cda journal, vol 28, nº 12
CDA Journal Volume 28, Number 12 Journal december 2000
departments
890 The Editor/A Quiet Wind of Change 892 Impressions/California Performs Poorly on Oral Health Report Card 984 Dr. Bob/Pigmalion
features
911 Herpesvirus-Induced Diseases: Oral Manifestations and Current Treatment Options This paper reviews the natural history, oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus-induced diseases. Catalena Birek, DDS, PhD
922 Papillary Lesions of the Oral Cavity: Relationship to Human Papillomaviruses This article looks at the human papillomaviruses and their ability to induce proliferative changes in cells that result in both benign and malignant tumors. Lewis Roy Eversole, DDS, MSD, MA
928 The Bullous Desquamative Lesions of Oral Mucosa This overview looks at the clinical features, diagnosis, and treatment of the most common of the bullous/desquamative diseases that affect the mouth. Sol Silverman, Jr., MA, DDS
933 Xerostomia – Clinical Evaluation and Treatment in General Practice This paper will help the general practitioner determining the cause of a patient’s xerostomia, estimate the severity of associated salivary function, and initiate appropriate treatment. Troy E. Daniels, DDS, MS, and Ava J. Wu, DDS
942 Candidiasis: Pathogenesis, Clinical Characteristics, and Treatment This review discusses the pathogenesis of candidiasis, the clinical characteristics of oral infection, local and systemic factors that predispose to infection, and treatment. Stanton S. Appleton, DDS, MPH, MSD
949 Focal, Flat Pigmentations of the Oral Mucosa: A Clinical Approach to the Differential Diagnosis This article will assist the clinician in establishing a clinical approach to the diagnosis of focal, flat pigmentations of the oral mucosa. William M. Carpenter, DDS, MS, and Mitchell Rudd, DDS
955 Diet Drugs and Cardiac Valvulopathy: A Survey of Dental Patients This study surveyed more than 1,300 dental patients and determined the prevalence of patients taking diet drugs and the percentage required to take antimicrobial endocarditis prophylaxis. Richard Rudin, DDS, MA, and William Carpenter, DDS, MS Editor cda journal, vol 28, nº 12
A Quiet Wind of Change
Jack F. Conley, DDS
he issues facing each American create a new single-state trustee district. Dental Association House of California, the largest constituency of ADA Delegates are usually quite members, has been one of five single- different from those that faced state trustee districts, each represented the previous annual session. by its own member on the ADA Board of TThe attitude of the delegates as they Trustees. The other states are combined debate the issues has also varied every in accordance with the ADA Bylaws to year, sometimes significantly from the form 11 multistate districts, each having preceding year. one trustee representative. Florida Dental As an example of the latter, during Association membership has increased in previous House sessions, we have seen the recent years to a level that qualified Florida delegates reject a budget resolution or a under the bylaws for consideration as a potential dues increase, sending the Board single-state district. of Trustees into a special session with a In simplified terms, this issue request to modify programs or identify was controversial to the majority of other funding sources for presentation the California delegation and other back to the House. Such sessions have been delegations as well, because the spirited and, often, contentious. membership total achieved by Florida In past House sessions, there has been is only slightly more than one-third of impassioned or even divisive debate over the current membership in California public awareness programs and proposed and about one-half of the membership dental specialties, to name just a few of in New York. It was natural that the the proposals reviewed by ADA delegates California delegates should question the in recent years. With an agenda that has obvious imbalance in representation been averaging between 100 and 125 under this formula and would want to resolutions for consideration, there have consider other mechanisms to ensure usually been at least a handful of issues that their constituents received equitable that have stimulated forceful debate representation. before reference committees or on the While the opposition of California House floor. delegates and a few allies was well-known, Given that background, the first in the final analysis, the delegation did ADA House of Delegates of the new not push the issue into a contentious floor millennium was decidedly different. debate. Our analysis here is that based on Within days after the close of the the existing bylaws language, the Florida House proceedings, we find it difficult position was correct and California would to pinpoint why this session seemed to have nothing to gain and a great deal to have a different mood than any of its lose in future ADA deliberations if this predecessors in the past few decades. issue were pursued. Sixty-eight percent Nonetheless, we would like to explore of the House approved the new district some of the factors and characteristics with a distinct lack of the contentious that lead us to this conclusion. debate often seen in past House sessions. The most divisive issue to face the 2000 And while progress was not made on the House of Delegates was a resolution to representation issue, by placing a focus on
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it, the CDA delegation has helped place lack of debate. The reasons are many and that would have directly addressed value- this issue on the agenda of the task force varied. Perhaps because there was only of-membership issues. on ADA governance structure that will one issue with major financial impact All things considered, a quiet wind be making a final report to the 2001 ADA (assessment for headquarters renovation), of change was experienced in the Windy House. there was a less emotional environment City of Chicago in October during the Despite officer and candidate to stimulate debate. It is also possible American Dental Association House of presentations that linked membership that increased levels of communication Delegates meeting. dues and a continuing decline in the -- including the Internet -- have helped market share of ADA membership, a educate more delegates so that they are slight increase in dues for 2001 to balance “on the same page” in their understanding the budget for programs voted by the of the issues. The regional differences that House was approved by more than 91 may have been the cause of emotional percent of the delegates. This was in debate in past ADA sessions may be fewer addition to a $30 annual assessment for in number. six years to cover renovation costs for Also of note were two important the ADA headquarters building that had announcements that preceded the already been approved by 85 percent of deliberations and could have affected the the delegates. The level of agreement mood of this House. It was announced and support for these measures was that Executive Director John Zapp surprising, given discussions that would retire at the end of March 2001 identified cost and value as stumbling and ADA Editor Lawrence Meskin would blocks to membership, particularly of be retiring at the end of 2001. These young dentists. unrelated personnel changes involving Even the consideration of specialty visible participants may have signaled a recognition for orofacial pain failed to transitional period with an expectation generate much debate. In a non-emotional for change that contributed to a quieter, review of the six requirements for a less contentious mood for this House. specialty, more than 76 percent of the The different mood of this ADA House delegates voted to deny specialty status to of Delegates seems to be symbolic of a the American Academy of Orofacial Pain. period of change immediately ahead for A review of our notes showed that a the American Dental Association. A new significant majority of issues for which a leader and a new voice in a year are only machine vote count was taken were either part of the equation. What may well be approved or defeated by 80 percent to most significant about the mood of the more than 95 percent of the delegates. 2000 House is that it seemed to be more As an example, a resolution initiated by agreeable, more respectful, and more California to create a task force to make understanding of the problems challenging recommendations on a position for the profession on a national basis. The pursuing antitrust relief for dentists and districts may be working together better health care professionals was approved by with less emphasis on political alliances more than 94 percent of the delegates. than has sometimes been the case in the This leads us to wonder why there was past. If there were any failing, it was the a high level of agreement and noticeable lack of resolutions under consideration
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California Performs Poorly on Oral low in the access-to-care category where a Health Report Card few C+ grades in Maryland, Oregon, and California’s Grades on By Debra Belt Wyoming were sprinkled among many National Oral Health The Golden State received a mediocre D’s, F’s, and I’s. In grading access to care in grade in oral health care and ranked only the individual states, Oral Health America Report Card slightly above the low national average on looked at the prevalence of dentists and STATE GRADE: C America’s first Oral Health Report Card, dental clinics, Medicaid programs, and PREVENTION: C- issued in October. California received an dental insurance for adults and elders. Fluoridation: F overall C grade while the nation as a whole California rated a C- in overall access to State oral health program: D rated a C- in the report that offers a state- care and a D in dental insurance for the Sealants: D by-state look at the specifics of oral care, elderly. Dental insurance for people over Visits to dentists -- Adults: C including prevention, access to care, and 65 received the most abysmal marks with Visits to dentists -- Elderly: B health status. an F grade issued in 41 states. Roughly Use of smokeless tobacco: B The report card, issued by the nonprof- 108 million people in the United States, it advocacy group Oral Health America including 85 percent of the elderly, lack ACCESS TO CARE: C- and reviewed by the federal Centers for dental insurance. Prevalence of dentists: C Disease Control and Prevention, made a These disappointing grades in access Prevalence of dental clinics: C significant splash as media from coast to confirm the long-standing recognition in Medicaid program: C coast transmitted the rather gray findings the dental health field that oral health is Dental insurance -- adults: C concerning the nation’s “pearly whites.” inextricably linked with general health Dental insurance -- elderly: D “We were hoping to alert America that and needs to be addressed this way in HEALTH STATUS: B- we are in the position of a student with shaping public policy. Oral health of children: B straight A potential in danger of failure,” “The most important information to Adult tooth loss: B said Robert Klaus, president of Oral Health come out of this report deals with the Edentulous elderly: B America. “The report card was not meant great disparity in access to care,” Klaus Oral cancer -- male: B to embarrass or put anyone on the spot, said. “We have really hit a mark in this Oral cancer -- female: D but was intended as an impact statement area and have to work to change the per- and a wakeup call to policy makers that ception of the public and of policy makers many of these oral health problems are so they understand that oral health care preventable and solutions are affordable.” is health care.” Klaus used the example “Our primary goal was to raise public of the health insurance offered to his Other issues illuminated by the report awareness,” said Elizabeth Rogers, direc- son, who is a teacher in Chicago’s public include fluoridation of community water, tor of communications for Oral Health school system. It did not include cover- where California received its only F. Sev- America. “We were looking to extend age for dental care. “Labor unions need to eral other states suffered a failing grade in the message of Surgeon General David understand that this is not an option, and fluoridation including Hawaii, Idaho, Mis- Satcher’s report on oral health and use it this kind of exclusion can’t be made. Oral sissippi, and Montana. States that ranked as an advantage to help raise the profile of health care is health care.” an A included West Virginia, Tennessee, oral health.” “The report confirms that public Illinois, Indiana, and Iowa. The Oral Health Report Card high- policy, which could contribute to oral “When California began its fluorida- lights significant variation between the health improvements, has been lagging tion efforts in the early ’90s, about 17 states on a number of issues, especially in in funding and resources when compared percent of the state’s water was fluoridat- the categories of prevention and health to medical resources,” said Jared I. Fine, ed,” said Tim Collins, DDS, MPH, dental status. In the general category of preven- DDS, MPH, of the Office of Dental Health director of Public Health Programs and tion, fluoridation grades ranged from in Alameda County. “When politicians talk Services for the County of Los Angeles A’s to F’s; and 24 state sealant programs about health coverage and insurance, they Department of Health Services and chair received an incomplete. Grades in the don’t mean dental. For every child who is of the California Fluoridation Task Force. health status category were also all over uninsured for medical care, there are two “With the fluoridation of Los Angeles’ the board with B grades in Arizona, North to three children who are uninsured for city water in 1998 and Sacramento in Carolina, and Utah contrasting with F’s in dental care. This report points to the gaps 2000, the percentage is up to about 25-30 Kansas and Minnesota. we need to bridge in the minds of policy percent, and we have not finished our Nationwide, grades were consistently makers at federal, state, and local levels.” work. The Oral Health Report Card shows
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how important fluoridation is and should sectors and types of industries within how trends in the stock market and serve to boost our efforts.” each sector: economy may affect investments and Klaus noted that Oral Health America nnBasic materials: aluminum, building how one can best take advantage of is aware of California’s diligent fluorida- materials, chemicals, containers, gold those trends. Individual financial objec- tion efforts. “Once the state’s fluoridation mining, metals, paper and forest tives should be kept at the forefront of grade is up, it will be one of the national products, steel. decision-making. Although represen- leaders in oral health.” nnCapital goods: aerospace/defense, tation from each sector may enhance Fluoridation was in the general cat- electrical equipment, engineering and diversification, other concerns, such egory of prevention in which California construction, machinery, pollution as the need for income or a short-term received an overall C-. In accessing the lev- control. investment time horizon, may indicate el of preventive care, Oral Health America nnConsumer cyclicals -- durable goods: a different sector structure for an indi- looked at state oral health programs, the automobiles, auto parts, hardware and vidual’s portfolio. use of sealants, visits to the dentist for tools, manufactured housing, furniture Marios P. Gregoriou is associate vice adults and elderly, and the use of smoke- and appliances. (Cyclical stocks tend to president financial adviser with Morgan less tobacco. The highest grade of a B+ in rise quickly before the economy turns Stanley Dean Witter in Sacramento. He prevention went to North Dakota. up and fall quickly before the economy can be reached by calling (800) 755-8041. Klaus hopes to see improvement when turns down.) This article is published for informa- the next Oral Health Report Card comes nnConsumer cyclicals -- nondurable tion purposes and is not an offer or out. “Right now, the plan is to issue an- goods: broadcast media, solicitation to sell or buy securities or other report at the same time next year. entertainment, hotels/motels, leisure- commodities. Any particular investment We look forward to collaborating with time companies, photography/imaging, should be analyzed based on its terms state dental associations and state and publishing, restaurants, retail stores, and risks as they relate to individual territorial dental directors on the next specialty printing, toys. circumstances and objectives. report and hope for incremental improve- nnConsumer noncyclicals: beverages, ments.” foods, household products, CDC Forecasts Top 10 Public Health The entire Oral Health Report Card housewares, shoes, textiles/apparel, Challenges can be viewed online at http://www.oral- tobacco. The Centers for Disease Control and healtharmerica.org. nnEnergy: integrated oils, oil and gas Prevention outlined the top 10 public drilling, oil exploration and production. health challenges the United States Look at Sectors When Diversifying nnFinancial: banks, insurance companies, must address and said the tools already Portfolio investment banking, real estate exist to combat them, in a commen- By Marios P. Gregoriou investment trusts. tary published in the Oct. 4 issue of Investors hear a lot about portfolio nnHealth care: Drugs, HMOs, hospital the Journal of the American Medical diversification, and there are a number management, medical products and Association. of ways to diversify. When it comes to services. Jeffrey P. Koplan, MD, MPH, direc- stocks, one way to help ensure adequate nnTechnology: airlines, railroads, trucking tor of the CDC, and David W. Flem- diversification is to include stocks from companies. ing, MD, deputy director for Science several different market sectors. nnUtilities: electric companies, and Public Health at the CDC, wrote An economic sector is made up of natural gas distribution pipelines, the commentary, which recognizes industries that have certain characteris- telecommunications. the past century’s advances in saving tics in common. The industries in a given In seeking to diversify the equity and improving lives through vaccines, sector tend to react similarly to trends in portion of a portfolio, individuals may fortified foods, clean water and many the overall economy. Good or bad news wish to consider reducing stocks from other public health achievements and affecting a major stock in one industry sectors in which they are overweighted cautioned that the United States must may trickle through to stocks in other and adding stocks in areas where they be prepared for both old and new chal- industries in the same sector. Thus, by in- lack exposure. Of course, certain sectors lenges to the country’s health. cluding stocks from more than one sector can be featured more prominently in “No doubt, unanticipated challeng- in a portfolio, one may be able to lessen one’s portfolio, based on current market es of similar magnitude lie ahead,” the the effect on investments from potential trends, economic conditions, and one’s authors wrote. “Whether working in losses in any one segment. own financial goals. the public, private, or academic arenas, Here are some of the key stock market It is best to ask one’s financial adviser physicians can only hope to have the
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Meskin to Retire, Search Begins for New JADA editor Although he will be on the job until the end of 2001, the search for a successor to JADA Editor Lawrence H. Meskin, DDS, has already begun. Meskin recently announced his decision to retire after 10 years as editor, effective to Kevin C. Chung, MD, one of the few Dec. 31, 2001. surgeons to perform the procedure in the At its meeting in September, the Board of Directors of ADA Business Enterprises United States. Inc. -- the ADA subsidiary that includes the publishing division -- approved a transition Chung, director of the University of plan that called for a search committee to begin the process of finding a new editor Michigan Hand Center in Ann Arbor, for the Journal of the American Dental Association. described his intricate surgical work dur- The eight-member committee, now in place, includes practicing dentists, dental ing the American Medical Association’s Science Reporters Conference. researchers and educators, publishing professionals, editors, and ADA leadership. “Because Michigan is in the farm belt, The committee’s role is to review applications from prospective candidates, we see a lot of farmers whose fingers or interview those who appear most qualified, narrow the field and make a thumbs are cut off from farming accidents. recommendation to the Business Enterprises board at its August 2001 meeting. Of course, without fingers or thumbs, it is The Board expects to appoint a new editor by Oct. 1, 2001, informing the ADA virtually impossible for them to perform Board of Trustees of its choice prior to next year’s annual session. The new editor the necessary tasks on the farm. So, I would be in place three months before Dr. Meskin’s departure. reconstruct the hand by transferring toes Dentists interested in the JADA editorship can obtain an application and position to make the thumb and a couple of fingers description by contacting Laura A. Kosden, publisher and chief operating officer, ADA so they can drive, pick things up and milk Publishing Division, ADA Business Enterprises Inc., Suite 2010, 211 E. Chicago Ave., cows,” Chung explained. Chicago, IL, 60611. Kosden also can be reached at (312) 440-4671 or at [email protected]. The procedure typically takes eight or nine hours, depending upon the amount The deadline for submission of applications is March 31, 2001. of reconstruction performed. It involves removing various parts from the foot, including tendons, nerves, veins, arteries, bone and skin and then re-connecting them at the hand. powers of observation to detect these nnUse new scientific knowledge and “When a patient has just lost a thumb, challenges early and the resources and will technologic advances wisely. making a new thumb is very standard. My to act wisely in response.” “In many of these areas -- child devel- preference is to remove the second toe to They point out that at least 10 public opment, mental health, obesity and physi- make a thumb, because it is not as notice- health challenges can be anticipated and cal activity, the environment, bioterror- able on the foot. However, some people the tools exist to address them. These ism, and aging -- promising science-based prefer to use the big toe because it is big- challenges are to: interventions are available and deserve ger and more resembles a thumb. When nnInstitute a rational health care system. support and broader implementation,” a patient presents without any fingers at nnEliminate health disparities. the authors wrote. “For example, missed all, that surgery has a higher magnitude of nnFocus on children’s emotional and opportunities for cost-effective preven- difficulty, and I take three toes to create a intellectual development. tive services in clinical settings, including thumb and two fingers that can be used to nnAchieve a longer “healthspan.” tobacco cessation counseling, pneumococ- pinch things and pick them up,” he said. nnIntegrate physical activity and healthy cal vaccine, and chlamydia screening, can It takes approximately three months of eating into daily lives. be identified.” rehabilitation to regain function. nnClean up and protect the environment. Chung said a collaborative study con- nnPrepare to respond to emerging Toes Make Good Replacements for ducted with a Taiwan hospital that also infectious diseases. Fingers performs the procedure was recently pub- nnRecognize and address the Patients whose fingers or thumbs are lished in the Journal of Hand Surgery and contributions of mental health to lost in an accident and have a toe or toes showed that toe transfers make the hand overall health and well-being. removed from their feet to take their place perform just as well as a normal hand. nnReduce the toll of violence in society. are able to function quite well, according As for the feet of those patients
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whose toes have been removed, Chung examination. He suggest setting new pri- mental retardation/developmental dis- said patients have no problem walking or orities for how dentists approach patients abilities grow older and that periodontal running, but that some complain of oc- so that patients can be educated about a disease is an increased possibility with a casional pain from the incision. practice’s full range of cosmetic services. maloccluded dentition, they answered. Se- The future of cosmetic dentistry will vere esthetic malocclusions can compro- Patient Education Key to Increasing depend more on patient education within mise already difficult social relationships Cosmetic Dentistry each practice than on broad-based media and potential employment opportunities, The majority of the American public and advertising, Levin wrote. the authors added. does not know or think about cosmetic Children and adolescents with spe- dentistry, and more than 50 percent of Orthodontic Needs Increasing Among cial needs exhibit a higher percentage of the population doesn’t care, wrote Roger Special Needs Patients malocclusions than the normal population. P. Levin, DDS, in the summer 2000 issue During the past 30 years, more than Children with mental retardation/devel- of the Journal of Cosmetic Dentistry. three-fourths of people with mental opmental disabilities may have dentition According to Levin, the American pub- retardation/developmental disabilities difficulties resulting from habits such as lic’s view of the dental practice is the same have been de-institutionalized, and there mouth breathing and tongue thrusting, di- as it has always been: the dentist’s job is has been a corresponding need to increase ets lacking enough rough and coarse foods to fix broken or decayed teeth. awareness among orthodontists about the that require thorough chewing, increased To learn why the public is not de- growing necessity for treatment of these levels of caries, and the loss of teeth and manding more cosmetic dentistry, Levin individuals within their communities, ac- space maintenance, the authors explain. conducted informal interviews with 400 cording to the an article in the July 2000 Individuals with mental retardation may people. He concluded that the American issue of the American Journal of Ortho- not comprehend the need for oral hygiene, public does not really think of dentists dontics and Dentofacial Orthopedics. the authors note, and those with physical as professionals who enhance smiles, but The authors -- H. Barry Waldman, disabilities may lack the dexterity to ac- rather as individuals who just “fix teeth.” DDS, PhD; Steven P. Perlman, DDS; and complish the needed oral hygiene. Levin said the concept of building the Mark Swerdloff, DDS -- noted that chang- cosmetic component of a practice does not ing social policies, favorable legislation for Honors mean eliminating other types of dentistry, people with disabilities, and class-action Gordon L. Douglass, DDS, has been but instead adding a subset of cosmetic legal decisions have led to the establish- installed as vice president of the American services for patients. The problem, he ac- ment of community-oriented group Academy of Periodontology. knowledges, is that patients are aware only residences, and enhanced personal family Gary Armitage, DDS, MS, has received of the more traditional services and are not residential settings, accompanied by the the Gold Medal Award, the highest honor learning about cosmetic services. closure of many large, state-run facilities. bestowed by the American Academy of Merely placing a few brochures in the However, the success of community- Periodontology. reception room has not created the revo- based programs depends on the avail- lution that some dentists had hoped for in ability of support services, the authors cosmetic dentistry. stated -- particularly private practitioners Levin said the first step in beginning who are convenient and accessible to de- to build a cosmetic practice is to change institutionalized individuals and trained all new-patient exam formats. Dentists and willing to deliver care. who truly want to build cosmetic services To provide some insight into the need should include the cosmetic services as the for orthodontic services for these young- first aspect of a dental exam, followed by a sters and adults, the authors asked: “Do we review of the medical and dental history. believe that persons with disabilities need Levin does not advocate giving up functional and esthetic considerations on the complete, comprehensive muscle, comparable to those of ‘normal’ persons?” tissue, periodontal, and tooth-by-tooth The reality is that youngsters with
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Herpesvirus-Induced Diseases: Oral Manifestations and Current Treatment Options
Catalena Birek, DDS, PhD
abstract The dentist is often the first health professional to be contacted by patients who develop acute orofacial symptoms of viral conditions such as shingles (varicella zoster) or herpetic gingivostomatitis. The diagnosis, treatment, and management of virally induced oral diseases is a challenge inasmuch as their presentation is atypical and may be complicated by immunosuppression. However, an increasing body of knowledge regarding the manifestations of viral infections in immunocompromised patients and the advances achieved in antiviral drug therapy during the past several years should make the task less daunting for the dentist. In this paper, the natural history, typical and atypical oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus-induced diseases are reviewed, with particular attention to primary and recurrent varicella zoster virus and herpes simplex type 1 infections.
author aricella zoster virus (VZV), and lymphotropic: VZV and HSV-1 and -2 Catalena Birek is an Herpes simplex virus types are considered neurotropic, and Epstein associate professor at 1 and 2 (HSV-1, HSV-2), Barr virus and cytomegalovirus are the Faculty of Dentistry, Epstein Barr virus and primarily lymphotropic. The morbidity University of Manitoba, Canada. cytomegalovirus are all associated with herpesviruses is Vcapable of causing oral mucosal disease considerably enhanced and potentially through damage to epithelial cells. These life-threatening in neonates and viruses, as do all eight of the human severely immunosuppressed patients. herpesviruses discovered to date, share The immunosuppression may be due to common features in virion and genomic infection with human immunodeficiency structure and in their ability to establish virus, cancer treatment with cytotoxic lifelong latent infections; but they differ agents, or immunosuppressive therapy in their patterns of infectivity and for the prevention of transplant rejection. pathogenicity. The human herpesviruses The prevalence of oralmucosal ulcerative can be classified broadly according to diseases of various etiology in HIV- tropism and pathogenicity as neurotropic infected individuals is high, especially december 2000 911 herpes
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in advanced cases.1-3 The past few years cord or extramedullary cranial nerve distribution in an area corresponding to have brought about dramatic changes in ganglia, especially the trigeminal ganglion), a single sensory neuron and complication the morbidity and mortality of HIV- and possibly in other neuronal and by pain. The term “herpes” (from the infected patients. In general, the profile nonneuronal sites such as lymphoid cells.5 Greek herpes, meaning snake) was of HIV-associated oral diseases in newer In the normal, healthy host, the dormant suggested originally for the snakelike cohorts of AIDS-affected populations virus is kept under surveillance by effective shape of the dermatomal lesions, while in the Western world is changing, immune mechanisms. In about one-fifth “shingles” (from the Latin cingulum with some conditions such as hairy of individuals, zona zoster develops when meaning belt) refers to the painful leukoplakia and necrotizing ulcerative the reactivation of the virus is associated girdle.10 Skin lesions most often periodontitis decreasing in prevalence.4 with considerable viral replication in affect the trunk. Unilateral orofacial Nevertheless, there appears to be little the ganglia. It is to be noted that even manifestations along the trigeminal nerve difference between the prevalence of modest decreases in immunosurveillance (ophthalmic, maxillary, and mandibular HSV-1-associated lesions in a cohort of due to oral prednisone dosages of less branches) include skin eruptions with patients treated by new, highly active anti- than 2 mg/kg of body weight and inhaled small vesicles coalescing then crusting HIV treatment protocols (by combined beclomethasone may precipitate a quickly and mucosal vesicles that rupture protease inhibitors and nucleoside severe clinical course of zoster.6 Even in easily to form crateriform ulcers8,9 (Figure analogues), as compared with that found individuals with no apparent underlying 1). In the immunocompetent or mildly in an earlier cohort, as documented in a condition, emotional stress, physical immunosuppressed patient, the ulcers large population from North Carolina.4 trauma, or surgical intervention may normally heal within a month. In some It is likely that the number of patients trigger reactivation of dormant VZV instances, pre-herpetic neuralgia develops presenting with viral orofacial mucosal infection. prior to the eruption. Persistent “stinging” diseases will increase as the HIV-infected VZV is highly infectious. Respiratory pain is consistently associated with the population lives longer. spread is probably an important route mucocutaneous eruptions. Chronic The aim of this review is to provide an of transmission. Patients are most postherpetic neuralgia is attributable update of the natural history, typical and contagious just before the onset of to inflammatory responses to injury atypical oral manifestations, diagnosis, and the rash. Even indirect contact – e.g., (demyelinization, necrosis) in sensory current treatment options for herpesvirus- through airflow between a patient’s neurons, but aberrant central nervous induced diseases, with special emphasis hospital room and a nurses’ station,6,7 system responses perpetuating the on VZV and HSV-1 disease severity in the between hospitalized patients, or perception of pain may also play a role.5 immunocompromised patient. between previously unexposed health Chronic pain is often a problem in the care personnel and patients – may carry management of varicella zoster. Less than Primary and Recurrent VZV Infections the risk of nosocomial transmission 2 percent of immunocompetent patients Herpes zoster, also known as shingles from patients with shingles to previously develop severe complications such as or zona zoster, is caused by the ubiquitous unexposed health care personnel.6 superinfection of the mucocutaneous human varicella zoster virus, a DNA virus The symptoms of the primary VZV lesions, blindness due to acute retinal and member of the herpesvirus suborder infection (varicella or chickenpox) are necrosis, and motor neuropath.6 Primary termed alpha herpesviridae, to which cutaneous hemorrhagic maculopapular VZV infection in the adult is rare, but HSV-1 and -2 also belong. VZV causes rash (which later may become secondarily the lesions may be more severe and varicella (chickenpox), the childhood infected by bacteria and leave a small scar persist longer, and they carry the risk of epidemic disease still affecting populations or “pox”), fever, malaise, sore throat, and interstitial pneumonia. The symptoms worldwide. The majority of individuals minor oral vesicular lesions that rupture and complications of varicella may be with primary VZV infection fully recover easily and resemble oral aphthous ulcers.8,9 particularly severe in pregnant women. and have lifelong immunity against re- The mucocutaneous manifestations of In the first trimester of pregnancy, VZV infection, but the virus remains in the zona zoster are characterized by grape- may induce fetal malformations with host in a dormant state in the sensory like clusters of vesicular eruptions that atrophy and scarring of the affected ganglia (dorsal root ganglia of the spinal exhibit a restricted unilateral geographic limb (fetal varicella syndrome). In
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HIV-infected children, even a modest HIV patients who have been on long-term that allow the oral lesions of zoster to decrease of CD4 lymphocyte counts may antiviral therapies.6 be easily distinguished from those of precipitate recurrent varicella. Individuals A case of alveolar bone necrosis due similar appearance in herpes simplex and infected with HIV are at increased risk of to maxillary herpes zoster has recently aphthous stomatitis. developing multiple zoster attacks. Severe been reported.11 Dental complications As the onset and symptoms of VZV disease with extensive hemorrhagic may also include loss of pulp vitality, infections are characteristic, laboratory pustules coalescing to cover the entire root resorption, and tooth exfoliation. confirmation of the diagnosis is not dermatome and prolonged healing Conditions associated with pain – usually necessary. Because the virus with extensive crusting, scarring, and including trigeminal neuralgia, maxillary does not grow well in culture, less pigmentation may develop in patients sinusitis, and atypical facial pain – should than 60 percent of the cultures are with significant decreases in CD4 be considered in the differential diagnosis positive.5 Detection of the virus in skin counts. Among the severe complication of zoster, especially in cases presenting or mucosal scrapings by VZV-specific, of VZV infection reported in advanced without a rash (zoster sine herpete).11-13 tagged antibodies is more sensitive AIDS are progressive retinal necrosis, However, these can be eliminated and specific F( igure 2). Amplification of meningoencephalitis, and fatal through careful clinical examination viral DNA sequences with specific DNA disseminated visceral disease. Verrucous and detailed history. The association primers (polymerase chain reaction) skin lesions that are resistant to anti-VZV with stinging or burning pain and the from the samples may be necessary for drug treatment have been reported in unilateral distribution are features the diagnosis of neurological disorders
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Figure 1. Herpes zoster of the third Figure 2. Tissue section from lesional tissue treated with an Figure 3. Primary herpetic gingivostomatitis affects movable division of the trigeminal nerve. Vesicles antibody to VZV tagged with a brown dye. The positivity is striking within mucosa of the lips and lesions of the gingiva. are distributed over the skin and stop epithelial cells confirming the identify of the virus. abruptly at the midline.
in severely immunosuppressed patients kinase), then further activation (di- and opportunistic infections (including those lacking VZV seropositivity or when the tri-phosphorylation) by cellular proteins caused by herpesviruses) have more cultures are negative. (kinases); the active acyclovir acts as both recently been reviewed.21 Drugs reported The timing of effective antiviral competitor and chain terminator for to interact with famciclovir include therapy for the treatment of varicella and the viral DNA polymerase. Nucleoside cimetidine (Tagamet, used commonly zona zoster is dependent on a limited analogues cannot prevent virally for peptic ulcers) digoxin (Lanoxin, time span of active viral replication: induced cell damage or death, but they cardiotropic drug), and theophylline within 72 hours after the onset of the rash reduce the number of virion produced products (in a variety of medications, in the normal host, but more extended in the cells and thus prevent or inhibit e.g., for bronchospastic conditions). in the severely immunocompromised the intercellular spread of infection. Intravenous administration of acyclovir because replication and virus shedding Valaciclovir is a chemical derivative of or foscarnet requires hospitalization, as are sustained in such individuals. Based acyclovir that has more recently been does oral antiviral therapy in patients on advances in the understanding of developed and tested. While less than 50 with pneumonitis, disseminated disease, the molecular mechanisms of viral percent of orally administered acyclovir is or drug-resistant lesions and in more infection and replication, a series of new bioavailable, oral valaciclovir is absorbed severely compromised patients. In antiviral drugs has been developed and readily and converted enzymatically into neonates, children, and women early tested recently in clinical trials.14-20 The acyclovir in the liver. Famciclovir is the in their pregnancies, valaciclovir and antiviral compounds found effective orally bioavailable analogue of penciclovir. famciclovir are not recommended because for the treatment of VZV infections are Penciclovir-triphosphate has a longer of the lack of trials concerning the toxicity acyclovir (Zovirax), valaciclovir (Valtrex), half-life in infected cells. Foscarnet, of the drugs. Famciclovir should be famciclovir (Famvir), and foscarnet. The another viral-DNA-polymerase inhibitor used with caution in patients with renal first three are guanosine (nucleoside) is recommended for intravenous use as function impairment. analogues that inhibit viral DNA an alternative treatment in acyclovir/ Early intervention is recommended synthesis by competing with deoxy- famciclovir resistance. The treatment for the treatment of pain in the acute guanosine triphosphate as substrate for regimens for the therapy of varicella and zoster phase before the onset of chronic the viral DNA polymerase. Acyclovir, zoster in patient groups classified by age, postherpetic neuralgia. Clinical trials the prototype of these drugs, has been cause, and level of immunosuppression attest to the efficacity of high-dose pursued in several clinical trials and – as recommended at a clinical staff acyclovir and its derivatives in alleviating experimental model systems since the conference held at the National Institutes acute pain and preventing chronic early 1980s. The mechanism of action of Health – have recently been reviewed neuralgia. However, there are no surefire of the drug is based on the selective in detail.6 The recommendations are cures for the acute pain of shingles, activation (monophosphorylation) by summarized in Table 1. The management and the management of chronic pain the product of a viral gene (thymidine of most common HIV-related remains difficult. Low doses of tricyclic
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antidepressants such as amitryptyline (Elavil) and the addition of the anticonvulsant gabapentin (Neurontin) to standard pain-management regimens have been effective.19 Regional blocks of Figure 4. Herpetic Whitlow. Figure 5. Herpes labialis. nerve roots or ganglia may provide relief in some patients. Topical anesthetics such as 2 percent lidocaine viscous applied with cotton swabs22 or in anesthetic rinses are helpful for lesions limited to the oral mucosa. Applications of over-the-counter to 90 percent effective, and children who Primary and Recurrent HSV-1 Infections preparations containing capsaicin (extract acquire chickenpox in spite of vaccination The cause of primary herpetic of chili pepper, Zostrix, Capzasin-P) experience significantly milder symptoms.6 gingivostomatitis is infection with HSV-1, may be beneficial in individual cases as In immunocompetent individuals, the but oral disease with identical clinical desensitizing regimens, but the active vaccine is safe. In most recipients, it manifestations may also be caused by ingredient causes extreme irritation and causes subclinical infection; in less than the genital type HSV-2 when the latter burning of the mucosa. Prescription 20 percent of cases, the vaccines may is transmitted by genito-oral or oral-oral narcotics are recommended for severe cause a fever or varicella-like rash. There contact. Recent molecular epidemiologic cases. The use of systemic corticosteroid is risk of infectious viral transmission studies have substantiated the notion that treatment to prevent postherpetic from vaccines that cause a rash (even most HSV-1 genotypes are often shared neuralgia (presumably by suppressing before the onset of the rash) to previously by genital and nongenital lesions.28 It is inflammation in dorsal root ganglia) has unexposed individuals; although the risk also apparent that initial genital HSV-1 been discussed critically for some time.23 is low, it is advisable for people at high risk may be acquired through oral contact, However, at least one placebo-controlled for complications from varicella (pregnant as evidenced by cross-sectional analyses clinical trial indicates that acyclovir/ women and the immunocompromised) to of data collected in urban sexually prednisone combination therapies provide avoid close contact with recently vaccinated transmitted disease clinics from patients considerable benefits in the management people. Zoster due to the reactivation who had positive genital HSV cultures.29 of postherpetic pain in patients in of the Oka strain in vaccine recipients The development of immunity to HSV is which high-dose corticosteroids are not is not considered to be a significant not well-understood, but cross-immunity contraindicated.14,24 problem as the incidence of zoster in between these two HSV types is known to In the United States, vaccination vaccinated children does not appear to develop so that previous exposure to one against VZV infection is indicated for exceed zoster rates found in naturally type results in milder manifestations of immunocompetent people older than 12 infected children (as reviewed by Krause infection with the other.30 months without history of varicella. In and Straus27). The Oka strain vaccine is Primary infection with HSV-1, or children older than 12 years and adults, the contraindicated in immunocompromised primary herpetic gingivostomatitis, seen administration of two doses of the vaccine, individuals, because of the significant most often in children, is characterized four to eight weeks apart, is recommended risk of severe vaccine-induced varicella; by fever, malaise, lymphadenopathy, and because they respond less well to a single in pregnant women, because of the multiple crops of vesicular eruptions dose.6,25-27 For the universal immunization risk of fetal varicella syndrome in early located on the attached gingiva and of children, several countries have adopted pregnancy and the risk of severe clinical movable mucosa of the oral cavity; the use of vaccine preparations containing infection in late pregnancy; and in the oropharyngeal mucosa and the live attenuated varicella virus derived people with history of hypersensitivity conjunctiva may be involved.8,9 The from the Oka-strain (originally isolated in to vaccine components. In these groups, vesicles rupture easily and leave small Japan from a child with varicella). The Oka postexposure prophylaxis with anti-VZV ulcers covered by a pseudomembrane and vaccine currently marketed in the United immunoglobulin, and in some cases with surrounded by erythema (Figure 3). The States is estimated to be about 70 percent oral acyclovir, is recommended.6 infected patient, as well as susceptible
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people in contact with the patient, may latency-associated transcripts, which are sometimes preceded by a prodromal show the typical sign of herpetic whitlow antisense to cellular regulatory proteins. tingling sensation (Figure 5). Oral mucosal (viral, primary or recurrent, vesicular or To date, however, there are no known lesions are rare, nonfebrile, and usually pustular dermatitis of the finger) F( igure encoded proteins associated with HSV- restricted to small clusters of microvesicles 4). In immunocompetent patients, the 1 latency-associated transcripts, and that rupture to leave punctate ulcers, primary infection runs its course within how the latency-associated transcripts typically on the palatal gingiva one to two weeks without scarring. In function in HSV-1 latency remains (occasionally elsewhere on the gingivae) children with herpetic gingivostomatitis, obscur.5 The models proposed to explain unilaterally (Figure 6). The lesions are self- eating and drinking difficulties, fever, and HSV-1 pathogenesis on reactivation limited, resolving within one to four days8,9. drooling may often lead to dehydration.31 from dormancy, and the putative role of Extensive or persistent lesions of both The prevalence of recurrent or mucosal immunity in reactivation have primary and secondary infections should recrudescent disease in the general been reviewed thoroughly by Oakley raise the suspicion of immunosuppression. population has been estimated as 20 and colleagues.34 It appears that in HSV In HIV-infected patients, there is a risk percent to 40 percent worldwide and reactivation, only a few neurons become of disseminated lesions with severe 35 percent to 38 percent in the United involved, whereas in VZV infection, morbidity, including herpes encephalitis. States.32 HSV-1 is ubiquitous and highly replication from numerous neurons is Such risk has declined with current contagious. Approximately 60 percent required for reactivation.5 This would antiviral therapies; but, in advanced AIDS, to 80 percent of American adults are account for the relatively small and focal it remains a serious problem, especially in latently infected, i.e., asymptomatic lesions in typical recrudescent HSV-1- developing countries. HSV-1 seropositive.27 De novo infections associated herpes, as compared to those The differentiation of uncomplicated similar in course to primary infections of zoster. However, the symptoms of oral mucosal HSV infection from may develop in seropositive individuals recrudescent or recurrent HSV infection recurrent aphthous ulcers is based on on contact with active lesions of other may range from subclinical to debilitating, the presence of elevated temperature patients or even through self-inoculation. depending on the level of impairment in primary herpetic gingivostomatitis The highest risk of transmission is during of the host’s immune surveillance and the unilateral appearance of the the limited time span of viral shedding mechanisms. microvesicles in the palatal mucosa in during active infection (one to four days, The list of known triggers of HSV typical recurrent intraoral HSV infections. but prolonged in immunocompromised reactivation includes stress, surgical The widely held distinction between patients). The possibility of contagion trauma, dental extraction, menses and recurrent aphthous ulcers and recurrent due to viral shedding into saliva or genital other hormonal changes, infectious febrile HSV on the basis of distribution (always secretions during asymptomatic infection conditions and hyperthermia, ultraviolet on the nonkeratinized mucosa in the should be taken into account, albeit the radiation, and drugs such as corticosteroids former, and mainly on the keratinized risk is considerably lower than in contact and prostaglandin E2.34,35 Two cases of oral surfaces of the palate, gingiva, alveolar with active lesions. Reports of viable mucosal HSV infection associated with mucosa or alveolar ridge in the latter) HSV contaminating door handles and the radiotherapy of the head and neck still largely holds true, as indicated passing through latex gloves damaged by have recently been described.34 In these by the findings of a recent study of 52 solvents32 emphasize the need for proper cases, a combination of triggering factors, immunocompetent patients with positive infection control in the dental office. including stress in one case and HIV- and HSV cultures.36 However, a minority Significant knowledge has drug-induced immunosuppression as well (roughly 10 percent in this series) of accumulated over the past few years as concurrent cytomegalovirus infection in HSV-positive ulcerations occurred on regarding the cellular/molecular the other, were recognized. In the general the nonkeratinized mucosa, a feature mechanisms of latency and reactivation population, the typical manifestation of often reported in immunocompromised of HSV infection.5,33 For example, latency- recurrent HIV-1 infection is herpes labialis individuals. The differential diagnosis of associated genes of several herpesviruses (“cold sores”): unilateral vesicular eruptions mucosal HSV-1 infection also includes have been discovered, and it is known surrounded by erythema, followed by the oral mucosal vesicles of hand-foot- that latent HSV genomes express crusting and healing. The eruptions are and-mouth disease. The latter, seen
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Figure 6. Recurrent palatal herpes. Figure 7. DNA in situ hybridization with red chromogen Figure 8. CMV ulceration in an HIV-seropositive patient. localizing HSV1 in oral epithelial cells from a herpetic lesion. This also harbored HSV. mostly in children, can be diagnosed and them can be subjected to multiple testing in reducing shedding time and the distinguished easily from HSV-1-induced for coinfection with other pathogens severity symptoms of genital herpes in herpetic stomatitis by positive Coxsackie and that the histopathological features HIV-infected patients.37 Multicentric, virus culture (from the lesions or stool) of viral cyptopathic changes such as controlled clinical trials have indicated and the presence of concomitant vesicular intraepithelial vesicles with eosinophilic that famciclovir (at 500 mg four eruptions on the skin of extremities. inclusion bodies and clear cell ballooning times daily) also promotes healing in Similarly, positive viral Coxsackie virus (common characteristic of infections with experimental UV-radiation-induced culture and the limited distribution of the herpesviruses) can be corroborated with labial herpes in volunteer subjects.38 vesicles on the oropharynx are diagnostic the molecular findings. However, in immunocompetent patients, of herpangiana. Primary and recurrent oral HSV the benefits of oral medications with For the definitive diagnosis of HSV, infections in immunocompetent patients nucleoside analogues should be weighed viral culture from swabs of active lesions are self-limited, generally requiring only against potential side effects, as well as has been considered the gold standard, symptomatic treatment. For first episodes costs. For acyclovir, the following have but the usefulness of this method is of painful mucosal HSV infection, been reported in the first year or so of limited by the relatively short time span acyclovir 5 percent ointment (Zovirax) use in 1 percent to 5 percent of patients: of viral shedding and by the relatively applied hourly at the onset of symptoms nausea, diarrhea, headaches, and rash. low number of viral particles present is known to reduce the extent of viral Paresthesia/esthesia, also in a minority in the samples. Immunocytochemistry shedding and pain, but it provides little of patients, is reported with more with anti-HSV antibodies and in-situ benefit in recurrent herpes labialis. For prolonged use. The frequency and severity hybridization with HSV-nucleic acid recurrent herpes labialis, penciclovir 1 of these symptoms rarely necessitate probes applied to biopsy sections of percent (Denavir) cream applied every discontinuation of the treatment with early lesions are sensitive alternatives to two hours (while awake) for four days, acyclovir, but famciclovir is expensive and viral culture (Figure 7). Polymerase chain starting at the onset of symptoms, is knowledge of its toxicity is still lacking. reaction-based methods, albeit less cost- recommended. This regimen has been The treatment of severe, complicated, and effective, are highly sensitive, specific, found to significantly decrease the mean disseminated HSV infections requires and applicable to samples in the absence duration of lesions and pain and to be hospitalization. Valaciclovir 500 mg of symptomatic shedding. However, the well-tolerated.17 However, more studies twice daily was found effective for HSV- sample collection and the interpretation are needed to establish the efficacy of this suppression in a randomized, controlled of positive polymerase chain reaction topical nucleoside analogue in primary study of HIV-infected subjects with CD4 results of the swabs should take into infections and immunocompromised lymphocyte counts higher than 100. For consideration the possibility of normal patients. Systemic medication is required the treatment of recurrent genital herpes, shedding of viral DNA in saliva, peripheral in patients experiencing six or more valaciclovir is relatively well-tolerated blood, and exfoliated epithelial cells painful episodes per year. Studies show at this dosage39 However, as found in distant from the active ulcers. This is less that at least in genital herpes, valaciclovir cases of advanced AIDS, valaciclovir of a problem in immunocytochemistry 500 mg only twice daily provides the prophylactic therapy with high doses (8 and in situ hybridization applied to pharmacological benefit of 200 mg of g/day) increases the risk of thrombotic biopsy samples. Biopsy samples have acyclovir administered more frequently microangiopathy, which is potentially the added advantage that sections from (five times daily).17 Famciclovir is effective fatal.39 Foscarnet has been shown to be
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effective in resistant herpetic infections in adults and in very severe cases in children.23,39,40 Several new strategies have been explored in the experimental development Figure 9. Oral hairy leukoplakia (Epstein Barr virus). Figure 10. Herpesvirus 8 is associated with Kaposi’s of genetically engineered HSV-DNA sarcoma in an HIV-positive patient. vaccines.27,41-46 The aim is to obtain vaccines that are highly immunogenic but nonpathogenic. Efforts have been directed primarily at preventing the acquisition by papules that develop into “target” Other Herpesviruses and recurrence of genital herpes, lesions (a zone of central necrosis with In immunocompetent individuals, which would be particularly important peripheral erythema). The lesions may cytomegalovirus infections are in preventing neonatal infection, for be limited to the skin, or they may be rare, but they are a cause of severe example. Earlier attempts with vaccines accompanied by mucosal lesions. In the morbidity (e.g., retinitis, esophagitis, containing killed viruses failed to produce oral cavity, they are characterized by pneumonitis) and mortality in severely adequate immunity. New strategies are bullae and vesicles that rupture to form immunocompromised patients. Even aimed at creating a live “mutant” virus raw, erythematous ulcerations or ragged in moderately immunocompromised with a limited replication capacity in vivo, erosions.8,9 The pathogenesis of HSV- adults and children, cytomegalovirus- or recombinant DNA plasmid vaccines; associated erythema multiforme has not associated mucosal lesions may genes that have been associated with been elucidated, but it has been postulated mimic those of other viral or nonviral virulence are deleted from the latter, but to be attributable to viral protein products ulcerative lesions, including those of they contain DNA sequences encoding for that act as superantigens in the tissues, recurrent aphthous ulcers, persistent viral proteins that are capable of eliciting eliciting specific cell mediated immunity and recurring herpetic stomatitis, and natural immunity when injected directly with the production of cytokines that necrotizing stomatitis34,40,49,50 (Figure into the tissues. Such strategies are mediate cellular signaling cascades 8). A definitive diagnosis can only be currently being tested with considerable ultimately leading to epithelial cell made through the specific identification promise in animal models of genital death.47,48 The treatment of HSV-associated of the virus in culture, or the detection herpes. Further, plasmid DNA carrying erythema multiforme is often difficult, of cytomegalovirus DNA or antigens sequences encoding for the glycoprotein and the various regimens suggested for in biopsy specimens. Characteristic D of HSV-1 are being tested for its management have not been proven ballooning of cytomegalovirus- immunogenicity in experimental animal by rigorous clinical trials. The therapeutic infected cells (cytomegaly) and typical models;46 however, much is still to be dilemma is whether priority should be inclusion-bodies are pathognomonic learned about the molecular mechanisms given to corticosteroid treatment of histomorphological features.49 Until of immunogenicity of both HSV-1 and -2. the immunopathologic condition of recently, Ganciclovir (administered erythema multiforme or to the antiviral intravenously in severe cases) has been HSV and Erythema Multiforme treatment of HSV. According to at least the drug of choice in AIDS-associated Erythema multiforme is an acute, one recent study,47 the treatment should cytomegalovirus infections; however, polymorphous mucocutaneous disorder be considered carefully in each individual it does have significant side effects due of complex etiology, often associated with case taking into consideration the severity to the toxicity of the drug.18 A number drugs, mycoplasma, and HSV infection. It of the lesions and individual response to of clinical trials are ongoing to establish is now accepted that erythema multiforme antiviral drug therapy, but corticosteroids the efficacy of alternative therapies. minor, erythema multiforme major, should be considered as a mode of Valaciclovir has been tested in preventing Stevens-Johnson syndrome, fixed drug treatment in all HSV-induced erythema cytomegalovirus infection in advanced reactions, and toxic epidermal necrolysis multiforme, especially in cases of failure of HIV-disease patients and bone marrow are parts of a single spectrum of disease. antiviral therapy. and renal transplant recipients.17,51 Recent The typical skin lesions are characterized data have confirmed the expectation
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that valaciclovir is effective not only in of lymphomas.56-58 In the oral cavity, or contribute to epithelial cell damage. the prophylaxis of cytomegalovirus- advanced Kaposi’s sarcoma may present However, the polymerase chain reaction- associated morbidity, but also in reducing as ulcerative lesions, but these are based detection of viral nucleic acids in the frequency of acute graft rejections in distinguishable from HSV-associated tissue scrapings or vesicular fluid is not transplant patients.39 ulcers as the former are “tumefactive,” sufficient for diagnosis unless it correlates Epstein Barr virus is the major cause or tumor-like lesions (Figure 10). They well with clinical and histomorphological of infectious mononucleosis, a significant are typically vascular (hemorrhagic), features of biopsy samples. etiologic cofactor in the development of initially presenting as macules or nodules; As a general rule, persistent Burkitt’s lymphoma and nasopharyngeal in Kaposi’s sarcoma, the ulceration is herpetiform lesions, especially those found carcinoma, and has been associated secondary to the tumor.1,9,53,59 to harbor VZV, HSV, cytomegalovirus with various other lymphoproliferative In immunosuppressed patients, oral or Epstein Barr virus should raise the disorders, mainly those of the B-cell ulcerations with an atypical presentation suspicion of immunosuppression. In these series. Organ transplant recipients are have also been attributed to coinfection of cases, hematologic testing for indicators particularly vulnerable to Epstein Barr HSV-1 with other herpesviruses, namely of immune functions (T4:T8 lymphocyte virus-induced lymphomas.52 While the Epstein Barr virus, cytomegalovirus, ratios and CD4 lymphocyte counts) is oropharyngeal epithelium is the site of and other opportunistic pathogens.12,49,60 recommended. Epstein Barr virus entry and replication, Generally, such lesions are described as and viral shedding can be detected in single large or multiple ulcerations on any References 1. Ficarra G, Oral ulcers in HIV-infected patients: an update on saliva, the virus establishes persistent keratinized or nonkeratinized mucosal epidemiology and diagnosis. Oral Dis 3 Suppl 1:S183-9, 1997. infection of lymphoid cells. In the oral surface (palate, interdental papilla, buccal 2. Zakrzewska JM, Robinson P, Williams IG, Severe oral cavity, ulcerations due to Epstein Barr mucosa, lateral surface, or tip of tongue). ulceration in patients with HIV infection: a case series. Oral Dis 1,49,53 3 Suppl 1:S194-6, 1997. virus infection are rare. Epstein 3. Meyer U, Kleinheinz J, et al, Oral findings in three different Barr virus is more commonly associated Other Pathogens in Recurrent Oral groups of immunocompromised patients. J Oral Pathol Med with oral hairy leukoplakia, which was Aphthous Ulcers 29(4):153-8, 2000. 4. Patton LL, McKaig R, et al, Changing prevalence of oral first defined as a clinical entity in HIV- The advent of highly sensitive and manifestations of human immunodeficiency virus in the era of infected individuals;54 and it is found specific methods for the detection of protease inhibitor therapy. Oral Surg Oral Med Oral Pathol Oral more commonly in patients who are viral and bacterial products in minute Radiol Endod 89(3):299-304, 2000. 5. Kinchington PR, Latency of varicella zoster virus; a immunocompromised. This white amounts of tissue specimens has persistently perplexing state. Front Biosci 4:D200-11, 1999. hyperkeratotic lesion develops primarily allowed for the investigation of the role 6. Cohen JI, Brunell PA et al, Recent advances in varicella- on the lateral border of the tongue (Figure of microorganisms in the pathogenesis zoster virus infection. Ann Intern Med 130(11):922-32, 1999. 7. Josephson A, Gombert ME, Airborne transmission of 9). Oral hairy leukoplakia and similar of mucosal ulcerative diseases with nosocomial varicella from localized zoster. J Infect Dis 158(1):8- Epstein Barr virus-associated lesions have multifactorial etiology. In several case 41, 1988 also been reported in immunocompetent series, HSV-1, cytomegalovirus, and other 8. Eversole LR, Clinical Outline of Oral Pathology: Diagnosis and Treatment, 3rd ed. Lea & Febiger, Philadelphia, 1992, pp patients, but the significance of this human herpesviruses have been found in 64-74, 91-8. condition as a harbinger of emergence association with recurrent oral aphthous 9. Sapp JP, Eversole LR, Wysocki GP, Contemporary Oral and from latency in HIV infection should be ulcers.61-64 A direct causal role for these Maxillofacial Pathology. Mosby, St. Louis, 1997, pp 196-211. 9,55 10. Oaklander AL, The pathology of shingles: Head and kept in mind. pathogens has not been established, Campbell’s 1900 monograph. Arch Neurol 56(10):1292-4, 1999. Human herpesvirus type 8 has been nevertheless it is plausible that products 11. Owotade FJ, Ugboko VI, Kolude B, Herpes zoster infection of implicated in the pathogenesis of several of the microorganisms have an indirect, the maxilla: case report. J Oral Maxillofac Surg 57(10):1249-51, 1999. diseases, most of them neoplastic. cofactorial role at least in a proportion of 12. Tidwell E, Hutson B, et al, Herpes zoster of the trigeminal Examples of human herpesvirus type classical recurrent aphthous ulcer cases. nerve third branch: a case report and review of the literature. 8-associated diseases are Kaposi’s Several hypotheses have been advanced Int Endod J 32(1):61-6, 1999. 13. Yura Y, Kusaka J, et al, Mental nerve neuropathy as a result sarcoma, a vascular neoplasm found for future testing. For example, products of primary herpes simplex virus infection in the oral cavity. A often in AIDS patients (The virus is also of HSV genes may act as superantigens in case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod known as Kaposi’s sarcoma-associated activating humoral and local cell-mediated 90(3):306-9, 2000. 14. Whitley RJ, Gnann Jr JW, Therapeutic approaches to virus.); multiple myeloma; and a subset immune responses that in turn may induce the management of herpes zoster. In, Mills J, ed, Antiviral
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Chemotherapy 5. Kluwer Academic/Plenum Publishers, New 34. Oakley C, Epstein JB, Sherlock CH, Reactivation of oral 51. Lowance D, Neumayer HH, et al, Valacyclovir for York, 1999, pp 159-65. herpes simplex virus: implications for clinical management of the prevention of cytomegalovirus disease after renal 15. Arvin AM, Management of varicella-zoster virus infections herpes simplex virus recurrence during radiotherapy. Oral Surg transplantation. International Valacyclovir Cytomegalovirus in children. In, Mills J, ed, Antiviral Chemotherapy 5, Kluwer Oral Med Oral Pathol Oral Radiol Endod 84(3):272-8, 1997. Prophylaxis Transplantation Study Group. N Engl J Med Academic/Plenum Publishers, New York, 1999, pp 167-74. 35. Hill TJ, Blyth WA, An alternative theory of herpes-simplex 340(19):1462-70, 1999. 16. Sacks SL, Wilson B, Famciclovir/penciclovir. In, Mills J, recurrence and a possible role for prostaglandins. Lancet 52. Okano M, Gross TG, A review of Epstein-Barr virus ed, Antiviral Chemotherapy 5, Kluwer Academic/Plenum 1(7956):397-9, 1976. infection in patients with immunodeficiency disorders. Am J Publishers, New York, 1999, pp 135-47. 36. Eisen D, The clinical characteristics of intraoral herpes Med Sci 319(6):392-6, 2000. 17. Bell AR, Valaciclovir update. In, Mills J, ed, Antiviral simplex virus infection in 52 immunocompetent patients. Oral 53. Eversole LR, Viral infections of the head and neck among Chemotherapy 5, Kluwer Academic/Plenum Publishers, New Surg Oral Med Oral Pathol Oral Radiol Endod 86(4):432-7, HIV-seropositive patients. Oral Surg Oral Med Oral Pathol York, 1999, pp 149-57. 1998. 73(2):155-63, 1992. 18. Spector SA, Oral ganciclovir. In, Mills J, ed, Antiviral 37. Schacker T, Hu HL, et al, Famciclovir for the suppression 54. Greenspan D, Greenspan JS, Significance of oral hairy Chemotherapy 5, Kluwer Academic/Plenum Publishers, New of symptomatic and asymptomatic herpes simplex virus leukoplakia. Oral Surg Oral Med Oral Pathol 73:151-4, 1992. York, 1999, pp 121-7. reactivation in HIV-infected persons. A double-blind, placebo- 55. Neville BW, Damm DD, et al, Oral and Maxillofacial 19. Rowbotham M, Harden N, et al, Gabapentin for the controlled trial. Ann Intern Med 128(1):21-8, 1998. Pathology. WB Saunders, Philadelphia, 1995, pp 202-3, 404-6. treatment of postherpetic neuralgia: a randomized controlled 38. Spruance SL, Rowe NH, et al, Peroral famciclovir in the 56. Gnann JW Jr, Pellett PE, Jaffe HW, Human herpesvirus trial. J Am Med Assoc 280(21):1837-42, 1998. treatment of experimental ultraviolet radiation-induced 8 and Kaposi’s sarcoma in persons infected with human 20. Boeckh M, Management of cytomegalovirus infections in herpes simplex labialis: A double-blind, dose-ranging, placebo- immunodeficiency virus. Clin Infect Dis 30 Suppl 1:S72-6, 2000. blood and marrow transplant recipients. In, Mills J, ed, Antiviral controlled, multicenter trial. J Infect Dis 179(2):303-10, 1999. 57. Mitsuyasu RT, Update on the pathogenesis and treatment Chemotherapy 5, Kluwer Academic/Plenum Publishers, New 39. Ormrod D, Scott LJ, Perry CM, Valaciclovir: a review of its of Kaposi sarcoma. Curr Opin Oncol 12(2):174-80, 2000. York, 1999, pp 89-103. long term utility in the management of genital herpes simplex 58. Cannon M, Cesarman E, Kaposi’s sarcoma-associated 21. Depaola LG, Human immunodeficiency virus disease: virus and cytomegalovirus infections. Drugs 59(4):839-63, herpesvirus and acquired immunodeficiency syndrome- natural history and management. Oral Surg Oral Med Oral 2000. related malignancy. Semin Oncol 27(4):409-19, 2000. Pathol Oral Radiol Endod 90(3):266-70, 2000. 40. Ramos-Gomez FJ, Flaitz C, et al, Classification, 59. Piluso S, Ficarra G et al, Cause of oral ulcers in HIV-infected 22. Siegel MA, Strategies for management of commonly diagnostic criteria, and treatment recommendations for patients: a study of 19 cases. Oral Surg Oral Med Oral Pathol encountered oral mucosal disorders. J Calif Dent Assoc orofacial manifestations in HIV-infected pediatric patients. Oral Radiol Endod 82(2):166-72, 1996. 27(3):210-9, 1999. Collaborative Workgroup on Oral Manifestations of Pediatric 60. Birek C, Patterson B et al, EBV and HSV infections in a 23. Snoeck R, Andrei G, De Clercq E, Current pharmacological HIV Infection. J Clin Pediatr Dent 23(2):85-96, 1999. patient who had undergone bone marrow transplantation: approaches to the therapy of varicella zoster virus infections: 41. Da Costa X, Kramer MF et al, Construction, phenotypic oral manifestations and diagnosis by in situ nucleic acid a guide to treatment. Drugs 57(2):187-206, 1999. analysis, and immunogenicity of a UL5/UL29 double deletion hybridization. Oral Surg Oral Med Oral Pathol 68(5):612-7, 24. Whitley RJ, Weiss H, et al, Acyclovir with and without mutant of herpes simplex virus 2. J Virol 74(17):7963-71, 2000. 1989. prednisone for the treatment of herpes zoster. A randomized, 42. Stanberry LR, Cunningham AL, et al, Prospects for control 61. Leimola-Virtanen R, Happonen RP, Syrjanen S, placebo-controlled trial. The National Institute of Allergy and of herpes simplex virus disease through immunization. Clin Cytomegalovirus (CMV) and Helicobacter pylori (HP) found in Infectious Diseases Collaborative Antiviral Study Group. Ann Infect Dis 30(3):549-66, 2000. oral mucosal ulcers. J Oral Pathol Med 24(1):14-7, 1995. Intern Med 125(5):376-83, 1996. 43. Sin JI, Kim J, et al, LFA-3 plasmid DNA enhances Ag-specific 62. Scott DA, Coulter WA, et al, Detection of herpes simplex 25. Prevention of varicella: Recommendations of the Advisory humoral-and cellular-mediated protective immunity against virus type 1 shedding in the oral cavity by polymerase chain Committee on Immunization Practices. Centers for Disease herpes simplex virus-2 in vivo: involvement of CD4+ T cells in reaction and enzyme-linked immunosorbent assay at the Control and Prevention. MMWR 45(RR-11):1-3, 1996. protection. Cell Immunol 203(1):19-28, 2000. prodromal stage of recrudescent herpes labialis. J Oral Pathol 26. Krause PR, Klinman DM, Varicella vaccination: evidence for 44. Simms JR, Heath AW, Use of herpes simplex virus (HSV) Med 26(7):305-9, 1997. frequent reactivation of the vaccine strain in healthy children. type 1 ISCOMS 703 vaccine for prophylactic and therapeutic 63. Lee S, Bang D, et al, Polymerase chain reaction reveals Nat Med 6(4):451-4, 2000. treatment of primary and recurrent HSV-2 infection in guinea herpes simplex virus DNA in saliva of patients with Behcet’s 27. Krause PR, Straus SE, Herpesvirus vaccines. Development, pigs. J Infect Dis 181(4):1240-8, 2000. disease. Arch Dermatol Res 288(4):179-83, 1996. controversies, and applications. Infect Dis Clin North Am 45. Gebhard JR, Zhu J, et al, DNA immunization utilizing a 64. Birek C, Grandhi R et al, Detection of Helicobacter pylori in 13(1):61-81, 1999. herpes simplex virus type 2 myogenic DNA vaccine protects oral aphthous ulcers. J Oral Pathol Med 28(5):197-203, 1999. 28. Umene K, Kawana T, Molecular epidemiology of herpes mice from mortality and prevents genital herpes. Vaccine To request a printed copy of this article, please contact/ simplex virus type 1 genital infection in association with 18(17):1837-46, 2000. Catalena Birek, DDS, PhD, University of Manitoba, clinical manifestations. Arch Virol 145(3):505-22, 2000. 46. Rogers JV, Hull BE, et al, Murine response to DNA encoding Department of Oral Pathology, 780 Bannatyne Ave., Winnepeg, 29. Lafferty WE, Downey L, et al, Herpes simplex virus type herpes simplex virus type-1 glycoprotein D targeted to the Manitoba R3E OW2, CANADA. 1 as a cause of genital herpes: impact on surveillance and liver. Vaccine 18(15):1522-30, 2000. prevention. J Infect Dis 181(4):1454-7, 2000. 47. Katz J, Livneh A, et al, Herpes simplex-associated erythema 30. Ashley RL, Wald A, Genital herpes: review of the epidemic multiforme (HAEM): a clinical therapeutic dilemma. Pediatr and potential use of type-specific serology. Clin Microbiol Rev Dent 21(6):359-62, 1999. 12(1):1, 1999. 48. Aurelian L, Kokuba H, Burnett JW, Understanding the 31. Amir J, Harel L, et al, The natural history of primary herpes pathogenesis of HSV-associated erythema multiforme. simplex type 1 gingivostomatitis in children. Pediatr Dermatol Dermatology 197(3):219-22, 1998. 16(4):259-63, 1999. 49. Regezi JA, Eversole LR, et al, Herpes simplex and 32. Scott DA, Coulter WA, Lamey PJ, Oral shedding of herpes cytomegalovirus coinfected oral ulcers in HIV-positive simplex virus type 1: a review. J Oral Pathol Med 26(10):441-7, patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997. 81(1):55-62, 1996. 33. Miller CS, Danaher RJ, Jacob RJ, Molecular aspects of 50. Epstein JB, Sherlock CH, Wolber RA, Oral manifestations herpes simplex virus I latency, reactivation, and recurrence. of cytomegalovirus infection. Oral Surg Oral Med Oral Pathol Crit Rev Oral Biol Med 9(4):541-62, 1998. 75(4):443-51, 1993.
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Papillary Lesions of the Oral Cavity: Relationship to Human Papillomaviruses
Lewis Roy Eversole, DDS, MSD, MA
abstract Human papillomaviruses are a group of genetically related organisms that infect stratified squamous epithelium. Unlike many other viruses that infect oral epithelium and induce lysis of the cells they penetrate, HPVs induce proliferative changes in these cells that result in both benign and malignant tumors. The common skin wart (verruca vulgaris) is induced by HPV 2 and 4. Genital warts (condylomas) and the common solitary oral papilloma are associated with HPV 6 and 11. Either HPV 13 or 32 causes focal epithelial hyperplasia. All of these wart-like lesions are benign growths of the stratified squamous lining of the oral cavity and lips and can be treated by surgical excision or laser ablation. HPV 16 and other less frequently encountered genotypes are associated with uterine cervix cancer in 95 percent to 98 percent of cases, and the evidence for a causal role is robust. There are emerging data that implicate HPV in certain subsets of oral cancer, particularly those that arise in the oropharynx/tonsillar region. Some instances of the various histologic subtypes subsumed under proliferative verrucous leukoplakia and verrucous carcinoma also harbor HPV.
author ental practitioners often are usually associated with and caused by discover mucosal nodules members of the human papillomaviruses. Lewis Roy Eversole, DDS, during the course of an oral There are more than 120 genetically MSD, MA, is a professor in the Department of soft tissue examination, and different, yet closely related HPVs that are 1 Pathology and Medicine these common lesions are referred to as genotypes. The genotypes at the University of Dusually traumatic fibromas. When found are numbered in order of their initial the Pacific School of on the lower lip however, they may also discovery (i.e., HPV 1 was the first human Dentistry. be mucous extravasatioin phenomena papillomavirus to be discovered; HPV (mucoceles). Occasionally, mucosal 118 is one of the more recent genotypes nodules will exhibit a bosselated or to be isolated from human tissues). cauliflower surface texture; or, indeed, The various genotypes have specificity some may have finger-like projections. for certain human cell types and cause These papillary or verrucous-type lesions distinct types of lesions. Table 1 lists the 922 december 2000 papillomaviruses
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more common HPVs that cause lesions of the head and neck. Most oral and labial papillary lesions are HPV-associated and are self-limited benign growths that do not progress to cancer. The so-called mucosatropic oncogenic HPVs have a tropism (affinity) for the stratified squamous epithelium of mucous membranes and are associated with carcinomatous transformation. The association between HPV 16, 18, 31, 33, 35 and a few others with squamous cell carcinoma of the uterine cervix is extremely high.1,2 HPV DNA can be detected in nearly 95 percent of cervical squamous cancers. Oral cancer is also found to harbor HPV genomes, yet the association is not as frequently detected as it is in the cervix, even though both mucous membranes are lined by the same type of epithelium. This article will briefly discuss the molecular basis for HPV- induced epithelial proliferation and detail the clinical features of HPV oral lesions. Figure 1. Mechanisms of HPV-associated carcinogenesis. HPV E6 binds to p53 and degrades it, or p53 is mutated and nonfunctional thereby leading the cell into uncontrolled mitosis. HPV Effects on Oral Epithelia The HPVs are small when compared with the large herpes group viruses that protein on the keratinocytes membrane termed Rb; and, similarly, cell cycle commonly infect the oral cavity (see the in order to be assimilated into the cell regulation is perturbed. article in this issue by Birek). HPV is a DNA by a process known as endocytosis The hallmark of malignancy is virus about 8,000 nucleotide bases long. (Figure 1). Once the virus has gained uncontrolled cell division and changes in Its genome is divided into two major gene entry into the cell, it divests itself of its the surface chemistry of cancer cells that groups: E, or early region genes, and L, protein coat, and the viral DNA may then allow for invasion and metastasis. It is or late region genes.3 These genes are also utilize host cell DNA building blocks to axiomatic that certain HPV early region known as open reading frames, and they replicate themselves. These clever viruses proteins are able to place the cell in a state of encode proteins with important biological elaborate early gene proteins that are able perpetual mitosis, thereby being candidates activity. The early region gene products to regulate the host cell cycle, or mitotic for inducing malignant change. Benign are proteins that are important for viral capabilities. The E6 and E7 proteins are HPV growths, caused by genotypes that replication and also have affects on host cell most important in this respect; they bind do not induce malignancy, must also affect gene expression, whereas the late region two host proteins that are regulators of cell cycling in order to induce epithelial genes encode the proteins that make up the keratinocytes’ cell division cycle.4 proliferation, yet these growths somehow the structural components of the virus, E6 binds to a protein designated p53, remain limited in extent and the cells lack particularly its capsid. It is the early genomic a molecule that arrests cell division; the properties of invasion and metastasis. In region that has the greatest significance for however, once bound, it is degraded, and this regard, experimental evidence has shown viral-induced changes in the host cells. this inhibition of keratinocyte mitosis is that HPV 11 can cause warty growths when HPV must adhere to a specific receptor abrogated. Likewise, E7 binds a protein inoculated onto normal mucosal epithelium.
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Table 1. Table 2. Human Papillomaviruses and Head and Neck Lesions Papillary Oral Lesions Without Genotype Disease Known Viral Association HPV 2, 4 Verruca Vulgaris Papillary hyperplasia (Papillomatosis) HPV 6, 11 Condyloma Acuminatum, Squamous Papilloma Verruciform xanthoma HPV 13, 32 Focal Epithelial Hyperplasia Cowden syndrome HPV 16 Proliferative Verrucous Leukoplakia Subtypes Nevus unius lateris HPV 6, 11, 16 Verrucous Carcinoma Acanthosis nigricans HPV 16, 18 Squamous Cell Carcinoma
Benign Papillary Growths pedunculated, on a stalk, or have a wide and red. Histologically, mushroom-like The three papillomavirus-induced sessile base. Papillomas range from coral polyps composed of a fibrous core with warts that arise on the lips and in the pink to white, depending upon the degree hyperplasia of the overlying epithelium oral cavity are verruca vulgaris, squamous of keratinization. Histologically, the are observed. papilloma, and condyloma acuminatum. exophytic papillary growths are supported Verruciform xanthoma (Figure 6): The genotypes associated with these three by fine connective tissue cores Papillary lesions that contain lipid-laden lesions are designated in Table 1. All are Condyloma acuminatum (Figure 4): foamy histiocytes in the submucosa are benign proliferations of keratinocytes Venereal warts, known as condylomas, referred to as verruciform xanthomas.8 that show minor histologic differences. In occur in the genital region and can be Clinically, they are broad-based sessile addition to these three lesions, there are transmitted to the oral mucosa. The lesions lesions with a papillary, pebbly surface numerous other papillary growths of the are rarely solitary; rather, they are multiple and are often slightly erythematous. They oral cavity for which a viral etiology has and confluent and generally quite bigger tend to occur on the gingiva and palate, not been discovered. Denture-induced than squamous papillomas.7 They are yet may be seen in any oral location. papillary hyperplasia, verruciform sessile and may be pink or white. Whereas Xanthelasma of the eyelids, a lesion of xanthoma, and a variety of other diffuse most condylomas are thought to be hyperlipidemia, is closely related in terms papillary lesions that are associated with transmitted through genito-oral contact, of the histologic features, yet verruciform particular syndromes do not appear to be oral-oral transmission is also feasible. xanthomas have not been correlated with HPV-related (Table 2). Microscopically, condylomas are papillary high blood cholesterol or lipid levels. Verruca vulgaris (Figure 2): The with a thickened parakeratin layer; and Histologically, the lesions are papillary common skin wart may be seen in the they differ from ordinary papillomas in with a prominently eosinophilic thickened oral cavity but is far more likely to be that they are sessile and show marked parakeratin layer. The submucosal papillae found on the lower lip where is appears thickening of the spinous cell layer that extend up between the papillary as a symmetrical round-to-oval nodule (acanthosis). Many also show HPV-specific epithelial projections are infiltrated with with a crusted hyperkeratotic center.5 cytologic changes. The infected upper foam cell histiocytes. Histologically, it is verrucous with spinous layer cells have irregularly shaped Syndrome-associated papillary lesions: marked hyperkeratosis and is entirely nuclei with a perinuclear clear halo and are As shown in Table 2, there are a number exophytic with abrupt margins. HPV termed koilocytes. of rare syndromes in which extensive and DNA can be readily detected using in situ Papillary hyperplasia (Figure 5): diffuse papillary lesions may be seen in hybridization techniques. Also known as papillomatosis, papillary the oral cavity.9 In Cowden syndrome, the Squamous papilloma (Figure 3): This hyperplasia is a reactive inflammatory gingival tissues are diffusely papillary, is the most common epithelial neoplasm proliferation that underlies maxillary yielding a cobblestone street pattern. in the mouth and is typically seen on the dentures. Negative pressure is probably Patients with Cowden syndrome also lingual frenum, lips, palate, and buccal the chief factor that contributes to the manifest thyroid tumors, skin nodules, mucosa.6 The lesion has fine finger-like lesion confined to the denture-bearing and other abnormalities. Nevus unius projections resembling a sea anemone region of the hard palate. The diffuse lateris is a skin lesion that may occur or it may show a more cauliflower pebbly surface is either of normal coral anywhere on the body. When in the configuration. Papillomas can be pink coloration or may be inflamed facial region, it may progress into the
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Figure 3. Papilloma on the lingual frenum.
Figure 2. Verruca vulgaris of the lip. Figure 4. Multiple papillary lesions represent condylomas.
Figure 5. Papillary hyperplasia of the palate. Figure 6. Verruciform xanthoma. Figure 7. Proliferative verrucous leukoplakia.
oral cavity. The skin lesions are verrucous contain HPV DNA, and the same surgical excision, these leukoplakias and keratotic, being oriented in a linear mechanisms involving binding of p53 by have a marked tendency to recur and streak. Orally extended lesions may cover HPV E6 may contribute to carcinogenesis spread laterally along the mucosal the lips and involve the buccal mucosa or of oral malignant disease. The oral surface. PVL is a clinical term under gingiva, assuming a pink diffuse papillary lesions that are malignant or potentially which a variety of histologic stages of appearance.10 Acanthosis nigricans is a malignant for which HPV has been disease can be observed. In the early pigmented papillary lesion of the lips and identified include proliferative verrucous stages, the histologic picture is that of mucosa that is often hereditary.11 One leukoplakia, verrucous carcinoma, a verrucous hyperkeratosis that may form is a harbinger of gastrointestinal papillary squamous cell carcinoma, and become progressively more keratotic and tract cancer. The lesions diffusely involve invasive poorly differentiated squamous acanthotic; it is then termed atypical the upper and lower lips; and because the cell carcinomas arising in the tonsillar/ verrucous hyperplasia. After many years, basal cell layer contains excess melanin base of tongue region. these lesions can progress to verrucous pigment, the lesions have a mottled gray Proliferative verrucous leukoplakia carcinoma, papillary squamous cell or brown coloration. is a unique type of leukoplakia that carcinoma, or invasive carcinoma. HPV tends to occur in elderly females, less DNA has been identified in many of Precancerous and Cancerous HPV- than 40 percent of whom have used these lesions and may be a significant Associated Lesions tobacco.12 The lesions are usually located carcinogenic factor, although a passenger As mentioned earlier, HPV likely on the buccal gingiva and extend into virus status cannot, at this time, be causes uterine cervix cancer. Recent the vestibule (Figure 7). They are white, eliminated.13 research has confirmed that some oral diffuse and have a rough warty or Verrucous carcinoma usually precancerous and cancerous lesions verrucous appearing surface. Following evolves from a pre-existing verrucous
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References been published linking the majority 1. zur Hausen H, Papillomaviruses in human cancers. Proc Assoc Am Physicians 111:581-7, 1999. of squamous cell cancers to HPV 16 2. Schoell WM, Janicek MF, Mirhashemi R, Epidemiology and when the lesions are localized to the biology of cervical cancer. Semin Surg Oncol 16:203-11, 1999. tonsillar pillar/base of tongue region.16,17 3. McGlennen RC, Human papillomavirus oncogenesis. Clin Lab Tumors in this location are generally Med 20:383-406, 2000. Figure 8. Verrucous carcinoma. 4. Ishiji T, Molecular mechanisms of carcinogenesis by human poorly differentiated. When HPV 16 is papillomavirus-16. J Dermatol 27:73-86, 2000. detected, p53 is not usually mutated 5. Eversole LR, Laipis PJ, Green TL, Human papillomavirus type 2 DNA in oral and labial verruca vulgaris. J Cutan Pathol thereby implicating an E6 mediated p53 14:319-25, 1987. leukoplakia and has a characteristic degradation mechanism. 6. Eversole LR, Laipis PJ, Oral squamous papillomas: detection histologic appearance, although of HPV DNA by in situ hybridization. Oral Surg Oral Med Oral Pathol 65:545-50, 1988. oftentimes the pathologist encounters Summary 7. Eversole LR, Laipis PJ, et al, Demonstration of human lesions that are midway between a The human papillomaviruses are papillomavirus DNA in oral condyloma acuminatum. J Oral verrucous hyperkeratosis and verrucous unique viral forms capable of inducing Pathol 16:266-72, 1987. 8. Iamaroon A, Vickers RA, Characterization of verruciform carcinoma. Clinically the lesions are cell proliferation, particularly in xanthoma by in situ hybridization and immunohistochemistry. J diffuse, involving the gingiva, alveolar keratinocytes. The benign lesions assume Oral Pathol Med 25:395-400, 1996. ridge, palate, and sulcus. They are rough, a papillary or verrucous appearance and 9. Holden KR, Dekaban AS, Neurological involvement in nevus unis lateris and nevus linearis sebaceus. Neurology 22:879-87, Figure white, and warty in appearance ( specific genotypes are responsible for 1972. 8). The term carcinoma is misplaced the clinicopathologic variations seen 10. Ramirez-Amador V, Esquivel-Pedraza L, et al, Oral here since verrucous carcinomas do not in papillary lesions. HPV 2 and 4 cause manifestations as a hallmark of malignant acanthosis nigricans. J Oral Pathol Med 28:278-81, 1999. have metastatic potential. In previous the common verruca vulgaris, whereas 11. Chaudhry SI, Shirlaw PJ, et al, Cowden’s syndrome (multiple articles, instances of metastasis have HPV 6 and 11 are involved in squamous hamartoma and neoplasia syndrome): diagnostic dilemmas in been reported, yet some of these cases papillomas and condylomas. HPV 13 three cases. Oral Dis 6:248-52, 2000. 12. Hansen LS, Olson JA, Silverman S Jr, Proliferative verrucous may have represented the recently and 32 are associated with the transient leukoplakia. A long-term study of thirty patients. Oral Surg described papillary variant of squamous rare mucosal disease, focal epithelial Oral Med Oral Pathol 60:285-98, 1985. cell carcinoma.14 Regardless, these hyperplasia. Premalignant lesions of 13. Palefsky JM, Silverman S Jr, et al, Association between proliferative verrucous leukoplakia and infection with human relentless lesions are locally aggressive the oral cavity, particularly proliferative papillomavirus type 16. J Oral Pathol Med 24:193-7, 1995. and have the potential to involve large verrucous leukoplakia, can harbor HPV 14. Ishiyama A, Eversole LR, et al, Papillary squamous surface areas of the oral cavity. HPV DNA, and the more aggressive verrucous neoplasms of the head and neck. 15 Laryngoscope. 104:1446-52, 1994. DNA is often detected in these tumors. carcinoma has also been shown to be 15. Miller CS, White DK, Human papillomavirus expression Microscopically, they show a verrucous associated with the virus. Recently, the in oral mucosa, premalignant conditions, and squamous cell surface with parakeratinized crypts majority of tonsillar region squamous carcinoma: a retrospective review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 82:57-68, 1996. that involute into enlarged rete-ridge cancers have been found to be associated 16. Mellin H, Friesland S, et al, Human papillomavirus (HPV) extensions. Actual invasion is not present. with HPV 16, a genotype that elaborates DNA in tonsillar cancer: clinical correlates, risk of relapse, and Squamous cell carcinoma is an any early gene product that degrades survival. Int J Cancer 89:300-4, 2000. 17. Badaracco G, Venuti A, et al, Human papillomavirus in invasive cancer that can metastasize p53, a key tumor suppressor gene. Once head and neck carcinomas: prevalence, physical status and to regional lymph nodes and distant degraded, the mitotic cycle continues relationship with clinical/pathological parameters. Anticancer sites via hematogenous routes. The unchecked thereby placing the affected Res 20:1301-5, 2000. To request a printed copy of this article, please contact/Lewis malignancy arises from stratified cell in a state of increased proliferative Roy Eversole, DDS, MSD, MA, UOP School of Dentistry, 2115 squamous epithelium, and while these activity. How HPV affects cell motility, Webster St., San Francisco, CA 94115 or at [email protected]. tumors may occur anywhere in the oral invasiveness, and metastatic potential is EDU cavity, the lateral tongue and floor of not yet understood. mouth are predilected sites. HPV DNA can be detected in many, yet not all oral carcinomas. About 30 percent will harbor HPV, and most of these are HPV 16. Recently, a group of reports have
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The Bullous Desquamative Lesions of Oral Mucosa
Sol Silverman, Jr., MA, DDS
abstract The most common of the bullous/desquamative diseases that affect the mouth include the erosive form of lichen planus, erythema multiforme, pemphigoid, and pemphigus. This overview looks at the clinical features and diagnosis of these diseases. In addition, treatment options are discussed.
author he blistering or bullous lichen planus, erythema multiforme, diseases comprise a group of pemphigoid, and pemphigus. This Sol Silverman, Jr., MA, mucocutaneous immunopathic overview will be limited to these entities. DDS, is a professor of inflammatory lesions that can oral medicine at the University of California at affect mucosal surfaces and/ Clinical Features San Francisco School of Tor skin. With few exceptions, these The cause of lichen planus is unknown. Dentistry conditions are not readily associated Lichen planus has three general forms: with any specific identifiable etiologic reticular (white lace-like keratotic pattern factors. As science progresses, the basic [Wickham’s striae]); atrophic (a red or explanation will no doubt be associated erythematous component); and erosive with genetic chromosome deletions, (varying degrees of ulceration along with transocations, or acquired mutations white and red changes) (Figures 1, 2 and that alter epithelial-epidermal chemistry, 3). The main patient complaints are pain, which in turn attract immune cells discomfort, and irritation, with concerns (lymphocytes), resulting in cytokine for infectiousness and the potential risk release-induced reactions.1 These reactions of malignant transformation.5 There most often have clinical and microscopic are oral conditions in which the clinical characteristics that allow a specific appearance resembles that of lichen diagnosis.2-4 planus as does the histology, yet the The most common of the bullous/ features are not classic (i.e., striae are desquamative diseases that affect the absent, basal cell lysis is not evident mouth include the erosive form of microscopically). Such lesions are often 928 december 2000 desquamative lesions
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Figure 1. Reticular lichen planus, buccal mucosa. Figure 2. Reticular lichen planus, tongue. Figure 3. Atrophic lichen planus, gingiva and buccal mucosae.
Figure 4. Erythema multiforme, palate. Figure 5. Erythema multiforme, lips. Figure 6. Mucous membrane pemphigoid, gingiva.
referred to as “lichenoid” and may be site, accounting for the archaic term Epidemiology indicative of a contact or delayed type “desquamative gingivitis.”6 Mucous Adequate population studies have not hypersensitivity to an exogenous antigen membrane pemphigoid in a small number been done to establish incidence rates such as cinnamon or mercury from dental of cases can affect the eyes, causing a or occurrence. Lichen planus is the most restorations. Yet other lichenoid reactions symblepharon (a fibrous scar between the common of these diseases. The blistering are idiopathic. lower eye lid and the conjunctiva). Bullous diseases occur in all ethnic groups, and Erythema multiforme can appear pemphigoid is the cutaneous counterpart the initial onset is most often beyond the as a red, red-white, or red-white- to mucous membrane pemphigoid yet third and fourth decades of life, with an ulcerative manifestation (Figures 4 and involves disparate immunologic targets increasing incidence beyond the age of 50. 5). Involvement of the lips is a typical and mechanisms. Clinical reports reflect a moderate female feature, but it is not always seen. The Pemphigus vulgaris is most frequently predominance. outbreak can be chronic or cyclical and is manifested by bullae and cavernous- These diseases are almost always chronic usually associated with pain. Erythema appearing ulcers. They can occur on any and are often characterized by flares and multiforme represents a hypersensitivity mucosal surface. While usually both skin mild remissions. While these lesions can reaction; but in oral erythema multiforme and mucosa are involved, in many cases occur on any mucosal surface, lichen planus in contrast to skin presentations, a the first signs and symptoms occur in most frequently presents on the buccal causative agent usually cannot be the mouth; and in some cases the skin mucosa and mucous membrane pemphigoid identified. Often the skin lesions present is never involved (Figures 8 and 9). The on the gingiva. Occurrence is not related as “target” or “bull’s-eye” lesions. vermilion borders of the lips are often to either tobacco usage or alcohol. There is Mucous membrane pemphigoid involved, and this then helps in the no evidence of a nutrition factor, although will usually occur as a red or red- clinical differentiation from mucous certain foods can cause flares, they are not erosive change (Figure 6 and Figure membrane pemphigoid. the basic causative agent. 7). The gingiva is the most common december 2000 929 desquamative lesions
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Table 1. Table 2. Immune Targets and Immunofluorescent Patterns in Oral Bullous Diseases Corticosteorid Strategy Disease Antigenic Target Location Fluorescent Pattern Systemic: high dose/short course Lichen planus Unknown Basal Layer BM fibrinogen Prednisone 40-80 mg daily Erythema multiforme Immune complex Perivascular IgG, C3 Less than two weeks, no taper Mucous membrane Adhesion molecules BM BM Igs, C3 Topical: potent corticosteroids pemphigoid (gel and ointment)* Pemphigus vulgaris Desmoglein Desmosome Pericellular Igs, C3 Lidex (fluocinoide) 0.05 percent Temovate (clobetasol) 0.05 percent BM: basement membrane; Ig: immunoglobulin; C3: complement fraction 3 Ultravate (halobetasol) 0.05 percent Mouth rinse: elixir dexamethasone 0.5 mg/5 ml Diagnosis histologic appearance. The epithelium 1 teaspoon three time daily, hold one minute, Clinical features are used to determine shows a marked inflammatory infiltrate then spit out a differential diagnosis, which is then as polymorphonuclear neutrophil * Paste: mix ointment with equal parts orabase confirmed by biopsy. In classical cases, leukocytes and round cells emigrate there are cell-tissue patterns that are out of vessels and transmigrate into characteristic of each entity, reflecting the overlying epithelium. There is Table 1 portrays the characteristic inflammatory patterns in some and intense submucosal inflammation; and patterns of antigen:antibody deposition sites of antigen-antibody reactions in eventually the epithelium undergoes encountered in these lesions. Importantly, others. In some cases in which specific necrosis and sloughs, leaving an ulcerated Michel’s transport medium is required to histopathologic patterns cannot be pseudomembrane composed of fibrin. preserve tissue for immunofluorescent confirmed, immunofluorescence is Mucous membrane pemphigoid shows microscopy and of even greater import helpful. This technique identifies sites of a characteristic sub-basilar clefting is the necessity of obtaining tissue for antigen-antibody reactions. that ensues subsequent to antibody routine hematoxylin and eosin staining. Since there is a slight increased and complement binding to basement Biopsies can be split, or two samples can risk of malignant transformation in membrane antigens. The submucosal be obtained. lichen planus, these patients should connective tissue is variably infiltrated be followed closely, and the diagnoses by mononuclear leukocytes, usually Treatment should be re-established when changes an admixture of plasma cells and None of these condition is curable; in signs and/or symptoms occur. The lymphocytes. Biopsies of gingival therefore, treatment is based upon differential diagnosis and biopsy are lesions often demonstrate extensive modifying patient discomfort and very important, since these are chronic, desquamation of the epithelium with pain. The principle of treatment is lifelong conditions, and it must be made total detachment from the underlying directed toward the immunopathologic certain that the clinical red/white/erosive connective tissue. In pemphigus vulgaris, processes that are reacting with the changes do not represent a dysplastic or a classic suprabasilar clefting occurs as epithelium and causing the symptoms. malignant process. antigens in the desmosomes are targeted If mild over-the-counter medications Histologically, lichen planus by antibodies that cause a loss of adhesion are helpful, they should be the first line is characterized by hyperkeratotic between contiguous keratinocytes. of control. However, the most effective epithelium, which accounts for the white The immunofluorescent patterns seen and predictive approach is to modify appearance; and in the subepithelial in these bullous disease are indicative immunologic activities. Corticosteroids connective tissue an infiltrate of of the autoimmune targets within the are the agents of choice.7,8 They can be lymphocytes lies in juxtaposition to the basement membrane, desmosomes, administered topically or systemically epithelium. The basal layer is disrupted or complexes in vessel walls. Direct (Figures 10a and b, 11a and b). and when completely lysed; desquamation immunofluorescent microscopy requires Topical corticosteroids must be occurs with resulting areas of ulceration. procurement of an oral biopsy from potent forms, since prolonged exposure is Thus, in the so-called erosive form of the perilesional mucosa. A site should be required for drug-lymphocyte interaction. disease, the entire epithelial layer is lost. selected adjacent to a clinical lesion and Table 2 lists the drugs and forms that Erythema multiforme has a nonspecific not directly in the zones of desquamation. are useful. Applications can vary from
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Figure 7. Mucous membrane pemphigoid, palate. Figure 8. Pemphigus vulgaris, gingiva. Figure 9. Pemphigus vulgaris, buccal mucosa.
Figure 10a. Lichen planus. Painful buccal mucosa lesion Figure 10b. After 60 mg prednisone daily for one week. present for six months. Patient was then maintained with topical fluocinonide-orabase with good control.
Care must be taken, since Imuran can cause bone marrow suppression and alter liver function.
References 1. Delves PJ, Roitt IM, The immune system. N Engl J Med 343:37-49, 2000. 2. Weinberg MA, Insler MS, Campen RB, Mucocutaneous features of autoimmune blistering diseases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 84:517-34, 1997. 3. Eversole LP, Immunopathogenesis of oral lichen planus Figure 11a. Mucous membrane pemphigoid. Painful Figure 11b. After two weeks, daily topical corticosteroids and recurrent aphthous stomatitis. Semin Cutan Med Surg gingival lesions present for four years. lead to complete control of the symptoms and almost complete 16:284-94, 1997. remission of signs. 4. Scully C, Carrozzo M, et al, Update on mucous membrane pemphigoid. A heterogeneous immune-mediated subepithelial blistering entity. Oral Surg Oral Med Oral Pathol Oral Radiol single daily applications (most effective manner, one can optimize efficacy and Endod 88:56-68, 1999. 5. Silverman S Jr, Bahl S, Oral lichen planus update. Clinical before bedtime) to up to five times daily. minimize side effects. In these situations, characteristics, treatment responses, and malignant Long-term studies have not shown any the treatment should be in conjunction transformation in 95 patients. Am J Dent 10:259-63, 1997. pathophysiologic adverse side effects. with the patient’s primary care physician. 6. Dayan S, Simmons RK, Ahmed AR, Contemporary issues in the diagnosis of oral pemphigoid. A selective review of the Occasionally, these topical agents might In systemic routes, there should be literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod stimulate overgrowth of Candida sp., and caution in patients with diabetes, 88:424-30, 1999. the subsequent oral candidiasis must gastrointestinal ulcers, hypertension, and 7. Wood AJJ, Management of acquired bullous skin diseases. N Engl J Med 333:1475-84, 1995. be treated with topical (clotrimazole) or glaucoma. 8. Lozada-Nur F, Miranda C, Oral lichen planus: topical and systemic (fluconazole or ketoconazole) Occasionally, when signs and systemic therapy. Semin Cutan Med Surg 16:295-300, 1997. antifungal agents. symptoms are not responding adequately, To request a printed copy of this article, please contact/ Sol Silverman, Jr., MA, DDS, UCSF School of Dentistry, 707 When systemic routes are utilized, the a combination of azathioprine (Imuran), a Parnassus Ave., Box 0422, San Francisco, CA 94143. strategy is high-dose, short-course. In this synergistic cytotoxic drug, may be helpful.
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Xerostomia – Clinical Evaluation and Treatment in General Practice
Troy E. Daniels, DDS, MS, and Ava J. Wu, DDS
abstract Xerostomia is a common symptom with various causes that, if ignored, can lead to serious oral consequences. Clinical evaluation of patients complaining of dry mouth must include some additional history and specific examination of the salivary glands, oral mucosa, and teeth. Additional evaluation may include consultation with the patient’s physician, request for microbial culture, or labial salivary gland biopsy. No one form of treatment for patients with chronic xerostomia is sufficient, but comprehensive treatment is effective in improving patient oral comfort and function, and preventing unnecessary loss of teeth. This treatment must include ongoing dental caries prevention and treatment, salivary flow stimulation, recognition and treatment of oral candidiasis, selective use of saliva substitutes, and possible changes in the patients’ prescription and nonprescription drug use.
authors erostomia (dry mouth) is Causes of Xerostomia Troy E. Daniels, DDS, MS, is a subjective symptom that As noted in Table 1, salivary a professor of oral medicine is usually, but not always, hypofunction can be divided into and oral pathology at the associated with salivary temporary and chronic forms, depending University of California at hypofunction, in which there on the cause. The chronic forms are of San Francisco School of are both decreased saliva production greatest concern because of their long- Dentistry. X and qualitative changes in saliva. This term potential to cause dental and oral Ava J. Wu, DDS, is an symptom is encountered with greater mucosal disease as well as to adversely associate clinical professor frequency in dental practice as a result of affect oral function. Another difference of oral medicine at UCSF increasing use of systemic prescription between the temporary and chronic forms School of Dentistry. drugs, which can singly or in combination of salivary hypofunction is that most affect salivary function, and because short-term salivary hypofunction affects of increasing public awareness of this only resting (basal) secretion, and patients symptom and its significance.1 retain their ability to respond normally
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Table 1. Differential Diagnosis of Salivary Hypofunction Temporary hypofunction (usually, only resting secretion is decreased): • Effects of short-term drug use (e.g. antihistamines) to gustatory, masticatory, or olfactory • Virus infections** (e.g. mumps) stimuli. However, most of the chronic • Dehydration (e.g. thermal or trauma) causes of salivary hypofunction decrease both resting and stimulated secretion • Psychogenic conditions (e.g. anxiety) rates, creating both greater symptoms and Chronic hypofunction (usually, both resting and stimulated secretion rates are decreased): potentially less response to treatment. • Effects of chronically administered drugs Prescription drug use is the most common cause of chronic salivary – Antidepressants (e.g. amitriptyline) hypofunction. Categories of drugs most – Neuroleptics (e.g. phenothiazines, lithium) frequently causing clinically significant – Parasympatholytics (e.g. anti-Parkinsonian drugs) salivary function are listed in Table 1. There are, however, literally hundreds of drugs – Some antihypertensive drugs (e.g. clonidine) and many combinations (e.g. beta-blocker and diuretic) that can produce symptoms of dry mouth, but most do so with lesser severity and • Chronic diseases affect a smaller proportion of patients. – Sjögren’s syndrome** It is interesting to note that patients’ – Sarcoidosis** salivary flow rates may decrease simply in proportion to the number of prescription – HIV** or Hepatitis C infection drugs they are taking.2 Thus, there may – Depression be an unknown additive or synergistic – Diabetes mellitus, uncontrolled effect on salivary function when multiple prescription drugs are taken. – Amyloidosis (primary or secondary) – Central nervous system diseases Clinical Effects of Chronic Xerostomia – Rarely, absent or malformed glands The results of a chronic lack of saliva follow from the well-known functions of • Other effects of treatment normal saliva,3 which include: – Therapeutic radiation to the head and neck nnMaintaining a neutral oral pH through – Graft vs. host disease (following bone marrow transplantation) various buffer systems; **may also cause major salivary gland enlargement nnSupporting ongoing remineralization of teeth by providing a reservoir of calcium and phosphate ions; nnCoating the oral mucosa and teeth hypofunction occur in approximate white plaques of pseudomembranous to protect them against harmful proportion to the severity of the candidiasis (thrush) are rarely seen in substances; hypofunction. These include progressive these patients. Patients with chronic nnLubricating the mouth to facilitate dental caries – primarily in cervical, salivary hypofunction may also develop chewing, swallowing, and speech; incisal, or marginal locations – and alterations in their sense of taste, with or nnProviding local antimicrobial activity various kinds of oral dysfunction (i.e., without candidiasis. through enzymes, immunoglobulin A, difficulty with chewing, dysphagia, and histatins; and dysphonia, or dysgeusia), and dysfunction Diagnosis of Xerostomia in General nnServing as a solvent for the taste of lower complete dentures. Signs of Practice mechanism. chronic erythematous candidiasis are Therefore, the loss of saliva is seen in about one-third of patients with History thought to be associated with a loss chronic salivary hypofunction4 and As generated from the routine of “protection.” Some of the oral caused by Candida albicans or other medical history, patients’ descriptions of consequences of chronic salivary Candida species.5,6 Interestingly, the prescription and nonprescription drug use
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Table 2. Symptoms and Signs Suggesting Chronic Salivary Hypofunction Symptoms • Positive responses to specific questions:7 – Do you sip liquids to aid swallowing dry foods? form. Two recent studies illustrate its – Does your mouth feel dry when eating? relationship to the symptom of xerostomia. One study of apparently healthy – Do you have difficulty swallowing any foods? individuals with normal unstimulated • Complaints of burning mucosa and/or intolerance to spicy foods (usually associated with and stimulated whole salivary flow rates, erythematous candidiasis) found symptoms of depression in 21 Signs percent of those who also had symptoms of dry mouth, but in only 3 percent of • Little or no pooled saliva in the mouth floor during examination those who did not have symptoms of • Dry or sticky mucosal surfaces dry mouth.8 Another study sampled all • Multiple caries in cervical, incisal, or marginal locations the 55-year-old men and women in a • Thick or cloudy saliva expressible from parotid or submandibular gland ducts European city and found that 26 percent of the men and 33 percent of the women • Bilateral salivary gland enlargement complained of the subjective sensation of • Signs of erythematous candidiasis: dry mouth. After dealing statistically with – Dorsal tongue with erythema, loss of filiform papillae, and fissured or cobblestone the confounding variables of smoking and appearance prescription drugs and diseases that could – Angular cheilitis cause xerostomia, the authors found that depressive symptoms were significantly – Patchy erythema on other mucosal surfaces associated with the symptom or oral dryness.9 In diagnosing such patients, it is important to remember that depression may reveal the cause of their symptoms of their mouth. Symptoms of dry mouth can mask a chronic disease associated with dry mouth. Given the rapid proliferation of occurring only at night, on awakening salivary hypofunction, and patients with new drug names, this analysis may require from sleep, usually are not associated xerostomia and self-identified depression a standard reference such as the Handbook with abnormal salivary function because or currently using antidepressant drugs of Clinical Drug Data, the Physicians Desk salivary flow normally approaches must be fully evaluated. Reference, or other source. As noted above, zero during sleep. There are also some medications are the most common cause additional questions to ask patients Physical Examination -- Extraoral of xerostomia and salivary hypofunction. If who complain of dry mouth, which, if For patients who complain of the drug history does not reveal a probable positive, are moderately predictive of xerostomia, it may be most convenient to cause, additional information must be salivary hypofunction: Do you sip liquids begin with the extraoral examination. As obtained from those patients complaining to aid swallowing dry foods? Does your noted in Table 1, some of the conditions of xerostomia. mouth feel dry when eating? Do you causing salivary hypofunction may also Learning the patient’s occurrence have difficulty swallowing any foods?7 cause enlargement of the parotid and/ pattern of dry mouth symptoms can be If patients complain of regional or or submandibular glands. For example, helpful. For example, the continuous generalized mucosal pain, often described between one-third and one-half of presence of dry mouth symptoms as “burning,” or they describe intolerance patients with Sjögren’s syndrome develop throughout the day is usually associated to spicy or acidic foods, which may have enlargement of major salivary glands. In with significant salivary hypofunction forced them to significantly alter their cases of Sjögren’s syndrome, sarcoidosis, and loss of the protective effects of saliva. diet, the labial angles and oral mucosa or HIV infection, this enlargement is Alternatively, the gradual daily onset should be carefully examined for signs of usually firm and nontender to palpation, of such symptoms may be associated erythematous candidiasis, as described affects all or most of the gland, and is with less severe hypofunction, mouth below (Table 2). usually bilateral, although one side may breathing, or an excessive awareness by Patients with depression may or may be larger than the other. It should be the patient of the amount of saliva in not include that diagnosis on a history noted, however, that while these patients
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can have clinically similar swelling of major salivary glands, the histological features are different. At the beginning of this examination, it is useful to visually examine the duct openings in the mucosa Figure 1. This man complained of xerostomia, had slight, Figure 2. This patient with primary Sjögren’s syndrome has for each parotid and submandibular diffuse, bilateral parotid enlargement and intraoral signs of severe salivary hypofunction. Note parchment-like mucosa on the gland, while applying gentle extraoral salivary hypofunction. This thickened, cloudy secretion was mouth floor and caries in incisal, cervical, and marginal locations. pressure to the corresponding gland expressible from the left parotid duct during examination, Caries are also detectable at the subgingival crown margins. but the major salivary glands were not painful or tender to (Figure 1). This permits observation of palpation. A labial salivary gland biopsy revealed noncaseating the saliva being expressed; is it clear, granulomas, confirming the diagnosis of sarcoidosis. water-like and flowing freely (the normal condition), or cloudy, viscous and hanging from the duct orifice, or does nothing come out when pressing on the gland? Parotid glands are easy to palpate because of their superficial location over the mandibular ramus, but they must be distinguished from the masseter muscle, which they overlie. Submandibular glands are best palpated between an index finger placed in the distal mouth floor Figure 3a. This 26-year-old woman complains of dry and Figure 3b. After about three months of treatment with and another placed extraorally on the burning mouth and intolerance to spicy foods. She has signs of topical antifungal drugs, her oral symptoms have resolved and skin medial to the mandibular angle. The erythematous candidiasis including angular cheilitis, erythema filiform papillae have returned to the dorsal tongue, but her of the dorsal tongue, and atrophy of the filiform papillae. chronic salivary hypofunction and primary Sjögren’s syndrome normal parotid or submandibular glands continue. are not usually palpable because they are softer than their surrounding tissues. Therefore, if the parotid or submandibular glands can be anatomically defined by and atrophy of the filiform papilla on Candida may be present in the normal palpation, then some degree of induration the dorsal tongue, leaving a smooth, oral flora.11 Adequate treatment of oral is probable. cobble-stone, or fissured surface on the candidiasis (described below) will usually dorsal tongue (Figure 3a). Other signs eliminate the patient’s symptoms of Physical Examination -- Intraoral include patchy oral mucosal erythema, mucosal burning and intolerance to acidic The intraoral examination of patients particularly on the palate or buccal or spicy foods, in spite of continuing complaining of xerostomia should focus mucosa, or under dentures, and angular salivary hypofunction, and it will lead to on the appearance and lubricity of the cheilitis. The latter rarely occurs without restoration of the mucosa4 (Figure 3b). mucosa and the location and distribution the presence of intraoral candidiasis10 Are there carious lesions or signs of of dental caries. Does a gloved finger (Table 2). In patients with these signs, decalcification in cervical or incisal areas slide easily over the mucosa during the diagnosis can be confirmed by fungal of the teeth? Are recurrent caries present examination; is there resistance to sliding; culture of a swab specimen from the in subgingival crown margins or around or is there a sticky quality to the mucosa? dorsal tongue, or other erythematous existing class five restorations? F( igures During the oral examination, has saliva lesion, from which a substantial number 2 and 4) In patients with chronic salivary pooled in the mouth floor? (Figure 2) of colony forming units (double digits or hypofunction, the extent of their dental Erythematous candidiasis involves more) can be identified through culture. caries may be greater than would be thinning of the mucosa, which causes the A colony forming unit assessment can be suggested by the adequacy of their plaque red color and symptoms described above. performed by the clinical laboratory and and calculus control. Clinically, it is characterized by erythema is necessary because small quantities of
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Figure 4. This 41-year-old patient with rheumatoid Figure 5. This patient underwent radiation therapy for a Figure 6. Several years prior to this photograph, this arthritis, mild secondary Sjögren’s syndrome, depression, and carcinoma of the oropharynx 21 months prior to this photograph. middle-aged patient complained of xerostomia and had many multiple drug treatment has rapidly progressing dental caries. At the onset of radiation treatment she had a bicuspid dentition, areas of cervical caries at the time these crowns and bridges Note the pattern of new and recurrent caries. a few small restorations, and no active caries. After completion were placed. Within a few years, recurrent caries had affected of treatment, she was non-compliant with home dental care the margins of most of the abutments, necessitating the procedures and failed her dental recall appointments. supplemental class V amalgam restorations. The patient has primary Sjögren’s syndrome and ongoing salivary hypofunction.
Clinically Assessing Salivary decayed, missing and filled teeth; and later develop the salivary and/or ocular Hypofunction dryness of the lips. In summary, salivary components (Figure 4). Patients in a Salivary flow rates can be measured hypofunction can be assessed by the dental practice may be suspected of for whole, parotid or submandibular clinical methods described in this section having Sjögren’s syndrome, because they secretions under resting or stimulated for clinical decision-making, without already have the diagnosis of a connective conditions. However, the range of flow measuring salivary flow rates T( able 2). tissue disease or, because they have rates for each of these is very wide Various tests have been proposed to clinical evidence of significant salivary among healthy individuals who have determine a patient’s risk of developing hypofunction that is not otherwise no known diseases and who are not caries. These tests include salivary explained from information in their taking any medications.12 Therefore, flow rates, salivary buffer capacity, and history and, on questioning, they may a clear distinction between “normal” quantifying mutans streptococci and complain of ocular symptoms (e.g. an and “abnormal” flow rates may not lactobacilli from the saliva. However, a inability to tear, ocular pain or burning, be possible.13 In addition, measuring review of these caries risk assessment or having a foreign-body sensation salivary flow rates is not a usual part notes that these tests are better at in their eyes). It is helpful to contact of most dental practices, can be quite selecting people who will not develop the patient’s physician concerning the time-consuming, and may be difficult to caries than they are at selecting people patient’s diagnoses and blood test results. standardize when done only occasionally. who will, and that no single test has yet Several serological markers that are Various investigators have tried to proven to be successful in predicting highly associated with the connective identify an unstimulated whole salivary caries development for the majority of tissue diseases are commonly seen in flow rate that distinguishes normal from populations studied.15 patients with Sjögren’s syndrome and abnormal function. In reviewing previous may raise the suspicion of it, but none of studies and conducting their own, Chronic Diseases Causing Xerostomia them are sufficiently specific to permit Navazesh and colleagues found that rates Sjögren’s syndrome is the second it to be diagnosed by blood tests. Those of 0.12 to 0.16 mL/min seem to define the most common connective tissue disease, that are commonly associated with range below which there is a higher rate of after rheumatoid arthritis. Patients Sjögren’s syndrome include the following oral soft and hard tissue abnormalities.14 with primary Sjögren’s syndrome have “autoantibodies”: antinuclear antibody, Using that as a baseline, they identified the salivary and ocular components of rheumatoid factor, anti-Ro (SS-A), and a set of four clinical measures that, when Sjögren’s syndrome and may develop anti-La (SS-B). used together in a formula, reasonably other organ system manifestations. In patients who have clinical evidence predicted the presence or absence of Patients with secondary Sjögren’s of significant salivary hypofunction salivary hypofunction. The clinical syndrome first have another connective but do not have another connective measures were dryness of the buccal tissue disease (e.g. rheumatoid arthritis, tissue disease, the dentist should refer mucosa; absence of saliva expressible systemic lupus erythematosus, or the patient to an ophthalmologist to from the ducts; the total number of mixed connective tissue disease) and assess whether they have the ocular
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Table 3. Products Selectively Useful for Treating Patients With Chronic Salivary Hypofunction Anti-caries agents • Professionally applied nnSalivary flow stimulation; – 1.23% fluoride in acidulated phosphate fluoride gel nnOral candidiasis recognition and treatment; – 2.26% fluoride varnish23 nnSelective use of saliva substitutes; and • Patient-applied nnReview of the patient’s current – 0.5% fluoride in neutral sodium fluoride gel prescription drug regimen and elimination, where possible, of – 0.05% sodium fluoride mouth rinse concurrent use of drugs having – 0.12% chlorhexidine gluconate mouth rinse anticholinergic effects.20 Saliva stimulants • Sugar-free chewing gum or hard candies Caries Prevention and Treatment Patients who develop severe salivary • Pilocarpine hydrochloride tablets, 5 mg, initially prescribed at one tablet three times daily hypofunction – for example, from Antifungal drugs radiation therapy to the head and • Fluconazole, 100 mg tablets, 200 mg on first day then 100 mg per day for 14 days neck – and do not receive nor follow necessary instructions and support to • Nystatin Vaginal Tablets, 100,000 units per tablet, dissolve slowly in mouth (15-20 minutes), us- prevent dental caries, can lose their entire ing sips of water as necessary to aid dissolution, 2 to 4 tablets per day, for 3 to 12 weeks, depend- dentition to caries in a few years. An ing on the severity and clinical response (see text) example of such a patient is seen in Figure • Nystatin or 1% Clotrimazole cream, 15 gm tube (see text) 5; similar results can occur in patients • Nystatin Topical Powder, 15 gm (see text) with Sjögren’s syndrome or on multiple Note: This table is meant as a supplement to the text. It is not a comprehensive outline for treatment. drug therapy, but more slowly. In a landmark study of caries prevention in patients who had undergone radiation therapy to the head and neck, component of Sjögren’s syndrome, called enlargement, or salivary hypofunction there were three treatment groups: 1) keratoconjunctivitis sicca.16 If they do only, respectively. They are both those receiving oral hygiene instructions have keratoconjunctivitis sicca, they definitively diagnosed by serological tests. only, 2) those receiving oral hygiene should then be referred to someone Diagnoses of amyloidosis, diabetes, or a instructions and daily 1 percent tray- experienced in performing a labial salivary central nervous system disease should applied sodium fluoride gel, and 3) those gland biopsy17 to assess whether they be apparent from the patient’s medical receiving both of the above and placed have focal lymphocytic sialadenitis in that history, as would therapeutic radiation on a sucrose restricted diet.21 Group 1 specimen, which represents the salivary to the head and neck or bone marrow had an average monthly increase in the component of Sjögren’s syndrome.18 A transplantation. As noted above, there is number of decayed, missing or filled patient having keratoconjunctivitis sicca an association between the symptom of dental surfaces of 2.51, which was 12 times and focal lymphocytic sialadenitis in a xerostomia and depression. greater than the DMFS increase seen salivary biopsy has primary Sjögren’s in group 2. Furthermore, group 2 had a syndrome, a diagnosis that should be Treatment of Patients With Xerostomia DMFS increase five times greater than that reported to the patient’s physician. A There is no one form of treatment seen in group 3. While each of the three labial salivary gland biopsy may also that is effective for patients with chronic prevention strategies studied on these reveal another systemic disease, such as salivary hypofunction, but there is clear patients with severe salivary hypofunction sarcoidosis (Figure 1), which can clinically evidence that comprehensive treatment had some effect, the combination of oral mimic Sjögren’s syndrome,19 and should is effective. Such treatment needs to hygiene instructions, daily topical fluoride be reported to the patient’s physician. consider five categories: application, and dietary sucrose restriction HIV or hepatitis C infections can cause nnOngoing dental caries prevention and was 63 times more effective in preventing salivary hypofunction and salivary gland treatment; caries than oral hygiene instructions alone.
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This is a good place to apply the old saying, subgingival margins should be avoided Oral Candidiasis the whole is worth more than the sum of wherever possible (Figure 6). Subgingival When erythematous oral candidiasis its parts. margins are difficult to clean and are less occurs in patients with only mild Patients with moderate to severe accessible to topical fluoride application. to moderate salivary hypofunction, salivary hypofunction must become part Recurrent caries at this location is fluconazole or other systemic antifungal of their treatment by being taught the common in these patients and difficult drugs can be used for a few weeks, with role of dietary sugars in the development to detect and treat. Full veneer crowns, if usually satisfactory results (as assessed of dental caries, the need to limit sugar ultimately necessary, should not be placed by the treatment end-points described intake to meals and eliminate it between until caries are under complete control below). More commonly, erythematous meals, and how to remove dental plaque (i.e., the patient has been free of new oral candidiasis occurs in patients with effectively. Strategies with topical fluoride lesions for at least one year). severe chronic hyposalivation,26 whose need to be based on the severity of the treatment is best accomplished with patient’s salivary hypofunction and their Salivary Flow Stimulation topical forms of polyene or imidazole caries experience. These can include Patients’ residual salivary function anti-fungal drugs27 for periods of weeks professionally applied high concentration can be stimulated by physiological or months. Because these patients are fluoride solutions in a tray (e.g. 1.23 or pharmacological means to reduce at very high risk for progressive dental percent fluoride in acidulated phosphate symptoms of xerostomia. Physiological caries, they must utilize forms of these fluoride gel for four minutes), or a 2.26 stimulation can be provided by topical drugs that are the least cariogenic, percent fluoride varnish applied directly masticatory or gustatory stimuli, through i.e. those that do not contain sucrose to the teeth, four times per year.22, 23 sugar-free chewing gum (e.g., xylitol or glucose. Topical forms are necessary Patient-applied sodium fluoride gel (0.5 gum) or sugar-free hard candies, used because in patients having severe salivary percent fluoride) in a custom-fitted as needed during the day to relieve oral hypofunction, systemically administered tray for five minutes daily can be used symptoms. To avoid enhancing dental antifungal drugs do not reach the mouth to supplement professionally applied caries development in high caries-risk of such patients in therapeutically fluoride. For lower risk patients, a daily patients, either of these physiological adequate amounts. rinse with a 0.05 percent sodium fluoride stimulatory methods must use sugar-free, All currently available “oral” topical can be a useful addition to professionally not “sugarless” products. Both methods antifungal drugs contain substantial applied fluorides. Neutral sodium fluoride can increase salivary flow, but only while amounts of sucrose or glucose (i.e. preparations are generally preferred to the stimulus is present in the mouth. brands of clotrimazole oral troches, stannous fluoride preparations because Pharmacological stimulation can be nystatin oral pastilles, and nystatin oral they are better-tolerated by patients. provided through prescription of various suspension), which creates significant risk For patients at highest risk of caries, systemically administered cholinergic for supporting dental caries development or those without evidence of lesion drugs, which may give the patient up to when used as directed. Therefore, the arrest or remineralization, additional several hours of increased salivary flow best topical antifungal drug to use with strategies can include the periodic use of and reduced oral symptoms. Pilocarpine patients at high risk for dental caries is chlorhexidine to control the quantity of has long been know to increase salivary nystatin vaginal tablets. These do contain mutans streptococci in the flora. This can secretion24,25 and is initially prescribed at lactose, which is a potentially cariogenic be in the form of a patient-applied 0.12 5 mg, three to four times daily. It should carbohydrate, but much less so than percent chlorhexidine gluconate rinse, one not be prescribed for patients with either sucrose or glucose. They must be minute daily for two weeks22 (Table 3). uncontrolled asthma or narrow-angle dissolved slowly in the mouth for 15-20 The caries associated with chronic glaucoma and should be used with caution minutes, two or three times per day. Such salivary hypofunction often attacks the in patients with significant cardiovascular patients usually must take frequent sips margins of existing restorations in both or pulmonary disease. There is no of water to allow the tablet to dissolve supragingival and subgingival locations evidence yet that either physiological or in that time. The treatment end-point (Figures 2 and 4). For the initial treatment pharmacological salivary stimulation will for erythematous candidiasis should be of such patients, dental restorations with prevent dental caries or oral candidiasis. resolution of all the mucosal erythema,
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return of filiform papillae to the dorsal functions of natural saliva, and none have Prescription Drug Review tongue, and resolution of associated oral long duration because they are swallowed. Patients’ current prescription drug use symptoms.4 There are several types available. Most should regularly be reviewed to identify For patients wearing partial are carboxymethylcellulose-based, while those drugs whose principal effect, or side or complete dentures, additional others are mucin-based or glycerate effects, contribute to decreased salivary instructions and treatment are needed: polymer gel-based. In comparative function. If such drugs are being used, nnDentures must be removed from studies, carboxymethylcellulose-based the problem should be discussed with the the mouth before using any topical preparations usually have the lowest prescriber of the drug; it may be possible to antifungal drug. objective and subjective ratings; mucin- eliminate the drug or to substitute with one nnDentures must be disinfected by based products are usually rated higher that has less effect on salivary function. soaking overnight in a fungicidal by patients, but are not available in the substance compatible with the denture United States. The glycerate polymer gel- Summary materials and rinsed before reinserting based product appears to provide better Xerostomia is a common clinical in the mouth. reduction in oral dry mouth symptoms problem. Patients with that symptom nnNystatin topical powder may be applied than carboxymethylcellulose-based must be evaluated by their dentists’ on the fitting surface of a clean denture substitutes28 particularly in patients obtaining additional history and (while wet) just before reinserting it in with severe xerostomia.29 None of these performing examinations that are clearly the mouth. Since this powder contains products has been shown to prevent in the scope of general dental practice. talc, care must be taken to insure that dental caries or oral candidiasis. The cause of a patient’s xerostomia should patients do not inhale the dry powder.20 be determined, the severity of associated The presence of angular cheilitis Water Consumption salivary function should be estimated, almost always indicates concurrent Some patients with chronic salivary and appropriate treatment initiated. The intraoral candidiasis.10 Angular cheilitis hypofunction consume water excessively. goal of that treatment is to improve the can be treated by nystatin or clotrimazole Patients should understand that dry patient’s oral symptoms and function creme, but in most cases this only should mouth is rarely associated with systemic and to prevent and restore dental caries. be done with concurrent treatment of dehydration and that consuming large Effective treatment of chronic salivary the intraoral infection. After treatment is quantities of water does not overcome hypofunction requires patient education completed, recurrence of erythematous oral dryness. Frequent small sips of and treatment, proportional to its severity candidiasis is common and the patient the water during the day will help reduce and include caries prevention, appropriate needs to be re-treated as described above. oral symptoms. However, excessive dental restoration, saliva stimulation, If recurrence is frequent, re-treatment consumption of water can remove the selective use of saliva substitutes and, should be followed by maintenance mucus coating the oral surfaces and where appropriate, changes in the therapy (e.g. continued use of half of a further increase the patients symptoms patient’s use of prescription drugs. nystatin vaginal tablet slowly dissolved in of dryness. Milk may be a better, but less the mouth each day).4 convenient, liquid to sip. Acknowledgment The authors are grateful to Dr. Hiromi Saliva Substitutes Nocturia Mochizuki for her valuable criticism of These over-the-counter products can Patients may have frequent sleep the manuscript. be helpful for patients with fairly severe interruption caused by nocturia if chronic hyposalivation, particularly those they consume water at night. To avoid References 1. Parker-Pope T, A common side effect, dry mouth, can cause wearing a complete denture, but are less nocturia, beginning one hour before sleep serious tooth decay. Wall Street Journal. March 10, 2000. helpful for patients with more saliva. patients should not drink water and when 2. Wu AJ, Ship JA, A characterization of major salivary gland These products are usually most effective they awaken during the night they should flow rates in the presence of medications and systemic diseases. Oral Surg Oral Med Oral Pathol 76:301-6, 1993. for patients at their bedside when use a small volume of a saliva substitute, 3. Mandel ID, The role of saliva in maintaining oral awakening during the night, while talking, instead of drinking water. homeostasis. J Am Dent Assoc 119:298-304, 1989. or while traveling. None replace all the 4. Hernandez YL, Daniels TE, Oral candidiasis in Sjögren’s syndrome: Prevalence, clinical correlations and treatment.
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Oral Surg Oral Med Oral Pathol 68:324-9, 1989. Med 151:1149-52, 1991. 5. Tapper-Jones L, Aldred M, Walker DM, Prevalence and 26. Abraham CM, Al-Hashimi I, Haghighat N, Evaluation of the intraoral distribution of Candida albicans in Sjögren’s levels of oral Candida in patients with Sjögren’s syndrome. syndrome. J Clin Path 33:282-7, 1980. Oral Surg Oral Med Oral Pathol 86:65-8, 1998. 6. Crockett DN, O’Grady JF, Reade PC, Candida species and 27. Ellepola ANB, Samaranayake LP, The in vitro post- Candida albicans morphotypes in erythematous candidiasis. antifungal effect of nystatin on Candida species of oral origin. Oral Surg Oral Med Oral Pathol 73:559-63, 1992. J Oral Pathol Med 28:112-6, 1999. 7. Fox PC, Busch KA, Baum BJ, Subjective reports of 28. Furumoto EK, Barker GJ, et al, Subjective and clinical xerostomia and objective measures of salivary gland evaluation of oral lubricants in xerostomic patients. Spec Care performance. J Am Dent Assoc 115:581-4, 1987. Dentistry 18:113-8, 1998. 8. Bergdahl M, Bergdahl J, Johansson I, Depressive symptoms 29. Regelink G, Vissink A, et al, Efficacy of a synthetic polymer in individuals with idiopathic subjective dry mouth. J Oral saliva substitute in reducing oral complaints of patients Pathol Med 26:448-50, 1997. suffering from irradiation-induced xerostomia. Quintessence 9. Antilla SS, Knuuttila ML, Sakki TK, Depressive symptoms as Int 29:383-8, 1998. an underlying factor of the sensation of dry mouth. Psychosom To request a printed copy of this article, please contact: Troy Med 60:215-8, 1998. E. Daniels, DDS, MS, School of Dentistry, S-630, University 10. Ohman SC, Dahlen G, et al, Angular cheilitis: a clinical and of California, San Francisco, CA 94143-0430 or at danielst@ microbial study. J Oral Pathol 15:213-7, 1986. dentistry.ucsf.edu 11. Arendorf TM, Walker DM, The prevalence and intraoral distribution of Candida albicans in man. Arch Oral Biol 25:1-10, 1980. 12. Ship JA, Fox PC, Baum BJ, How much saliva is enough? Normal function defined. J Am Dent Assoc 122:63-9, 1991. 13. Skopouli FN, Siouna-Fatourou HI, et al, Evaluation of unstimulated whole saliva flow rate and stimulated parotid flow as confirmatory tests for xerostomia. Clin Exp Rheumatol 7:127-9, 1989. 14. Navazesh M, Christensen C, Brightman V. Clinical criteria for the diagnosis of salivary gland hypofunction. J Dent Res 71:1363-9, 1992. 15. Powell LV, Caries risk assessment: relevance to the practitioner. J Am Dent Assoc 129:349-53, 1998. 16. Bloch KJ, Buchanan WW, et al, Sjögren’s syndrome: a clinical, pathological and serological study of sixty-two cases. Medicine 44:187-231, 1965. 17. Daniels TE, Benign lymphoepithelial lesion and Sjögren’s syndrome. In, Ellis G, Auclair P, Gnepp D, eds, Surgical Pathology of Salivary Glands. WB Saunders, Philadelphia, 1991, 83-106. 18. Daniels TE, Whitcher JP, Association of patterns of labial salivary gland inflammation with keratoconjunctivitis sicca: analysis of 618 patients with suspected Sjögren’s syndrome. Arthritis Rheum 37:869-77, 1994. 19. Sack KE, Whitcher JP, et al, Sarcoidosis Mimicking Sjögren’s syndrome: Histopathological Observations. J Clin Rheumatol 4:13-6, 1998. 20. Daniels TE, Newbrun E, Oral Treatment and Prevention of Dental Decay. In, Carsons S, Harris E, eds. The New Sjögren’s Syndrome Handbook. Oxford Press, 1998, pp156-62. 21. Dreizen S, Brown LR, et al, Prevention of xerostomia- related dental caries in irradiated cancer patients. J Dent Res 56:99-104, 1977. 22. Newbrun E, Current treatment modalities of oral problems of patients with Sjögren’s syndrome: Caries prevention. Adv Dent Res 10:29-34, 1996. 23. Beltrán-Aguilar ED, Goldstein JW, Lockwood SA, Fluoride varnishes. A review of their clinical use, cariostatic mechanism, efficacy and safety. J Am Dent Assoc 131:589-96, 2000 24. Greenspan D, Daniels TE, Effectiveness of pilocarpine in postradiation xerostomia. Cancer 59:1123-5, 1987. 25. Fox PC, Atkinson JC, et al, Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia). Arch Intern
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Candidiasis: Pathogenesis, Clinical Characteristics, and Treatment
Stanton S. Appleton, DDS, MPH, MSD
abstract Candida organisms live on the skin and mucous membranes of up to 75 percent of the population. They can live commensally without causing harm or can change to an aggressive form and invade tissue, causing both acute and chronic disease in the host. Oropharyngeal candidiasis manifests clinically as acute pseudomembranous, acute atrophic, chronic atrophic, chronic hypertrophic/hyperplastic, and angular cheilitis. Systemic infection leading to candidemia can be devastating and cause up to a 60 percent mortality rate in medical or post-surgical intensive care wards. Oral nystatin, clotrimazole, and fluconazole usually provide appropriate therapy; although resistance to medications is increasing, particularly in immunocompromised hosts.
andida organisms are fungi the fourth most common isolate recovered author that normally inhabit the oral from blood cultures in the United States3 Stanton S. Appleton, DDS, cavity, gastrointestinal tract, among patients with severe infection MPH, MSD, is a professor other mucous membranes, and acquired while in the hospital. This review of oral medicine at Loma skin. In most humans, this is a will discuss the pathogenesis of candidiasis, Linda University School of commensal relationship; and only a few the clinical characteristics of oral infection, Dentistry. C Candida carriers actually go on to develop local and systemic factors that predispose clinical signs of candidiasis because yeast to infection, and treatment. growth and colonization are impaired by the resistance of the host.1 When changes Candida Microbiology and occur in the host environment causing Pathogenesis imbalance of the flora or a decrease Though dentists commonly treat in resistance, Candida becomes an the oropharyngeal signs of Candida opportunistic pathogen. Clinical problems infection and colonization such as range from relatively mild candidiasis to denture stomatitis, angular cheilitis, chronic recurrent candidiasis and life- and thrush, they must realize that threatening disseminated infections. These when dissemination and invasion problems are growing, and Candida has of internal organs occur, Candida been called the most important fungal becomes life-threatening.2 This has pathogen in humans.2 It has been listed as become exceedingly important in recent 942 december 2000 candidiasis
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years as the dental patient pool has Candida filaments but not in the yeast depending on the study and sampling expanded to include more of the elderly, form. This protein forms a covalent and techniques. Current large-scale sampling with an additional increase in organ permanent bond to epithelial cells with methods such as saliva sampling or transplant, immunocompromised, AIDS, the help of the enzyme transglutaminase. oral rinse procedures may identify the chemotherapeutic, and antibiotic- or Without Hwp1, the adherence to human presence of yeast but do not diagnose steroid-laden patients. oral mucosal cells is reduced 80 percent. clinical candidiasis or colonization. Candida is a human fungal pathogen Mice infected with Candida strains Patients who have intraoral candidiasis that grows as a round yeast and replicates containing Hwp1 develop more severe have been found to have greater than by budding. Of the 150 fungal species disease than those infected with Hwp1- 400 colony-forming units per ml of of Candida, about seven are known to free Candida.11 saliva while carriers of C. albicans had be medically important pathogens: C. C. albicans also has the ability to less than this amount.14 High levels albicans, C. tropicalis, C. parapsilosis, produce secreted aspartyl proteinases that may thus suggest the possibility of C. krusei, C. kefyr, C. glabrata, and C. degrade many human proteins found at systemic candidiasis, particularly in the guilliermondii.1 Other species have been lesion sites. The proteins affected include immunocompromised patient, but do isolated from humans but are considered albumin, hemoglobin, keratin, collagen, not prove deep-seated infection. This is opportunistic in immunocompromised mucin, and secretory immunoglobulin particularly true in the hospital setting in patients. C. albicans is by far the most A . Nine secreted aspartyl proteinase that the problem of candidiasis is clear, prevalent pathogenic fungal species found genes have been identified in Candida, but there are difficulties in establishing in the human body, yet C. dubliniensis has and laboratory studies have evaluated the an early or even specific diagnosis. In been found primarily in the oral cavities regulation of secreted aspartyl proteinase hospital-acquired infections, Candida of immune-suppressed individuals;4,5 and expression through analysis of mRNA and isolates from blood have become a although it is a low-level constituent of protein synthesis. In vivo studies indicate common finding in the United States;3 the human oral flora, it has the potential that secreted aspartyl proteinase 1, 2, and 3 similarly instances of candidemia have to cause oral candidiasis.6,7 C. albicans and are expressed by yeast cells. Only secreted increased in Europe. Usually one-half C. dubliniensis as well as other Candida aspartyl proteinase 4, 5, and 6 expression of these occur in surgical intensive species can be differentiated from one is seen in C. albicans when it is undergoing care units, while the other half occur another by polymerase chain reaction transition from yeast form to hyphal form. in medical units. In these settings, the techniques that are being developed to aid In patients with oral candidiasis, the hyphal mortality rates attributable to candidemia in diagnosis.8 forms with increased adherence have range from 40 percent to 60 percent.15,16 Though C. albicans can exist in several been found to express secreted aspartyl Antibodies against C. albicans or forms, from the yeast to the hyphal, the proteinase 4, 5, and 6. Interestingly, in vivo Candida-derived molecules in the sera yeast form is commensal and relatively studies have now found that yeast cells, of a patient may point to deep-seated harmless, while the hyphal form is normally thought to be non-invasive, may at infection. Investigations to detect C. invasive, pathogenic, and the cause of times express secreted aspartyl proteinase albicans proteins,17-19 metabolites,20 clinical candidiasis. Hyphae are not always 4, 5, 6, and 7.12 Additionally, the fact that DNA,21-23 and polysaccharides are being seen in lesions, but this could reflect a secreted aspartyl proteinase genes are done. For example, studies looking at sampling error.1,9,10 Studies indicate that each expressed differently in the mouth mannans, which are a major component when the yeast forms grow hyphae, they may in time help to explain the variety of of C. albicans’ cell wall structure, may help then act like adherent filaments to spread clinical candidiasis that is commonly seen determine the presence of C. albicans across, attach, and burrow between and (i.e., pseudomembranous, erythematous, systemically by evaluating the antibody into epithelial cells. This is commonly seen atrophic, and hyperplastic).13 reaction to the organism. Thus, enzyme in the more serious tissue invasion and immunoassays for sensitive detection especially in immunocompromised hosts.11 Oral Candidiasis, Candidemia, and of circulating C. albicans mannan and Adherence by the hyphae to oral Invasive Disease antimannan antibodies look promising in keratinocytes may be partially due to a Candida is present in the mouths of 25 the diagnosis of systemic candidiasis.24 protein called Hwp1, which is present in percent to 75 percent of the population,
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Predisposing Factors for Oral Candidiasis A decreased amount of saliva has been related to a possible increase in Candida organisms and intraoral candidiasis Figure 1. Acute pseudomembranous candidiasis. Figure 2. Acute atrophic candidiasis. in some but not all studies. Increased C. albicans carriage has been reported with decreased salivary flow in patients with salivary gland dysfunction14,25-29 or clinical signs of disease. Efforts to increase of 921 oral specimens taken from HIV- Sjögren’s syndrome30-34 and secondary the salivary flow rate may thus be an positive patients with oral candidiasis, to radiation therapy and anticholinergic important part of antifungal therapy. 95 yielded non-albicans species, mainly drug use.14,25-27,32,34,35 Glossodynia has Hyposalivation occurs in the presence from patients with low CD4 lymphocyte also been associated with C. albicans of numerous drugs such as sedatives, counts and extensive previous azole carriage.14,25-27,32,34,35 Other studies show hypnotics, antidepressants, psychotropics, exposure. Eighty-five of these were no increase in C. albicans carriage pain medications, and antihistamines. resistant to fluconazole.45 The need for a with hyposalivation due to medicines One study has shown a decrease of 60 new generation of antifungal medications and primary or secondary Sjögren’s percent in the flow rate of patients taking is imminent. syndrome.36 In one study, C. albicans two or more hyposalivatory drugs.40 The The tongue is the primary oral was detected in only a few subjects with evaluation of the medications taken by reservoir, particularly the midline of the hyposalivation37 (see the article by Daniels patients who have oral candidiasis and dorsal surface. This is followed by the in this issue). hyposalivation should be considered a cheek and the palate.46 Acrylic in dental Of interest is one recent study part of antifungal therapy. prostheses should also be considered a of primary and secondary Sjögren Antimicrobial properties are known reservoir. Dentures have been implicated patients treated only with pilocarpine to be present in saliva and are important as a reason for increased levels of oral hydrochloride to increase salivary flow. in the defense against C. albicans.40-42 This yeasts. In denture stomatitis, counts of C. At the start of the study, 75 percent of the is partially due to lysozymes, histatins, albicans and C. glabrata are substantially subjects were positive for Candida, and lactoperoxidase, immunoglobulins, higher than in non-stomatitis denture- 75 percent had clinical manifestations of lactoferrin, and salivary IgA.43,44 Each of wearing subjects. In patients who have infection. After one year of treatment these plays a particular role. For example, denture stomatitis, the counts of C. with pilocarpine hydrochloride (5 mg, the sensitivity of Candida species to albicans and C. glabrata are higher on t.i.d.), 75 percent of the subjects presented lysozymes is rated in decreasing order: C. the denture-bearing areas that do not with no cultivable Candida and no clinical krusei (most susceptible), C. parapsilosis, show signs of stomatitis.40 Patients manifestations.38 C. tropicalis, C. guilliermondii, C. albicans. with denture stomatitis thus need In another study, decrease in whole and C. glabrata.41 This helps to explain the treatment of all denture-bearing surfaces. salivary flow rate was correlated with an high intraoral carriage rates of C. albicans Additionally, the appliances should be increase in C. albicans counts.29 In fact, and the increase in the other species thoroughly scrubbed along with the several have concluded that susceptibility seen in some saliva-deficient or immune- denture container at least daily. This is to oral C. albicans infection is partially deficient patients. Therapy directed at often overlooked in the care of disabled predicted by the whole unstimulated increasing the immune status should be or bedridden patients and those in a rest salivary flow rate.29,38,39 It appears that considered in the treatment of patients home or even a retirement center. Soaking low salivary flow rates do not necessarily with recalcitrant candidiasis. dental prostheses in chlorhexidine is also predict the entrance of C. albicans, but AIDS patients with candidiasis recommended. in patients who already have C. albicans are easily treated initially with azole commensally, diminished flow rates may antifungals; however, as the disease Clinical Manifestations help increase the quantity of C. albicans, progresses, failure of these medications Five specific clinical oral its colonization, and the emergence of is becoming more common. In one study manifestations of candidiasis have
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Figure 3b. Chronic atrophic candidiasis.
Figure 3a. Chronic atrophic candidiasis. Figure 3c. Chronic atrophic candidiasis on a finger.
been described: pseudomembranous, edentulous ridges, and are frequently usually initiated by pseudomembranous acute atrophic/erythematous, chronic encountered under dentures. Predisposing candidiasis and then proceeds to a chronic atrophic, angular cheilitis, and chronic factors include ill-fitting or poorly cleaned form. A familial form, possibly autosomal hypertrophic/hyperplastic. The clinical dentures, as well as those enumerated for recessive, also exists, with about half of presentation may include more than one the other forms of candidiasis. the patients presenting with associated of these manifestations but usually one is Angular cheilitis (perleche) (Figure 4): endocrinopathy (hypoparathyroidism, predominant. Angular cheilitis is the same as intraoral Addison’s disease, hypothyroidism, or Acute pseudomembranous candidiasis chronic atrophic candidiasis, just in a diabetes mellitus). Other familial forms (Figure 1): The lesions are superficial different location. Clinically, there are are associated with abnormalities of iron curd-like white patches that wipe off, fissures at the commissural angles that metabolism or cell-mediated immunity.47 leaving an erythematous base. They allow pooling of saliva and incubation are located on any or all mucosal of yeast forms, crusting with underlying Treatment surfaces, particularly the buccal mucosa, erythema. The lesions are localized to The first line of treatment in most mucobuccal folds, oropharynx, and the corners of mouth. Predisposing cases of Candida infection is the use of dorsal tongue. Infants and the elderly are factors include ill-fitting dentures with frequent normal saline rinses, which predilected. Predisposing factors include overclosure, drooling at corners of mouth, can be found in all hospitals for bedside a history of broad-spectrum antibiotics, lip-licking habits, and thumb/digit- use or can be mixed at home using 1/2 steroids, nutritional deficiency, diabetes, sucking habits. teaspoon of salt in 1 quart of water. This malignancy, chemotherapy, radiation Chronic hypertrophic/hyperplastic helps to decrease the fungal counts and therapy, and cell-mediated immunity candidiasis (Candida leukoplakia) (Figures is soothing to the mucous membranes. dysfunction including HIV infection. 5a and b): Chronic nodular hard lesions The temperature of the rinse should be Acute atrophic candidiasis (Figure appear white, cream-colored, or red. These adjusted for comfort. If the epithelium 2): Loss of the Candida organism hypertrophic lesions are located on the is intact and not sloughing, the patient pseudomembrane causes small to surface of tongue, buccal mucosa, palate, should gently swab or brush the mouth generalized large red lesions with denture-bearing areas, central dorsum and use a tongue scraper. inflammation of surrounding tissues. of tongue (median rhomboid glossitis), Medication therapy falls into three The tongue typically shows depapillation as papillary nodules on palate usually basic categories; however, fungal and dekeratinization. Atrophic lesions under dentures (papillary hyperplasia), resistance is a growing problem, and a are most often seen on the tongue and and in areas of epithelial hyperplasia new generation of drugs is needed.48 The palate. Predisposing factors include broad- (pre-existing leukoplakias and keratotic polyenes, which include amphotericin spectrum antibiotics and corticosteroid papillomas). Predisposing factors include B and nystatin, help destroy the protein aerosols as may be used by asthmatics. cellular hyperplasia, oral precancerous gradient in the cell due to leakage Chronic atrophic candidiasis (Figures lesions, smoking, and denture wearing. of cellular components. Resistance 3a through c): The lesions are chronic There is a generalized mucocutaneous to amphotericin B is rare except for showing erythema and edema with a form of candidiasis that presents as C. lusitaniae, C. guilliermondii, and slight velvety/pebbly surface. Small chronic infection of the oral mucosa, Trichosporon beigelli.49 It is highly erosions may also be seen. The lesions are nails, skin, and vaginal mucosa. effective when given intravenously but located on the palate and upper and lower Resistance to therapy is common. This is toxicities and renal dysfunction are
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Figure 4. Angular cheilitis. Figure 5a. Leukoplakia of the soft palate. Figure 5b. Papillary hyperplasia.
problematic. Nystatin is easy to use but treatments also vary widely and include 60:313-8, 1994. 11. Staab JF, Bradway SD, et al, Adhesive and mammalian some dislike the taste. The azoles – which the elimination of specific foods, transglutaminase substrate properties of Candida albicans include ketoconazole, clotrimazole, detoxification, herbal cleansing, multiple Hwp1. Science 283:1535-7, March 5, 1999. fluconazole and itraconazole – inhibit vitamins, special diets, colonics, and 12. Naglik JR, Newport G, et al, In vivo analysis of secreted 48 aspartyl proteinase expression in human oral candidiasis. ergosterol biosynthesis. Fluconazole high enemas. This makes for interesting Infect Immun 67(5):2482-90, May 1999. has been the drug of choice for AIDS- surfing, but the scientific literature does 13. Axell TA, Baert C, et al, An update of the classification and associated fungal infections, but not support such contentions. diagnostic criteria of oral lesions in HIV infection. J Oral Pathol Med 20:97-100, 1991. resistance is rapidly becoming a problem, A useful Web site is provided by 14. Epstein JB, Pearsall NN, et al, Quantitative relationships particularly among the non-albicans the Centers for Disease Control and between Candida albicans in saliva and the clinical status of species (e.g.: C. krusei, C. glabrata, C. Prevention, which lists health topics from human subjects. J Clin Microbiol 12:475-8, 1980. 4-7,50-53 15. Pittet D, Nosocomial bloodstream infections. In Wenzel RP, lusitaniae, and C. dubliniensis). A to Z in a short-form encyclopedia of ed, Prevention and Control of Nosocomial Infections, 2nd ed. The third category, 5-Flucytosine, diseases. The address is www.cdc.gov/ Williams & Wilkins Co, Baltimore, 1993, p 512-55. disrupts the DNA and protein synthesis health/diseases.htm. Click on Candidiasis. 16. Wenzel RP, Nosocomial candidemia: risk factors and attributable mortality. Clin Infect Dis 20:1531-4, 1995. of the cell. It is used in connection A comprehensive literature search can 17. Matthews R, Burnie JP, et al, The application of epitope with amphotericin B, fluconazole, be performed at www.ncbi.nlm.nih.gov/ mapping in the development of a new serological test for and itraconazole. The development of pubmed/. systemic candidiasis. J Immunol Methods 143:73-9, 1991. 18. Mitsutake K, Miyazaki T, et al, Enolase antigen, mannan resistance to 5-FC is common. The use of antigen, Cand-Tec antigen, and beta-glucan in patients with References multiple agents is necessary in cases of candidemia. J Clin Microbiol 34:1918-21, 1996. 1. Cannon RD, Holmes AR, et al, Oral Candida: Clearance, 19. Walsh TJ, Hathorn JW, et al, Detection of circulating candida fungal resistance. colonization, or candidiasis? J Dent Res 74(5):1152-61, 1995. enolase by immunoassay in patients with cancer and invasive 2. Odds FC, Candida and Candidosis. Bailliere Tindall, For most cases seen in the general candidiasis. N Engl J Med 324:1026-31, 1991. Philadelphia, 1988. dental arena, various forms of nystatin or 20. Switchenko AC, Myada CG, et al, An automated enzymatic 3. Jarvis WR, Epidemiology of nosocomial fungal infections, method for measurement of D-arabinitol, a metabolite of clotrimazole are sufficientT ( able 1). with emphasis on Candida species. Clin Infect Dis 20:1526-30, pathogenic Candida species. J Clin Microbiol 32:92-7, 1994. 1995. The Internet has many sites that 21. Flahaut M, Sanglard D, et al, Rapid detection of Candida 4. Sullivan D, Coleman D, Candida dubliniensis: characteristics address Candida or candidiasis. Many albicans in clinical samples by DNA amplification of common and identification. J Clin Microbiol 36:329-34, 1998. regions from C. albicans-secreted aspartic proteinase genes. J of these espouse the concept that 5. Sullivan DJ, Westerneng TJ, et al, Candida dubliniensis sp. Clin Microbiol 36:395-401, 1998. Nov. = phenotypic and molecular characterization of a novel chronic systemic candidiasis is the cause 22. Talluri G, Mangone C, et al, Polymerase chain reaction used species associated with oral candidosis in HIV-infected of multiple symptoms and diseases to detect candidemia in patients with candiduria. Urology individuals. Microbiology 141:1507-21, 1995. 51:501-5, 1998. including constipation, diarrhea, bloating, 6. Coleman DC, Sullivan DJ, et al, Candidiasis: the emergence 23. Burnie JP, Golbang N, et al, Semiquantitative polymerase fatigue, lethargy, poor memory, difficulty of a novel species, Candida dubliniensis. AIDS 11:557-67, 1997. chain reaction enzyme immunoassay for diagnosis of 7. Sullivan D, Haynes K, et al, Widespread geographic focusing, moodiness, numbness, burning, disseminated candidiasis. Eur J Clin Microbiol Infect Dis distribution of oral Candida dubliniensis strains in human 16:346-50, 1997. tingling, muscle aches, nasal congestion immunodeficiency virus-infected individuals. J Clin Microbiol 24. Sendid B, Tabouret M, et al, New enzyme immunoassays or discharge, swollen joints, erratic vision, 35:960-4, 1997. for sensitive detection of circulating Candida albicans 8. Kurzai O, Werner JH, et al, Rapid PCR test for discriminating endometriosis, menstrual problems, mannan and antimannan antibodies: Useful combined test for between Candida albicans and Candida dubliniensis isolates diagnosis of systemic candidiasis. J Clin Microbiol 37(5):1510-7, prostatitis, impotence, chronic fatigue, using primers derived from the pH-regulated PHR1 and PHR2 May 1999. fibromyalgia, anger, and frustration. genes of C. albicans. J Clin Microbiol 37(5):1587-90, May 1999. 25. Epstein JB, Truelove EL, Izutsu K, Oral candidiasis: 9. Kerridge LH, Fungal dimorphism: a sideways look. In, Vanden Scientific verification of the cause-and- Pathogenesis and host defense. Rev Infect Dis 6:96-106, 1984. Bossche H, Odds FC, Kerridge D, eds, Dimorphic Fungi in 26. Brown LR, Dreizen S, et al, Effect of radiation-induced effect relationship is debatable and Biology and Medicine. Plenum Press, New York, 1993, pp 3-10. xerostomia on human oral microflora. J Dent Res 54:750-4, probably impossible. The recommended 10. Odds FC, Candida species and virulence. ASM News 1975.
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Table 1. Drug Regimens Used to Treat Oral Candidiasis • Nystatin (Mycostatin) oral suspension, 100,000 units/ml, dispense 60 ml. Swish and swallow 2-5 ml four times daily. • Nystatin cream or ointment. Dispense 15 or 30 g. Apply to corners of mouth four times daily. The cream can also be used as a coating for the denture and then placed in the mouth. • Nystatin troche 200,000 units to 400,000 units. Dissolve one troche four times daily. • Nystatin topical powder 15 g. Apply thin layer under the denture after each meal. • Clotrimazole (Mycelex) troche 10 mg. Dissolve one tab in mouth five times per day • Clotrimazole cream 15 g, 30 g, 60 g, and 90 g tubes • Amphotericin B (Fungizone) suspension 100 mg/ml. Swish and swallow 1 ml four times daily. • Ketoconazole (Nizoral) 200 mg, one to two tabs per day (watch for liver dysfunction). • Ketoconazole cream 2% 15 g, 30 g, and 60 g tubes (contains sodium sulfite anhydrous, to which some patients have al- lergic reactions) • Fluconazole (Diflucan) 50 mg, 100 mg, 150 mg, 200 mg. Take 200 mg on day 1 then 100 mg per day for 14 days. • 5-Flucytosine (Ancobon) 250 mg, 500 mg caps. Take 50 to 150 mg per kg per day in divided doses every six hours. Used in combination with amphotericin B, fluconazole or itraconazole. • Itraconazole (Sporanox) 100 mg caps, oral solution 100 mg/10 ml. Dispense 150 ml. Take 200 mg per day. Dose may be increased 100 mg per day to 400 mg per day. Doses greater than 200 mg per day should be given in two divided doses.
27. Rossie KM, Taylor J, et al, Influence of radiation therapy on use of pilocarpine hydrochloride: A pilot study. Quintessence factors that contribute to antifungal drug resistance. Clin Candida albicans colonization: A qualitative assessment. Oral Intl 29(11):705-10, 1998. Microbiol Rev 11:382-402, 1998. Surg Oral Med Oral Pathol 64:698-701, 1987. 39. Navazesh M, Christensen CM, Brightman VJ, Clinical 50. Wingard JR, Merz WG, et al, Increase in Candida krusei 28. Hauman CHJ, Thompson IO, et al, Oral carriage of Candida criteria for the diagnosis of salivary gland hypofunction. J Dent infection among patients with bone marrow transplantation in HIV-seropositive persons. Oral Surg Oral Med Oral Pathol Res 71:1363-9, 1992. and neutropenia treated prophylactically with fluconazole. N 76:570-2, 1993. 40. Kreher JM, Grase GN, et al, Oral yeast mucosal health and Engl J Med 18:1274-7, 1991. 29. Navazesh M, Wood GJ, Brightman VJ, Relationship between drug use in elderly denture-wearing population. Spec Care 51. Vazquez JA, Dembry LM, et al, Nosocomial Candida glabrata salivary flow rates and Candida albicans counts. Oral Surg Oral Dent 11:222-6, 1991. colonization: An epidemiologic study. J Clin Microbiol 36:421-6, Med Oral Pathol 80:284-8, 1995. 41. Tobgi RS, Samaranayake LP, MacFarlane TW, In vitro 1998. 30. MacFarlane TW, Mason DK, Changes in the oral flora in susceptibility of Candida species to lysozyme. Oral Microbiol 52. Merz WG, Khazan U, et al, Strain delineation and Sjögren’s syndrome. J Clin Pathol 27:416-9, 1974. Immuno 3:36-9, 1988. epidemiology of Candida (Clavispora) lusitaniae. J Clin 31. Tapper-Jones L, Aldred M, Walker DM, Prevalence and 42. Pollock JJ, Denepitiya L, MacKay BJ, Fungistatic and Microbiol 30:449-54, 1992. intraoral distribution of Candida albicans in Sjögren’s fungicidal activity of human parotid saliva histidine rich 53. Kirkpatrick WR, Revankar SG, et al, Detection of syndrome. J Clin Pathol 33:282-7, 1980. polypeptides of Candida albicans. Infect Immun 44:702-7, Candida dubliniensis in oropharyngeal samples from human 32. MacFarlane TW, The oral ecology of patients with severe 1984. immunodeficiency virus-infected patients in North America Sjögren’s syndrome. Microbios 41:99-106, 1984. 43. Oppenheim FG, Xu T, et al, Histatins, a novel family of by Primary CHROMagar Candida screening and susceptibility 33. Daniels TE, Silverman S, et al, The oral component of histatine-rich proteins in human parotid secretion: isolation, testing of isolates. J Clin Microbiol 36:3007-12, 1998. Sjögren’s syndrome. Oral Surg Oral Med Oral Pathol 39:875-85, characterization, primary structure, and fungistatic effects on To request a printed copy of this article, please contact/ 1975. Candida albicans. J Biol Chem 263:7472-7, 1966. Stanton S. Appleton, DDS, MPH, MSD, LLU School of 34. Hernandez YL, Daniels TE, Oral candidiasis in Sjögren’s 44. Challacombe S, Immunology of oral candidiasis. In, Dentistry, Loma Linda, CA 912350, or at [email protected] syndrome: Prevalence, clinical correlations and treatment. Samaranayake LP, MacFarlane TW, eds, Oral Candidiasis. Oral Surg Oral Med Oral Pathol 68:324-9, 1989. Wright, London, 1990, pp 104-23. 35. Budtz-Jorgensen E, Candida-associated denture stomatitis 45. Cartledge JD, Midgley J, et al, Non-albicans oral candidosis and angular cheilits. In, Samaramayake LP, MacFarlane TW, in HIV-positive patients. J Antimicrob Chemotherap 43:419-22, eds, Oral Candidiasis. Butterworth, London, 1990, pp 156-83. 1999. 36. Beighton D, Hellyer PH, et al, Salivary levels of mutans 46. Arendorf TM, Walker DM, The prevalence and intra-oral streptococci, lactobacilli, yeasts, and root caries prevalence in distribution of Candida albicans in man. Arch Oral Biol 25:1-10, non-institutionalized elderly dental patients. Community Dent 1980. Oral Epidemiol 19:302-7, 1991. 47. Regezi JA, Sciubba JJ, Oral Pathology: Clinical-Pathologic 37. Almståhl A, Wikström M, Oral microflora in subjects with Correlations. WB Saunders Co, 1989. reduced salivary secretion. J Dent Res 78(8):1410-6, August 48. Wynn RL, Jabra-Rizk MA, et al, Antifungal drugs and fungal 1999. resistance: The need for a new generation of drugs. General 38. Rhodus NL, Liljemark W, et al, Candida albicans levels in Dentistry July-August 352-5, 1999. patients with Sjögren’s syndrome before and after long-term 49. White TC, Marr KA, et al, Clinical, cellular, and molecular
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Focal, Flat Pigmentations of the Oral Mucosa: A Clinical Approach to the Differential Diagnosis
William M. Carpenter, DDS, MS, and Mitchell Rudd, DDS
abstract The purpose of this article is to assist the clinician in establishing a clinical approach to the diagnosis of focal, flat pigmentations of the oral mucosa. These pigmentations include lesions that may be blue, purple, red, black, or brown. The etiopathogenesis may be variable and the pigment may originate from an exogenous (extrinsic) or endogenous (intrinsic) source. Exogenous pigmentations are of a traumatic or iatrogenic origin. Intrinsic pigmentations are either vascular or melanocytic. Clinical approaches include a thorough history and physical exam coupled with diascopy (blanchability), radiographs, and tissue examination (biopsies). An algorithm is presented to clarify the diagnostic approach. The diagnosis may vary from pathologic entities that require no treatment to others that may involve malignancies and their associated management. It is therefore extremely important that these lesions are identified and properly managed in an expeditious manner.
authors ocal pigmentations of a flat due to many etiologic factors but basically William M. Carpenter, Mitchell Rudd, DDS, is (macular) nature are frequently can be considered of an exogenous DDS, MS, is professor a dental resident with encountered on the oral (e.g., amalgam, root canal sealer) or Pocatello Family Dentistry and chairman in the mucosa. A large number of endogenous (e.g., vascular, melanocytic) Department of Pathology Clinic at Idaho State and Medicine at the University. lesions must be considered origin. The coloration of these University of the Pacific Fin the differential diagnosis, and the pigmentations may be red, blue, purple, School of Dentistry. treatment may vary from observation black, gray, or brown. The determination to radical surgery. It is therefore crucial of the exact coloration may be helpful in that the appropriate course of action be beginning the differential workup F( igure followed. These pigmentations may be 1) and several clinical aids (diascopy, december 2000 949 pigmentations
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Figure 1.The differential workup.
radiographs, biopsy) may be useful to be helpful in this regard. Diascopy is a reactions may appear red but are continue this diagnostic approach and clinical test of applying pressure with a usually more diffuse (e.g., erythematous arrive at a definitive diagnosis.1-7 transparent object to allow visualization candidiasis). A focal red or blue macule of the blanchability of the underlying may also represent a vascular proliferation Vascular Lesions mucosa.8 A glass slide can be used but such as a hemangioma (port-wine stain) Lesions that are red, blue, or purple with caution, since the edges are sharp. A (Figures 6 and 7) or a malignant vascular are most frequently of a vascular origin; more suitable choice is a flat, clear plastic proliferation (e.g., Kaposi’s sarcoma). and the color is due to the hemoglobin object with smooth, polished edges, such Lesions that are nonblanchable by in the blood. Oxygenated hemoglobin in as a ruler. If a lesion is blanchable (see diascopy may still represent intravascular the arterial system will usually appear Figure 1), the lesion would represent blood that cannot be emptied due to reddish, while unoxygenated blood in vasodilation or vascular proliferation a large number of feeder vessels or the venous system will take on a blue- in which blood is extruded by pressure small vascular lumens. However, these purple appearance. The first decision from within patent blood vessels. nonblanchable lesions will mostly in diagnosing vascular lesions is to Vasodilation is found as an inflammatory represent extravascular blood (purpura). determine whether the blood is within response as in the erythema associated This condition occurs spontaneously in the vessels (intravascular) or has been with gingivitis (Figure 2), post-trauma several pathologic conditions or may extravasated (extravascular) into the (Figure 3), hypersensitivity (Figure 4), be induced by trauma with submucosal submucosal tissues (see Figure 1). A a varix (varicose vessel) (Figure 5), or hemorrhage (Figures 8 and 9). The exact clinical test called diascopy may often telangiectasia. Other inflammatory coloration is determined by the length of
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Figure 2. Focal zone of gingival erythema associated with Figure 3. A palatal erythema secondary to a traumatic Figure 4. A contact mucositis as a result of gold a severe periodontal defect. event. hypersensitivity.
Figure 5. Several blue, purplish varices in the anterior Figure 6. A port-wine stain (capillary hemangioma) of the Figure 7. Blanching of the hemangioma following diascopy. floor mouth. right lower lip and skin.
the time the blood is in the submucosal usually culminate in the appearance deficiencies are also encountered in late- tissue with the hemoglobin undergoing of petechiae rather than ecchymoses. stage renal disease and among patients degradation to biliverdin and bilirubin. Thrombocytopenia may be ideopathic with steatorrhea. This extravascular blood can be seen (autoimmune), HIV-associated, in small pinpoint areas (petechiae), leukemia-associated or drug-induced. Epithelial Thinning larger areas (ecchymosis) or swellings Thrombocytopathia is a defect in platelet Other nonblanchable red macules (hematomas) (Figure 10). History taking function and may be a hereditary disorder are inflammatory reactions including may be helpful in differentiating these of platelet adhesion molecules, such as burns or erosions with partial loss of etiologic possibilities, and further the von Willibrand group of diseases, the epithelium. This thinning of the oral laboratory tests may be indicated to or the defect may be drug-induced as mucosa (epithelial atrophy) will allow a establish systemic conditions such as is seen in patients taking high doses reddish appearance due to the underlying a thrombocytopenia (petechiae) or of aspirin. The coagulopathies are vasculature as in this thermal injury coagulopathies (ecchymosis). These deficiencies in clotting factors that may (Figure 12). This same histologic finding may include platelet count, partial involve either the intrinsic or extrinsic of epithelial thinning can occur in a thromboplastin and prothrombin pathways of coagulation and typically neoplastic condition such as erythroplakia time (international normalized result in ecchymosis. The hereditary with a diagnosis of epithelial dysplasia, ratio). Palatal petechiae (Figure 11) types include hemophilia A and B, among carcinoma-in-situ or microinvasive may occur secondary to trauma or others; although the most common squamous cell carcinoma (Figure 13). Any suction, infectious mononucleosis, or a is coagulopathy induced by coumadin lesion that fails to show signs of healing platelet problem (thrombocytopenia or among patients with thromboembolic should be subjected to cellular analysis. thrombocytopathia). disease. It must be recalled that most Recognition of coagulopathic and of the clotting factors are made in the Exogenous Pigmentation hemostatic disorders is extremely liver; and, therefore, patients with liver Other discolorations of the oral mucosa important. The platelet defects disease may be bleeders. Clotting factor may appear as black or gray (Figure 14),
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Figure 8. Hematoma of the left lower lip. Figure 9. Diascopy revealing extravascular blood and Figure 10. A focal hematoma following a traumatic nonblanchability. incident.
Figure 11. Palatal petechiae that have coalesced in areas, Figure 12. A mucosal burn following pizza ingestion. Figure 13. Erythroplakia of the anterior floor of mouth representing extravascular blood. which represents an early squamous cell carcinoma.
and these often represent an exogenous a graphite tattoo, most commonly seen on syndrome). There are other systemic pigmentation from iatrogenic sources.9,10 the palate (Figure 17). conditions, particularly palatal melanosis, A radiograph (Figure 15) of the area that can occur as a result of several will commonly reveal a metallic source Endogenous Pigmentation – Melanin medications (e.g. antimalarials and responsible for the pigmentation, usually Other pigmented lesions of a blackish, minocycline), smoking or pulmonary amalgam (focal argyosis) (Figure 14) or bluish or more frequently brownish disease12 (Figure 19). root canal sealer that has been embedded coloration may be of melanocytic origin. Melanocytic proliferations are very in the submucosa or periapical tissue. The color is dependent on the amount common on the skin and are known as If these metals are not large enough to and location of the melanin. Melanocytic a pigmented nevi, lesions that progress be detected radiographically (Figure 16), lesions may represent a basilar melanosis through histologic stages and ultimately further history taking and evaluation are or a melanocytic proliferation. The basilar enter a final period of growth arrest F( igure necessary. Lesions that are on the gingiva melanosis or ephelis (freckle) on the skin 20). Nevi are fairly uncommon in the oral or alveolar mucosa in close proximity to is actinically induced. In the oral cavity, mucosa and are of four histologic types, amalgam restorations or at the apices of the etiology is unknown, although a depending on the location of the nevus endodontically treated teeth are often history of antecedent trauma may be cells (junctional, compound, intradermal clinically diagnosed. Other cases are more noted.11 Frequently they are solitary, and intramucosal and blue).13 These lesions problematic, and a decision must be made the appellation oral melanotic macule may frequently be nodular. Nevi should to evaluate these lesions periodically. is applied (Figure 18). The diffuse or be excised for a definitive diagnosis. The Since these lesions can slowly enlarge as multifocal lesions are most commonly main concern with pigmented lesions they are absorbed by the tissue, it may seen in racial pigmentations that are is that they may represent a malignant be necessary to perform a biopsy for genetically controlled. They also may melanocytic proliferation or melanoma definitive diagnosis. Another exogenous be associated with several systemic (Figure 21). Melanomas of the oral mucosa source occurs as a result of children falling conditions, including Addison’s disease are rare and usually begin de novo but with pencils in their mouths and creating or intestinal disorders (Peutz-Jeghers may occur as a progression of a nevus
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Figure 14. Two focal areas of a grayish black pigmentation Figure 15. A radiographic view of this exogenous Figure 16. An amalgam tattoo that was not visible of the alveolar ridge. pigmentation (amalgam). radiographically.
Figure 16. Two black pigmentations of the palate Figure 18. A brownish, focal pigmentation in which the Figure 19. A palatal melanotic macule associated with an representing graphite tattoos. biopsy revealed an oral melanotic macule. antimalarial medication.
(junctional type). Any changes in a lesion with regard to irregular borders, enlargement, and/or color changes are ominous signs. A rapid referral for a biopsy is crucial to allow expeditious and proper management. Oral melanomas are most frequently seen on the anterior maxillary gingiva and palate.14 The early lesions may be macular, representing superficial spreading melanomas that Figure 20. Blackish pigmentation of the mid-hard palate Figure 21. A brownish black pigmentation of the left have not invaded into the submucosal representing an intramucosal nevus. lower lip that was rapidly enlarging and represented an early connective tissues. When invasion occurs, malignant melanoma. a nodular mass will appear. In most oral melanomas, there is a mixture of macular and nodular pigmentation. Whereas oral mucosal melanomas are very rare, those This paper has presented a practical, References 1. Regezi JA and Sciubba J, Oral Pathology Clinical Pathologic arising on the facial skin, particularly the clinical approach to the diagnosis of focal, Correlations, 2nd ed. WB Saunders Co, Philadelphia, 1993. malar region, are common.15 These facial flat oral mucosal pigmentations that will 2. Eversole LR, Clinical Outline of Oral Pathology: Diagnosis skin melanomas are typically superficial allow dentists to be confident in their and Treatment, 3rd ed. Lea & Febiger, Philadelphia, 1992. 3. Neville BW, Damm DD, et al, Oral & Maxillofacial Pathology. spreading types referred to as lentigo initial recognition and management. WB Saunders Co, Philadelphia, 1995. maligna melanoma. They are multicolored Biopsy is always recommended in 4. Wood NK and Goaz PW, Differential Diagnosis of Oral with foci of hypopigmentation and cases that are not readily recognized as Lesions, 4th ed. Mosby-Year Book, St. Louis, 1991. 5. Eversole LR, Oral Medicine: A Pocket Guide. WB Saunders classically have irregular, jagged traumatic vascular lesions or amalgam Co, Philadelphia, 1996. boundaries. tattoos. 6. Coleman GC and Nelson FN, Principles of Oral Diagnosis.
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Mosby-Year Book, St. Louis, 1993. 7. Bhaskar SN, Synopsis of Oral Pathology, 7th ed. Mosby Co, St. Louis, 1973. 8. Rudd MG, Eversole LR, and Carpenter WM, Diascopy. Academy of General Dentistry, Submitted for publication June 2000. 9. Seward GR, Amalgam tattoo. Br Dent J 184:470, 1998. 10. Owens BM, Johnson WW, Schuman NJ, Oral amalgam pigmentations (tattoos): a retrospective study. Quintessence Int 23(12):805-10, 1992. 11. Kaugars GE, Heise AP, et al, Oral melanotic macules. A review of 353 cases. Oral Surg Oral Med Oral Pathol 76:59-61, 1993. 12. Meyerson MA, Cohen PR, Hymes SR, Lingual hyperpigmentation associated with minocycline therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 79:180-4, 1995. 13. Buchner A, Leider AS, et al, Melanocytic nevi of the oral mucosa: a clinicopathologic study of 130 cases from northern California. J Oral Pathol Med 19:197-201, 1990. 14. Gorsky M, Epstein JB, Melanoma arising from the mucosal surfaces of the head and neck. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 86:715-9, 1998. 15. Massi D, Nardini P, et al, Simultaneous occurrence of multiple melanoma in situ on sun damaged skin (lentigo maligna), solar lentigo and labial melanosis: the value of dermoscopy in diagnosis. J Eur Acad Dermatol Venereol 13:193-7, 1999. To request a printed copy of this article, please contact/ William M. Carpenter, DDS, MS, UOP School of Dentistry, 2155 Webster St., San Francisco, CA 94115 or e-mail the author at [email protected].
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Diet Drugs and Cardiac Valvulopathy: A Survey of Dental Patients
Richard Rudin, DDS, MA, and William Carpenter, DDS, MS
abstract The recent finding that several appetite suppressant drugs (fenfluramine and dexfenfluramine) were linked to cardiac valvular disease in a significant percentage of the population led to their voluntary withdrawal. The Centers for Disease Control and Prevention issued a series of recommendations in 1997 for evaluating dental patients who had taken these drugs. Since that time, several studies have further investigated the prevalence of valvular abnormalities. This information is crucial because of the problem of dentally associated bacterial endocarditis. This study surveyed more than 1,300 dental patients and determined the prevalence of patients taking these diet drugs and cardiac valvulopathy and the percentage of dental patients required to take antimicrobial endocarditis prophylaxis before “at risk” dental procedures. It remains important for dentists to query their patients for this information.
authors n 1997, fenfluramine and or in combination with other agents, dexfenfluramine (Fen/Dex), should undergo a medical history and Richard Rudin, DDS, MA, is William M. Carpenter, an assistant professor of DDS, MS, is professor components of several diet drugs cardiovascular examination by their diagnosis and management and chairman in the (appetite suppressants), were physicians to determine the presence at the University of the Department of Pathology linked with cardiac valvular disease or absence of cardiopulmonary signs or Pacific School of Dentistry. and Medicine at UOP Iin possibly 32.89 percent of patients.1 symptoms. School of Dentistry. Because of this association, the companies 2. An echocardiographic evaluation producing the drugs voluntarily removed should be performed on all people who them from the market.2 were exposed to Fen/Dex for any period When the public and profession of time, either alone or in combination were notified by the Centers for with other agents, and who exhibit new Disease Control and Prevention3 of the cardiopulmonary signs (including a new valvulopathology associated with diet murmur) or symptoms suggestive of drugs, the following recommendations valvular disease. and guidelines were stated: 3. Although the clinical importance 1. All people exposed to Fen/Dex of a symptomatic valvular regurgitation for any period of time, either alone in exposed patients and the risk for december 2000 955 diet drugs
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Table 1. UOP Medical History (Supplemental Question)
YES NO Have you ever taken prescription medication for weight reduction (Diet Pills)? developing bacterial endocarditis If “YES,” did you take any of the below listed drugs? (Please indicate with an X on line). in these patients are unknown, practitioners should strongly consider ______Fen-Phen (fenfluramine - phentermine) performing echocardiography on all people – regardless of whether they have ______Pondimin (fenfluramine) cardiopulmonary signs or symptoms – who have been exposed to Fen/Dex for ______Redux (dexfenfluramine) any period of time, either alone or in combination with other agents, before YES NO If you have taken any of the above drugs, have you had a medical exam to ensure that the patient undergoes any invasive your heart valves were not affected? procedure for which antimicrobial Patient's Signature ______Date______endocarditis prophylaxis is recommended by 1997 American Heart Association Please Print Name ______guidelines. Any echocardiographic finding that meets the AHA criteria for prophylaxis – regardless of whether they are attributable to possible Fen/Dex use – should be recognized as an indication for occurs.1,11-14 Several organizations have having their health history updated. antimicrobial endocarditis prophylaxis. made recommendations relative to the The questionnaires were printed on The invasive procedures, including need for antimicrobial endocarditis duplicate forms; the original was placed certain medical or dental procedures prophylaxis prior to invasive into the patient’s chart, and the copy where antimicrobial endocarditis procedures.3,15-19,21 was turned in at a central collecting prophylaxis is recommended, are In the present study, the authors station each day. Patients who responded defined in the 1997 AHA guidelines.4 For surveyed patients presenting to a dental positively to any of these questions emergency procedures for which cardiac school clinic to determine the incidence were evaluated by a faculty member. If evaluation cannot be performed, empiric of diet drug utilization (Fen/Dex) and valvular damage was diagnosed and the antimicrobial endocarditis prophylaxis whether they had been evaluated for physician recommended antimicrobial should be administered according to the cardiac valvular damage. endocarditis prophylaxis, then, depending 1997 AHA guidelines. on the nature of the dental procedure, 4. Because of the prevalence of Study Design the current antimicrobial endocarditis minimal degrees of regurgitation in the A health history questionnaire was prophylaxis was prescribed. general population, the current case designed to elicit from patients (1) definition of drug-associated valvulopathy whether they had ever taken diet drugs Results should include exposed patients with and (2) whether the diet drugs taken were A total of 1,373 questionnaires echocardiographically demonstrated ones that contained Fen/Dex. If answered were tabulated. Forty patients (0.03 aortic regurgitation of mild or greater in the affirmative, they were then asked percent) had a history of diet drug use. severity and/or mitral regurgitation of whether they had seen their physicians Twenty eight of these patients (0.02 moderate or greater severity, based on for cardiovascular examinations (Table 1). percent) met the criteria for the use published criteria.5,6 Patients were then followed to determine of diet drugs containing fenfluramine Since the initial notification by the prevalence of a cardiac valvulopathy (Pondimin), dexfenfluramine (Redux), or the CDC, a number of studies have and the need for antimicrobial fenfluramine-phentermine (Fen-Phen). been published, and court cases have endocarditis prophylaxis. Twelve patients reported the diet drugs transpired.7 Studies have looked at the The questionnaire was filled out by but not Fen-Phen, Pondimin or Redux. evidence of valvulopathy8-10 as well as all new adult patients presenting to Eighteen of these 28 patients (64 the exact location of the pathoses8 and the dental school, as well as existing percent) were evaluated for cardiac the mechanism by which the damage patients who were in the process of damage. The other 10 were lost to
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follow-up. Four of these 18 patients (22 percent) were diagnosed with some degree of cardiac valvulopathy. In two of these cases, the physician recommended antimicrobial endocarditis prophylaxis to be used prior to invasive dental procedures. The other two were believed to have only a mild valve dysfunction, which did not require antimicrobial endocarditis prophylaxis.
Discussion Much of the research related to cardiac disease following the use of Fen/Dex diet drugs has focused on the incidence of valvular pathosis.1,2,8,11-14 Much of this discussion centered around whether, in fact, the valvulopathy actually occurred secondary to the use of diet drugs, or whether the incidence of cardiac valvular damage found in this group was high due to other risk factors (e.g., obesity). Some investigators attributed the high incidence of valvular disease to the detail and intensity of the evaluation process.8,20 Studies also disclosed a relationship between valvulopathy and the length of time Fen/Dex was taken and the dosage.10 The two most common abnormalities discovered by echocardiogram were atrial and mitral regurgitation. In a 1998 study by Jick and colleagues,9 equal numbers of patients had newly discovered valve disorders, with or without predisposing conditions (congenital or rheumatic heart disease). All idiopathic patients (those with no predisposing conditions) had received Fen/Dex for more than three months. Approximately 1 percent of patients receiving Fen/Dex were diagnosed with asymptomatic atrial regurgitation and between the groups taking the drugs for symptomatic valvulopathy. mitral regurgitation in patients taking less than three months or more than A recent study by Gardin and Fen/Dex. This study provides data on three months. This percentage increases colleagues10 demonstrates a significant the relationship of duration and use. to 21.2 percent if the drugs were taken prevalence of both primarily mild An 11.6 percent difference was noted for more than 18 months. The majority
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of the echocardiographic studies in as to the types of dental procedures that not associated with valvular heart disease. Arch Inter Med asymptomatic patients receiving Fen/Dex are considered “at risk.” This is a clinical 158:1278-9, 1998. 13. Shivley BK, Roldan CA, et al. Prevalence and determinants reveal that the most common abnormality decision made by the dentist predicated of valvulopathology in patients treated with dexfenfluramine. is atrial regurgitation, which appears to be on guidelines published in 1997 by the Circulation 100:2161-7, 1999. minor or benign. AHA and ADA for prevention of infective 14. Hick J, Summary, editorial. J Am Med Assoc 283 No 13, April 3 5, 2000. Prior to 1997, Fen/Dex was commonly endocarditis. 15. ACC/AHA Guidelines on Valvular Heart Disease. prescribed for diet control. The substantial Currently almost all dental health 16. ACC Oct. 18, 1997, Nov. 18, 1997. Available at http://www.acc. majority of patients in the United States histories ask about heart problems or org/pubs/news/statement.html 17. The Dentists Insurance Company, Fen-Phen and Redux received the drugs for less than three heart murmurs. While only a minority of alert. TDIC memorandum to policy holders, May 5, 1998. months. For these patients, the risk of American patients (4 to 5 million) took 18. Loitz G, CDA Council on Dental Research and valvular disorders appears small. The the specific diet drugs mentioned in this Developments. TDIC Risk Management Jan 28, 1998. 19. Pallasch TJ, An expert addresses Fen-Phen. CDA Update increased risk of valvulopathy is real, article for longer than 3 months and many 9(12):1, 15. symptomatic, and clinically significant have been evaluated by their physicians for 20. Weisman N, Tighe J, Gottdiener J, An assessment of heart in patients who have taken the drugs for valvular disease, it is still appropriate to valve abnormalities in obese patients taking dexfenfluramine, sustained release dexfluramines or placebo. N Eng J Med longer than three months. ask patients about their diet drug history 339:725-32, 1998. The prevalence of cardiac valvulopathy and consult their physicians regarding 21. Pallasch TJ, Current status of fenfluramine/ in the current study of dental patients any resulting valvulopathy and need for dexfenfluramine-induced cardiac valvulopathology. J Cal Dent Assoc 27(5):400-4, 1999. taking Fen/Dex was 22 percent. However antimicrobial endocarditis prophylaxis. To request a printed copy of this article, please contact/ the current survey did not question Richard Rudin, DDS, MA, UOP School of Dentistry, 2155 duration and dosage of drug use. Detailed References Webster St., San Francisco, CA 94115. 1. Connolly HM, Crary JL, et al, Valvular heart diseases information was not received regarding associated with fenfluramine-phentermine. N Engl J Med the degree of valvulopathy. However 337:581-8, 1997. antimicrobial endocarditis prophylaxis was 2. Food and Drug Administration, FDA analysis of cardiac valvular dysfunction with the use of appetite suppressants. recommended for 11 percent of the patients. http://www.fda.gov/cder/news. When a valvulopathy occurs it can 3. Cardiac valvulopathy associated with exposure to range from mild and asymptomatic to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services interim public health recommendations, severe and symptomatic. The decision as November 1997. MMWR 46:1066, 1997. to what degree of valvulopathy requires 4. Dajani AS, Taubert KA, et al, Prevention of bacterial antimicrobial endocarditis prophylaxis endocarditis: Recommendations by the American Heart Association. J Am Dent Assoc 128:1142-50, 1997. prior to invasive procedures remains a 5. Perry GJ, Helmcke F, et al, Evaluation of aortic insufficiency point of discussion. by doppler color flow mapping. J Am Coll Cardio 9:952-9, 1987. Proper dental referral for patients 6. Helmcke F, Nanda NC, et al, Color doppler assessment of mitral regurgitation with orthogonal planes. Circulation at risk would be an examination by a 75:175-83, 1987. physician. Depending on the risk or 7. Nationwide class-action settlement agreement findings, a referral to a cardiologist with American Home Products Corp. http://www. settlementdietdrugs.com/ Accessed July 17, 2000. may be indicated. If warranted, an 8. Kahn, M., Herzogg C, et al, The prevalence of cardiac valvular echocardiographic evaluation should insufficiency assessed by transthoratic echocardiography in be done. However, the valvulopathy obese patients treated with appetite-suppressant drugs. N Engl J Med 339:713-8, 1998. may progress; and a repeat cardiac 9. Jick H, Vasilakis C, et al, A population-based study of evaluation should be performed in six appetite suppression drugs and the risk of cardiac valve to eight months. Once a diagnosis has regurgitation. N Engl J Med 339:719-24, 1998. 10. Gardin JM, Schumacher D, et al, Valvular abnormalities and been made and the severity evaluated cardiovascular status following exposure to dexfenfluramine with recommendations for antimicrobial or phentermine/fenfluramine. J Am Med Assoc 283:1703-9. endocarditis prophylaxis, the dentist 11. Griffen L, Anchors M, Asymptomatic mitral and aortic valve disease is seen in 1/2 patients taking “Phen-Fen.” Arch Intern has clear recommendations from the Med 1998:158, 102. AHA and American Dental Association 12. Griffen L, Anchors M, The “Phen-Pro” drug combination is
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s if they didn’t have enough on rigamarole for securing a patent depends their plate to worry them what on whether the thing or idea is an with the FDA’s acceptance of entirely new concept or a demonstrable RU-486, experts in medical improvement on a pre-existing one. ethics have discovered that a What makes the medical ethics people Awild and crazy cloning team has managed nervous is the fact that the pending patent to cross pig and human DNA. has a strong chance of being granted. We’re not making this up – Jonathan Apparently European law says the scheme Leake and Nick Fielding writing in is not illegal because the embryo is not the United Kingdom’s Sunday Times technically human. In the United States, , Robert E. reveal that scientists have successfully the fine distinction between what is Horseman, produced an embryonic pig-human human and what is not has been blurred by DDS hybrid by inserting human DNA into pig several decades of punk rock, heavy metal, cells. This is why young children should rap and hip-hop “music.” never be given a home chemistry set as Obviously, God already holds a patent a gift. You’ve seen what they can do with on pigs and humans, so it will be up to computers, sending stocks tumbling, the applicants to prove that their clone is hacking their way into top-secret stuff like an improvement. Certainly the human is KFC’s confidential herb and spice recipe. not going to improve the pig, but there No sooner are they in their late teens than is a good chance that the reverse might they get a government grant and this sort benefit us. It couldn’t hurt. of pig-human katzenjammer thing occurs. Dr. Richard Nicholson, editor of the At this time, we are not sure of Bulletin of Medical Ethics is appalled. He what happened to these porcine-homo insists, “This kind of research depends on embryos, because the researchers devaluing human beings.” We can all agree have dummied up upon submitting an that human beings need no assistance application for a patent to the European from researchers; we can devalue Patent Office, says the Times. The usual ourselves very nicely on our own.
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We have tracked down the perps in opinion is good for nothing more than this caper. They turn out to be big players providing endlessly boring documentaries in the biotechnology industry, namely on public television depicting their Stem Cell Sciences in Australia and feeding habits, mating proclivities, thirst Biotransplant in the United States. Even for surfboarders, ad infinitum. This these guys don’t know for sure whether overexposed animal has been described as the hybrid embryos could have become the perfect eating machine and for good living beings. reason. Shortchanged in the warm-and- Ninety-seven percent of the DNA is fuzzy department, the Great White and in the nucleus, which was human. There the rest of his ilk have more than made up would be 3 percent pig DNA, however, for the oversight by having the niftiest set indicating that the end result would of choppers you can imagine, including likely be more human than pig. Except those of Julia Roberts. for a tendency to shed its clothes and If the lads in the biotechnology dodge happily wallow in the mud, the hybrid ever get around to crossing a shark with clone might be indistinguishable from human DNA, the game is up for dentists. normal people, especially at male- Fillings, root canals, orthodontics, the lot dominated sporting events. –we’re out of business, because, as we all It is our hope that these scientists are know, sharks keep growing new teeth and not laughed out of the club and forced to moving them forward in a never-ending go back to finding a cure for the common cycle. That’s OK; when you get right down to cold. As dentists, we can immediately it, poking around in other people’s mouths see the advantage of combining human is hardly a dignified way for grown men and DNA with, say, that of a shark. Of all our women to making a living anyway. various organs, none suffer such a deficit in engineering know-how as the human dentition. Consider the shark, which in our
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