Periodontal Disease Impact and COVID-19 Severity

It is well-established that periodontal diseases are infectious and inflammatory and that the inflammatory burden of periodontal diseases can impact systemic health and create a hyperinflammatory state.^51-53 During the COVID-19 pandemic, a puzzling aspect of disease presentation was the heterogeneity of symptoms experienced by infected patients with presentations ranging from asymptomatic infections to severe disease resulting in hospitalization or death.^54,55 Underlying systemic disease and hyperinflammatory conditions, including obesity, cardiovascular disease, diabetes mellitus and tobacco use, were associated with increased morbidity and mortality from COVID-19 infections.^56-59 Much of the link between such diseases as COVID-19 severity has been attributed to the impact of a “cytokine storm” mounted by host defenses during the course of the infection.⁵⁷ Because of the inflammatory nature of both periodontitis and severe COVID-19, multiple investigations have focused on the impact of periodontitis on COVID-19 disease severity.^60-70

Common risk factors have been associated with both periodontitis and severe COVID-19, including smoking, increased age, obesity, diabetes mellitus, and cardiovascular disease.^56,61 It was initially unclear if these common comorbidities were responsible for any association between periodontitis and COVID-19 severity or if specific pathophysiology linked periodontitis and COVID-19 severity.^65,66 Studies conducted early in the pandemic demonstrated that moderate to severe periodontitis (stage 2-4) was significantly associated with an increased risk of COVID-19 complications and mortality and that radiographic alveolar bone loss was associated with increased COVID-19 seropositivity and disease severity.^67,68

Mechanisms for this association have been proposed to include: 1) the periodontal pocket as a reservoir for infectious material and/or micro-RNAs associated with upregulating ACE2 expression, 2) periodontitis as a contributor to systemic inflammation and thus the “cytokine storm”, and 3) periodontitis resulting increased bacterial aspiration into the lungs as a contributor to secondary pneumonias.⁶⁵

Periodontal Pockets as Reservoirs of Disease

Cadaveric biopsies in COVID-19 patients have demonstrated SARS-CoV-2 present within periodontal tissues.⁶⁹ As periodontal disease is associated with ulcerated pocket epithelium,⁵² the presence of periodontitis could represent a pathway for entry of SARS-CoV-2 into the systemic circulation, either directly through ulcerated epithelium or via uptake into cells through ACE2 receptors, which may be upregulated in the presence of periodontal pathogens (e.g. F. nucleatum) and micro-RNAs 146a and 155, which are increased in the periodontal pocket at sites with periodontitis.^70-72

Periodontitis and Systemic Inflammation

Systemic inflammation in periodontitis is characterized by high levels of pro-inflammatory cytokines and C-reactive protein.^73,74 Periodontitis has also been shown to prime the immune response to react to an infectious challenge with an exaggerated innate response through activation of polymorphonuclear leukocytes (PMNs) that results in their chemotaxis and activation in response to local and systemic triggers.⁷⁵ The contribution of pro-inflammatory cytokines, including those cytokines associated with periodontitis, to the “cytokine storm” which is associated with significant morbidity and mortality after COVID-19 infection could indicate that the systemic inflammation associated with periodontitis could help induce and/or potentiate this cytokine activity.^76-79 PMNs with an activated phenotype have also been noted in COVID-19 patients, resulting in increased oxidative bursts and phagocytosis which contribute to the acute respiratory distress syndrome. These activated PMNs may be upregulated or primed by pre-existing periodontitis.⁷⁹

Periodontal Bacterial Aspiration

The oral microbiome has been connected to pneumonias and other respiratory diseases.^80-81 This connection is especially pronounced in individuals with suboptimal oral hygiene, periodontitis, immune dysfunction and in nosocomial settings.⁶⁰ In such cases the oral cavity can serve as a reservoir for respiratory pathogens.^82-84 Because the oral cavity has been demonstrated to be a niche for SARS-CoV-2, viral seeding through aspiration along with other oral pathogens may also serve to enhance severity of COVID-19 or potentiate secondary pneumonias.⁶¹ Further, the combination of periodontopathogenic bacteria which may upregulate ACE2 receptors could also enhance patients’ susceptibility to SARS-CoV-2 infections.^70-72 It has also been observed that opportunistic oral pathogens, including Capnocytophaga and Veillonella can be present in pulmonary tissues and fluids of individuals with COVID-19 acute respiratory distress syndrome.⁶⁰ These pathways for secondary infection and/or potentiation of SAR-CoV-2 infection highlight the importance of oral disease prevention and the maintenance of oral health.