, 153 Thrush, 259 Progesterone, 152-1 53, 156 Serotonin agonists, 65 Tissue plasmin activator, 72 Prognosis, 55 Sertraline, 153 Tobacco toxicity, 100-1 0 1, 110 Prostaglandin E2, 51 Sharpey’s fibers, 5, 7 Tobacco use, 99-1 19. See also Prosthetic valve endocarditis, 69 SkilUlearning updates, 274 Smoking contraindications for dental Smokeless tobacco, 16 “4 A’s,” 107-112 treatment, 69-70 Smoking, 99-1 19. See also Tobacco biohmards, 110 Protease, 91 use Cost, 99-103 Protease cascade, 72, 73 bone density and, 175-177 reduced response, 103 Protein metabolism, abnormal, 214 IgG2 and, 16 as risk factor, 15-16 Prothrombin (PT) test, 4142, 232 IL-1 and, 53-54, 278 Tobramycin, 92 INR, 42,70,213,236 as risk factor, 15-16, 25, 54, 85, Tooth loss, 53-56, 179 Pseudomembranous colitis, 250 99, 175-177 coronary heart disease and, 76 antibiotics and, 250 second-hand smoke, 99 and osteoporosis, 172 Psychological disorders stroke and, 77 Topical clotting agents, 70 as risk indicators, 19-20 Sodium valproate, 23 Total dental index, 73-74, 75, 76 Puberty, 151-152 Soft tissue necrosis, 197 Tranexamic acid, 239-240 Pulpal infection, as risk factor, 25 Solid tumors, 198-1 99 in oral rinses, 214 Pyogenic granulomas, 154 Spiramycin, 249 Trans-septal fibers, 3 Spirochetes, as risk factor, 11 Transplantation Race, as risk factor, 15 Spongiosa, 5 dental management in, 2 10-2 12 Radiation therapy, 195-196 Standard of care, 273,275 treatment planning for, 210 Re-evaluation, 276 risk factors, 277-280 Triclosan, 26 1-262 Red blood cell (RBC) count, 38, 41 Streptococcus pneumonia Trimethoprim, 2 17 Referral to specialists, 274 and COPD, 85 Trisomy 21, 21, 46 Refractory periodontitis, 52, 102 Stress, 19-20 Troglitmone, 143 Refusal to treat, 276 diabetes and, 122, 123 Tumor necrosis factor (TNF)-a, 12, Renal failure, 205-208 as risk indicator, 15, 25, 174,278 45, 51, 91 Renal transplantation, 209-212 with financial strain, 20 bone cells and, 168 immunosuppressive therapy, Stroke, 76-78 in diabetes, 129, 134 209-2 10 Study designs, 12-14, 13 genetics of, 22, 49 nephrotoxic antibiotics, 21 I Substance dependency, 104 Twin studies, 22, 46, 50-51 Repaglinide, 138 Sulfamethoxmole, 217 Research evidence, 283-285 Sulfonamides, 208 Ulcerative mucositis, 197 Respiratory diseases, 83-97 Sulfonylurea, 138, 143 Retinopathy, 125-1 26 Supra-alveolar connective tissue, 34 Valvar heart disease, 63-69 Rhabdomyolysis, 206 Susceptibility, 48, 50 Valvar prostheses, 66 Rheumatic fever, 65, 244 SyndromeX, 124, 125 Ventilated patients, 93 and infective endocarditis, 64 Syphilis, tests for, 4 1 Verapamil hydrochloride, 23 and mitral valve stenosis, 65 Systemic lupus erythematosus (SLE), Vitamin C, 15, 177 Rheumatic heart disease, 69 66 in smokers, 19 Risk analysis, 25, 26 VitaminD, 167, 177 Risk categories, 42 Teledyne Water Pik, 25 1-253 Vitamin E, 72 Risk factor, 12 Temporomandibular disorders, 19 Vitamin K administration, 70 Risk factors, 11, 277-280 Tetracycline, 69, 136, 245-248 Vitamin K supplementation, 214 Risk indicator, 12 with contraceptives, 244, 28 1 Von Willebrand disease, 23 1, 239 contraindications for, 70, 246 Saliva, 262-263 dairy products and, 245 Warfarin, 42,231,236 in diabetes, 130-1 3 1 diabetics and, 26, 135 Wellbutrin, I 10 enzyme activity in, 90 fibers (Actisite), 253-254, 28 1 White blood cell (WBC) count, 38 pneumonia and, 87, 90 in nephrosis, 208 Wilson’s disease, 2 12 Salivary dysfunction, 19, 152 photosensitivity, 28 1 Women’s Health Initiative (WHI), 172 Salivary pellicles, 90 prothrombin activity and, 28 1 Sanguinaria, 254,260 side effects, 247 Xerostomia, 130-131, 157 Scorbutic gingivitis, 19 toxicities, 247 medications causing, 263