1.

Oral Infectious Diseases

Introduction

Oral infections constitute some of the most common and costly forms of infections in humans. In this regard, dental caries and periodontal diseases occur in nearly 95% of the general public, particularly in the expanding aging sector. Although fluoride and other preventive efforts have led to a dramatic decline in caries, the ability to control the actual infection has been limited. Attempts to block oral infections by preventing colonization of the tooth, epithelium or gingival sulcus by oral pathogens is still largely based on labor-intensive and nonspecific personal hygiene measures. Similarly preventing viral or opportunistic fungal infections of the oral mucosal tissues is a growing challenge due to the increased frequency of compromised individuals with suppressed salivary flow or immune protection due to pharmacological medical treatment of an aging population.

The oral cavity is a complex ecosystem in which a rich and diverse microbiota has evolved. The wide range in pH, Eh, nutrient availability, shedding and non-shedding surfaces, salivary and crevicular fluids select for localized, discrete microbial climax communities which may fluctuate in composition and metabolic activity but reach a kind of homeostasis in balance with the host. Changes in the environment, whether imposed by illness, debility, behavior, diet, or medications disturb the homeostasis and lead to endogenous infections or susceptibility to exogenous infections.

v  Unique Features of Oral Cavity

The mouth is the major portal of microbial contamination at the entrance to the alimentary tract. It is a moist environment through which microorganisms pass to distal sites if they are not able to adhere to or be retained on one of the diverse oral surfaces. The mouth can be contaminated by any infected object it contacts, either intentionally or accidentally. Why particular microorganisms colonize and others pass through as transients is an intriguing question in oral microbial ecology.

The oral cavity is bathed in saliva, a fluid with remarkable properties for protecting the host from microbial infections. About one liter is produced per day from the major glands (parotid, submandibular, sublingual) and minor glands. Antimicrobial activity of saliva is provided by various proteins which protect by different mechanisms. Certain proteins (mucinous and nonmucinous glycoproteins; lysozyme) have microbial agglutinating activity, which would foster the disposal of bacteria by the bathing fluid or competitively block access of bacteria to their natural binding sites on mucosal surfaces or on the teeth. Salivary immunoglobulins, predominantly secretory IgA, recognize and bind surface molecules specifically and provide analogous but acquired protection. Several proteins, such as lysozyme histatins, transferrin, lactoferrin, and lactoperoxidase, have antimicrobial properties in vitro. Saliva also contains buffering systems, such as bicarbonate and low molecular weight peptides, which neutralizes harmful acid end products of microbial metabolism.

Salivary proteins as well as soluble bacterial products, such as glucosyltransferases, serve as bacterial receptors that initiate the formation of the biofilm called dental plaque. Saliva is also the repository for populations of shed microorganisms and their metabolites and enzymes, such as proteinases and sialidases, which can degrade salivary and epithelial surface molecules and affect the colonization of non-oral pathogens. Since saliva has such a protective function, salivary deficiency often leads to opportunistic infections with pathogenic bacteria, fungi, and viruses.

Saliva

Of all the organs in the craniofacial-oral-dental complex, it is perhaps the salivary glands and their remarkable secretory product, saliva, that forge the strongest link between oral and systemic health. Salivary function is extremely sensitive to changes in our general well-being, ranging from subtle effects of over-the-counter cold medications to the devastation of life-threatening disease.

Even the ancients recognized an association between the human condition and saliva, which served as judge and jury in cases of wrongdoing. A suspect was given a mouthful of dry rice. If his anxiety reduced his saliva flow so that he could not swallow it, the verdict was guilty as charged. To this day, "cotton mouth" betrays all of us at some point in our lives, signaling to the world that our nerves have taken control.

Gatekeeper

With its vast antimicrobial arsenal, saliva represents a remarkable evolutionary selective advantage for the host against invading pathogens such as HIV, the fungus Candida albicans, and a host of bacteria associated with oral and systemic diseases. Secretory antibodies, for example, directed against viral pathogens such as poliovirus and cold viruses, as well as the anti-HIV agent SLPI, are found in saliva. Large salivary glycoproteins called mucins appear to have antiviral properties as do cystatins, a family of cysteine-rich proteins that are active against herpes viruses.

Saliva also contains histatins, antifungal proteins that are potent inhibitors of candida, which is normally kept in check at extremely low levels in the mouth. When the oral balance is upset, however, by HIV infection or other immunosuppressive and debilitating disorders, antifungal defenses are overwhelmed and candida flourishes uncontrolled.

Reinforcing saliva's antiviral and antifungal activity are salivary constituents that thwart bacterial attack. These enzymes destroy the opposition by various mechanisms, including degrading bacterial membranes, inhibiting the growth and metabolism of certain bacteria, and disrupting vital bacterial enzyme systems.

Functioning in concert, these and other protective factors in saliva help to maintain the oral environment in optimal working order and restore it to more normal conditions when disturbed.

Immune protection in the oral cavity derives from mucosal and systemic immunity pathways common to most body surfaces, including IgA, IgG and IgM, neutrophils, macrophage, and lymphocytes. Antigens traversing the oral mucosa can stimulate tonsils ringing the oropharynx, as well as regional lymph nodes. Being a major site for mucosal protection, the tissues surrounding the oral cavity can serve as a research model for studying lymphocyte traffic and local antibody synthesis.

The mouth is also unique for being lined with stratified squamous epithelium, which can be keratinized (e.g., tongue dorsum) or nonkeratinized (e.g., gingival crevice). The mucosa presents a unique structure and ecological pressure, as the mitotic rate apparently increases in response to microbial burden. In addition to providing a barrier function, desquamation serves as an innate defense. Epithelia lining the gingival crevice might also act as a source of antimicrobial peptides (defensins) and inflammatory mediators generated in response to periodontal infections.

Certainly the teeth, themselves, represent a unique feature of the human body, being the only mineralized, non-shedding structures that protrude through the mucosa into a contaminated environment. This provides an opportunity for microbial communities to congregate as biofilms on smooth surfaces as well as in stagnant environments like the fissures and interproximal surfaces.

The site of penetration of the teeth through the mucosa provides an anatomically shallow gingival crevice, which may become deeper and inflamed in response to periodontal infections. The pocket is a stagnant environment which supports a highly diverse, mixed microbial community. The environment is highly reduced, an ecological condition that selects for fastidious anaerobes. Due to their metabolism, the environment becomes rather alkaline, which promotes the mineralization of the bacterial masses into calculus, which binds them tenaciously to the dental root surface. The infection causes an increased flow of tissue transudate, crevicular fluid, which is enriched for serum proteins. Polymorphonuclear leukocytes routinely migrate across the junctional and sulcular epithelium into the gingival crevice, in response to host and bacteria chemotactic factors.

Restorative and prosthetic materials provide additional surfaces that are unique to the oral cavity. With the advent and popularity of osseointegrated implant replacements for missing teeth, the surfaces to which salivary proteins and bacteria bind to form biofilms is becoming even more diverse. Since infections of implanted devices present such a challenge in medicine, readily accessible dental implants may serve as a convenient and appropriate in vivo model for testing concepts of prevention of such infections.

Infections Unique to the Oral Cavity

Periodontitis

"Periodontitis" includes a group of inflammatory conditions of infective etiology which lead to loss of tooth support manifested as net resorption of alveolar bone and collagen attachment to the tooth's cementum. Decades of research have identified a mixed but limited consortium of bacterial species, among the dozens to hundreds of species in the subgingival community, as particularly virulent or associated with disease progression. These include Porphyromonas gingivalis, Bacteroides forsythus, Actinobacillus actinomycetemcomitans, Prevotella intermedia, Prevotella nigrecens, Treponema denticola and other Treponema sp., Campylobacter sp., Selenomonas sp., Fusobacterium sp., Peptostreptococcus, and some Streptococcus sp. The inflamed periodontal pocket offers a unique, anaerobic, environment, enriched with host transudates and exudates, which favors the growth and opportunistic emergence of fastidious species which usually comprise a minor proportion of the microbiota of the gingival crevice in health. It is an alkaline environment which favors mineralization of the microbial biofilm to form tenacious calculus, which complicates the clinical management of the infections.

Peri-implantitis

"Peri-implantitis" is a reactive inflammatory condition of the tissues surrounding dental implants in response to bacterial communities which establish in the periimplant sulcus. It is analogous to periodontitis, but the contribution of the chronic inflammation and the bacterial infection to loss of stability and loss of osseointegration, i.e. failure of the implants, is more controversial than the contribution of infection to progression of periodontitis. Implants placed in the mouths of partially edentulous individuals become colonized by periodontal pathogens from reservoirs on the remaining teeth. Failed implants with clinical signs of infection usually yield elevated levels of many of the Gram-negative anaerobes associated with periodontitis, but association of P. gingivalis and A. actinomycetemcomitans with failing implants is less frequent than reported for progressive periodontitis. The soft tissue infection around implants can be treated by the same antimicrobial protocols that are successful in the arrest of periodontitis activity, but reestablishment of osseointegration has not been reported as a consistent outcome. One major difference between periodontitis and peri-implantitis is the lack of cementum and calculus in the latter. Combined with the absence of a periodontal ligament, these may account for distinct pathways of pathogenesis. There is little depth and precision in the published research into the course of peri-implantitis and unique features of such infections. Yet, peri-implantitis has the potential to serve as an interesting and significant model for studying biofilm-associated infections. The major outcome variable can be monitored by survival analysis, and thus peri-implantitis may have a more clearly defined endpoint than that used for monitoring outcomes related to periodontitis.

Dental Caries

Caries is a unique disease in which diet selectively drives shifts in the proportional distribution and metabolic activities among commensal bacteria, such as mutans streptococci (S. mutans and S. sobrinus) and Lactobacillus sp., in dental plaque. In this regard, teeth provide a unique opportunity to study biofilm-related infections confined to mineralized tissue. Periodic availability of fermentable carbohydrates drives an existing biofilm microbiota toward sustained glycolysis and resultant acidogenesis. Dietary sucrose can also be metabolized into polysaccharides that serve as receptors for cariogenic bacteria. The organic acid end products cause subsurface demineralization and then cavitation of the tooth surface. Although industrialized countries have experienced a remarkable reduction in caries incidence in children during the past few decades, the prevalence of children and adults who experience caries on retentive tooth surfaces, including roots, is still more than 90%. Recent evidence suggests cariogenic bacteria are transmitted from mothers to their children during the eruption of primary molars and initial lateral tooth contacts.

Pulpitis/Periapical Periodontitis

Like periodontitis, pulpal and periapical conditions are due to mixed infections most often following a shift in the microbiota toward Gram-negative anaerobes. The most compelling research over the past decade has been the clear demonstration in animals, including primates, that periapical lesions occur only in response to infection and that immunological responses tend to limit rather than exacerbate the extent of the lesions. While these infections are distinct in distribution and precipitating factors from periodontitis, (most follow pulp exposure from deep carious lesions, infected periodontal pockets via accessory canals, or fractures), research into the virulence factors of pulpal and periapical pathogens has relied heavily on advances in periodontal research. There is some complementary work in the area of cytokine biology by one group concentrating on pulpal and periapical infections. The critical mass of biologists studying root canal infections is comparatively very small, and much of the biology done would fall into the arena of applied clinical research.

Opportunistic Mucosal Infections

The mucosal surfaces of the mouth are susceptible to a wide range of fungal and viral infections which are most usually opportunistic relative to the host's immune, salivary flow, or prosthodontic status. These infections are most common at the extremes of the age spectrum except for their occurrence in youths, young adults, and middle aged individuals who are either immunodeficient or chemotherapeutically immunosuppressed. The clinical significance of such infections can range from bothersome to lethal. They can occur as isolated oral infections or become systemically disseminated. They are often the result of suppressed cell-mediated immunity.

Oral candidiasis. There are several clinical manifestations of oral candidiasis, most often evident under conditions in which the host defenses and indigenous bacterial microbiota are unable to suppress the emergence of Candida albicans. This may occur in infants just past their peak passive immune protection from their mothers; in individuals with acquired immunodeficiency, severely reduced salivary flow due to chemo- or radiotherapy for cancer; or in unhygienic denture wearers. Additional species of Candida as well as Histoplasma, Blastomyces, Aspergillus, and Cryptococcus also have the potential to cause oral lesions, often as part of a systemically disseminated condition.

Pathogenesis and treatment of candidiasis is a major thrust in infectious diseases research. There is considerable activity in the areas of adhesion, extracellular enzymes and cellular dimorphism, and their effects on virulence. A gene for regulating dimorphism has recently been cloned. One of the major challenges in mycology is to develop useful antifungal agents. The most common oral agent now in use, fluconazole, is experiencing a rise in resistance among Candida strains. Moreover, immunodeficient and immunosuppressed individuals who take this drug are experiencing more frequent infections with diverse Candida species that are more resistant. Research into the pathogenesis and treatment strategies for oral candidiasis has potential to contribute greatly to knowledge impacting on fungal infections in the gastrointestinal tract and vagina.

Viral infections . Several species of viral pathogens are transmitted by body fluids, including saliva, and can infect cells and cause lesions in the oral cavity. These include minor vesiculo-ulcerative lesions, self-limiting febrile illnesses like mononucleosis, disseminated life-threatening conditions, and even a few types of neoplasms. Many viruses with impact in the oral cavity belong to the Herpes virus group.

Herpes simplex (HSV) 1 causes the majority of cases of oral and pharyngeal infections and is transmitted via saliva. Primary infection is most often subclinical. Herpetic gingivostomatitis is an acute form which is most common in infancy and less frequent with age. It is characterized by painful ulcers accompanied by fever and malaise. Protective immunity is usually acquired, but like most herpes infections, HSV 1 can be reactivated from the latent stage in neural ganglion cells and give rise to clinically bothersome manifestations like "cold sores" and oral vesicular lesions. Immunologically compromised and immunosuppressed individuals are at high risk for severe or potentially lethal recurrent infections. HSV 2 is of genital origin but can cause oral lesions if transmitted by oral-genital contact.

Cytomegalovirus (CMV) also causes clinically significant infections in neonates and immunosuppressed individuals. It can be transmitted by saliva, and the salivary glands are among the organs affected in the disseminated form of infection. CMV is a risk to persons with suppressed cell-mediated immunity following organ transplants. It has also been associated with mixed infections in AIDS patients.

Epstein-Barr Virus (EBV) transmits via infected saliva and infects B lymphocytes. It is associated with clinical cases of infectious mononucleosis, a condition characterized by lymphadenopathy, fever, malaise, oral and pharyngeal ulcers, and splenomegaly. This condition can either be self-limiting, in most cases, or give rise to severe systemic complications. EBV has also been associated with malignancies such as Burkitt's lymphoma, nasopharyngeal carcinoma, and lymphomas in immunocompromised patients. In HIV-infected individuals, EBV is considered the agent which causes the clinical condition hairy leukoplakia which most often manifests on the lateral border of the tongue.

Varicella-Zoster Virus (VZV) is involved in the primary infection chickenpox, which is spread by nasopharyngeal secretions and manifests commonly with oral vesicluar lesions. The virus can remain latent in dorsal root or cranial nerve ganglia and reemerge later in life to cause the very painful condition known as herpes zoster. Lesions often involve the skin and oral mucosa overlying the course of the trigeminal nerve. The infection can be life-threatening in immunosuppressed individuals.

Hepatitis viruses B and C (HBV and HCV) are significant to oral infection research in that they are readily transmitted via contact with infected blood, and thus pose a risk to health-care workers, including dentists and dental hygienists. HBV is also present in saliva. Though there is substantial reduction of risk by immunization with a recombinant hepatitis B vaccine, the virus is used in research as an important target for improving disinfection methods.

Human immunodeficiency virus (HIV), through its global impact on the increased risk of serious opportunistic infections, is a key pathogen which should continue to be the focus of oral infectious diseases research. HIV seropositive individuals can manifest periodontal conditions, candidiasis, and some clinical signs of viral infections as early indicators of conversion to AIDS or they may suffer from an increased frequency of minor oral infections. HIV viral load is detectable in oral tissue by reverse transcriptase-PCR.

v   Unique Infectious Diseases Research Opportunities Using the Oral Cavity As a Model

Ecology . The essence of most problems of infection and immunity in the oral cavity is the imbalance of established homeostasis due to opportunistic emergence of pathogenic species within the mixed microbiota in susceptible hosts. The most advanced disease conditions, for example early onset advanced periodontitis or rampant dental caries, affect persons whose individual characteristics, both biological and behavioral, put them at considerable risk for extreme manifestations of tissue damage in the face of infection with the most virulent oral microorganisms. Oral infections are essentially problems in microbial ecology. Thus the oral cavity provides a unique and accessible group of environments in which to study concepts and principles of the dynamics of mixed microbial communities and their impact on maintenance of health and susceptibility to disease.

There is enormous potential to use the oral cavity to define paradigms for microbial life within mixed communities in vivo. Whether driven by population density, metabolites, or physiologic stress, knowledge of intermicrobial regulatory pathways is just beginning to emerge. The oral environment offers a unique opportunity to study such relationships in models that have both ecological and pathogenic significance, and to study many of them in vivo.

Biofilms . The penetration of tooth surfaces and implants through the mucosa provides a "real life" situation for studying parasitic life in biofilms of significance for health and disease. Several avenues of research that have emerged in the past decade indicate that the physiology of microorganisms growing on a surface or in a dense community on a surface differs from that of microorganisms growing in suspension. Even their antimicrobial sensitivity appears to be altered. Many conceptual, technological, methodological, and applied research advances relevant to biofilms have been advanced through studies of oral microorganisms. Yet, it is only since the recent introduction of genetic methods to study transcriptional regulation that attention has been focused on the underlying mechanisms which account for the observed phenomena of altered physiological properties of bacteria existing in biofilms. Moreover, in terms of pathogenesis of dental disease, especially dental caries, the physical properties of the biofilm, including the polysaccharide matrix as well as its microbial composition, is considered a highly significant determinant of disease progression.

Ready access to biofilms in the oral cavity and decades of experience designing in vivo experiments in humans should provide an opportunity to study principles of density-dependent physiological responses, gene regulation relevant to colonization, and pathogenicity of infections. Some investigative work has been initiated in this topical area, but greater intensity is probably warranted.

Without doubt, the next several decades will see an increased prevalence of dental implants to replace teeth in partially edentulous individuals. Considering the ease with which the superstructure of dental implant prostheses can be removed, a model for studying intact oral biofilms, formed in vivo, over time is feasible. Since implanted medical devices in extraoral tissues are usually beyond ready access, the oral implants offer a unique opportunity for defining principles of preventing and treating biofilms associated with prostheses which penetrate mucosal tissues.

Secretions . A parasitic lifestyle on mucosal or tooth surfaces requires adaptation to avoid disposal by bathing secretions. In the case of saliva, a great deal is already known of the composition and antimicrobial properties, including considerable knowledge of the potential for harnessing secretory immunity as a preventive strategy. Yet, precise knowledge of bacteria-combining domains of most salivary molecules still remains to be studied, even those known to serve as bacterial receptors when absorbed as salivary pellicle constituents on teeth. Although some definition of mucosal pellicles has been advanced in the past decade, little is known of its contribution to epithelial barrier function or if biotechnical enhancement of protective functions of such pellicles is feasible. Similarly, the potential to use saliva as a delivery vehicle for boosted antimicrobial therapy remains to be explored. Therefore, salivary-bacterial interactions in the oral cavity may serve as a model for generating knowledge of the infection protection role of secretions in general.

Opportunistic Infections in the Medically Compromised

The oral cavity is a sensitive site for early onset of infections in a compromised host. This is probably due to its being a common route of contamination and due to its amphipathic microbiota, which harbors potential pathogens held in balance by less pathogenic species. Reduction in salivary flow or reduction in immune competence can lead to serious fungal and viral infections. These often appear as multiple infections simultaneously, either prior to or concomitant with serious systemic involvement. The oral cavity, then, can serve as a target for research into the nature of opportunistic infections in general and certainly as a test site for antiviral and antifungal therapy.

Source of less virulent vectors . The oral cavity provides dozens of indigenous species which evidently colonize humans efficiently and yet induce no deleterious clinical outcomes. Such species may provide a wide array of vectors for studying regulation of single genes or clusters of genes of pathogenic bacteria in vivo. More thought could also be directed to the use of indigenous oral organisms as vaccine carriers in place of the attenuated pathogens which have been investigated in detail.

Thus the oral cavity can be viewed as a primary research target for unique infections such as dental caries, periodontal diseases, infections of mucosa lined with squamous epithelium, and opportunistic infections due to diet, malnutrition, lifestyle habits, immunodeficiency, or immunosuppression. Alternatively, the oral cavity can also be viewed as a primary research target for advancing fundamental understanding of mixed infections, biofilms on natural and implanted non-shedding surfaces, microbial interactions with components of secretions, and innate/acquired mucosal immunity. The study of oral infections is also critical for the long-term maintenance of systemic health, considering the recently emerging data relating oral infectious diseases to cardiovascular disease, stroke, pneumonias, untoward outcomes of reproduction, gastroenteric disorders, and a source of oral viruses with putative significance in carcinogenesis. Therefore, in this age of advancing biotechnology and integration of biological and health sciences, accelerated scholarly research into the nature of oral infections should discover new directions, avenues, and innovations for preventing oral disease and potentially for reducing the morbidity of some major systemic illnesses or conditions.

Prevention and Control of Oral Infectious Diseases

Background

Effective strategies to prevent and control infectious diseases require a basic understanding of the causative agent, the pathogenesis of the disease, and the individuals at risk. Intervention can occur at any of these three points in the natural history of the disease. Attempts to control oral infections have met with limited success. Two of the most common oral infectious diseases, caries and periodontal disease, are among the most common bacterial infections of humans. Although many years of research on these diseases have helped elucidate the pathogens, pathogenesis, and host response, efforts to rationally control these diseases are limited and often infective.

Caries and Periodontitis: The causative organisms and pathogenic mechanisms of both caries and periodontal disease appear to be members of the commensal flora. Under the appropriate environmental conditions, these pathogens increase in numbers and directly exert damaging effects on the oral tissues (e.g., tooth or gingival tissue.) In addition, the host response to the biofilm and to products released by the plaque bacteria, is marked by chronic inflammation, enhanced production of matrix metalloproteinases and other histiolytic enzymes and destruction of the gingival connective tissue and bone surrounding the teeth. Thus, any attempts to prevent and control oral infections, such as caries and periodontitis, must be aimed at selectively blocking the growth of the bacteria, production and release of virulence factors, and, in the case of periodontitis, perpetuation of host inflammation. Unfortunately, the individuals most at risk for these oral infections are still poorly defined. Therapy is directed at removing the infectious agents, and repairing the lesions. Traditional paradigms for restoring carious lesions are being replaced by newer strategies that emphasize disease prevention and conservation of tooth structure. Periodontal diseases are generally treated with scaling and root planning together with adjunctive antimicrobial agents. Advances in periodontal regeneration techniques promise to lead to effective repair and regeneration of gingival connective tissue and supporting alveolar bone.

Viral Infections : Other infections of the oral cavity are relatively rare, affecting a small percentage (less than 5%) of the population. For example, there are a series of viral infections of the mucous membrane that produce disease with a primary acute phase and a secondary recurrent phase. This transmissible infection is caused by herpes simplex virus, usually type 1, and less commonly type 2. Patients develop painful intra- and extra-oral ulcers which are painful with or without regional lymphadenitis, fever, and malaise. The disease is usually self-limiting with healing in 7 to 10 days. Treatment involves relieving symptoms, preventing secondary infection, and the use of systemic acyclovir, especially in immunocompromised patients who are more susceptible to herpes simplex infection. Prevention now is limited to several empirical approaches with unknown efficacy. Varicella zoster can also occur in the oral cavity and represents a reactivation of the latent herpes varicella virus present after initial varicella infection, usually chickenpox. Reactivation is precipitated by factors including thermal, inflammatory, radiologic, or mechanical trauma. Lesions are usually unilateral, following the distribution of nerve branches and dermatome. Therapy with acyclovir is reasonably successful, however, prevention is not presently effective.

Opportunistic microbial infections : Oral opportunistic infections occur in immunosuppressed patients, and patients receiving antineoplastic agents and radiation therapy. These may be caused by overgrowth of opportunistic oral organisms which infect ulcerated areas that chemotherapeutic agents have destroyed. Treatment includes the use of chlorhexidine gluconate mouthrinse which helps control the infection. Other treatment is directed to providing comfort. Candidiasis also occurs in the oral cavity and is caused by Candida albicans, a yeast-like fungus. C. albicans is an opportunistic organism which tends to proliferate with the use of broad spectrum antibiotics, corticosteroids, medicines that reduce salivary output, and cytotoxic agents. Xerostomia, diabetes mellitus, poor oral hygiene, prosthetic oral appliances, and suppression of the immune system, e.g., as occurs with HIV infection, are often predisposing conditions for development of candidiasis. Candidiasis may appear as pseudomembranous, atrophic erythomatus, or in chronic hyperplastic forms. Disinfection of all infected oral surfaces and prostheses with antifungal agents such as nystatin ointment or ketoconazole creams are effective. Prevention of candidiasis is presently not effective.

Emerging infectious diseases with oral manifestations : Many infectious diseases have oral manifestations, including actinomycoses; necrotizing ulcerative gingivitis; hand, foot, and mouth disease; leprosy; mycoses; NOMA and oral infections associated with gonorrhea, syphilis, tuberculosis, HIV infections, papovaviridae infections. Management of these infections is accomplished through topical therapy as well as management of any underlying systemic condition. Prevention is not possible with present knowledge.

Efforts to control infectious diseases have generally targeted the pathogen, the mechanisms of pathogenesis, or the host. These include the following approaches:

Cleanliness and Physical Removal of Pathogenic Bacteria

Sanitation is still the most effective way to prevent many types of transmissible diseases. The principles of sanitation are used daily by the general public (e.g., hand washing) and clinicians (e.g., sterilization of surgical instruments). In the oral cavity, complete removal of the bacterial flora is impractical and, since the oral flora protects against serious infections, undesirable. A certain level of oral hygiene is possible through brushing, flossing and professional care, and reduces the buildup of dental biofilms (i.e., plaque) associated with malodor, caries and gingivitis/periodontitis. Oral hygiene may not be effective in preventing infections caused by viruses and fungi. Since oral pathogens are frequently found in normal "healthy" oral biofilms, more information is needed on what is an acceptable level of pathogens in plaque. 

Block Transmission/Acquisition of Pathogens

This approach is closely associated with cleanliness and sanitation. Examples include the use of masks, gloves, and condoms to prevent the spread of the pathogen (e.g., hepatitis viruses and HIV). Recent studies indicate that oral bacteria are transmitted between spouses, and from parents to children. These data suggest methods to prevent transmission of the oral bacteria may be one strategy for preventing oral infectious diseases. 

Physical Barriers Between Host and Pathogen

Dental sealants have proved to be highly effective in preventing pit and fissure dental caries, particularly when provided to patients at high risk for dental caries, i.e., previous caries history, high salivary mutans streptococci levels, inadequate oral hygiene, deficient fluoride exposure, low socioeconomic status, xerostomia and familial caries patterns. 

Control Environment Conditions That Favor Virulence

Reduced intake of processed sugars to reduce caries and the elimination of periodontal pockets that favor growth of gram negative anaerobic bacteria are examples of this approach. 

Early Detection

This approach assumes that the pathogen cannot be completely blocked and pathogenesis will inevitably occur. Early diagnosis of the onset of the disease can limit damage to the host tissues. In oral diseases, research on identifying the precavitation stage for caries, and biomarkers for periodontititis are examples of this approach. 

Biological Modifiers

Research on disease pathogenesis has produced a wealth of information on host biological molecules (e.g., cytokines and proteinases) that are critical to the diseases process. Parallel studies in protein chemistry and immunology have revealed inhibitors and enhancers of these molecules. Intervention studies using biological response modifiers, such as interleukin-1 receptor antagonist and matrix metalloproteinase inhibitors, show promise for this approach.

Antibiotics/Antimicrobial/Chemotherapy

In infectious disease medicine, the most rational approach to prevention and control of the diseases is to eliminate the pathogen or reduce the number of pathogen organisms to the point that the host defenses can easily block infection. However, this paradigm for disease control is not completely acceptable for oral infections, in which a normal flora is desirable and the microbial pathogen is often a member of the normal "healthy" flora. Fluoride treatments have been used to strengthen the teeth against acid demineralization and may also have antimicrobial effects on cariogenic bacteria. Additional research is underway on antimicrobial and anti-biofilm approaches to reducing caries.

Chlorhexidine and iodine solutions are examples of antimicrobial approaches to prevention of caries and gingivitis/periodontitis. Local and systemic antibiotics are particularly useful in treating residual infections with subgingival microflora. Systemic antibiotics show promise in treating A. actinomycetemcomitans-related infections and some P. gingivalis-associated forms of periodontitis where the organism invades the tissue and is inaccessible to normal host defenses and mechanical removal by the clinician.

Vaccines

Since the demonstration by Jenner in 1776 of active protection against smallpox, vaccination has been shown to be one of the safest and most cost-effective ways to prevent infectious diseases. Interestingly, more deaths are prevented by vaccines than by antibiotics. With almost two hundred years of empirical and experimental research on the immune system, much is now known about the stimulation and functioning of the host immune system. These studies have resulted in some remarkable successes: deaths due to diphtheria, tetanus, whooping cough, have dropped sharply; vaccinia (smallpox) was eradicated from the world in 1979; and polio was eradicated from the Americas in 1994. Public health officials expect polio to be totally eradicated in 2000. Other viruses considered reasonable targets for elimination are measles and rubella. Vaccination against meningococcal meningitis may also be worldwide within the next few decades. It should be emphasized that approximately one third of world deaths are from infection; however approximately one third of these could be prevented by complete use of existing vaccines.

Research to reduce dental caries and periodontitis by vaccination is underway and shows some promise for success. Vaccination with various antigens of S. mutans, including peptide vaccines and glucosyltransferase, successfully protects rodents and primates from dental caries. Vaccines to bacteria associated with periodontitis, particularly Porphyromonas gingivalis, may be useful in preventing the adult forms of periodontitis. Vaccines to boost the host innate immune system (e.g., stimulation of neutrophils, release of lactoferrin or defensin peptides), are being tested and show some promise.

Education/Behavior Modification

Behavior, such as smoking, diet, brushing/flossing, plays a major role in the development of the common forms of oral infectious diseases. A logical assumption is that a change in disease-promoting behavior would reduce the risk of disease and thus lead to oral health. Efforts to educate the public regarding good oral hygiene practices and change behaviors have met with mixed success. Nevertheless, this approach holds great promise and deserves increased attention.

Research Needs, Opportunities and Recommendations

Prevention and Control of Oral Infectious Diseases

 

Recommendation

Need

Opportunities

Develop fast, economical and accurate ways to diagnose oral infections. Biomarkers for oral infections could accelerate epidemiology research as well as studies on pathogenesis. Support the identification of biomarkers and development of corresponding diagnostic assays of oral infectious diseases.

 

Develop new ways to block the pathogenesis of oral infections. Tissue destruction associated with oral infection and chronic inflammation could be reduced. Support research to develop specific inhibitors of microbial proteases and other potential virulence factors produced by oral pathogens.

Investigate probiotic approaches (i.e., whole bacteria replacement therapy) to eliminate pathogenic members of the microbiota.

Continue studies of species-specific antimicrobial molecules (e.g., bacteriocins) that influence microbial colonization and growth. 

Gain more knowledge on all forms of immunity, including innate immunity. This is an opportunity to learn more about how the host protects itself from oral infections. Characterize innate antimicrobial factors found in saliva and produced by epithelial cells.  

Support basic and clinical research on mucosal immunity and oral tolerance. Fully characterize human tonsils, adenoids, and associated tissues as possible mucosal inductive sites.

New vaccines, biological modifiers and therapeutic agents are needed to combat oral infectious diseases.  

In particular, ways to enhance the immune response to biofilms are needed.

Traditionally, vaccines have been a successful way to prevent infectious diseases.

 

Support research on the development of vaccines for oral infections. For example, identify virulence-associated antigens and develop better adjuvants for mucosal immune responses.  

Study the effect of biofilms on the activity of antibodies and other host-derived antimicrobial molecules.

Reduce or eliminate the effects of oral infections on systemic health. Recent evidence suggests a link between oral infections and systemic diseases or conditions. These studies could help to elucidate the link between the oral cavity and the rest of the body. Examine the association of oral infection and hematogenous spread to the etiology and pathogenesis of systemic diseases.
In vivo models are needed to evaluate vaccines and the role of oral infections in systemic diseases. Animal experimentation continues to be useful approach to translate basic science into clinical practice. Identify better animal models to test the efficacy of potential vaccines for oral infectious diseases, as well as intervention studies to assess the relationship between oral infections and systemic disease.

Source: Report from the NIDR Infectious Diseases Planning Workshop Held Nov. 10-12, 1997, Bethesda, MD

 

2.

First Encounters: Transmission 

of Infectious Oral Diseases

From Mother to Child

 

It is an interesting paradox that a mother can expose an infant to infectious microbes through intimate contact, yet she can also transfer a number of diverse antibodies through her breast milk that confer immunity against some of the very microbes that infected her during pregnancy. Furthermore, the mother's oral health can be a major determinant of or risk factor in the health of the developing fetus or newborn infant.

Recently, a number of new basic, translational and patient-oriented research studies have identified a potentially remarkable association between maternal transmission of infectious oral microbes from mother to fetus during pregnancy, during the birth process and from mother to child after birth. Understanding these first encounters is potentially very significant in trying to understand the etiology and pathogenesis of many opportunistic oral infections.

The Link Between Oral Microbes and Low Birth Weight

The human fetus, the newborn infant and the young child are all exposed to infectious microbes and are at increasing risk of developing infectious diseases. Ironically, most of the microbes to which we are exposed are transmitted from our primary caregiver, usually our mother. The presence of disease-causing microbes_viruses, bacteria, yeast and parasites _can actually influence the term length of a pregnancy, the birth weight and development of the newborn, and even the ability of newborns to thrive in the world they enter. Transient or prolonged viremia or bacteremia may induce extreme maternal or fetal tissue responses and result in serious disease conditions.

Just as the state or condition of pregnancy can affect the mother adversely, it now appears that a mother's poor oral health can adversely affect the health of the fetus and newborn. Low birth weight, or LBW, of less than 2,500 grams or 1 pound is a major worldwide public health problem. For example, more than 6 percent of the nearly 4 million infants born in the United States in 1995 were LBW. LBW infants confront a significant survival disadvantage that accounts for almost one half of our nation's infant mortality, as well as a number of congenital malformations and disorders, including respiratory distress syndrome and neurodevelopmental, cardiovascular and craniofacial malformations.

Now there is a new clue to the origins of LBW. Recent studies from the University of North Carolina, Chapel Hill, and the University of Alabama at Birmingham have indicated that poor maternal periodontal health can increase the infant's potential for LBW and possibly for preterm or premature birth (at less than 37 weeks' gestation). In the North Carolina study, the scientific research team discovered that women with periodontal disease were seven times more likely to deliver LBW babies prematurely.

A larger case-controlled study conducted at the University of Alabama at Birmingham (reported by A. Dasanayake) used extensive data analyses to determine whether periodontal health was an independent factor influencing LBW. Compared with control subjects and with a low probability of natural occurrence, the number of healthy sextants (in other words, the division of each arch dentition into bicuspid, molar and cuspid regions) in the mouths of mothers with LBW babies was significantly lower (0.4 vs. 1.1, P = .001). The numbers with bleeding gingiva (5.6 vs. 4.9, P = .001) and dental calculus (4.0 vs. 3.2, P = .01) were significantly higher. Comparing the ratio of the probability of the occurrence of LBW to nonoccurrence of LBW under these conditions (odds ratio, or OR) within a 95 percent confidence limit, or CL, the scientific team discovered that mothers with more healthy sextants (OR= 0.3, 95 percent CL = 0.12 to 0.72) had a statistically lower risk of giving birth to LBW babies. These studies provide a potentially significant association between LBW and a mother's poor periodontal health as an independent risk factor.

Many other factors are also involved in both premature and low birth weight, or PLBW, babies. Gram-negative fusiform bacteria, and other bacterial infections in both the genitourinary tract and the mouth, may either release bacterial endotoxins or induce a maternal and/or fetal tissue response to these opportunistic infections, thereby producing PLBW infants. The gram-negative anaerobic infection is postulated to provide a reservoir of lipopolysaccharides that can trigger maternal and/or fetal tissue-derived cytokines, mediators of inflammation such as interleukin-1 [(beta) (IL-1 (beta)), tumor necrosis factor alpha (TNF-alpha) and prostaglandin E2 (PGE2). Each of these maternal or fetal tissue-derived molecules has been found to be capable of inducing preterm labor.

First Encounters: Transmission of Infectious Oral Diseases From Mother to Child

It becomes reasonable to surmise that maternal transmission of oral microbes initiated through a transient bacteremia during the third trimester of pregnancy could invoke upper and lower genitourinary tissue release of cytokines and prostaglandins, which subsequently induce premature development and preterm labor. The anatomical pathways may include transit through the vascular system of the placenta, through the amniotic fluid and across the gut endothelium (Figure).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure. Suggested anatomical pathways for maternal transmission of oral microbes or their tissue-derived inflammatory mediators during pregnancy.
Placenta



Oral Cavity
Oral Infectious Diseases

v Transmitting Infection, Transferring Immunity

The newborn human infant draws its first breath into a mouth that is usually devoid of microbes. Within minutes to hours, the newborn mouth is colonized with viruses, bacteria, yeast and protozoa that may remain in his or her mouth until death. The microbial oral flora, most of which are considered beneficial, are transmitted into the baby's mouth from a variety of environmental sources: saliva droplets in the air, a breast, a nipple, a finger or even breast milk.

Breast milk, in fact, is important in supplying the infant with immunological components, or humoral antibodies. Some of these factors are selective factors that can affect the intestinal microflora by enhancement of the growth of desirable bacteria and by nonspecific inhibition of some microbes through the biological activity of lysozyme, lactoferrin, interferon and leukocytes (macrophages; thymus-derived Iymphocytes, or T cells; bone marrow-derived Iymphocytes, or B cells; and granulocytes).

Antibodies produced by the mother to various challenges from the environment are known to be transmitted from the mother to the developing fetus through the placenta. The concentrations of the diverse antibodies that confer passive immunity to the newborn baby are even higher in the colostrum (first milk) at the initiation of maternal nursing of the baby (Box, "Targets of Colostrum/Breast Milk Secretory IgA"). Importantly, all classes of immunoglobulins, or Ig _including IgG, IgM, IgE and even high levels of secretory IgA, or sIgA_are found in varying amounts in the human maternal colostrum. Secretory IgA attaches to the infant mucosal epithelium and prevents the attachment of specific infectious agents. Levels of sIgA in maternal milk have been isolated, characterized and found to be specific against certain infectious pathogens such as enteric and respiratory viral and bacterial microbes.

It has been learned that the concentration of this kind of passive immunity transferred from mother to infant can increase in response to maternal exposure to specific antigens. Thus, the infant is provided with environmentally specific antibodies in the colostrum/ breast milk that provide the baby with a level of protection during the first 6 months of immunological system development and maturity (Table).

First Encounters: Transmission of Infectious Oral Diseases From Mother to Child

Targets of Colostrum/Breast Milk Secretory IGA

Bacteria Viruses

Escherichia coli Cytomegalovirus

Pneumococci Poliovirus

Haemophilus influenzae Respiratory syncytial virus

Klebsiella pneumoniae Rotavirus

Rubella

Proteins Eukaryotic Parasites

Toxins Chlamydia trachomatis

Virulence factors Giardia lamblia

E. coli toxin

Lipopolysaccharide

Vibrio cholerae

Fungi (Yeast)

Candida albicans

Oral Infectious Diseases

Nonantibody Defenses in Colostrum/Breast Milk

Agent Effect

Nonantibody Antibacterial Factors

GM l-like gangliosides Inhibit Escherichia coli and Vibrio cholerae enterotoxin

Oligosaccharide growth factor for Lactobacillus growth creates acid gut

Lactobacillus bifidus conditions that suppress harmful organisms

Fatty acids and monoglycerides Activation of lipids with a lipase gives these

products, which act on gram-positive bacteria

Lactoferrin Binds Fe+++ and inhibits bacterial growth

Lysozyrne Lyses bacteria by cleaving N-acetyl muraminc acid

Lactoperoxidase Inhibits growth/kills bacteria

Peroxide and ascorbate Inhibits growth/kills bacteria

Nonantibody Antiviral Factors

Alpha-2 macroglobulinlike protein Inhibits influenza and parainfluenza

hemagglutinin activity

Nonimmunoglobulin factor Inhibits rotavirus infections

Fatty acids (polyunsaturated) Inhibit envelope viruses

Interferon-a Inhibits respiratory syncytial virus infection

Anti Inflammatory Factors

Lactoferrin Inhibits complement

Lysozyme Inhibits chemotoxins

Catalase Degrades H202

Lipid and nonlipid factors Inhibit leukocytes

Prostaglandin E Inhibits T cells

Pregnancy-associated glycoprotein Inhibits T cells

 

First Encounters: Transmission of Infectious Oral Diseases From Mother to Child

v The Lifelong Growth of Oral Microbes

In the human mouth, there are often more microorganisms than there are people in the entire world. Some of these opportunistic microorganisms prefer the cheek for habitation; others prefer the back of the tongue in an anaerobic crevice; still others enjoy the wet, oxygen-deprived area between the tooth surface and the periodontal tissues. Of course, the microbial ecological conditions in the mouth are extremely sensitive to the challenges that confront the human throughout the lifespan and, therefore, can often change precipitously. From birth to death, the mouth's continued exposure to opportunistic infectious pathogens is in balance with host immunity; the balance between these profoundly important processes often serves as a mirror for the detection of not only oral pathology but major systemic diseases.

The growth of these microbes in the infant's mouth follows a pattern of microbial ecological succession. A few pioneer species settle and nest, creating a habitat that is friendly to other species, which then move in to join the microbial ecosystem. When the first deciduous teeth begin to erupt into the mouth, another group of microbes_including the dental caries-causing Streptococcus mutans_join the microbial ecosystem and take up residence. When the composition of saliva changes during puberty, yet another group of microbes immigrates and flourishes in the ecosystem. Finally, the average adult mouth contains a complex group of organisms, consisting of more than 400 different microbial species (mostly bacteria) and each with its own preferred habitat. In a so- called "clean mouth," there can be 1,000 to 100,000 bacteria attached to each tooth surface.

 

 

 

 

 

 

 

 

Oral Infectious Diseases

v All in the Family

Epidemiologists have published many studies determining the transmission of organisms within families and larger communities and populations. Some of the best documented studies involving the mouth describe the transmission of microbes associated with the etiology of dental caries and periodontal diseases and, most recently, the transmission of AIDS from mother to child.

Communicating S. mutans. In 1959, NIDR-sponsored research scientists isolated the bacterial species S. mutans, now considered the major etiological agent in human dental caries. S. mutans consists of a number of different subspecies or different strains that vary in growth characteristics and in the pathology they produce. Because the presence of teeth or other nondesquamating surfaces is a prerequisite for stable colonization of the microbe, infants acquire these bacteria during deciduous tooth eruption in their sixth month of life.

Published reports have suggested that children acquire S. mutans from their mothers, through frequent and intimate contact, in the first two years of life when the bacteria are initially transferred. Scientists in the dental school at the University of Alabama in Birmingham recently reported the results of a longitudinal study of 34 mother-infant pairs and seven fathers, who shared a specific household. Their study provided important documentation supporting the hypothesis that maternal transmission of S. mutans is critical to the formation of the microbial ecosystem in the newborn infant's mouth. They determined individual strains of S. mutans using genotyping or DNA fingerprinting. The sensitivity and specificity of this technology provided the scientific team with the necessary confidence to identify and characterize the oral bacteria of mothers and their infants from birth to approximately 3 years of age, with sampling at 3-month intervals.

The genotypes of S. mutans isolated from the infants at the time of initial acquisition were homologous to those isolated from the mother's saliva in 71 percent of the mother- infant pairs. The fidelity between strains of S. mutans in mothers and their female infants (88 percent), in contrast to those isolated from the male infants (55 percent), indicated that in the group studied the conservation of S. mutans within the mother-infant pairs was sex­specific. In no instance did they determine homology of genotype between father and infant, or between fathers and mothers, further supporting the hypothesis that transmission and acquisition of S. mutans follows maternal lines very early in infancy and early childhood.

The lack of maternal-paternal sharing of microbial genotypes may indicate that S. mutans is difficult to transmit outside of the theoretical "window of infectivity" period,
First Encounters: Transmission of Infectious Oral Diseases From Mother to Child
which occurs during childhood at a median age of 26 months. It is also possible that mothers transfer to their infants not only maternal immunoglobulins via the placenta and colostrum, but also a complementary set of indigenous microbes capable of coexisting with these maternally derived or directed immunity factors. If the passively acquired maternal immunoglobulins play a role in determining which strains of microbes can colonize the infant, they also may function in excluding the father's microbial strains. Additional research is required to substantiate these interpretations.

Communicating periodontal pathogens . Another area of active molecular epidemiological investigations involves the transmission of the periodontal pathogens between members of extended families. Because of the prevalence of periodontitis in the adult population, this disease and its transmission within the population have been extensively studied. Molecular tools such as genetic fingerprinting technology have been applied to the identification and characterization of anaerobic bacteria_the microbes that live without oxygen and that are associated with the etiology of periodontal diseases. Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Treponema denticola, Bacteroides forsythus and Prevotella intermedia are some of the specific bacteria assumed to be engaged in the etiology of periodontal diseases.

A moderate form of periodontitis occurs in 40 percent of the population older than 12 years of age, and moderate periodontal destruction has been reported in 80 percent of the population older than 65 years of age. A recent collaborative study between faculty in the schools of medicine and dentistry at The Ohio State University linked P. gingivalis with clinical indicators of periodontal disease such as increased periodontal pocket depth and increased tooth attachment loss. The study was designed to better identify the risk factors associated with the varying disease process and thus facilitate the eventual development of preventive strategies.

The Ohio State investigators used the polymerase chain reaction, or PCR, a procedure that allows amplification and sequencing of DNA between primers. PCR is specific and sensitive enough to detect the very low levels of P. gingivalis found in children but has the efficiency needed to analyze a large number of samples with a high confidence level. They determined the colonization status of 564 members of 104 multigenerational families and compared it with concordance in the general American population. Statistical analyses of the concordance in each entire family were obtained; a core unit was considered to consist of three generations and included the oldest child, both parents and a grandparent. The concordance within entire families and for spouses, children and their mothers, children and their fathers, adults and their mothers, and siblings was studied and compared with the concordance that would be expected if P. gingivalis was randomly distributed in the entire human population studied.

Oral Infectious Diseases
The researchers discovered that contact with an infected family member substantially increased the relative risk of colonization of these intrafamilial pairs. Microbial colonization between spouses suggests that although P. gingivalis is most commonly acquired during childhood, it may also be acquired later in life. Importantly, the results support the hypothesis that transmission of P. gingivalis, while common within families (especially between mother or primary caregiver and child), would seem to be rather unusual outside the immediate family.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

First Encounters: Transmission of Infectious Oral Diseases From Mother to Child

v Conclusion: The Prospect Ahead

Studies on maternal transmission of oral microbial infections indicate the requirement for close contact and sharing of microorganisms, and new approaches to preventing and treating diseases of the mouth are being investigated. One area of interest involves the prevention of the maternal transfer of infectious bacteria to the child during the so- called window of infectivity. One potentially important question to consider is the following: If women who carry very infectious strains of S. mutans have their teeth, gingiva and oral mucosa rigorously treated with antiseptics or antibiotics and then their tooth surfaces varnished during the critical time of their child's susceptibility, will the children avoid contracting the infectious microbes from their mothers? Studies focusing on this question are now under way.

The development of vaccines against the most infectious oral bacteria, such as S. mutans, has long been discussed but is now receiving renewed effort. Further study of the approximately 60 proteins found in saliva could disclose additional components like the antibacterial lysozyme or an antiviral component that is active against components of the microbial oral flora. Research is also being conducted that surveys many different infectious oral bacteria in hopes of finding one that produces an antibiotic-like molecule active against opportunistic infectious bacteria. Yet other research teams are studying how to block or inhibit bacteria in producing their unique adhesives, which aid in attachment and eventual colonization, thus producing biofilms on tooth or even implant surfaces. In the next 5 or 10 years, we should expect that such NIDR- supported scientific research will make important clinical progress toward understanding and controlling the transmission of infectious microbes into and through the mouth.

 

 

 

 

 

 

 

 

 

Oral Infectious Diseases

For Additional Information

Resources

Chaouat G, ed. The immunology of the fetus. Boca Raton, Fla.: CRC Press, Inc.; 1990.

Dasanayake AP. Pregnant women's poor health and low birth weight. Presented at Sunstar Chapel Hill Symposium, Periodontal Disease and Human Health; March 24-25, 1997; Chapel Hill, N.C.: University of North Carolina, Chapel Hill.

Hauth JC, et al. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis. N Engl J Med 1995;333 (26): 1732- 6.

Li Y, Caufield PW. The fidelity of initial acquisition of mutans streptococci by infants from their mothers. J Dent Res 1995;74(2):681- 5.

Offenbach S, et al. Periodontal infection as a possible risk factor for preterm low birth weight. J Periodontol 1996;67(10) (Supplement):1103 -13.

Tuite-McDonnell M, et al. Concordance of Porphyromonas gingivalis colonization in families. J Clin Microbiol 1997; 35(2):455-61.

 

Organizations

National Institute of Allergy and Infectious Diseases

Office of Communications

National Institutes of Health

Bethesda, MD. 20892

(301) 496-5717

National Institute of Child Health and Human Development

Public Information and Communication Branch

National Institutes of Health

Bethesda, MD 20892

(301) 496-5133

National Institute of Dental Research

Information office

National Institute of Health

Bethesda, MD 20892

(301) 496-4261

 

 

3.

Oral Opportunistic Infections:

Link to Systemic Diseases

 

The periodontium, comprised of the gingiva, bone and other supporting tissues that anchor the teeth, plays a key role in the interplay between oral health and systemic disease. Infection in these tissues, primarily by gram-negative anaerobic bacteria, can initiate a series of inflammatory and immunologic changes leading to the destruction of connective tissue and bone. Long considered a localized infection, periodontal diseases are now linked to a variety of conditions with systemic implications.

 

Chronic Degenerative Diseases

Periodontitis, advanced infection of the periodontium that often causes tooth mobility and tooth loss, appears to share genetically determined risk factors with several other chronic degenerative diseases such as ulcerative colitis, juvenile arthritis, and systemic lupus erythematosus. Recent research points to specific genetic markers associated with increased production of the pro-inflammatory cytokines interleukin-1 and TNF

as strong indicators of susceptibility to severe periodontitis. This recent finding could lead to early identification of people at most risk for severe periodontal disease and initiation of appropriate therapeutic interventions.

 

Diabetes Mellitus

The destructive inflammatory processes that define periodontal disease are closely intertwined with diabetes. Persons with non-insulin-dependent diabetes mellitus (NIDDM) are three times more likely to develop periodontal disease than nondiabetic individuals. Add smoking to the mix, and the chances of developing periodontitis with loss of tooth-supporting bone are 20 times higher. An increased risk for destructive periodontal disease also holds for persons with insulin-dependent diabetes mellitus (IDDM).

Oral Infectious Diseases
Much of what is known about the periodontal complications of diabetes has been learned from the Pima Indians of Arizona, who have the highest reported rates of NIDDM in the world. NIDCR-supported research in the Pima community has shown that periodontal infection is more prevalent, more severe, and develops at an earlier age in this population than in nondiabetic persons. As diabetes increases in severity, the rate at which vital tooth-anchoring bone is lost accelerates. Pima Indians with NIDDM are 15 times more likely to be edentulous than those without diabetes.

Now there is evidence that a history of chronic periodontal disease can disrupt diabetic control, suggesting that periodontal infections may have systemic repercussions. The exact nature of this complex relationship is not clear. It is likely, however, that increased genetic susceptibility to infection, impaired host response, and the excessive production of collagenase found in periodontal disease may all play important roles in NIDDM. Similarities in the etiology of periodontal and other complications of diabetes have also emerged.

Studies have shown, for example, that hyperglycemia is the common basis for diabetic complications in the eyes, kidneys and nerves. Glucose in high concentrations attaches to other molecules, stimulating chemical reactions that produce advanced glycosylation end products. These large molecules accumulate in tissues, causing damage and disrupting normal function. Scientists suspect that these cellular reactions figure as well in the tissue destruction seen in periodontal disease.

 

Investigators are also examining the interplay between periodontal infection and metabolic control. Acute viral and bacterial infections are known to induce insulin resistance, which disrupts blood glucose control. Factors including stress, fever, catabolism, and elevated levels of hormones antagonistic to insulin such as growth hormone, cortisol, and glucagon likely play a role in the development of insulin resistance during infection.

It is possible, then, that chronic gram-negative infections with persistent production of bacterial toxins, like periodontal disease, could have the same deleterious effect. If so, would elimination or control of periodontal infection improve metabolic control of diabetes?

To explore this hypothesis, researchers designed a treatment protocol specifically to manage diabetes-associated periodontitis in a group of Pima Indians with poorly con


Oral Opportunistic Infections: Link to Systemic Diseases
trolled NIDDM. They found that debridement (deep cleaning to remove hardened plaque below the surface of the gingiva), combined with an antimicrobial solution and a 2-week regimen of the antibiotic doxycycline_chosen for its anticollagenase activity _resulted in significant short-term improvement in the concentration of hemoglobin A1c, a measure of average blood glucose levels over 3 months.

A control group receiving only debridement did not share the gains in periodontal health, improved hemoglobin A1c levels, and reduced hyperglycemia that the treatment group experienced.

These findings offer evidence that chronic infections such as periodontal disease worsen glycemic control and that eliminating these infections could enhance metabolic control in persons with diabetes. Additional large-scale studies are needed to further evaluate the effects of treating periodontitis on blood glucose levels. Future research should also examine, in other populations, the relationship between severe periodontal disease and poor glycemic control that has been evidenced in the Pima Indian community.

While work proceeds on the oral complications of diabetes, other studies are exploring the molecular pathogenesis of the disease. NIDCR researchers have identified an important marker protein, IA-2ß, for insulin-dependent diabetes mellitus, an autoimmune disorder which affects close to one million people in the United States alone.

Destructive autoantibodies, which attack the body's own insulin-producing beta cells, are the basis of the existing, labor-intensive diagnostic test for IDDM. However, the recent identification of target proteins in the pancreas, such as IA-2ß, that react with these autoantibodies makes it possible to develop a rapid and effective test to screen large populations for IDDM.

IA2ß, when used in combination with two other known marker proteins, IA-2 and GAD65, recognized autoantibodies in 90 percent of persons with IDDM. The presence of autoantibodies to the marker proteins in otherwise normal individuals was also highly predictive in identifying those at risk of developing the disease. In addition, these proteins are candidates for immune tolerance studies, which attempt to prevent the development of destructive autoantibodies and subsequent IDDM.

The investigators are hopeful that their demonstration of the proteins as major targets of the autoimmune attack will aid in uncovering the actual cause of the disease process.

 

Oral Infectious Diseases

Heart Disease

A number of studies have shown that people with periodontitis are more likely to develop cardiovascular disease than individuals without periodontal infection. One such study suggests that the risk of fatal heart disease doubles for persons with severe periodontal disease.

Part of the link between these two diseases may be discovered through novel investigations of the opportunistic, infectious bacteria that colonize the mouth. Scientists theorize that certain types of these bacteria, which form biofilms and cause periodontal disease, also activate white blood cells in the body to release pro-inflammatory mediators that may contribute to heart disease and stroke.

To explore the underlying inflammatory responses common to both diseases, NIDCR grantees are examining periodontal disease measures (pocket depth where gingival tissues have pulled away from tooth surfaces and where there is loss of tissue) and biological responses in 14,000 people enrolled in an extensive study of heart disease sponsored by the National Heart, Lung and Blood Institute. Scientists will also analyze gingival crevicular fluid constituents that may contain pro-inflammatory mediators associated with heart disease, as well as blood samples to identify antibodies to periodontal pathogens.

The research team will compare these measures with clinical indicators of heart disease, ultrasound measures of carotid vessel thickening, and the occurrence of heart attacks, stroke, and death to determine if there is a correlation. Should the link between oral disease and heart disease be firmly established, future studies will focus on identifying the specific biological factors involved and transferring this knowledge to prevent disease.

 

 

 

 

 

 

Oral Opportunistic Infections: Link to Systemic Diseases

Preterm Low Birth Weight Babies

Emerging evidence may link severe periodontal disease in pregnant women to a sevenfold increase in the risk of delivering preterm low birth weight babies. NIDCR-supported researchers estimate that as many as 18 percent of the 250,000 premature low-weight infants born in the United States each year may be attributed to infectious oral disease.

The emotional, social, and economic costs associated with these small babies are staggering. Hospital costs alone surpass $5 billion annually. When costs to society in terms of suffering and managing long-term disabilities often associated with prematurity are considered, this figure escalates dramatically.

In a recent study, mothers of preterm low-weight newborns were found to have significantly more severe periodontal disease than did mothers of fullterm, normal weight babies. Investigators believe that the molecular pathogenesis may be similar to that characterized for other maternal, bacterial, opportunistic infections, such as genitourinary infections, that are associated with low-weight preterm births.

Scientists theorize that oral pathogens release toxins that reach the human placenta via the mother's blood circulation and interfere with fetal growth and development, which has been shown to occur in animal studies. The oral infection also prompts accelerated production of inflammatory mediators PGE2 and TNF that normally build to a threshold level throughout pregnancy, then cue the onset of labor. Instead, the elevated levels of these inflammatory mediators trigger premature delivery.

Taking into account all the known risk factors for premature birth, the researchers could identify no other reason for the relationship they had found between severe periodontal disease and preterm low-weight births. Additional research is needed to confirm this intriguing finding and to determine if treating and preventing periodontal disease would reduce the incidence of these high risk births.



 

4.

Acquired Immunodeficiency Syndrome

 

 

The oral effects of systemic disease are by no means limited only to the periodontium. All of the tissues in the oral cavity are fair game for a variety of insults, either directly from infection, or indirectly as part of the systemic disease process. There is perhaps no better illustration of the involvement of oral tissues in systemic disease than the oral manifestations of AIDS.

 

v Oral Lesions

Since the acquired immune deficiency syndrome was first recognized in the United States in 1981, the mouth has provided a remarkable laboratory for the study of this emerging infectious disease that targets the immune system for destruction. The first clinical reports of this syndrome indicated that lesions in the oral cavity were common and often occurred early in the course of the disease. Oral health scientists initiated not only clinical studies to define the oral signs and symptoms, but also a basic research strategy to understand the molecular virology and immunology of AIDS.

Studies of the natural history and epidemiology of HIV/AIDS documented that the fungal disease oral candidiasis is the most common opportunistic infection seen in HIV-infected patients, followed by a second oral lesion termed hairy leukoplakia. A whitish lesion frequently seen on the side of the tongue, hairy leukoplakia is strongly associated with the Epstein-Barr virus and is a reliable predictor of AIDS.

A comparison of HIV-positive patients with similar CD4 counts (a measure of the body's immune response) revealed that those with oral candidiasis or hairy leukoplakia tend to develop major opportunistic infections or progress to AIDS more rapidly than patients without these lesions. Also, the odds of developing oral candidiasis increase as the CD4 counts of infection-fighting T cells decrease. In parts of the world where diagnostic blood tests for HIV are not available, the presence of these oral lesions in otherwise asymptomatic adults can be used as an indicator of HIV infection.

A number of studies are examining candida species to determine the mechanisms involved in the conversion of this harmless fungus commonly found in the mouth to an
Oral Infectiouis Diseases
aggressive infectious pathogen. NIDCR-supported research to characterize the entire genome of Candida albicans will accelerate this process. Other studies are focusing on drug resistant candida and the potential use of gene therapy to bolster levels of histatin, a potent antifungal agent normally found in the saliva. Clinical trials are also under way to determine if scrupulous oral hygiene, the use of antimicrobial mouthrinses, and regular dental care can prevent or reduce oral complications in HIV patients with severely compromised immune systems.

 

Anti-HIV Action

Despite the presence of HIV-associated lesions in the mouth and their implications for escalating disease, studies by NIDCR and other NIH-supported scientists suggest that HIV is not spread through casual contact with saliva. Research has shown that HIV is easily cultured from the blood and spinal fluid of AIDS patients, but not from the saliva of HIV/AIDS patients with oral lesions. Of particular interest is the finding that human saliva demonstrates anti-HIV activity.

The intense search for protective constituents in saliva led NIDCR investigators to a relatively small protein called secretory leukocyte protease inhibitor, or SLPI, which attaches to the surface of monocytes and T cells and blocks infection by HIV. SLPI may help explain why AIDS does not appear to be spread by saliva, but much about its possible protective effect remains unknown. The next steps are to determine the protein binding sites on monocytes and T cells, the role SLPI plays in HIV entry into host cells, and its potential as a protective agent against HIV transmission.

Future NIDCR directions in HIV/AIDS research include expanding both our knowledge of the natural history and epidemiology of oral transmission and manifestations of HIV in various populations (including women, children, adolescents and minorities), and our understanding of opportunistic infections and mucosal immunity. The search for therapeutic interventions, synthetic drugs and vaccines, and innovative delivery systems will also be an important part of the NIDCR research portfolio.

 

Binding Site Identified

Essential to progress in this area is a better understanding of just what happens at the


Acquired Immunodeficiency Syndrome
HIV/monocyte and HIV/lymphocyte interface. One of the long-standing challenges in AIDS research has been figuring out exactly how gp120, the large protein on the surface of HIV, latches onto the CD4 target receptor on T cells in the first step in HIV infection. Studies spearheaded by NIDCR scientists have now identified that binding site, called C4, and determined how it recognizes its target receptor. These findings open the door not only for the design of new drugs and vaccines to fight HIV infection, but also for the development of interventions to block the initial interaction between HIV and cells and thereby inhibit infection.

 

Macrophages: HIV Reservoirs

Studies continue on the cellular and molecular mechanisms underlying immune dysfunction in HIV/AIDS, as well as on the pathogenesis of AIDS-related opportunistic infections. A new finding in this area underscores the importance of controlling opportunistic infections in AIDS patients.

It has been known for some time that CD4 T cells are the primary target of HIV infection and that their destruction leads to a weakened immune system and susceptibility to opportunistic microorganisms. As HIV infection progresses toward AIDS, the CD4 T cells are the chief source of new virus, creating a cycle of escalating virus production and T cell death. The paradox has been how the levels of HIV continue to increase over the course of AIDS, at the same time the T cell population dramatically decreases.

Investigators have now identified tissue macrophages as an unexpected source of new virus and point to opportunistic infections as a trigger that sets off a wave of HIV production. Examination of lymph nodes from AIDS patients with a variety of common opportunistic infections revealed from 5 to over 100 times the number of virus-producing macrophages than were found in the nodes of HIV patients free of such infections.

The individual macrophages also demonstrated a much higher level of virus production.

Although the actual mechanism that switches macrophages from HIV carriers to producers is not yet known, the research has important implications. Preventing or eliminating opportunistic infections is not only essential to the immediate well-being of the patient, but can also slow the cycle of virus production that leads to further immune system damage.

 

Source: National Institute of Dental and Craniofacial Research

National Institutes of Health

 

 

 

 

 

 

 

 

 

5.

Biofilms, Microbial Ecology and

Antoni Van Leeuwenhoek

 

 

Bacteria are remarkably adept at surviving feast and famine, capable of adjusting their needs to accommodate highly diverse environments. Scientific inquiry has discovered a number of the microbial characteristics that facilitate bacteria's agile adaptations to changing environments. Among them is the capacity to form and maintain biofilms. Many of us have had the experience while hiking to have slipped or fallen on wet rocks near a stream. This is not only because water tumbles over these rocks and makes them hazardous, but also because colonies of slippery, slimy creatures often will have made such rock surfaces their home. Among the culprits most likely to fell a hiker is something called "biofilm," a community of affluent and well-fed bacteria.

Biofilm is the communcal form in which bacteria prefer to live. Ironically, though, it is not how most people or even microbiologists have thought about the habitat of bacteria. The common perception is that they are isolated individual microbes. But when food is truly plentiful, bacteria adopt the sedentary life of living in a biofilm community. They adhere to an inviting surfacebe it a rock, a tooth, a dental implant, removable dental prostheses or even water-pumping machinery or the hull of a boat. In such environments, they switch on the genes that make the thick, slimy covering that gives them their community name.

This slime protects them; a bacterium residing in a biofilm is hidden from predators and is 500 times more resistant to antibiotics than when free floating. It also acts as a net to catch food.

In the 17th century, a dry goods merchant named Antoni van Leeuwenhoek first observed "animalcules" swarming on all living or dead matter. Leeuwenhoek's curiosity and inventiveness were remarkable. He documented one microscopic observation after another. He discovered the "animalcules" in the tartar on his teeth and, even after meticulous cleansing, the remaining opaque deposits isolated between his teeth "as thick as if it were batter." These deposits, he observed, contained a mat of various forms of bacteria. Biofilms per se were not recognized until 1978 and it has taken almost two
Oral Infectious Diseases
decades for clinicians and scientists to take another and even more serious look. In July 1996, the National Institute of Dental Research in Bethesda, Md., hosted an international conference called "Microbial Ecology and Infectious Disease", which included Nobel laureate Joshua Lederburg. Two months later, the American Society for Microbiology hosted a conference on biofilms in Snowbird, Utah. All this renewed interest arose in part from a growing recognition of the sheer havoc that biofilms can wreak.

For instance, biofilms are implicated in the rejection of artificial dental and medical prostheses and in a number of infectious diseases. We now appreciate that biofilms are everywhere: on teeth, inside the gut and the bladder, on rocks by streams and even in water pumping machines.

A number of scientific investigations are beginning to unravel the conditions under which bacteria form or do not form biofilms. Bacteria can subsist in extreme habitats. If biofilms are what happens to bacteria that fall on good times, shrinkage to an ultramicro bacterium, or UMB, is what happens when times get very tough.

Bacteria faced with overt starvation pack their DNA into tight bundles, virtually shut down their metabolic activities and shrink by two-thirds. These UMB then can remain dormant in this state for years, decades or possibly centuries, floating in fresh or salt water or buried far underground.

These UMB are extremely difficult to detect. For example, UMB forms of cholera (the bacteria genus and species Vibrio cholerae) cannot be detected in water using so-called standard testsand once detected, they are too small to be observed by light microscopy and require transmission or scanning electron microscopy for detection and identification.

However, when these bacteria encounter a new source of food, they unpack their bundled DNA, switch their genes back on and resume their free-floating or stationary community lifestyle.

One of the best ways to test for cholera in water is to add a lot of food, wait for four hours and then look for the free-floating form of a developing cholera community. Feed this planktonic form a little more food, and these cholera bacteria will fatten up and form a biofilm. The reverse is true as well. All bacteria, when starved, take the UMB form. It is this ability to change from one form to another that makes biofilms so interestingand so able to evade antibiotic therapy.

The vast majority of microbes such as bacteria (examples: Streptococcus mutans, Actinobacillus actinomycetemcomitans) and yeast (example: Candida albicans) grow as biofilms in an aqueous environment. In the mouth, biofilms naturally form on the sur
Biofilms, Microbial Ecology and Antoni Van Leeuwenhoek
faces of teeth, dental prostheses, implants and oral epithelium. These biofilms can be benign or pathogenic, releasing harmful products and toxins from harboring pathogenic microbes. Infectious diseases such as dental caries, periodontal diseases and infections associated with dental implants are reminders of our need to improve our scientific understanding of biofilms.

Biofilms also appear to be responsive to host factors such as diet and immune status. Immunodeficiencies such as those connected with HIV-related infections often are associated with overt expansions in bacteria as well as yeast biofilms. The formation of biofilms on heart valves, hip and other joint prosthetic replacements, catheters, intrauterine devices, waterlines and even contact lenses has become an almost $20 billion health problem for the American people.

Advances in scientific instrumentation as well as experimental designs are rapidly advancing our knowledge of biofilms in health and disease. For example, confocal microscopy and atomic-force tunnel microscopy, coupled with computer-assisted digital imaging instrumentation, provide scientists with novel strategies to observe and analyze biofilms in their natural environments. Progress in developing biomarkers for nucleic acids, proteins and carbohydrates further enables scientists to assess bacterial or yeast growth, viability and even metabolism under various biofilm community conditions. The dense and compact arrangement of bacteria in oral biofilms makes dental plaque_appreciated by Leeuwenhoek as he peered through his hand held microscopes almost 300 years agoone of the most promising ecology niches in which to investigate behavioral, biological and physical properties.

Such scientific approaches, which include gene transfer between bacteria, are beginning to disclose the ultrastructure, molecular genetics, physiology and virulence of defined biofilms with respect to varying host responses.

From such investigations into the basic biology of bacteria and yeast living in biofilms, it is anticipated that new strategies for increasingly more specific and more sensitive antibacterial or antifungal therapies will emerge for clinical dentistry and medicine. The early 20th century was plagued by horrible infectious diseases that took a severe toll on humanity: pneumonia, cholera, tuberculosis, diphtheria and whooping cough. In 1928, Sir Alexander Fleming discovered the first antibioticpenicillin. Ironically, as we move into the 21st century almost 70 years later, infectious diseases remain the leading cause of death worldwide.

As we continue into the next millennium and acknowledge a time of changing demographics and changing patterns of human disease, it becomes imperative to accelerate scientific and technological progress toward understanding and controlling biofilms. In addition, what is also different today, as compared with the beginning of the 20th century, is that the world is a smaller community, and these new or reemerging infectious
Oral Infectious Diseases
diseases are now only a plane ride away.

"The microbe that felled one child in a distant continent yesterday can reach yours today and seed a global pandemic tomorrow", said Joshua Lederburg, Ph.D., the Nobel Laureate from Rockfeller University, New York.

Meanwhile, the products of biofilms continue to inflict a burden of suffering on the American people. A large proportion of the population suffers from dental caries and periodontal diseases. Although the prevalence of dental caries among school-aged children has declined in the last several decades, recent national surveys indicate that the average schoolchild has at least one cavity in permanent teeth by age 9, three cavities by age 12 and eight cavities by age 17.

We are learning that vertical transmission of certain bacteria from the caregiver to the child may be significant in the etiology of rampant infant deciduous tooth decay.

Concurrent infections and the mother's nutritional status during pregnancy can further compromise the integrity of the forming dental mineralized tissues as well as the infant's developing immune system. We need a broader focus than one based only on improper infant-feeding practices to address this devastating and costly condition.

We clearly have a great deal more to learn about the beterogeneity of infant dental caries. Nearly 25 percent of children 5 to 17 years of age (almost 24 million American

children) have five or more decayed, missing, or filled teeth. According to a 1986-87 NIDR survey, about 50 percent of children aged 5 to 17 years were completely free of decay and of restorations in their permanent teeth. However, the average adult in the United States has from 10 to 17 decayed, missing or filled permanent teeth.

Patients need to be informed of the infectious nature of oral diseases and the currently available measures to control and prevent infection. For dental caries, fluorides in a variety of forms are available and, together with dental sealants, can ensure prevention in most cases. Fluoride and chemotherapeutic mouthrinses for dental plaque (biofilm) prevention are recommended, based on evidence of risk reduction from these interventions. In addition, phenolic antiseptic mouthwashes have been associated with a 28 to 34 percent reduction in dental plaque biofilms at six-month follow up. Chlorhexidine gluconate rinses, when combined with tooth brushing, have been reported to reduce oral biofilms such as dental plaque by 50 to 55 percent. At the time this article was written, this product was not readily available in the United States without a prescription.

About half of all adults have gingivitis and 80 percent have experienced some degree of periodontal disease. And in the context of changing demographics, with almost 32 million Americans now 65 years of age or older, 95 percent of this population has periodontitis and more than one-third has moderate-to-severe periodontal disease.
Biofilms, Microbial Ecology and Antoni Van Leeuwenhoek
Almost 22 percent of American adults over the age of 45 years and half of adults over 65 years (15 million people) are edentulous.

Infectious diseases such as dental caries and periodontal diseases can be exacerbated by personal behaviors such as poor diet, alcohol abuse and tobacco product use. They also can be aggravated by medications used to treat coexisting diseases, such as diabetes, Sjogren's syndrome and a number of immunodeficiency diseases and disorders (including HIV infection). Under these moderate-to-extreme conditions, oral bacteria and yeast biofilms are highly responsive as reflected in their biological and physical propertiesthe delicate balance between opportunistic infections and a compromised host immunity. The host immune response to pathogenic microbes is often not effective and cannot remove the biofilm. Oral bacteria or yeast within biofilms are highly resistant to host immunoglobulins or antibiotic and antifungal treatments because of changes in diffusion polysaccharide polymers that support the biofilm.

This presents an opportunity for investigators to revisit previously held assumptions and, as a result, to investigate the complexities of biofilms. Research may guide the development of "smart therapies" and approaches to inhibit or eliminate microbes under various environmental conditions. The NIDR is currently supporting several research studies designed to improve the removal of biofilms and to assist in the delivery of highly sensitive and specific therapeutics to oral bacterial and yeast microbes within biofilms. The scientific discoveries and new knowledge about oral microbes in biofilms will serve as catalysts for translational research, which may lead to patient-oriented clinical trials and eventual final regulatory approval of new therapies (such as new antimicrobial therapies and new antibiotics).

Basic and translational scientific research provides the fuel required for the engine of biotechnology and clinical trials. Our challenge is to make this science transfer more effective and more efficient to the benefit of patients, health professionals and pharmaceutical companies alike.

As health professionals, we have an excellent opportunity to provide mentoring and counseling for our patients and our staff members on the principles of microbial ecology in terms of biofilms. We can advise them of the associations between opportunistic microbes (viruses, bacteria, yeast and parasites) and the host immune system, the challenges of multi-drug resistant bacteria, the principles and practice of a healthy diet and approaches for the reduction of risk factors that influence health.

 

1. Slavkin HC, Cohen DW. Oral microbiology. Curr Adv Oral Biol 1979:1(5).

 

Source: National Institute of Dental Research

National Institutes of Health

 

6.

Infection and Immunity

 

 

Most americans think of it as a cold sore that comes and goes. But, the herpes virus is a highly contagious microbe that never really leaves.

 

Eight out of every 10 American adults are infected with the herpes simplex virus, or HSV. The virus is either dormant within a variety of tissues or is activated and highly contagious. As a contagious virus, HSV is either the direct cause or a cofactor associated with a number of different diseases and disorders. Its best known manifestation: the common cold sore. The cold sore, or herpetic lesion, typically shows redness, swelling, pain and heat over an eight to 10 day period. After that, its clinical signs and symptoms appear resolved, leaving no apparent scar. But the virus leaves with a promise to return.

The virus, infecting the lips, oral mucosa or tongue, can be transmitted to the hand or eyes_and it can be transmitted to another person, expanding the sphere of influence of this highly contagious microbe.

HSV also can be associated with other diseases or disorders that compromise the immune system such as protein-calorie malnutrition and AIDS. The virus provides oral health professionals an excellent opportunity to reassess their appreciation of infection and immunity. We can learn from HSV.

For thousands of years, redness and swelling, with pain and heat, have been recognized as the four cardinal signs of inflammation. Aulus Cornelius Celsus in the first century described the typical reaction of flesh to microbes. Since then, astute health-care professionals have appreciated that inflammation is the host's response to traumatic injuries as well as to microbe infections.

Inflammation is our protective response to dilute, destroy or compartmentalize both the infectious agent (infectious microbes such as viral, bacterial, fungal or parasitic invasion) and the injured tissue.

Oral Infectious Diseases
Redness, swelling, pain, heat and loss of function are clinical characteristics of HSV. Microscopically, the virus involves:

 

  1. • dilation or injury to capillaries, arterioles and venules;
  2. • exudation of fluids including plasma proteins;
  3. • leukocytic migration into the inflamed area with the release of cytokines.

Twentieth-century science has provided a foundation from which we can appreciate the sequence and timing of the drama that unfolds when infection meets immunity. The HSV strategically uses two viral gene productsglycoproteins D and B_to attach to the host cell. Immunologically, the HSV products are identified as foreign antigens by immunoglobulins (IgA antibodies) or by receptors on thymus-derived lymphocytes that bind to specific determinants (viral specific gene products or epitopes) associated with HSV products.

The inflammatory process activates the inflammatory reaction with increased blood flow (redness), increased vascular permeability (swelling), increased leukocyte migration and infiltration with attendant production of cytokines and eventual destruction of the infectious agents (pain, heat and possibly loss of function).

The actual destruction of HSV antigens is a function of the immune mechanisms mediated by phagocytic cells. The phagocytic cells may either live in the tissue site or be recruited into the tissue from a distance. Macrophages and Kupffer's cells are central players in this drama between infection and immunity.

HSV is a clever virus, capable of producing molecules on the surfaces of HSV-infected cells that mimic normal immunoglobulins, thus faking the host immune response. HSV also has learned to produce lymphokine and cytokine inhibitors, curbing the host's attempts to destroy the infection.

From a Darwinian perspective, infection-meets-immunity is high drama. It is a drama that presents a sophisticated confrontation of the opportunistic microbe (virus, bacteria, fungi, parasite) vs. the highly evolved human immune system, with its enormous capacity to confront diversity and provide an advantage for the host against a changing microbial environment.

The "simple" cold sore has many lessons to teach. Humanity's recognition of cold sores is so long-standing that it has led to complacent acceptance. Descriptions of the infection have been documented in early Greek manuscripts, particularly in the writings of Hippocrates (460-377 B.C.). Scholars of Greek civilization define the word herpes to
Infection and Immunity
mean "creep or crawl," describing the spreading nature of the visual skin lesion. The early, imprecise visual descriptions of the sore ended in the 20th century when, in 1919, Lowenstein described the infectious nature of the causative virus (herpes simplex) and demonstrated that the virus retrieved from the lesions of the sore produced a similar lesion on the cornea of a rabbit.

Herpes viruses are ubiquitous and have been isolated from baboons, chimpanzees, monkeys, cows, horses, birds and fish. Most animal species have yielded at least one herpes virus upon examination. Nearly 100 herpes viruses, from all sources, have been characterized, at least partially.

In humans, six members of the virus family Herpesviridae have been isolated:

 

  1. • HSV type 1 (cold sores) and type 2 (genital lesions);
  2. • varicella-zoster, or VZV (chickenpox, shingles);
  3. • human cytomegalovirus, or HCMV;
  4. • Epstein-Barr virus, or EBV (mononucleosis);
  5. • human herpes virus 6, or HHV-6 (roseola);
  6. • herpes B virus, an old-world monkey virus that results from the bite of a monkey, is highly pathogenic in humans but rarely passes from one person to another.

A new herpes virus identified in 1996, human herpes virus 8, or HHV-8, is associated with Kaposi's sarcoma, or KS. KS produces purplish lesions throughout the body as a result of uncontrolled growth of blood vessels. Proof of HHV-8's role in KS will require many additional long-term studies.

Like many viruses, the herpes viruses take up permanent residence in the body once they are introduced. After an initial infection, the virus goes into hiding, escaping the host's immune system by remaining latent in a specific group of cells, causing no apparent harm to the host. The exact cell in which they remain latent varies from one virus type to the next. In cells harboring the latent virus, the viral genomes take the form of closed molecules and only a small subset of virus genes are expressed. Production of infectious progeny virus is invariably accompanied by the irreversible destruction of the infected cell. All of the human herpes viruses have been detected in the saliva sometime during infection.

The HSV types 1 and 2 are the best known. Type 1 is usually responsible for the sores on
Oral Infectious Diseases
or near the face (cold sores, fever blisters or oral herpes). Most adults in the United States carry this virus and some suffer periodic bouts of cold sores.

Type 2 usually is involved in producing genital sores (genital herpes). About 16 percent of Americans between 15 and 74 years of age (30 million people) carry this virus. The two virus types are very similar, and either type can infect the mouth and genitals. Some people are infected with both types.

Most people infected with HSV never develop any symptoms. Reports from a number of studies indicate that about half of the people with HSV-2 antibodies do not know that they're infected, yet they are still capable of transmitting the infection.

Primary infection with HSV can produce great variability in clinical symptomsfrom being totally asymptomatic to suffering with combinations of sore throat, ulcerative and vesicular lesions, gingivostomatitis, edema of the mucosal membranes, localized Lymphadenopathy, anorexia and malaise.

The incubation period for HSV ranges from two to 12 days. In children, the infection characteristically involves a swelling of the gingival and buccal mucosa, making it difficult or impossible to swallow liquids. The clinical illness, accompanied by fever and pain from the lesion, generally lasts two to three weeks. After infection, the virus goes into hiding, entering nerve endings and traveling to ganglia (clusters of nerve cells).

How often the viral infection recurs varies from patient to patient. Factors that trigger recurrence in humans are poorly defined but include fever, stress and exposure to ultraviolet light. Infection recurs when the virus is activated in the ganglia and travels down the nerve to the surface of the skin where it replicates.

Recurrence takes place in phases:

 

  1. • prodrome: warning symptoms that last less than six hours and include tingling and itching at the site of outbreak;
  2. • inflammation: swelling and redness at the site before outbreak, indicating that both virus and antibodies have arrived;
  3. • blisters: appearance within 24 to 48 hours after prodrome of one or several small fluid-filled vesicles or tiny red bumps or tenderness most commonly at the vermilion border of the lip;

Infection and Immunity

  1. • ulcers: occurring within 72 hours after prodrome, often accompanied by pain; the blisters leak fluid, leaving wet-looking sores;
  2. • crusts: sores dry within 96 hours, forming a scab that indicates healing; virus diminishes, with healing over two to three days;
  3. • healing: complete within eight to 10 days; new skin forms; virus replication is complete, and the virus retreats back up to the host ganglia where it remains, protected from the host's immunological attack.

For most people, a herpes outbreak is confined to recognizable variations of the classical symptoms. While outbreaks can be physically and emotionally uncomfortable, and sometimes painful, the infection is usually self-limiting and results in complete healing of the infected site.

The virus in the inflamed site, however, is infectious and can be transmitted to a new site on the host's body (autoinoculation) or to another person through contact with any part of the body where the virus finds a way to penetrate the skin.

Transmission in most cases requires direct skin-to-skin contact between the infected site and a receptive site. Risk of transmission is highest when the virus is active. But first outbreaks or primary lesions are the most infectious because they include more virus particles on the skin, and the lesions persist for a longer period.

HSV also can be transmitted when the infected person is asymptomatic. About 1 percent

of the time, most people symptomatically shed traces of the virus, sometimes from lesions that are too small to be noticed.

Autoinoculation and transmission by skin contact can have serious complications. Dental professionals are at particular risk of developing a complication known as herpetic whitlow. Caused by HSV-1 or -2, whitlow develops on the hand and is found often among health professionals who treat herpes-infected patients. It is the same disease as oral or genital herpes with the same symptoms, but it is very visible and often very painful. The constant use of protective gloves and other universal precautions, including sterilization and disinfection techniques, can prevent herpetic transmission in the dental office.

Ocular herpes, an infection of the eye, is most often caused by autoinoculation. Fortunately, ocular herpes resolves itself without treatment about half the time and does not recur. Still, the infection can lead to serious damage and even blindness.

Oral Infectious Diseases
Ocular herpes can take the form of conjunctivitis or "pink eye," an inflammation of the mucous membrane under the eyelid and over the whole sclera of the eyeball. Conjunctivitis is irritating but causes no permanent damage.

Herpetic infection of the cornea is called keratitis, which causes superficial branching ulcerations called "dendrites." This condition is often self-limiting and may or may not cause permanent damage.

Herpetic iritis, an infection of the iris and other parts of the inner eye, becomes chronic and can lead to opacification of the cornea and blindness. Early treatment is key to averting the more serious consequences of all forms of ocular HSV.

Eight of 10 people with first time HSV infectionsand a few with recurrencesalso contract viral meningitis. The virus inflames the meninges surrounding the brain, but not the brain itself. Symptoms include severe headaches, aversion to light and nausea, which go away on their own, leaving no permanent damage.

Among the rarest of complications is herpes encephalitis, affecting fewer than one in 65,000 Americans each year. In adults, this encephalitis is usually caused by HSV-1, and in newborns by HSV-2. The brain infection causes swelling and inflammationand unless quickly controlled can result in permanent brain damage and death. The most serious concerns about herpes virus infections are the consequences for infected newborns.

Herpes viruses, as permanent residents of the body, affect several other diseases. Recent research shows that HSV may cause acute, idiopathic facial paralysis (Bell's palsy), though more studies are needed to confirm this observation.

A number of studies dating back to the late 1970s suggest that women with a history of genital herpes are at greater risk of contracting cervical cancer. Here, too, further study is needed.

As noted earlier, herpes may have a link to Kaposi's sarcoma. It is also being investigated for a possible causal relationship with the human immunodeficiency virus, which causes AIDS. These examples underscore the interest research scientists have in determining whether the often-dismissed "cold sore" virus has a more devious and influential role in the pathologies of the human body.

Diagnosis of an HSV infection is often done by the naked eye. But there are several more definitive diagnostic methods, some of which can distinguish between HSV-1 and HSV-2. The gold standard for diagnosing a virus is always isolation and culture. But this takes several days, and a negative culture does not necessarily mean absence of virus.

Infection and Immunity
Other methods include:

 

  1. • immunofluorescence, or IF, where cells are scraped from the lesion, placed on a slide and stained with fluorescent-tagged HSV antibodies, which bind specifically to any HSV present in the cells;
  2. • immunoperoxidase, or IP, which also binds with cells but can amplify the virus content for easier identification;
  3. • the enzyme-linked immunosorbent assay, or ELISA, which is more sensitive than either IF or IP; the infected specimen is combined with commercial HSV antibodies, an enzyme and their chemicals and followed for a color change that occurs only in the presence of HSV.

Still other serological assays measure antibodies that show prior infection with either HSV-1 or HSV-2, although the distinction between types is difficult.

Research on drug therapies for HSV has focused mainly on treating genital herpes to prevent sexual transmission and the effects on newborns. Since its introduction in 1985, oral acyclovir has been the preferred treatment for genital herpes. It also has been found effective in treating oral herpes. The U.S. Food and Drug Administration is reviewing an application that would extend oral acyclovir's use in treating oral herpes.

People who suffer from frequent bouts of HSV can take acyclovir daily for up to one year. Unfortunately, though, it is not a cure for the virus that remains in the body. The drug interferes with virus expression; it doesn't kill it.

Foscarnet also disrupts HSV replication but must be given intravenously because it is not readily absorbable in the stomach. Idoxuridine and vidarabine have been effective in treating ocular herpes but are ineffective in treating other forms of HSV.

Vidarabine is useful in treating herpes encephalitis, herpes zoster and neonatal herpes. Many other compounds have been reported as having anti-HSV impact in the laboratory, but further studies are needed to determine their effectiveness in humans.

Oral herpes is usually treated by the time-tried methods of keeping the blisters clean and dry, being careful not to touch the sores and spread the virus to new sites, and avoiding contacts with people in ways that could transmit the virus.

Researchers at the National Institute of Dental Research confirmed that sunscreen on the lips can prevent sun-induced recurrences of herpes. Most other preventive measures have not been examined under controlled studies.

Oral Infectious Diseases
In late September 1996, the first topical antiviral cream for treating cold sores received FDA approval. Marketed as Denavir, the cream contains penciclovir, which, like acyclovir, is active against HSV replication. Denavir is reported to reduce the duration of HSV pain and speed lesion healing.

The central goal in researching the herpes virus is the development of a vaccine because prevention is the best defense. A vaccine would be effective only in people who have not contracted HSV. It would offer protection and start to break an infectious cycle that involves so much of the population.

Small clinical studies show that a new vaccine consisting of viral glycoproteins found on the virus' exterior is capable of safely stimulating an immune response in both infected and uninfected study participants. Larger studies are needed to demonstrate the vaccine's effectiveness in preventing infection.

Other potential vaccines would use a live-virus preparation in which the HSV virulence factors have been removed.

In the dental office, oral herpes must be treated with respect and with all the precautions due an infectious, opportunistic disease. There is clearly much more to the common cold sore than most of us ever imagined.

 

 

Infection and Immunity

FOR ADDITIONAL INFORMATION

Centers for Disease Control and Prevention Web site

http://www.cdc.gov

Herpes Hotline

open Monday through Friday, 9 a.m. to 7 p.m. Eastern time

1-919-361-8488

Herpes Resource Center

P O Box 13897

Research Triangle Park, N.C. 27709

National Institute of Allergy and Infectious Diseases

Offce of Communications

National Institutes of Health

Bethesda, MD. 20892

(301) 496-5717

NIAID Web site: http://www.niaid.nih.gov

National Institute of Dental Research

Information office

National Institutes of Health

Bethesda, MD 20892

(301) 496-4261

NIDR Web site: http://www.nidr.nih.gov

 

 

 

 

 

 

 

 

 

 

7.

The A, B, C, D and E

of Viral Hepatitis

 

 

The word "hepatitis" conjures up a vision of someone whose skin and/or conjunctiva is yellowed (jaundice) because of the deposition of bile pigments that a damaged liver is unable to remove from the circulating blood. Liver inflammation can be caused by factors such as alcohol abuse, some medications and trauma, as well as by certain viruses.

General dentists, oral surgeons, physicians, dental hygienists, dental assistants, nurses and health-profession students top the list of the people at high risk for whom vaccination protection is recommended. Since 1987, the American Dental Association has encouraged dentists and their staff members to take advantage of the hepatitis B vaccine and postvaccination testing to protect themselves, their co-workers and their patients from hepatitis B infection. In 1992, the ADA expanded this recommendation to include the vaccination of dental students, preclinical and clinical faculty and staff against infectious diseases (for example, mumps, measles, rubella and hepatitis B).

The viral inflammation has some aspects that make the infected person potentially harmful to others. People may be chronically or acutely infected but not know that they have the disease because they have no symptoms. However, they still have the ability to spread the disease. A person can become an asymptomatic chronic carrier of the disease after being infected with any one of the several hepatitis viruses (such as B, C or D). The only protection against infection for the health-care provider and the patient is vaccination.

 

v The Five Types of Hepatitis

Viral hepatitis comprises at least five different viruses that differ in surface antigens, type of nucleic acid, mode of infection, length of viral incubation and pathogenicity and the ability to produce a chronic disease that can progress to fulminating liver failure or
Oral Infectious Diseases
hepatocellular carcinoma. All five forms of viral hepatitis can cause an acute illness, and all five have virulence and induce pathology primarily on the infected liver.

Hepatitis A virus . Each hepatitis A virus, or HAV, is a small virus about .026 micrometers in diameter and is transmitted by the oral-fecal route. HAV can produce an acute illness with a viremia of four-to-eight weeks. Its debilitating symptoms are often flu like: fever, fatigue, muscle and joint aches, as well as possible nausea, vomiting and pain in the liver area. Recovery may take as long as a year. The acute infection is clinically silent in approximately 90 percent of infected people. In about 10 percent of patients, acute HAV infection results in jaundice, but the risk of liver failure is very low, and there is no risk of chronicity. Recovery is associated with lifelong immunity. The virus is spread by eating contaminated food or drinking contaminated water or ice cubes, by close personal contact or by sharing dirty needles. In the United States each year, 138,000 people become infected by and 100 die of HAV.

Hepatitis B virus . HBV, the cause of "serum hepatitis," is classified as a hepadnavirus. Electron micrographs of infected sera of people has shown three morphological forms of hepatitis B virus: complete, spherical and filamentous. The complete virion (Dane particle) is about .042 mm. The spherical and filamentous forms of the virus represent viral coat material, or HBVsAg, produced in excess by the infected hepatocyte.

After infection of hepatocytes or mononuclear cells, viremia either is transient, lasts four-to-eight weeks or is chronic. In 90 percent of infected people, acute infection is clinically silent or produces symptoms that mimic flu, including fever, headache, muscle ache and fatigue. About 15 to 20 percent of patients develop short-term arthritis like problems. In 10 percent of patients, acute infection can result in jaundice. In acute hepatitis with jaundice, the risk of fulminant liver failure is about 1:100. Ten percent of patients, irrespective of any acute reaction, can develop a chronic infection, either inactive or active. Patients with chronic active hepatitis caused by HBV have a high risk of developing cirrhosis. Antibodies against the HB surface antigen, HBsAg, can neutralize the virus, thus preventing infection. The antigen has been used as a vaccine since 1975 and became generally available in 1982.

Two other HBV-antigens have been detected in humans: hepatitis B Core antigen, or HBcAg, which is not detectable free in the serum, and the hepatitis E antigen, HBeAg, associated with high infectivity. Antibody to the core antigen can be detected during acute illness, especially at the beginning of the illness, and antibody to the E antigen may point to a lower degree of infectivity and reduced likelihood of becoming a carrier.

HBV infection and its sequelae, however, still are one of the major causes of morbidity and death in man. Globally, more than 2 billion people are infected with HBV, and 350 million people are chronic carriers, at high risk of death from chronic active hepatitis,
The A, B, C, D, E of Viral Hepatitis
cirrhosis and primary hepatocellular carcinoma. Between 1 million and 1.5 million people die each year of HBV infection, making it one of the major causes of morbidity and death worldwide. If the vaccine was used more widely, the disease could be prevented almost completely.

By the end of 1992, 41 countries worldwide crafted national policies to give HBV vaccine to all newborns. In some parts of the world, the major mode of transmission is from child to child or mother to child, and vaccinating newborns would break this cycle. The vaccine is 90 to 95 percent effective in preventing virus infection and the carrier state.

Although HBV vaccine is easily obtained in the United States each year, an estimated 300,000 people become infected. The virus is most commonly transmitted by shared needles, by high-risk sexual behavior, from a mother to her newborn and in the health- care setting. Saliva, blood, semen, tears, vaginal secretions, milk and other bodily fluids are the major sources of infection. In approximately 30 to 40 percent of cases, the method of transmission is unknown.

Children are at the greatest risk. About 90 percent of babies who become infected at birth with HBV and up to half of the youngsters who are infected before the age of 5 years become chronic carriers. In an effort to eliminate chronic carriers, the U.S. Centers for Disease Control and Prevention, or CDC, recommends that all newborns be vaccinated. Other groups recommend that pregnant women be screened for HBsAg as part of their routine prenatal care. If they are infected, their babies should be given hepatitis B immune globulin as well as vaccine immediately after birth.

Dentists, oral hygienists and oral surgeons who are routinely exposed to blood on the job are at the top of the list for contracting HBV. Safe and protective HBsAg vaccines against HBV exist. To be fully protective, three injections are required: the second injection one month after the first and the third injection six months later. The vaccine provides immunity for 10 to 20 years.

In 1987, the CDC estimated that 12,000 of the 300,000 hepatitis B virus infections occurred among health-care workers, and approximately 250 of those people died as the result of infection. In 1991, 81 percent of the dentists who participated in the ADA's Health Screening Program, conducted each year at the ADA annual session, reported having received the HBV vaccine_a substantial increase from the 1987 level of 56 percent. Serologic data from the HSP for the years 1981 to 1989 indicated a decrease in the number of dentists naturally infected with HBV from 15 percent to 8 percent. Immunization and increasing use of universal precautions probably were responsible for the decrease.

Oral Infectious Diseases
Hepatitis C virus
. Acute infection with hepatitis C virus, or HCV, is clinically silent in 95 percent of infected people. The remaining 5 percent develop jaundice. In 60 to 70 percent of patients exposed to HCV, a chronic infection develops that is associated with chronic hepatitis and fluctuating serum transaminase activities. Cirrhosis develops in 10 to 20 percent of these patients. The delay from initial infection to the development of cirrhosis usually is 10 to 30 years but sometimes is shorter (five to 10 years). With the advent of new tests to screen blood donors, a very small percentage of people with HCV currently became infected through blood transfusions. HCV appears to be spread mainly through unprotected sexual contact, shared needles, recipients of previously untested blood products and health-care workers, although the method of infection is unknown in many cases. HCV is the most common form of chronic viral hepatitis in the United States and appears to be a major factor in the 25,000 deaths each year that are caused by chronic liver disease.

Hepatitis D virus or delta hepatitis . Infection with the hepatitis D virus, or HDV, is the

severest form of viral hepatitis. It leads to cirrhosis in up to 70 percent of cases, often within a few years of the onset of disease. It accounts for less than 5 percent of the cases of chronic hepatitis. HDV occurs only in patients who have acute or chronic HBV hepatitis and are HBsAg positive. HDV is coated by the HBV coat antigen HBsAg. An anti-HDV assay is available for diagnosing the infection, which should be suspected in patients who have chronic HBV infection but have clinical signs of acute hepatitis. Vaccine protection against HBV also serves against HDV.

Hepatitis E virus . Hepatitis E virus, or HEV, is an epidemic form of hepatitis that shares some characteristics with HAV, such as a lack of a chronic phase and enteric transmission primarily in underdeveloped countries with contaminated water supplies. Outbreaks have not been observed in the United States, but at least 20 epidemics have occurred in 17 other countries.

 

 

 

 

 

 

The A, B, C, D, E of Viral Hepatitis

 

v Diagnosis

Diagnosing any of the hepatitis viruses is generally done with tests that recognize either circulating viral antigens or circulating antibodies to viral antigens. Hepatitis E remains a diagnosis of exclusion, as clinically applicable serologic assays for it are not readily available.

Hepatitis A. Tests for hepatitis A virus are available to screen for antibody to hepatitis A. The antibody is detectable at the onset of illness and persists for the patient's lifetime.

Hepatitis B. A number of laboratory tests, including radioimmunoassay or enzyme_ linked immunosorbent assay, can detect HBsAg. The antigen often appears before symptoms develop and disappears with recovery. If the antigen remains six months after recovery, the person may have chronic disease or be a carrier of the virus. Antibody to the antigen usually persists for many years and protects against further infection.

HBcAg cannot be detected in the blood, but antibody to the antigen can be detected at high levels during the beginning of the illness and decrease over time. In chronic carriers, high levels of antibody may persist for a lifetime.

HBe antigen and antibody to the antigen can be detected by commercial tests. Presence of the antigen indicates high infectivity.

Liver function tests often are diagnostic of hepatitis virus infection. High levels of the liver enzymes aspartate transaminase, or AST, and alanine transaminase, or ALT, are of

particular importance.

Hepatitis C. A new test is now available to detect antibody to hepatitis C. The antibody is present in 50 percent of people who have acute antibody and in almost all people who have hepatitis C.

Hepatitis D. Until recently, this virus could be diagnosed only by liver biopsy. A blood test is now available to detect antibody to delta antigen (a protein found inside the hepatitis D virus).

 

 

 

Oral Infectious Diseases

v Treatment

There are no treatments of proven benefit for acute viral hepatitis except bed rest, a healthy diet and avoidance of alcoholic beverages. Usually, acute viral hepatitis is self­limiting. Most patients experience complete recovery, with restoration of liver function and clearance of the virus. Specific therapy must be approached with caution. The hepatic dysfunction accompanying acute hepatitis alters drug metabolism in the liver so that medications are often not well-tolerated. Also, by the time symptoms appear, the viral replication is usually decreasing or has ceased and antiviral drugs would have little effect.

Antiviral agents . Two antiviral agents have been shown to have some benefit for some patients with acute hepatitis: ribavirin and alpha interferon.

Ribavirin resembles the nucleoside guanosine, a building block of nucleic acid. It can substitute for guanosine in nucleic acid synthesis but, because of its different structure, it interferes with further synthesis of the nucleic acid molecule. It has broad activity against a number of RNA and DNA viruses in vitro with few side effects. However, its effectiveness against hepatitis viruses has not been evaluated in well-controlled studies and may give modest results.

Alpha interferon is a natural human cell protein made by macrophages and B cells in response to viral infection. Alpha interferon and the related beta interferon attach to a cell surface receptor, which induces a set of intracellular enzymes that inhibit the virus's infection of the cell and its replication. There is little evidence to suggest that alpha interferon is effective in treating acute hepatitis B and D and some preliminary evidence that it may be beneficial in treating acute hepatitis C.

Alpha interferon has been shown to be effective for some patients in inducing sustained remissions in all three types of chronic hepatitis, B, C and D. In chronic hepatitis B, therapy for 16 weeks can induce long-term remission in 25 to 40 percent of patients and, ultimately, loss of HBsAg in 50 percent of those who respond to treatment. In chronic hepatitis C, therapy for 24 to 48 weeks can induce temporary remission, including lack of detectable viral RNA and improvement in liver histology in 50 percent of patients and sustained remission in 25 percent of the patients. In chronic hepatitis D, prolonged treatment with alpha interferon can cause remission in up to 50 percent of the patients; however, the remission rarely is sustained after treatment.

However, a number of side effects are attributed to alpha interferon treatment, including sustained flulike symptoms; decrease in platelets, white blood cells and hematocrit; development of autoantibodies; psychological symptoms; and neurological symptoms. More research is needed to increase the agent's efficacy and safety and to understand why some patients do not respond to it at all.

The A, B, C, D, E of Viral Hepatitis

v Conclusion

Recent breakthroughs in understanding hepatitis B make the future therapy of this disease promising. In the past few years, animal models have been developed for drug testing, and cell culture has been found that can allow replication of the virus. Other technological advances offer new areas for possible therapy for hepatitis, including monoclonal antibodies against HBsAg, HBV-antigen_specific T cells and antisense oligonucleotides. Many antiviral and immunomodulary agents are under evaluation, including interleukin-2, gamma interferon, acyclovir, ganciclovir and suramin and combinations of drugs. Much work remains to be done.

Our best approach to the control and prevention of hepatitis is vaccination of susceptible populations, especially health-care workers, with HBV vaccine and, under special circumstances, with HAV vaccine. We also must continue to observe good barrier protection techniques when dealing with patients.

 

Oral Infectious Diseases

For Additional Information

American Liver Foundation

1425 Pompton Avenue

Cedar Grove, NJ 07009

Phone (800) 223-0179 or (201) 256-2550

Centers for Disease Control and Prevention/National Center for Infectious Diseases

Division of Viral and Rickettsial Diseases

Hepatitis Branch

Atlanta, GA 30533

Phone (404) 332-4555 (The Hepatitis Hotline)

National Digestive Diseases Information Clearinghouse

2 Information Way

Bethesda, MD 20892-3570

Phone (301) 654-3810

National Institute of Allergy Infectious Diseases

Information Office

31 Center Drive, MSC 2560

Bethesda, MD 20892-2560

Phone (301) 496-5717

 

 

 

 

 

 

 

 

 

8.

AIDS Research

 

 

 

• Oral Transmission of HIV: Discussion • Oral Transmission of HIV: Recommendations • Opportunistic Infections: Discussion • Opportunistic Infections: Recommendations • Mucosal Immunity and Vaccines: Recommendations • Therapeutics: Discussion

 

Based on review of the past decade of NIDR intramural research and extramural AIDS and HIV-related research, two important concepts relevant to HIV infection and oral medicine have emerged:

 
1. Of the almost 500 million dental visits every year, only 1 report of HIV transmission has been substantiated. Furthermore, salivary levels of cultivable HIV are extremely low or undetectable even in situations where infected blood occurs in the mouths of patients. This suggests that components of saliva/oral fluids provide some level of protection from oral transmission of HIV. Opportunities for development of therapeutics potentially derived from such oral fluid/salivary components should be investigated.
2. Intrinsic differences between the oral mucosa and other mucosal surfaces in the body (e.g., nasopharyngeal, gastrointestinal, vaginal) may mediate unique interactions with HIV. In addition, the immunology and natural defenses of the oral cavity may have novel characteristics that merit further study.

Other questions that arise from research to date include the following.

 
1. Immunosuppression as a result of HIV infection appears to create permissive condi

Oral Infectious Diseases
tions for the activation of other viruses found in the human host. In the oral cavity, these include the herpes simplex viruses (HSVs), Epstein-Barr virus (EBV), human Herpes-8 (HHV-8) and human papillomavirus (HPV). How immunosuppression results in viral reactivation of all these agents should be further explored.
2. The associations of oral hairy leukoplakia with EBV, HPV with oral papillomatosis and Kaposi's sarcoma with HHV-8 as a result of HIV-related immunosuppression are well recognized. Does activation of these viruses influence the development of oral malignancies/neoplasms?
3. How does the viral load in saliva correlate with that in serum? Could noninvasive salivary diagnostic assays be used to monitor the progression or treatment of HIV disease?
4. Novel lymphoid compartments in the oral cavity such as the tonsils, and Waldeyer's ring may be critical reservoirs of both viral pathogens and immune cells; as such, they warrant further investigation.
5. The neurotropism of HSV for trigeminal ganglia and the central nervous system (CNS) merits further study as a model of HIV neurotropism.

 

 

 

 

 

 

 

 

 

 

 

AIDS Research

v Oral Transmission of HIV: Discussion

Oral (receptive) sex may be a more prevalent route of HIV transmission than currently perceived. Dr. Daniel Malamud, University of Pennsylvania, reported on a study (Schacker et al. Annals of Internal Medicine, 1996) showing that in 12 subjects where the precise date of seroconversion could be identified, 4 (= 33 percent) reported oral-genital contact as their sole risk factor. Young people and adolescents are particularly at risk, because they increasingly perceive oral sex as a safe, "nonintimate" activity. While only suggestive, these studies indicate a need to derive reliable estimates of the risk of HIV infection as a consequence of oral sex.

Oral viral load needs to be assessed to determine whether it is sufficient to provide a significant risk of infection and warrants intensive study. It is important to determine whether salivary factors are protective (and to what degree) and what role they may play in the casual transmission of HIV via the oral cavity/fluids.

Oral markers: It is also of interest to determine whether components of the oral cavity/fluids may provide markers for the development of diagnostic reagents either for HIV or for genetic factors that influence susceptibility to HIV/AIDS. Secondary receptors, using correlates of oral transmission with those at other mucosal surfaces, and postexposure oral prophylaxis are related topics that deserve attention.

Viral entry: The site(s) of virus entry after oral exposure to HIV may differ by age; tonsils may play an important role for oral HIV transmission in adults, while the primary virus entry point(s) along the gastrointestinal tract may be different in neonates/infants and could involve the stomach.

Breast feeding as a route of HIV transmission may have different implications for worldwide populations than it does for U.S. subjects, the central issue being exposure to milk-borne HIV over nursing periods of short or long duration.

Cofactors: Many cofactors may contribute to oral transmission of HIV. These include viral (HSV, EBV, HHV-8, HPV), fungal (Candida) and other fungal and microbial infections, as well as xerostomia, oral cancers, oral ulcers, leukoplakia, and the inflammation that accompanies any of these conditions. Whether opportunistic infections simply occur with HIV or affect susceptibility to HIV transmission requires clarification in infant, adolescent, and adult populations, where effects may vary.

Mechanisms of disease and pathogenesis associated with opportunistic infections should be further explored at the molecular, genetic and genomic levels. Such studies are important not only in the fundamental scientific nature of their investigation, but
Oral Infectious Diseases
also in relation to their increasing reliance on the development and refinement of emerging technologies in DNA sequence analysis and genomic informatics. DNA sequence analysis and assembly of select genomes such as Candida albicans and oral microbial pathogens should be supported and can provide a basis for interdisciplinary and interagency linkages.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AIDS Research

v Oral Transmission of HIV: Recommendations

Oral transmission is a route of HIV infection in neonates and infants and several recent publications suggest that oral-genital contact in adults leads to systemic HIV infection and AIDS. Oral transmission includes in utero, intrapartum, postpartum (breast milk), and exchange of body fluids during heterosexual and homosexual oral-genital sexual activity. The risks of becoming infected through individual acts of unprotected rectal/vaginal intercourse, single incidents of professional needle-stick injury, or IV drug injection are known. In contrast, the relative risks of infection through the oral route remain unknown.

 

Natural History and Epidemiology

Epidemiological investigations need to be conducted to evaluate the possible contribution of oral transmission of HIV, taking into account carefully evaluated individual (homosexual and heterosexual) practices of oral-genital contact. Modulating factors might include conditions or practices that influence the integrity of the oral mucosa, oral health, nutrition, inhibitory substances in saliva, and the influence of alcohol, drugs, and other substances.

As viral load is known to be an important determinant of risk of HIV transmission, it is necessary to determine the viral load in body fluids, including pre-ejaculatory fluid, ejaculate, cervical/vaginal fluids, oral fluids, and breast milk, during both primary and chronic HIV infection. The same fluids should also be examined in HIV-infected individuals undergoing antiviral therapy.

 

Etiology and Pathogenesis

The mechanism of virus entry after oral exposure should be studied in applicable model systems, including primates. Key issues are the site(s) of viral entry after oral exposure along the oropharyngeal and gastrointestinal tract across mucosal surfaces, the identity of initial target cells, initial site(s) of replication, and the relative efficiency of oral infection as compared to other routes of exposure. Other factors that should be studied include virus tropism, coreceptor usage, and cell-free versus cell-associated virus transmission. The influence of host factors such as age on permitting systemic infection after oral exposure needs to be investigated. Whenever possible, correlates of primate and human studies should be investigated to ensure relevance.

 

Oral Infectious Diseases

Behavioral and Social Science Research

Social and behavioral studies are needed to document the types of sexual activity related to oral-genital contact, and effective approaches to both understanding and changing these behaviors need to be explored.

 

Therapeutics

Should oral transmission of HIV prove to be a significant risk, the potential for prophylaxis before and after oral exposure needs to be assessed. Depending on the site of virus entry after oral exposure, this could include systemic as well as topical agents.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AIDS Research

v Opportunistic Infections: Discussion

Predisposing factors: Poor dental hygiene, poor nutrition and inadequate dental care may contribute to or serve as predisposing factors for increases in the development or severity of oral lesions in HIV-infected individuals. However, periodontal disease occurs in HIV-infected individuals without these factors. There are uncommon manifestations of periodontal diseases that appear to be unique to HIV-infected persons, such as necrotizing ulcerative periodontitis. Whether or not periodontal disease or other oral lesions play a role in, or contribute to, oral transmission of HIV or other opportunistic infections has not been determined.

Candidiasis as a sentinel condition in the onset of AIDS is manifest in 80-100 percent of the HIV-infected population. Studies of the organism and its mechanisms of pathogenesis and interaction with the host provide a bridge between NIDR-sponsored AIDS research and other research on the role of HIV immunosuppression in the activation of and susceptibility to opportunistic infections (OIs). Candidiasis further allows a comparison of the oral mucosa with vaginal and gastrointestinal mucosal surfaces. Because one of the important roles of mucosal tissue is barrier protection, chronic inflammation due to Candida or other pathogens may affect susceptibility to HIV or other infections.

Potentiation of infection: The role of opportunistic pathogens in potentiating/facilitating HIV transmission/infection and pathogenesis should be further explored.

Correlates of immune dysfunction: While the correlation between opportunistic infections and immune dysfunction is well recognized, the cellular/molecular correlates of mucosal and systemic immunocompromise have not been defined. Changes in systemic and mucosal immune function in relation to susceptibility and presentation of opportunistic infections should also be defined. The short- and long-term effects of anti-retroviral therapy on the reduction or elimination of opportunistic infections need to be determined.

Cancers of the oral cavity, particularly Kaposi's sarcoma and lymphoma, relate directly to HIV/AIDS and are associated with prior infection with EBV, HSV, HHV-8 or HPV. Squamous cell carcinoma, the primary cancer of the mouth, does not appear to be more frequent in HIV/AIDS, although the role of chronic inflammation due to opportunistic infections, periodontal disease, and HIV-associated immunosuppression has not been defined.

Aphthous ulcers: The etiology of these lesions is another matter of concern. While these are common in HIV-infected individuals, a pathogenetic link with HIV may exist.

 

Oral Infectious Diseases

v Opportunistic Infections: Recommendations

A number of opportunistic infections have unique oral manifestations and are of special relevance to oral health and HIV disease. Agents causing these OIs may serve as facilitators of HIV infection, and infection due to these pathogens may promote HIV spread through immunosuppression and other effects on the host. Notably, our knowledge of opportunistic infections in the oral cavity and their relationship to HIV disease is more complete than the relationship between these infections and HIV at other sites in the body. Consequently, the molecular mechanisms of host-pathogen interactions should now be addressed.

Areas of particular interest include the following:

 

Etiology and Pathogenesis

Viral Pathogens

 
1. The role of viruses (HHV-8, EBV, HPV) as etiologic agents of tumors of the oral cavity should be explored further. In particular, the role of HHV-8, the least well-known of the herpes family of viruses, should be explored in relation to Kaposi's sarcoma.
2. Studies of herpes and human papillomaviruses as transactivators of HIV gene expression are warranted.
3. Research on how EBV and cytomegalovirus (CMV) affect HIV pathogenesis through their effects on immune function should be explored. Reciprocally, the effects of HIV immunpathogenesis on the activation/reactivation of EBV, CMV and HSV should be studied.
4. Studies should be conducted of HSV as a model for neurotropic spread, gene expression, and reactivation of HIV in lymphocytes, macrophages, and neurons of the peripheral and central nervous systems.
5. The mechanisms of HHV-8 transmission and pathogenesis, specifically at the mucosal surface, should be explored.

 

 

Infection and Immunity

Bacterial Pathogens

 
1. The extent to which destruction of mucosal integrity, chronic inflammation and other host immune effects associated with gingivitis and periodontal diseases facilitates HIV infections and spread should be investigated.
2. The effects of HIV infection on oral microbial ecology in relation to diseases caused by opportunistic pathogens merits further study.

 

Fungal Pathogens

Candida should be studied as a model for understanding the host-pathogen relationship at the mucosal, cellular, and molecular level.

 

Therapeutics

Research should be conducted to identify novel molecular targets for prevention and control of opportunistic oral infections.

 

 

 

 

 

 

 

 

 

 

 

Oral Infectious Diseases

v Mucosal Immunity and Vaccines: Recommendations

Therapeutics: Discussion

Opportunistic infections of the oral cavity offer unique opportunities for NIDR to partner with other ICDs and the pharmaceutical industry in developing new drugs and other interventions as well as new methods of administration (e.g., transmucosal) for proven therapies. Oral cavity lesions that facilitate HIV infection and/or transmission and opportunistic pathogens that may include HIV are among the targets.

Clinical evaluation of oral fluids presents another partnering opportunity, particularly with regard to monitoring pharmacokinetics, HIV viral load, immunoglobulins/antibodies, surrogate markers, and broad diagnostics. Studies of the role of oral fluids in evaluating efficacy of treatment and progression of disease in adults and children are still in their early stages, but NIDR is an appropriate partner in such research.