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Gingivitis and periodontitis are inflammatory diseases of the supporting structures that surround the teeth, which include the gingiva, periodontal ligament, alveolar bone, and cementum.1 All individuals are susceptible to developing gingivitis, a reversible form of gingival inflammation; however, gingivitis can be a precursor to the development of more serious, irreversible forms of periodontal disease.2 Gingivitis is caused by dysbiotic dental biofilm and, in general, its severity is related to the type and amount of bacteria that have accumulated at and just below the gingival margins throughout the mouth. In addition, modifying factors for gingivitis include both local (eg, dental biofilm retentiveness, oral dryness) and systemic (eg, smoking, metabolism, nutrition, pharmacologic agents, sex steroid hormone elevation, hematologic conditions) ones.2-4 The removal of biofilm and resolution of local etiologic factors reverses the clinical and histologic symptoms of gingivitis and results in the reduction of local and systemic inflammatory markers in patients.2,4,5
Periodontitis is a chronic, multifactorial inflammatory disease of the hard and soft tissues supporting the teeth that is initiated by dysbiotic dental biofilm. In a susceptible host, after the accumulation of dysbiotic biofilm, the underlying host immuno-inflammatory response to the biofilm and its virulence factors can result in progressive destruction of the periodontal ligament and alveolar bone if not adequately resolved.1,6 The average progression of periodontal disease is slow to moderate and involves approximately 0.1 mm of attachment loss and 0.2 teeth lost annually.7 Accelerated attachment loss has been associated with a lack of access to comprehensive dental care as well as the presence of local and/or systemic factors.7
In an updated classification system from the American Academy of Periodontology (AAP) and the European Federation of Periodontology, individuals are classified using both a stage and a grade to characterize their disease severity and risk of future disease progression, respectively.6,8 The stage of periodontitis is assigned a value of I through IV based on the patient's current disease presentation, including attachment, bone, and tooth loss as well as case complexity, whereas the grade of periodontitis is defined using the letters A, B, or C based upon the patient's risk and evidence of the rapidity of disease progression over time.6,8
Regarding the prevalence of periodontitis, it has been estimated to affect more than 42% of US adults older than 30 years of age, which amounts to 64.7 million individuals.9 These statistics suggest that the prevalence of periodontitis among US adults is nearly twice that of diabetes mellitus10 and four times greater than that of coronary artery disease.11 As a chronic immuno-inflammatory disease, periodontitis may pose a significant systemic burden for individuals and can influence systemic health in myriad ways.12
Evidence of Periodontal-Systemic Interaction
Chronic inflammation has been associated with many chronic diseases, and the World Health Organization (WHO) has identified chronic inflammatory conditions as the largest threat to public health.13 The periodontal tissue breakdown seen in periodontitis is a result of a host inflammatory response to bacterial stimuli.3 Specifically, periodontal tissue breakdown is mediated by proinflammatory cytokines and other proinflammatory biomarkers. As these proinflammatory mediators interact with bacteria and the surrounding tissues, they also elevate proinflammatory markers systemically.14-17 Due to this influence of periodontal disease on levels of systemic proinflammatory markers, much interest has been paid to the potential impact of periodontal disease on overall health. Recent evidence has highlighted the importance of periodontal health and appropriate periodontal therapy in the maintenance of overall health.
Periodontal Disease and Hypertension
A recent case-control study highlighted the relationship between periodontal disease and hypertension.18 It has been well established that elevated arterial blood pressure, particularly if it is chronic, increases the risk of complications from cardiovascular diseases such as stroke and myocardial infarction.19 In the United States, approximately 30% of adults have hypertension, and it has been estimated that 15% to 50% of these individuals may be unaware of their condition.20,21 Furthermore, many individuals with a diagnosis of hypertension demonstrate suboptimal control with behavioral and pharmaceutical interventions.19 Inflammation is considered an important driver of vascular dysfunction and has been implicated in the development and progression of hypertension.22,23
The case-control study demonstrated a link between periodontitis and high blood pressure, finding that individuals with severe periodontitis (defined as affecting ≥ 50% of the teeth with pocket depths of ≥ 5 mm and marginal alveolar bone loss of ≥ 30%) exhibited a two-fold higher risk of having an elevated systolic blood pressure (ie, > 140 mmHg) when compared with those without periodontitis (14% versus 7%, respectively).18 In addition, the study found that participants with periodontitis exhibited increased plasma levels of glucose, low-density lipoproteins (LDLs) (ie, "bad" cholesterol), high-sensitivity C-reactive proteins (hs-CRPs), and white blood cells as well as lower levels of high-density lipoproteins (HDLs) (ie, "good" cholesterol) when compared with those in the control group.18 The study's findings are also noteworthy because the participants were relatively young, averaging 35 years of age, and unaware of their hypertension.18 This investigation highlights the importance of screening for hypertension in the dental office and the potential benefit that periodontal therapy may have for a common health condition that has a significant societal impact.
Periodontal Disease and COVID-19 Severity
The first case of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in the United States on January 21, 2020.24 A feature of the disease's severity is a "cytokine storm" in which the virus harnesses the host immuno-inflammatory response mechanism and sends it into overdrive.25 Initial data during the pandemic indicated that many patients who suffered from serious COVID-19 symptoms, such as those requiring hospitalization and the need for ventilation or those with the potential to result in death, had other comorbidities, particularly ones that were related to chronic inflammatory conditions and/or an immunocompromised status.26 It follows that these chronic inflammatory conditions and others, including periodontitis, could impact the severity of the inflammatory response and the subsequent cytokine storm.25,27 A recent study found that among hospitalized COVID-19 patients, preexisting periodontitis was a significant risk factor for more severe COVID-19 symptoms and that it increased the risk of death by nearly 9 times.28 This study and others underscore the mantra that oral health is integral to overall health and highlight the critical role of dental healthcare providers in the healthcare system.
Point-of-Care Diagnostic Technologies
Clinical parameters that are currently used to make a periodontal diagnosis, including pocket depth and the presence of bleeding on probing, are measures of historical attachment loss, but these parameters may fail to predict future periodontal breakdown.2,6 Because of this, the development of point-of-care diagnostic technologies that are able to identify markers of periodontal breakdown prior to clinical evidence of tissue destruction is of keen interest to facilitate early identification of and intervention for periodontal diseases. Salivary diagnostics have targeted many inflammatory markers and enzymes, and much interest has focused on five promising biomarkers for the early diagnosis of periodontitis: matrix metalloproteinase-8 (MMP-8), macrophage inflammatory protein-1 alpha (MIP-1α), interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), and hemoglobin (Table).29 Much of the development of point-of-care technology to detect these and other biomarkers in saliva involves "lab-on-a-chip" mechanisms.29,30 In addition, research has shown that advances in the utilization of microRNAs and oxidative stress markers have shown promise in identifying periodontal disease progression.31-33
Advanced Host Modulation Strategies
Traditional periodontal therapy is focused on the mechanical removal of dysbiotic biofilm, the elimination of biofilm-retentive factors, and the repair of the destruction caused by past disease. However, given the significant influence of the host immuno-inflammatory response on periodontal disease progression and hard- and soft-tissue destruction, emerging research has focused on novel mechanisms that may modulate and reduce this response that could be used in addition to traditional therapies to control the progression of periodontitis.
Currently, the only pharmaceutical host modulation therapy approved by the US Food and Drug Administration (FDA) is low-dose doxycycline, which inhibits matrix metalloproteinases.34 Although anticytokine therapies, which are generally used to treat rheumatoid arthritis and other autoimmune conditions, may help to control the progression of periodontitis, these drugs also carry a risk of untoward side effects and are expensive, which has limited their application in treatment.34 Pro-resolving lipid mediators, such as lipoxins, resolvins, protectins, and maresins, which can be derived from dietary fatty acids, have been shown to play a critical role in the resolution of inflammation; therefore, their adjunctive use in the treatment of periodontitis is promising.35 In addition, small molecule therapeutics, such as histone deacetylase inhibitors, that target specific cytokine-mediated processes are emerging as promising host modulation target therapies. One benefit of these small molecule therapeutics is their ability to be administered orally and even topically, which could improve compliance.34 These treatments may have significant potential to improve the practitioner's ability to deliver more targeted, patient-centered care, but further research is needed to confirm their safety and efficacy.
Summary
Emerging science has highlighted that the proper diagnosis and treatment of periodontitis is a critical component in establishing overall wellness. Furthermore, as diagnostic technologies evolve, the use of salivary and other biologic markers to detect the initial stages of periodontal disease may enable dental healthcare practitioners to intervene earlier, and these technologies may be leveraged as surveillance tools as a part of screening and public health measures. Finally, emerging treatments for periodontitis that combine an anti-infective approach with host modulation therapy, including pro-resolving lipid mediators and small molecule therapeutics that influence inflammatory responses, may offer potentially impactful options with minimal side effects.
About the Author
Maria L. Geisinger, DDS, MS
Professor and Director
Advanced Education Program in Periodontology
University of Alabama at Birmingham School of Dentistry Birmingham, Alabama
References
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