Does periodontitis influence the risk of COVID‐19? A scoping review

Abstract Objective Research has shown that the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) significantly influences the oral microbiome to expedite systemic diseases by invading harmful oral pathogens near and distant organs. To identify, explore, and map the possible mechanisms underlying periodontitis in severe coronavirus disease 2019 (COVID‐19) cases. Material and Methods Relevant articles published from December 2019 to February 2022 were identified and screened using keywords and inclusion criteria from various databases. Results This review sheds light on multiple pathways of periodontitis, the spread of periodontal infection and microbial metabolites to the lungs, and the dysregulated immune system with elevated cytokines, reactive oxygen species generation, nuclear DNA damage, and senescence, which have the potential to promote stronger viral attachment to host cells and the onset of COVID‐19 manifestation with increased severity and risk of mortality. In addition, the cytokine connection to SARS‐CoV‐2, T‐cell responses against periodontitis, its connection with COVID‐19, the role of host factors, and periodontal therapy have been discussed. Conclusions The relationship between COVID‐19 and periodontitis needs further investigation along with the development of alternative therapies to prevent periodontitis for better management and control of COVID‐19.

individuals with other chronic health conditions. The duration from the onset of COVID-19 symptoms to death ranges from 6 to 41 days, with a median of 14 days (W. Wang, Tang, et al., 2020). In addition to acute respiratory distress and pneumonia, SARS-CoV-2 is associated with various systemic symptoms, including gastrointestinal (GI) disturbances and impairment in the function of the central nervous system (Y. C. Li, Bai, et al., 2020;Mao et al., 2020).
SARS-CoV-2 may induce alterations in the central nervous system without directly crossing the blood-brain barrier, instead of synthesizing inflammatory cytokines, created a "cytokine storm," which triggers neurological dysfunction (J. Wang, Jiang, et al., 2020). Variations in the symptoms and classical signs of  have been reported as new variants of the SARS-CoV-2 clan.
The severe clinical course of the COVID-19 infection has been linked to chronic disorders, such as cardiovascular disease, hypertension, diabetes mellitus, obesity, and chronic renal disease (Pfützner et al., 2020;Rapp et al., 2021). Additionally, SARS-CoV-2 infection results in dysgeusia in patients, as well as oral lesions and cutaneous manifestations of COVID-19, due to the presence of angiotensin-converting enzyme-2 (ACE2) receptors on the oral mucosa, with a higher density on the dorsum of the tongue and salivary glands than on the buccal or palate mucosa (Iranmanesh et al., 2021;H. Xu, Zhong, et al., 2020). Poor oral health has been associated with the activation of several systemic diseases, including diabetes, obesity, atherosclerotic heart disease, Alzheimer's disease, and disease-related consequences (Jepsen et al., 2015;Wu & Nakanishi, 2014). Additionally, lung infection may occur as a result of oral pathogen colonization of the lower respiratory tract or modification of mucosal surfaces, which accelerates the senescence of the lung epithelium, thus producing a favorable environment for severe SARS-CoV-2 infection (Aquino-Martinez & Hernandez-Vigueras, 2021;Botros et al., 2020). Periodontal disease has been linked to an increased risk of acquiring severe COVID-19 infection, hospitalization, and mortality (Anand et al., 2021;Gupta et al., 2022;Marouf et al., 2021). Hence, this scoping review aimed to focus on the probable mechanisms underlying COVID-19 and periodontitis.

| METHODOLOGY
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews checklist was used to perform this review (Tricco et al., 2018). The study protocol was designed before the study was performed following a preliminary review of the previous literature (Colquhoun et al., 2014;Peters et al., 2015). The primary question of the scoping review was "Does periodontitis affect the risk of COVID-19?" This review aimed to explore and map the existing literature to determine whether periodontitis is associated with COVID-19. MeSH terms, keywords, and other free terms related to "Periodontitis," "Periodontopathogens," "SARS-CoV-2," "cytokines," "cytokine storm," "oral-lung axis," "senescence," "dysbiosis," or "COVID-19," were included in the initial screening. Additionally, references to relevant studies and manual searches were performed for other potentially appropriate publications.
A total of 480 articles were found in the preliminary search, of which 283 were excluded during the title and abstract screening based on the eligibility criteria. Duplicate articles were excluded with the help of a citation/reference manager (EndNote version 9). Two reviewers examined the remaining 197 articles in full length based on the inclusion and exclusion criteria. In case of disagreement, a third reviewer was contacted, who resolved the differences through discussion, and a final consensus was reached to include five studies. three were case-control studies (Anand et al., 2021;Larvin et al., 2020;Marouf et al., 2021), whereas the other two were crosssectional studies (Gomes et al., 2021;Gupta et al., 2022). The studies have been reported in India (Anand et al., 2021;Gupta et al., 2022), Brazil (Gomes et al., 2021), the United Kingdom (Larvin et al., 2020), and Qatar (Marouf et al., 2021) between 2020 and 2022. The sample sizes ranged from 70 (Gomes et al., 2021) to 13,253 (Larvin et al., 2020). These studies attempted to further answer questions related to the impact of periodontal disease on hospital admission and mortality during COVID-19 (Larvin et al., 2020), association between periodontitis and poor oral hygiene with that of COVID-19 (Anand et al., 2021), presence of SARS-CoV-2 RNA in the dental biofilm of symptomatic COVID-19 patients (Gomes et al., 2021), association between periodontitis and COVID-19-related outcomes (Gupta et al., 2022), and association between periodontitis and COVID-19 complications (Marouf et al., 2021).
Various parameters were used to answer these research questions, such as self-reported oral health indicators of periodontal disease (Larvin et al., 2020); detailed periodontal examination such as plaque scores, calculus scores, tooth mobility, gingival bleeding,   (Marouf et al., 2021).

| DISCUSSION
This scoping review aimed to summarize the existing literature on the association between periodontitis and COVID-19. The findings are inconclusive owing to a lack of evidence linking periodontal disease to an increased risk of COVID-19 (Larvin et al., 2020). However, a case-control study discovered a link between periodontitis severity and COVID-19 (Anand et al., 2021). This first-of-its-kind study assessed all the potential periodontal markers and oral hygiene levels by directly examining patients with COVID-19 (Anand et al., 2021).
Another study discovered that periodontitis was associated with a higher risk of ICU admission, assisted ventilation, and death in patients with COVID-19, as well as elevated biomarker levels that were associated with poor disease outcomes (Marouf et al., 2021). Additionally, current research has established a link between oral microbiota and periodontal inflammation (Van Dyke et al., 2020). The primary role is played by the inflammatory continuum, followed by microbial specificity (pathogenicity). This concept is also consistent with the most recent periodontal disease classification (Caton et al., 2018), which now focuses on how the resolution of inflammation brings a change in microbial composition and restoration of microbiological homeostasis.

| Periodontal disease and its relationship with COVID-19
In addition, saliva appears to be another easy mode of transmission for COVID-19, either via infected persons' nasal secretions, microdroplets, or coughs or via inhalation of salivary droplets into their own lower respiratory tract (Carrouel et al., 2021).
However, this aspiration axis may not always promote the spread of harmful bacteria; rather, proinflammatory cytokines generated during periodontal inflammation disseminate into the circulation and contribute to the development of systemic diseases such as COVID-19.

| Oral microbiota and influence on human lung diseases
The pathogens of the oral cavity (Warinner et al., 2014 Capnocytophaga, which also colonize the oral cavity of healthy humans (Wypych et al., 2019).
Patients with ventilator-assisted pneumonia (VAP) demonstrate the oropharyngeal colonization of pathogens underlying the pathophysiological mechanism behind VAP development (Bao et al., 2020). Another important aspect is the role of salivary glands as reservoirs for the SARS-2 virus. The virus found in saliva arises not only from the oral cavity/periodontal pockets but also from the salivary glands (J. .

| Lung inflammation and cytokine connection to SARS-CoV-2
The invasion of SARS-CoV-2 is mediated by the adherence to ACE2 receptors through the enzymatic cleavage of the SARS-CoV-2 spike protein involving furin-TMPRSS2-elastase, which is located on the host cell surface (Bestle et al., 2020;. According to previous studies, ACE2 is highly expressed in type II alveolar epithelial cells, indicating that these cells serve as the primary targets for the viral attack, with 83% of cells positively stained for ACE2 receptors . In the presence of oxidative stress and severe inflammation, ACE2 acts as an anti-inflammatory and antioxidant factor, contributing to the protection and maintenance of cellular integrity by inhibiting the nuclear factor-κB pathway (Fang et al., 2019). However, the entry of SARS-CoV-2 into the host cells, which is facilitated by the viral spike protein causes the virus-receptor complex internalization and ACE2 downregulation in infected cells . As a result, the NF-κB pathway is triggered, leading to p38/MAPK activation and an elevated level of cytokine release, including IL-6 and tumor necrosis factor-α (TNF-α) (Bouhaddou et al., 2020;Fang et al., 2019;Hirano & Murakami, 2020).

| Host factors and periodontal therapy
Middle-aged and older adults with periodontitis and other comorbidities, or those harboring an unhealthy oral microbiome with impaired immune functions, are more susceptible to SARS-CoV-2 infection and its associated complications, even after eliminating the virus from the system . Cancer malignancies, chronic obstructive pulmonary disease, diabetes, and hypertension appear to be driving factors for promoting viral entry and evasion of host immune defense, leading to severe disease progression and eventually death . Since microbial dysbiosis, bacterial superinfection, and host hyperresponsiveness play vital roles in the severity of COVID-19, emphasis should be placed on periodontal maintenance (Sukumar & Tadepalli, 2021). Interestingly, evidence indicates a potential role of Galectin-3 mediated increased immune response and increased viral attachment in the association between periodontal disease and COVID-19. Moreover, an area in the coronavirus spike protein depicts a morphology that is highly similar to that of Galectin-3. Therefore, the maintenance of a healthy periodontal status appears critical in SARS-CoV-2 infection F I G U R E 1 Multiple pathways of periodontitis contribute to cellular senescence in the lungs epithelium and influencing the risk of SARS-CoV-2 infection to host cells. ACE2, angiotensin-converting enzyme-2; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; NF, nuclear factor; OLAA, oral-lung aspiration axis; ROS, reactive oxygen species; SARS-COV-2, severe acute respiratory syndrome coronavirus-2; TNF, tumor necrosis factor; T-regs, regulatory T cells.
In addition, a strong correlation between the severity of COVID-19 and type 2 diabetes in patients with periodontitis was recently reported, showing that the number of ACE2 receptors was prominently higher in those with periodontal disease and diabetes than in those with periodontal disease alone (Casillas Santana et al., 2021). In other words, diabetes and periodontal disease significantly contributed to the increase in the number of ACE2 receptors among individuals, thereby enhancing the susceptibility to SARS-CoV-2 infection and subsequently accelerating the disease prognosis. However, further clinical studies are needed to explore whether patients with COVID-19 might benefit from periodontal treatment, as it could reduce the severity of complications (Shamsoddin, 2021).

| CONCLUSION AND FUTURE PERSPECTIVE
The

ACKNOWLEDGMENT
Open access funding was provided by the Qatar National Library.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.