Collaborative Patient Care and the Oral-Systemic Link

As the body’s systems and organs are tightly connected, the impact of oral health on systemic health is biologically obvious and supported by emerging evidence.¹ However, the effect of oral inflammation and the exposure time required to trigger a measurable medical incident may vary significantly among individuals. The main challenges to conducting interventional clinical trials and establishing the causative perio-systemic link are the difficulty in reaching an “end-point” treatment outcome in patients with severe periodontitis and the long-term follow-up time needed to capture a resolving medical incident.² Additionally, each clinical study has its own limitations and positive incremental relief of the systemic inflammatory burden has yet to be defined and is challenging to measure. Future studies must continue to investigate the targeted strategic link applicable to susceptible hosts with personalized precision medicine. However, from a clinical perspective, our passion and obligation as a “doctor” to care for patients’ health and general well-being should not be discounted. Another, more important question is how can we contribute to optimal total patient care? How can we move forward collectively as oral healthcare providers to advance our interprofessional patient care with our medical colleagues? Following are some recent updates about the periodontal-systemic link and potential mechanisms for its causative and bidirectional relationship.

What Are the Established Links?

Periodontal disease is the sixth most common human illness,³ but the severity and rate of disease progression varies significantly among individuals. This is why the revised American Academy of Periodontology’s classification system for periodontal disease incorporated a new dimension of grading to stratify the risk of disease progression. While mild periodontitis affects half of adults, severe periodontitis impacts about 11% of the global population. Periodontal disease has also been associated with many of the chronic diseases related to aging and premature mortality.⁴ According to the National Center for Health Statistics at the United States Centers for Disease Control and Prevention, the seven leading causes of death in 2010 were heart disease, cancer, chronic lower respiratory disease, stroke/cerebrovascular diseases, unintentional accidental injuries, Alzheimer’s disease, and diabetes.⁵ All of these except one are chronic inflammatory diseases associated with periodontitis.

In 2012, experts from the American Academy of Periodontology and the European Federation of Periodontology conducted consensus reports that focused on the three most associated diseases: cardiovascular disease, diabetes mellitus, and premature birth.^6-8 Later, systemic reviews, meta-analyses, and additional studies further established the association between periodontitis and these three diseases.^9-11 This field of research has expanded to 57 diseases over the years, and more than one-third of registered clinical trials were conducted to investigate the association between periodontitis and systemic diseases.¹²

Diabetes has become a solid risk factor for periodontal disease as shown in a longitudinal study, which found that patients with diabetes had a two to three times higher incidence of newly diagnosed periodontitis when their glucose levels were not under control (HbA1c > 7.5%). Additionally, the rate of periodontal disease progression and tooth loss was also significantly higher in patients with diabetes.¹³ Pre-diabetic conditions, such as metabolic syndrome and obesity, also demonstrated a modest odds ratio of 1.38.¹⁴ It is important to note that periodontal disease is multifactorial, and most reported odds ratios pooled all of the patients together without risk stratification. For example, the association of cardiovascular and periodontal diseases is established more specifically in patients with severe periodontitis.^15,16

Maternal periodontitis is associated with an increased risk of adverse pregnancy outcomes, which not only includes pre-term birth but also low birthweight, still-birth and miscarriage.¹⁷ This link does exhibit heterogeneity of results, and another limitation to the research is the fact that the diagnostic criteria of periodontitis with attachment loss does not correspond well to the level of oral inflammation in this population. Severe gingivitis in pregnant women is very common and could be challenging to treat and maintain.

Last but not least, other emerging associated diseases include, rheumatoid arthritis,^18-19 osteoporosis,²⁰ certain kinds of cancer,^21,22 pneumonia,²³ chronic obstructive pulmonary disease,²⁴ Alzheimer’s disease,²⁵ and stroke.²⁶ Many of the links are still under investigation but several convincing mechanisms have been proposed.

Potential Mechanisms

Approximately 500 known species of bacteria reside in the oral cavity. The gingival sulcus is the first barrier to bacteria, and it serves as the frontline battlefield for the fight between microbes and immune cells. There are several potential mechanisms why a local infection and inflammatory lesion may impact the whole body. The oral cavity is indeed an entry point for many bacteria: either through the esophagus, airway or blood vessels. Poor oral hygiene and periodontal infection are associated with increased obligate anaerobes, such as Porphyromonas. gingivalis, Fusobacterium nucleatum, and Prevotella intermedia, in the lungs of patients with lower respiratory track infection and pneumonia.^27-28 It is typically assumed that most bacteria cannot survive gastric acid. However, in an animal model, oral application of P. gingivalis alone can cause changes in the gut microbiota and lead to systemic inflammation indirectly through endotoxaemia.²⁹

What’s more striking is the fact that the DNA of specific oral pathogens can be identified in the human brain,²⁵ atherosclerotic tissue,³⁰ joint,³¹ uterus,³² and pancreatic islet.³³ The only explanation is that the bacteria are traveling through the bloodstream and a dead bacterium can also elicit serious immune response and generate auto-reactive antibodies. The endotoxin released locally from the pathogen may also cause low-grade systemic inflammation and distant tissue damage. Additionally, at the frontline of the battlefield against bacteria, millions of immune cells produce significant pro-inflammatory cytokines and matrix proteinase that not only cause local collateral tissue damage but also impact the whole body. Inflammation in the circulation will induce acute-phase response in liver to release C-reactive protein, which is a biomarker for such systemic impact. ³⁴

Collaborative Patient Care to Promote Overall Health

As part of the larger healthcare system designed to promote patients’ overall health, dentists should make proper medical referrals and communicate closely with primary care physicians. We need to educate the public about the importance of oral health and how it impacts their systemic health. Improving overall health will also support the ability of patients’ immune systems to fight against oral infections and inflammation.

Longitudinal human studies have demonstrated that treatment of periodontal disease can reduce systematic inflammation, improve endothelial function, inhibit the progression of carotid atherosclerosis^35,36 and reduce the incidence of stroke.²⁶ Improved periodontal health can positively impact glycemic control in patients with diabetes—reducing HbA1c ranging from 0.2% to 1.03%, which is clinically significant and equivalent to the effect of certain medications.³⁷ Additionally, improved oral hygiene and periodontal health can reduce the risk of pneumonia³⁸ as well as the mortality rate from aspiration pneumonia.³⁹ There are many more emerging health benefits of good oral health that need to quantified with high-quality studies and then we need to refine our precision periodontal medicine to maximize the impact.

Conclusion

Periodontal health is tightly connected with systemic health. Oral infection and inflammation can cause significant impact on overall health through three main pathways: bacteremia, disseminated endotoxin, and systemic inflammatory cytokines. We must support patients’ immune systems so they can fight against this silent inflammatory burden before it is too late. Interprofessional patient care to promote health is warranted in our healthcare system.

References

1. Genco RJ, Sanz M. Clinical and public health implications of periodontal and systemic diseases: An overview. Periodontol 2000. 2020;83:7–13.
2. Beck JD, Papapanou PN, Philips KH, Offenbacher S. Periodontal medicine: 100 years of progress. J Dent Res. 2019;98:1053–1062.
3. Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386:743–800.
4. Söder B, Jin LJ, Klinge B, Söder PO. Periodontitis and premature death: a 16-year longitudinal study in a Swedish urban population. J Periodontal Res. 2007;42:361–366.
5. Murphy SL, Xu J, Kochanek MA. Deaths: final data for 2010. Nat Vital Stat Rep. 2013;61:1-11.
6. Tonetti MS, Van Dyke TE and on behalf of working group 1 of the joint EFP/AAP workshop. Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol. 2013;40(Suppl. 14):S24-S29.
7. Chapple ILC, Genco R, on behalf of working group 2 of the joint EFP/AAP workshop. Diabetes and periodontal diseases: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol. 2013;40(Suppl. 14):S106-S112.
8. Sanz M, Kornman K, on behalf of working group 3 of the joint EFP/AAP workshop. Periodontitis and adverse pregnancy outcomes: consensus report of the JointEFP/AAP Workshop on Periodontitis and Systemic Diseases. J Clin Periodontol. 2013;40(Suppl. 14):S164-S169.
9. Ide M, Papapanou PN. Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes—systematic review. J Periodontol. 2013;84(4 Suppl):S181–S194.
10. Mauri-Obradors E, Jané-Salas E, del Mar Sabater-Recolons M, Vinas M, López-López J. Effect of nonsurgical periodontal treatment on glycosylated hemoglobin in diabetic patients: a systematic review. Odontology. 2105;103:301–313.
11. Roca-Millan E, González-Navarro B, del Mar Sabater-Recolons M, Marí-Roig A, Jané-Salas E, López-López J. Periodontal treatment on patients with cardiovascular disease: systematic review and meta-analysis. Med Oral Patol Oral Cir Bucal. 2018;23:e681–e690.
12. Monsarrat P, Blaizot A, Kemoun P, et al. Clinical research activity in periodontal medicine: a systematic mapping of trial registers. J Clin Periodontol. 2016;43:390-400.
13. Genco RJ, Borgnakke WS. Diabetes as a potential risk for periodontitis: association studies. Periodontol 2000. 2020;83:40-45.
14. Jepsen S, Suvan J, Deschner J. The association of periodontal diseases and metabolic syndrome and obesity. Periodontol 2000. 2020;83:125-153.
15. Bahekar AA, Singh S, Saha S, Molnar J, Arora, R. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: a meta-analysis. Am. Heart J. 2007;154:830–837.
16. Herrera D, Molina A, Buhlin K, Klinge B. Periodontal diseases and association with atherosclerotic disease. Periodontol 2000. 2020;83:66-89.
17. Bobetsis YA, Graziani F, Gürsoy M, Madianos PN. Periodontal disease and adverse pregnancy outcomes. Periodontol 2000. 2020;83:154-174.
18. Joseph R, Rajappan S, Nath SG, Paul BJ. Association between chronic periodontitis and rheumatoid arthritis: a hospital-based case-control study. Rheumatol Int. 2013;33(1):103-109.
19. Wang CW, Lu HK. Relationship between periodontal disease and rheumatoid arthritis- significance of interleukin-17. Chin Dent J. 2007;26: 9-16.
20. Wang CJ, McCauley LK. Osteoporosis and periodontitis. Curr Osteoporos Rep. 2016;14:284-291.
21. Söder B, Yakob M, Meurman JH, Andersson LC, Klinge B, Söder PÖ. Periodontal disease may associate with breast cancer. Breast Cancer Res Treat. 2011;127:497-502.
22. Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: Epidemiologic studies and possible mechanisms. Periodontol 2000. 2020;83:213-233.
23. Scannapieco FA, Genco RJ. Association of periodontal infections with atherosclerotic and pulmonary diseases. J Periodontal Res. 1999;34:340-345.
24. Scannapieco FA. Individuals with chronic obstructive pulmonary disease (COPD) may be more likely to have more severe periodontal disease than individuals without COPD. J Evid Based Dent Pract. 2014;14:79–81.
25. Dominy SS, Lynch C, Ermini F, et al. Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv. 2019;23;5:3333.
26. Lee YL, Hu HY, Huang N, Hwang DK, Chou P, Chu DC. Dental prophylaxis and periodontal treatment are protective factors to ischemic stroke. Stroke. 2013;44:1026–1030.
27. Hata, R, Noguchi S, Kawanami, T, et al. Poor oral hygiene is associated with the detection of obligate anaerobes in pneumonia. J Periodontol. 2020;91:65-73.
28. Scannapieco FA, Genco RJ. Association of periodontal infections with atherosclerotic and pulmonary diseases. J Periodontal Res.1999;34:340-345.
29. Desvarieux M, Demmer RT, Jacobs DR, Papapanou PN, Sacco RL, Rundek T. Changes in clinical and microbiological periodontal profiles relate to progression of carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology study. J Am Heart Assoc. 2013;2, e000254.
30. Kozarov EV, Dorn BR, Shelburne CE, Dunn WA Jr, Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler Thromb Vasc Biol. 2005;25:e17-18.
31. Moen K, Brun JG, Valen M, et al. Synovial inflammation in active rheumatoid arthritis and psoriatic arthritis facilitates trapping of a variety of oral bacterial DNAs. Clin Exp Rheumatol. 2006;24:656–663.
32. Han YW, Fardini Y, Chen C, et al. Term stillbirth caused by oral Fusobacterium nucleatum. Obstet Gynecol. 2010;115:442-445.
33. Ilievski V, Toth PT, Valyi-Nagy K, et al. Identification of a periodontal pathogen and bihormonal cells in pancreatic islets of humans and a mouse model of periodontitis. Sci Rep. 2020;10:9976. 
34. Schenkein HA, Papapanou PN, Genco R, Sanz M. Mechanisms underlying the association between periodontitis and atherosclerotic disease. Periodontol 2000. 2020;83:90-106.
35. Tonetti MS, D’Aiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. N Engl J Med. 2007;356:911–920.
36. Offenbacher S, Beck JD, Moss K, et al. Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol. 2009;80:190-201.
37. Genco RJ, Graziani F, Hasturk H. Effects of periodontal disease on glycemic control, complications, and incidence of diabetes mellitus. Periodontol 2000. 2020;83:59-65.
38. Yang LC, Suen YJ, Wang YH, Lin TC, Yu HC, Chang YC. The association of periodontal treatment and decreased pneumonia: a nationwide population-based cohort study. Int J Environ Res Public Health. 2020;17:356.
39. Müller F. Oral hygiene reduces the mortality from aspiration pneumonia in frail elders. J Dent Res. 2015 Mar;94:14S-16S.