The Bidirectional Association Between Periodontitis and COVID-19: A Review of Current Evidence

1. Introduction

On March 11, 2020, the World Health Organization declared a global coronavirus disease of 2019 (COVID-19) pandemic [1]. The COVID-19 pandemic is caused by the newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). When an infected individual speaks, sneezes, coughs, sings, or breathes; SARS-CoV-2 can spread from their mouth or nose via microscopic droplet particles. COVID-19 complications are more likely in older individuals and those with underlying medical disorders like cancers, diabetes, cardiovascular diseases, or chronic respiratory diseases [2,3,4]. These comorbidities are also associated with periodontitis [5,6,7,8,9].

According to the American Dental Association, periodontitis is an inflammatory disease of bacterial etiology resulting in the loss of periodontal tissue attachment and alveolar bone [10]. It is among the most widespread conditions affecting the oral cavity and continues to be a worldwide health concern. Periodontal disease must be treated quickly since it may impact the patient’s general health [11].

The potential pathway for the relationship between periodontal health and systemic health includes periodontitis associated putative pathogenic oral microbiota, overexpression of local and systemic pro-inflammatory destructive cytokine [12,13]. In addition, the reactivation of latent systemic herpesvirus infections has been associated with the onset of aggressive periodontal disease [14]. Active human cytomegalovirus infection has been detected in deep periodontal pockets in localized aggressive periodontitis patients [15]. Therefore, at least several viruses have recently been implicated in potentiating periodontal infections. It is plausible that this herpetic viral coinfection may have an additive effect on COVID-19 risk.

Research has shown that SARS-CoV-2 enters the body through ACE-2 receptors on the surface of host cells. ACE-2 receptor expression related to systemic conditions like hypertension, chronic obstructive pulmonary disease (COPD), hepatic disorders, renal dysfunctions or diabetes, can facilitate viral entrance into host cells [16]. The primary function of the angiotensin-converting enzyme (ACE) in the renin-angiotensin system (RAS) is to inhibit the levels of angiotensin II and raise the levels of angiotensin I-7, this activates molecular signaling pathways associated with tissue damage and inflammation [17].

Studies have shown that ACE-2 receptors in human pulmonary epithelial cells are upregulated by periodontopathic bacteria [18]. Additionally, the ACE-2 receptors found on periodontal tissue cells allow the virus to enter and circulate throughout the body. When compared to the lungs, the oral cavity expresses many ACE-2 receptors [19,20,21]. SARS-CoV-2 found in dental biofilm and periodontal tissues showed that the periodontal and oral environments may contribute to COVID-19 infectivity [22]. Additionally, the blocking of SARS-CoV-2 invasion via the blocking the ACE-2 receptors and decreasing transmembrane serine protease 2 (TMPRSS2), may also prevent SARS-CoV-2 infection of the periodontal epithelium [23].

2. Effect of periodontitis on SARS-CoV-2 entry molecules

For a person to be vulnerable to the SARS-CoV-2, the virus must first successfully enter the host cells. There are multiple pathways by which SARS-CoV-2 can enter human cells [24]. These pathways involve the virus targeting these SARS-CoV-2 entry molecules present on the host cells. These molecules include ACE-2 receptors, TMPRSS2, and furin. These SARS-CoV-2 entry molecules promote virus entry into the host cells and are determinants of COVID-19 infection [25,26].

SARS-CoV-2 entry molecules are present on the dorsal tongue and gingiva. Saliva and tongue coatings were sampled to determine the presence of these molecules in the oral cavity. Immunohistochemical studies detected ACE-2 receptors in the stratified squamous epithelium of the dorsal tongue and gingiva. The ACE-2-positive cells were 2.2% of the oral tissue, of which 92% were epithelial cells [27]. Similarly, TMPRSS2 was found in the stratified squamous epithelium of the gingival keratinized surface layer. TMPRSS2 was also detected in saliva and tongue coatings via Western blot. Furin was localized mainly in the lower layers of the stratified squamous epithelium. Furin was detected in the saliva but not in tongue-coating samples [25,26]. ACE-2, TMPRSS2, and furin mRNA expression were present in taste bud-derived cultured cells, and this was further supported by immunofluorescence observations [27].

The periodontal pocket epithelium may be an entry point for SARS-CoV-2, because it expresses both ACE-2 receptors and TMPRSS2. In addition, the pocket epithelium cell layer may be thin and exhibit microulcerations; thus, increasing the risk of SARS-CoV-2 entry and infection [28].

Other factors such as salivary levels of ACE-2 were found to increase with the severity of the periodontitis and were positively associated with the alveolar bone loss [29].

ACE-2 receptors were identified in 2003 as the entry receptor for SARS-CoV. SARS-CoV-2 shares 79.5% genome sequence identity with SARS-CoV [30]. Thus, SARS-CoV-2 and SARS-CoV can enter the host cell via the same receptor. Organ dysfunction caused by SARS-CoV-2, such as acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, and acute hepatic injury, is common in severe cases. However, the overall mortality rate of COVID-19 caused by SARS-CoV-2 was lower than SARS and MERS [30].

SARS-CoV-2 entry into cells is particular to ACE-2 expressing cells; other coronavirus receptors like aminopeptidase N and dipeptidyl peptidase (DPP4) do not have the same effect [30]. The binding affinity of the SARS-CoV-2 spike glycoprotein to the ACE-2 receptor is 10–20 fold higher than that of SARS-CoV [31,32]. The ACE-2 receptor in the host cell membrane and furin cleavage site of SARS-CoV-2 allowed the virus to invade the host cells [33,34,35]. ACE-2 and TMPRSS2 are also expressed in various organs throughout the body, including the lung, heart, pancreas, kidney, bladder, small intestine, and skin [25,26].

TMPRSS2 is another essential factor that facilitates SARS-COV-2 entry and infectivity. TMPRSS2 cleaves viral spike protein and is a cofactor to ACE-2 for viral entry. It is a crucial serine protease for SARS-CoV-2 invasion [36].

In a gene expression analysis study of TMPRSS2, the Gene Expression Omnibus (GEO) dataset analysis in an experimentally induced periodontitis model showed increased TMPRSS2 expression in gingiva with periodontitis. The keratinocyte cell membrane of the periodontitis gingiva is strongly stained immunohistochemically for TMPRSS2 [13].

SARS-CoV-2 spike protein binds the cell membrane when activated by specific cellular enzymes like furin [28]. Furin cleaves the glycoprotein viral envelop, enhancing the viral fusion with the host cell membrane. Genomic characterization revealed that the furin enzyme might activate the specific site of the SARS-CoV-2 spike protein [27]. The furin cleavage site in the SARS-CoV-2 spike protein facilitates the virus-cell fusion [37]. This furin cleavage site is not found in SARS-CoV. Single-cell sequence dataset analysis found furin expression in potential target organs such as the lung, nose, heart, intestine, colon, rectum, and ileum [27]. Among the furin-expressing cells analyzed, epithelial cells make up more than 55% [27]. Sites with active periodontitis exhibit elevated expression of furin and cathepsin L proteases and may have an increased risk for virus binding and tissue infection [38].

3. Clinical studies associating periodontitis and COVID-19

Periodontitis can increase complications and the risk of death from COVID-19 (Table 1), and COVID-19 infection can aggravate periodontitis (Table 2). Research studies (Table 1 and Table 2) in the form of prospective studies, retrospective studies, cross-sectional studies, longitudinal studies, case-control studies, case series, and case reports regarding this bidirectional relationship have been published. The statistical significance and the risk of morbidity and mortality were reported in these studies.

3.1. Periodontitis associated with COVID-19 Severity

Studies (Table 1) reported that periodontitis is significantly associated with COVID-19 complications, the severity of COVID-19 symptoms, the need for assisted ventilation, ICU admissions, and death [39,40,41,42,43,44]. Furthermore, COVID-19 patients with non-treated stage 2–4 periodontitis were significantly associated with an increased level of inflammatory biomarkers of COVID-19, such as D-dimer and ferritin [40]. Subjects with the moderate form of COVID-19 had more severe periodontitis when compared to those with the mild form of COVID-19 [43]. These collective studies appear to clearly demonstrate a biologic gradient for periodontitis severity and risk for progressive COVID-19. On the contrary, one study reported no statistical significance associated with COVID-19 and periodontitis; this could be attributed to the limitations of self-reported data on periodontal disease [45].

Of significance, COVID-19 patients with periodontitis have a high risk of mortality from COVID-19 and a medium risk of COVID-19 complications, ICU admission, and assisted ventilation [46]. There was a suggestive risk of periodontal disease in the obese, presenting a higher incidence of hospitalization and mortality from COVID-19 [47]. In patients with painful, bleeding gums and loose teeth, there was a suggestive risk of hospitalization and mortality following COVID-19 infection [48].

3.2. Effects of COVID-19 on periodontitis

COVID-19 can exacerbate periodontal disease and inhibit periodontal healing, affecting patient’s response to treatment (Table 2). In a case-control study, COVID-19 is significantly associated with periodontitis severity and increased gingival inflammation [49]. Furthermore, patients with a moderate form of COVID-19 had more severe forms periodontitis than those with a mild form of COVID-19 [43].

A case report of a 38-year-old woman with generalized stage III, grade C periodontitis reported abnormal postoperative bleeding after contracting COVID-19 right after periodontal surgery. This contrasts with her uneventful postoperative visits from previous periodontal surgeries. The patient was diagnosed with COVID-19 during the postoperative phase after the third periodontal surgery on the maxillary anterior sextant. Therefore, abnormal postoperative bleeding was reported to be associated with an active degree of COVID-19 [50].

In a case series of three systemically healthy patients who contracted COVID-19, these patients experienced gingival bleeding, which was not present before active signs of COVID-19. After the COVID-19 infection subsided, gingival bleeding markedly declined in these patients. This report suggested that gingival bleeding may be attributed to COVID-19 [51].

4. Inflammatory biomarkers involved in COVID-19

Inflammatory markers identified in COVID-19 included C-reactive protein (CRP), procalcitonin (PCT), IL-6, albumin, cytokines, serum amyloid A, serum ferritin, D-dimer, cardiac troponin, and renal biomarkers such as urea and creatinine [52,53,54]. The laboratory tests for infection and inflammation in COVID-19 are elevated for erythrocyte sedimentation rate (ESR), lactose dehydrogenase (LDH), leukocyte and platelet count.

The inflammatory markers positively correlated with the severity of COVID-19 included CRP [55], PCT, Interleukin 6 (IL-6) [56], and ESR. Biomarkers in COVID-19 can be helpful in the following areas: (1) early suspicion of disease; (2) confirmation and classification of disease severity; (3) framing hospital admission criteria; (4) identification of high-risk cohort; (5) framing ICU admission criteria; (6) rationalizing therapies; (7) assessing response to therapies; (8) predicting outcomes; (9) framing criteria for discharge from the ICU and hospital [55]. Interestingly, studies reporting COVID-19 biomarkers such as CRP, D-dimer, ferritin, PCT [56], N-terminal-pro-brain natriuretic peptide (NT-proBNP) [57,58], and IL-6 also found periodontal disease progression in these systemically healthy patients.

5. Inflammatory biomarkers linked with periodontitis

Periodontal inflammatory markers include serum and salivary biomarkers [59,60]. Serum biomarkers in periodontitis include TNF-α, IL1- [61,62,63], IL-6, CRP, surfactant protein-D, cortisol, osteocalcin, oncostatin M, albumin matrix metalloproteinases-3 (MMP-3), MMP-8, MMP-9 [64]. Salivary biomarkers in periodontitis include IL-6, IL1-beta, MMP-8, macrophage inflammatory protein-1 α, TNF- α, tissue inhibitor of metalloproteinases-1 (TIMP-1), receptor activator of nuclear factor kappa-Β ligand (RANKL), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine transaminase (ALT) [65]. Studies reported increasing these above-mentioned periodontal biomarkers in COVID-19 infection with associated comorbidities [66,67].

6. Inflammatory biomarkers associating periodontitis and COVID-19

Inflammatory biomarkers (Table 3) found in COVID-19 patients that have been associated with periodontal disease progression include C-reactive protein (CRP), D-dimer, ferritin, procalcitonin (PCT) and pro-brain natriuretic peptide (Pro-BNP) [57,58]. Elevation of these inflammatory COVID biomarkers could reduce extubation survival and prognosis, increase the risk of stroke and mortality, and increase the risk of developing acute respiratory disease syndrome (ARDS) and acute kidney injury [68]. HbA1C, lymphocyte, and CRP in periodontitis patients were significantly increased in the moderate form of COVID-19 compared to the mild form [43].

Bidirectionally, periodontitis biomarkers can be increased by COVID-19 infections [68]. These periodontitis biomarkers in COVID-19 patients can contribute to periodontitis disease progression in these patients [69]. These periodontitis markers include aspartate aminotransferase (AST), IL-1β [61,62], and TNF-α [70,71,72]. Elevation of these periodontitis biomarkers could increase the probing depth and clinical attachment loss, insulin resistance, acute ischemic events, autoimmune disorders, osteoarthritis, rheumatoid arthritis, inflammatory bowel disease, noninfectious uveitis, atherosclerotic lesions, vascular dysfunction, and hypertension [69].

6.1. C-reactive protein

CRP is increased in acute infections and inflammation. CRP is produced by hepatocytes. CRP is an inflammatory marker that is detected in the plasma when there is inflammation [73]. CRP is increased in COVID-19 pneumonia [74]. Increased CRP levels in patients with COVID-19 are correlated with worse periodontal outcomes. CRP secretion commences 4–10 hours after an inflammatory stimulus, peaking at 48 hours, and has a half-life of 19 hours.

Increased CRP associated with worse outcomes may be correlated to a COVID-19-related “cytokine storm.” When evaluating a range of hematological and immunological markers, it was found that CRP was one of the markers predictive of death from COVID-19 [75]. Patients with periodontitis reported a higher risk of COVID-19 complications and a higher level of CRP [46]. There was a statistically significant link between CRP levels and the different stages of periodontitis [43].

6.2. D-dimer

D-dimer is a by-product of blood clotting. The clinical significance of D-dimer is related to pulmonary embolism, deep vein thrombosis, and disseminated intravascular coagulation [59]. D-dimer is a marker for fibrin production; high D-dimer levels indicate hypercoagulability of the blood.

In a case-control study, it was reported that D-dimer levels were elevated in patients with COVID-19 infection and became significantly higher with critical illness [76]. D-dimer was also observed in higher concentrations in chronic periodontitis [77]. Similarly, COVID-19 patients with documented periodontal care had significantly lower D-dimer levels than COVID-19 patients without [40]. The D-dimer levels in periodontitis have been significantly correlated with a higher risk of COVID-19 complication [40,42,46].

6.3. Ferritin

Human ferritin is composed of a ferritin heavy chain (FTH) and a ferritin light chain (FTL). The synthesis of ferritin is regulated by nitrous oxide, glutathione, and other “reactive oxygen species.” An increased ferritin level indicates activation of the monocyte-macrophage system. The magnitude of inflammation reflected by high ferritin levels at the admission of COVID-19 patients is independently predictive of in-hospital mortality [78].

6.4. Procalcitonin

PCT is a precursor of calcitonin and has been used as a biomarker for the diagnosis of bacterial infection. PCT has shown clinical significance by providing physicians with a positive correlation between disease severity and elevated PCT serum levels in patients [79]. The mean serum PCT levels were over four times greater in severe COVID-19 patients than in moderate COVID-19 patients [80]. The PCT levels were over eight times higher in critical COVID-19 patients than in moderate COVID-19 patients. High PCT levels have been associated with high rates of severe COVID-19 infections in patients admitted to the emergency department [81].

6.5. Pro-BNP

Patients with elevated levels of NT-proBNP values have a significantly increased risk of death from COVID-19 compared to patients with lower values [82,83]. The plasma NT-proBNP values were mainly related to the severity of pneumonia [83]. The serum levels of pro-BNP were also reported to be associated with periodontitis [84,85,86,87].

7. Herpesvirus reactivation linking periodontitis and COVID-19

Herpesvirus infection and their reactivation have been reported in varying degrees of COVID-19 severity. Viral coinfection [14,88] and active herpesviruses [15] have also been reported in aggressive periodontitis.

In severe COVID-19 patients admitted to the Intensive care unit (ICU), reactivation of herpes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6) have been reported [89,90,91]. Covid-19 patients with severe infection had a higher rate of positive EBV DNA compared to patients with mild symptoms. The median EBV DNA levels were also significantly higher in the severe COVID-19 patients compared to the mild COVID-19 patients [92]. In a cross-sectional study of mild to severe COVID-19 patients, the patient group with EBV viremia reported more severe pneumonia than the EBV-negative group [93]. On the other hand, non-geriatric patients with severe COVID-19 presented with high prevalence of CMV-seropositivity compared to patients with mild COVID-19. Interestingly, CMV-seropositivity was not significant in older patients with COVID-19. Thus, CMV-seropositivity may be a potential risk factor for severe COVID-19 in non-geriatric individuals [94].

Herpesvirus reactivation [15] and coinfections [14,88] have been linked to aggressive forms of periodontal disease. Reactivation of these herpesviruses by COVID-19 infections may have the potential to aggravate aggressive periodontitis towards rapid attachment loss and bone loss. It may also have the potential to aggravate chronic or quiescent periodontitis towards more attachment loss and bone loss.

It is well known in medicine that viral synergistic infections potentiate one or more of the indicated viral etiologic agents.

8. Conclusion

The most important finding of this literature review is to provide evidence for the increased risk of mortality and accompanying undesirable complications from COVID-19 in patients with periodontitis. Proper periodontal management with periodontal therapy and oral health maintenance may reduce death from COVID-19 infections and complications. Therefore, it is essential to understand the bidirectional relationship between periodontitis and COVID-19 infections. Better management of COVID-19 patients with periodontitis and periodontitis patients with COVID-19 may reduce the morbidity and mortality from COVID-19.