Corresponding author and reprint requests: R. Rautemaa, University of Helsinki, Faculty of Medicine, Haartman Institute, Department of Bacteriology and Immunology, PO Box 21, 00014 University of Helsinki, Finland E-mail: firstname.lastname@example.org
The relationship between oral and general health has been increasingly recognised during the past two decades. Several epidemiological studies have linked poor oral health with cardiovascular disease, poor glycaemic control in diabetics, low birth-weight pre-term babies, and a number of other conditions, including rheumatoid arthritis and osteoporosis. Oral infections are also recognised as a problem for individuals suffering from a range of chronic conditions, including cancer and infection with human immunodeficiency virus, as well as patients with ventilator-associated pneumonia. This review considers the systemic consequences of odontogenic infections and the possible mechanisms by which oral infection and inflammation can contribute to cardiovascular disease, as well as the oral conditions associated with medically compromised patients. A large number of clinical studies have established the clinical efficacy of topical antimicrobial agents, e.g., chlorhexidine and triclosan, in the prevention and control of oral disease, especially gingivitis and dental plaque. The possible risks of antimicrobial resistance are a concern, and the benefits of long-term use of triclosan require further evaluation. Oral infections have become an increasingly common risk-factor for systemic disease, which clinicians should take into account. Clinicians should increase their knowledge of oral diseases, and dentists must strengthen their understanding of general medicine, in order to avoid unnecessary risks for infection that originate in the mouth.
Advances in the understanding, prevention and treatment of oral diseases during the past 50 years have led to a significant increase in the number of individuals retaining more of their natural teeth for longer periods of time. However, many of these teeth have been heavily restored and are prone to further breakdown, and this increasingly dentate population is at risk for periodontal disease. The goal of modern dental care is oral health, but this cannot always be achieved or maintained. Often, only an arrest of disease progression can be attained, and chronic asymptomatic infections may persist. In addition, chronic or malignant diseases of the mucosa are increasingly common. The mouth has thus become a significant potential source of both infection and inflammation that contributes to the total burden of disease and to overall health and well-being.
The oral microbiota is both rich and unique. A similar microbiota does not exist elsewhere. In healthy individuals, viridans group streptococci constitute the majority of the indigenous oral flora. However, the most common bacteria isolated from pus samples from odotontogenic infections are facultative anaerobic streptococci and anaerobic Gram-negative bacilli, e.g., Prevotellae and Fusobacterium spp. [1,2]. Currently, a significant proportion of Prevotellae isolates worldwide are β-lactamase producers, and β-lactam antibiotics alone are thus ineffective against these organisms. For this reason, metronidazole has been used in combination with penicillin in order to achieve improved efficacy against anaerobes.
Actinobacillus (now Aggregatibacter) actinomycetemcomitans and Porphyromonas gingivalis are also key oral pathogens and have frequently been associated with periodontal diseases. It is also interesting to note that both of these organisms can invade oral epithelial cells, which contributes to their immune evasion and resistance to antibiotic treatment [3,4]. Actinomyces spp. are part of the normal oral microbiota and constitute the bulk of the structural elements of the dental plaque biofilm. These organisms are also found in cases of peri-implantitis, which is an infection of dental implant supporting tissues, and which may result in loss of the implant . In addition, they can cause actinomycosis of jaws. Candida albicans is the most common yeast found in the oral cavity, although the proportion of non-albicans Candida isolates has increased in recent years, especially in patients with fragile health.
The spread of oral infections is generally confined by anatomical barriers or tissue planes, e.g., muscle and bone. However, spread of infection back and down to the larynx and the mediastinum can occur . A central principle is that oral infections cannot be resolved merely by use of antibiotics, and successful treatment is always based on properly conducted dental procedures. Nevertheless, antibiotic treatment is important and, as stated above, a combination of penicillin and metronidazole should be considered. An odontogenic infection can spread very rapidly, and the airway may become obstructed within a few hours. If this occurs, rapid intubation or tracheostomy and intensive care may be required. An example of a life-threatening infection originating in the mouth is Lemierre's syndrome, which is a rare septic condition that usually requires intensive care. Isolation of Fusobacterium necrophorum is common, and a suppurative thrombophlebitis in the vena jugularis interna and metastatic abscesses in the lungs or the brain can develop .
The mouth clearly represents an important reservoir of microorganisms and any infection caused by these organisms should alert the clinician to the possibility of an oral source [6–8]. While there have been a number of reports of brain abscess being caused by oral microorganisms , the classical example is endocarditis caused by viridans group streptococci. According to the infectious diseases register of the Finnish National Public Health Institute (http://www.ktl-fin/tartuntatautirekisteri), the number of adult septicaemias caused by viridans streptococci has almost doubled in the past 10 years, which is directly proportional to the number of individuals remaining dentate throughout their lives. Viridans group streptococci are currently the fifth most common cause of septicaemia among adults in Finland.
In this context, it is therefore important for infectious disease physicians to give increasing attention to oral health. The possibility of an oral source should be considered for any infection of unknown origin. Oral infections often remain asymptomatic, and may still result in bacteraemia despite an absence of overt symptoms. Minor oral procedures, including brushing of teeth, as well as invasive dental procedures, e.g., removal of dental calculus, root treatment and surgery, may all result in bacteraemia, even in an otherwise healthy individual [10,11]. Furthermore, an oral infection may provide the physician with clues for diagnosis of a systemic disease. For example, oral candidosis, in the absence of any other explanation, could suggest infection with human immunodeficiency virus at a stage when the CD4+ cell count is still high and the disease is still otherwise asymptomatic.
The medically compromised patient
An increasing number of systemic diseases, e.g., gastroenterological and rheumatological, are treated with moderate-to-severe immunosuppressive agents. Malignancies, with their associated therapies, also affect an increasingly large proportion of the population. The oral health of medically and immunologically compromised patients is fundamental to the overall care of these patients. Oral infections are typically chronic and often present with minor symptoms; however, they remain controlled while the immune defences and tissue responses of the patient remain intact. In a susceptible immunocompromised patient, even an asymptomatic, chronic osteitis or a mild Candida mucositis (Fig. 1) can become a source of life-threatening generalised infection [12,13]. It is therefore important to ensure that all foci of oral infection are eliminated whenever possible before commencing treatment. This is also important before cardiac surgery or the placement of joint prostheses . Imaging of the teeth and tooth-supporting bone and jaws should be the minimum routine (Fig. 2). A thorough clinical examination by a dentist experienced in oral medicine is also highly recommended.
Poor oral health (Fig. 3) and extensive stomatitis, responsible for significant morbidity, are common in patients receiving cancer therapies [15–18]. Oral mucosal lesions may provide a portal of entry for systemic infection that may prevent or delay the continuation of cancer treatment [19–21], thereby having a significant effect on the final prognosis (including mortality), and a major impact on the costs of care . Regular removal of bacterial plaque from tooth surfaces is important in order to keep the microbial load and challenge to a minimum during cancer treatments [23,24]. In this context, toothbrushing alone may be insufficient or impossible to carry out because of pain, and the use of antimicrobial toothpastes and mouthwashes may be necessary [17,25]. When the mucosa is damaged, brushing may lead to substantial bacteraemia, and the use of an antimicrobial mouthwash is therefore recommended before or instead of brushing. Several reports have demonstrated that a chlorhexidine mouthwash is effective in controlling both the oral infection per se and the consequences of any bacteraemia [17,25]. Careful mechanical (brushing and flossing) or chemical (antimicrobial mouthwashes) oral hygiene should always be a part of cancer therapy. Barker et al.  highlighted considerable variation among centres in their understanding and appreciation of the significance of oral health in medically compromised patients; they concluded that an increase in oral complications has evolved with the development of cancer therapies, and that medico-dental collaboration is therefore important.
Osteomyelitis of the jaw is a rather uncommon infection, with diabetes and haemodialysis being known risk-factors . However, there is increasing evidence of osteonecrosis of the mandible being associated with high-dose or long-lasting bisphosphonate therapy. Bisphosphonates, which are pyrophosphate analogues, are strong osteoclast inhibitors that are used in the treatment of osteoporosis and solid tumours with bony metastasis. The safe optimal dose and duration of treatment should be evaluated and the subset of patients at increased risk for osteonecrosis should be identified, as the necrosis seems to be irreversible and the treatment of these patients is very difficult .
Actinomycosis of the cervicofacial region, caused primarily by any of several members of the bacterial genus Actinomyces, is another rare infection, usually presenting as a mass adjacent to the mandible, which may penetrate the surrounding bone and muscle and form a fistula to the skin. Carious teeth, dental manipulations and maxillo-facial trauma are known sources of infection [1,27]. The pathogenesis is related to the ability of these organisms to act as intracellular parasites and thus resist phagocytosis. Actinomycosis has a tendency to spread without respect for established tissue planes or anatomical barriers, and this can sometimes be confused with malignancy.
Significance of oral infections in the development of systemic diseases
The importance of the role of infection and inflammation in the initiation and progression of the endothelial damage in atherosclerosis is now widely accepted [28–30]. Chronic inflammatory periodontal diseases are found worldwide and are among the most prevalent chronic infections in humans. Individuals with severe chronic periodontitis have been reported to have a significantly increased risk of developing cardiovascular disease, including atherosclerosis, myocardial infarction and stroke, even after adjusting for many of the traditional risk-factors [31–33].
Since the early work carried out in Finland [28–34], there have been >50 studies investigating the relationship between periodontal and cardiovascular disease, with the majority showing a significant, albeit modest, positive association, even after adjusting for confounders. However, while epidemiological studies indicate associations, they do not establish causality. Care must be taken in interpreting these cross-sectional epidemiological studies and, as emphasised by Hujoel et al. , studies of longitudinal intervention and pathogenic mechanisms are urgently required. A number of short-term studies examining the effect of periodontal treatment on the surrogate markers of cardiovascular disease have been performed [36–38]. In general, these studies show that periodontal treatment results in a significant reduction in such markers of cardiovascular disease, e.g., interleukin-6 and C-reactive protein. These changes are also accompanied by an improvement in endothelial function and arterial elasticity.
Possible biological mechanisms linking periodontal and cardiovascular disease include molecular mimicry between the bacterial heat-shock protein GroEL and human heat-shock protein 60 (hHSP60). This hypothesis, first suggested by Wick et al. [39,40], involves cross-reactivity between the immune response mounted against a bacterial infection and hHSP60 expressed on stressed or damaged endothelial cells. Yamazaki et al.  have shown that T-cells reactive with both GroEL and hHSP60 have identical nucleotide sequences in their T-cell receptor β-chain genes, and that such T-cells exist both in the atherosclerotic plaques themselves and in the periodontal tissues. Cross-reactive T-cells have also been shown to be present in the peripheral blood of patients with atherosclerosis [42,43], and antibodies to GroEL cross-react with hHSP60, and vice versa. In addition, P. gingivalis has been shown to enhance the development of atherosclerosis in an animal model, and this enhancement is associated with increased levels of anti-GroEL antibody .
Other possible mechanisms linking periodontal and cardiovascular disease include direct infection of the blood vessel walls by periodontal organisms. Leukocytes do not adhere to healthy endothelium, but if the endothelium is damaged, e.g., by direct infection, the endothelial cells will express adhesion molecules to which white blood cells adhere. Monocytes adhere and migrate into the intima, where they phagocytose the oxidised low-density lipids that form the so-called foam cells. The foam cells then release matrix metalloproteinases that degrade extracellular matrix components in the vessel wall, resulting in atherosclerosis . These cholesterol plaques that form at the site of injury can rupture, increasing the likelihood of myocardial infarction or stroke. An interesting finding is that the known matrix metalloproteinase inhibitor tetracycline is as effective as periodontal treatment in lowering the level of C-reactive protein in coronary heart disease patients with periodontitis . Extensive studies have shown that systemic diseases, e.g., diabetes and cardiovascular disease, and periodontitis share links between biomarkers of systemic inflammation (C-reactive protein, interleukin-6, tumour necrosis factor-α, matrix metalloproteinase-9).
These pathogenic mechanisms are not mutually exclusive, but clearly establish the role of infection in the pathogenesis of atherosclerosis. Despite the lack of definitive long-term intervention studies, the importance of preventing and treating infections, especially chronic infections such as periodontitis, should become paramount in terms of the advice and treatment given to patients with coronary heart disease.
Prevention of oral infections
Oral infection continues to be a major public health problem worldwide. Good oral hygiene is essential for good oral health, and the routine control of dental plaque is fundamental. However, the widespread prevalence of oral disease indicates the inability of most individuals to achieve a level of plaque control consistent with good oral health. Approaches aimed at improving the oral hygiene of the population have therefore included the addition of antibacterial agents to oral care products. While chlorhexidene is considered to be the reference standard, it has significant side-effects that limit its widespread long-term use.
Triclosan is an alternative antimicrobial agent with a broad spectrum of activity against oral microorganisms. This agent is more suitable for long-term use, as it does not have significant side-effects and, importantly, it has a long history of safe use in consumer products. Its dual antimicrobial and anti-inflammatory properties offer advantages in the management of periodontal diseases and oral mucosal conditions, and there are now numerous studies demonstrating its effectiveness in reducing plaque and gingivitis . Triclosan has also been shown to slow the progression of periodontal disease over a 3–5-year period in adults and adolescents with pre-existing disease [46–48]. It is expected that these benefits will compound with continued use over even longer periods of time . This could have a significant impact on disease expression in the population at large. The consequences of long-term use of any antimicrobial agent are a concern, and the therapeutic advantages have to be weighed against the possibility of reduced susceptibility and the emergence of resistant strains. To date, there is no evidence that triclosan formulations for oral use will select for triclosan-resistant strains [49,50], but there are well-documented therapeutic benefits. It is interesting to note that the major therapeutic benefit, in terms of chronic periodontitis, is seen in susceptible patients or those with pre-existing disease. Medically and immunologically compromised patients represent a susceptible population, such that it would be reasonable to expect that triclosan-containing toothpastes would be of value in the control of oral infection in these patients. However, this remains to be shown, and further studies are necessary to determine the effect of these products in medically compromised patients.
The number of individuals retaining more of their natural teeth for longer periods of time has increased during the past few decades. Adequate oral hygiene is difficult to achieve, and chronic asymptomatic infections of teeth, their supporting tissues and oral mucosa are common. Maintenance of oral health is a special challenge for medically compromised patients or those with acute illness. The mouth is a significant potential source of infection and inflammation that contributes to the total burden of disease, and to overall health, which should be systematically taken into account by all clinicians.
R. Rautemaa declares support during recent years from the Finnish Dental Society Apollonia, Helsinki University Central Hospital Research Funds (EVO), and the University of Helsinki, Finland. G. Seymour and M. Cullinan declare support during recent years from the NHMRC of Australia, the Australian Dental Research Fund, Colgate Oral Care Australia and Colgate Palmolive Ltd, USA.