Proposed Mechanisms for the Relationship between Periodontal Diseases and the Severity of Covid-19: Common Pathogens, Inflammatory Mediators, and Risk Factors

Abstract

Periodontal disease (PD) is a chronic inflammatory disease with some cytokine involvement, associated with several risk factors such as diabetes, obesity, etc., Corona Virus Disease 2019 (COVID-19), a new viral infection, also appears to be related to cytokine storm and similar risk factors. In this review, we intend to evaluate the possible relationship between PD and COVID-19. For data collection, English literature was searched in databases including PubMed and Google Scholar. The keywords searched were COVID-19, SARS-CoV-2, PD, respiratory Impact of Oral pathogens on respiratory diseases: Epidemiological studies indicated that oral pathogens are related to acute and chronic lung disease, and dental plaque is a likely reservoir for respiratory pathogens. Viral presence in the periodontal pocket: SARS-CoV-2 may be released from infected periodontal cells into periodontal pockets. Common inflammatory mediators: Several studies showed that the serum levels of interleukins (IL)-1, 6, 17, etc., increase in most patients with severe COVID-19. C-reactive protein (CRP) and endothelin 1(ET-1) may also be related to COVID-19 progression, and these mediators also increase in periodontitis. Common risk factors: Due to studies, diabetes mellitus (DM), obesity, aging, and male sex are the most important risk factors common between PDs and COVID-19 and may affect treatment outcomes and prognosis. PD seems to play a significant role in exacerbating COVID-19 and even affects the mortality rate of disease.

INTRODUCTION

Periodontal diseases (PDs), which are considered a silent pandemic, affect about 10% of the world's population and assent to a multifactorial and immune-mediated disease with some cytokines involvement.[1] On the other hand, the oral cavity is a considerable source of pulmonary pathogens. Poor oral hygiene may develop post-viral complications, especially in individuals prone to biofilm changes such as diabetics, smokers, elderly, hypertensive, and cardiovascular patients.[2]

Corona Virus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in late 2019 and rapidly became a global pandemic.[3] It is a viral infection and in severe cases is expected to cause bacterial superinfection which leads to some complications including pneumonia.[2] The symptoms of COVID-19 appear to have intercommunication with cytokine storms which contain increased levels of some cytokines in serum.[4] There are also some risk factors linked with severe COVID-19 and a higher risk of complications and death like obesity, diabetes, old age, male gender, and some of them.[5]

The case-control studies have shown the relationship between PDs and the severity of COVID-19.[6,7,8] Therefore, this review will investigate the relation between COVID-19 and PDs in three sections: the importance of oral microbiomes and PDs in respiratory diseases including COVID-19, common inflammatory mediators affecting periodontitis and COVID-19, and common risk factors between the two diseases and suggest that poor periodontal status may worsen the prognosis of COVID-19. Considering the periodontal status may help physicians identify patients with a higher risk of disease progression and prompt timely invention and may decrease morbidity and mortality rates.

Importance of oral microbiomes in respiratory tract infections including COVID-19

Impact of oral pathogens on respiratory diseases

Some studies claimed that one of the possible reasons for such severe symptoms in some COVID-19 patients is bacterial superinfection and complications such as pneumonia and acute respiratory distress syndrome (ARDS). Bacterial superinfection following viral infections causes more serious conditions and increased mortality and morbidity. Bacterial superinfection was reported in more than 50% of COVID-19 deaths.[2] It was shown that bacterial superinfection is very common in severe COVID -19 patients.[9] On the other hand, antibiotics are necessary in many patients with COVID-19, emphasizing the major role of bacterial infection to exacerbate disease symptoms.[2] Evidence-based studies have shown that SARS-CoV-2 can be present in saliva in three ways: transmission through the respiratory tract by the respiratory droplet, by gingival crevicular fluid (GCF), and by salivary glands infection, with subsequent release of particles in saliva via salivary ducts.[10] Respiratory pathogens isolated from dental plaque and bronchoalveolar lavage fluid from patients with pneumonia are similar. They indicate that dental plaque is a likely reservoir for pulmonary pathogens, so saliva aspiration can cause anaerobic lung infection.[11,12] Some mechanisms have been suggested to clarify the possible role of oral pathogens in respiratory tract infection including: Aspiration of oral pathogenic bacteria into the lung; PD-associated enzymes may facilitate oral bacterial colonization, change salivary pellicles and interfere with oral bacterial clearance; and respiratory epithelium alterations (due to the periodontal cytokines) that increase the risk of respiratory infection. A key point about COVID-19 patients is that disease risk factors (age, gender, and comorbidities) are likely to affect the formation and alteration of the oral microbiome. Studies have shown that periodontal pathogenic bacteria are found in the metagenome of patients with severe COVID-19 infection.[2]

On the other hand, many patients with COVID-19 require mechanical ventilation in the Intensive Care Unit (ICU), and the plaque score is higher in ventilated patients than in other patients. These patients have a higher rate of potential respiratory pathogens (especially Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Enterobacter cloacae) in dental plaque and oral mucosa.[13] In general, oral health status is likely to affect bacterial superinfection in COVID-19 patients and thus influence disease severity and prognosis.[14] Studies showed that using chlorhexidine mouthwash in ventilated patients reduces the incidence of ventilator-associated pneumonia, the need for systemic antibiotics, and the period of mechanical ventilation in ICU.[13]

Viral presence in the periodontal pockets (PPs)

Microorganisms like the Herpes family of viruses, Cytomegalovirus, Epstein Barr Virus-1, Papillomaviruses, Human Immunodeficiency Virus, Hepatitis B Viruses, Hepatitis C Viruses, and even Helicobacter Pylori exist in PPs.[15,16,17,18] The following may be potential routes through which viruses initially infect periodontal tissues: directly infected gingival epithelial cells exposed to the oral cavity, migration of virus via the circulation, or presence of immune cells, which are infected by viruses, in the periodontal inflammatory infiltration.[19] Pocket depth was greater in virus-positive sites than in virus-negative sites.[15,16] These findings suggest that PPs are suitable environments for viruses to infect and survive. By polymerase chain reaction (PCR) test, viruses were discovered in several locations of PPs: GCF, subgingival plaque, and gingival tissues.[20] GCF is a blood filtrate and an exudation of inflamed periodontal tissue. As GCF comprises the majority of the humoral and cellular immune factors present in serum, it may indicate systemic diseases.[21] GCF may contain SARS-CoV-2, which is released from infected periodontal cells or terminal capillary complexes in periodontal tissues. The virus could arrive in the oral environment by entering PPs and mixing with saliva that was shown to contain visible SARS-CoV-2.[20,22] Furthermore, periodontal treatments can markedly reduce subgingival numbers of viruses, and this can lead to a reduction in the number of viruses in saliva.[23] It may be concluded if the SARS-CoV-2 is in the PPs, periodontal treatments can play an effective role in reducing the risk of survival of this disease. This virus may also play a role in worsening PDs and causing a destructive cycle (PDs could be worse by the virus, and more severe PDs can hurt COVID-19 disease). So, periodontal therapy could be deemed a factor of care to manage COVID-19-positive patients around the world clinically. These issues need further investigation.

SARS-CoV-2 receptors in the mouth

Coronaviruses (CoVs) have a glycoprotein called spike (S), which is responsible for various CoVs and host tropism, mediating CoVs coupling with surface-specific receptors of host cells and fusing viral cell membrane.[24] SARS-CoV-2 interacts with the angiotensin-converting enzyme 2 (ACE2) on the surface of human cells via S, leading to the infection of human respiratory epithelial cells.[25] On the other hand, Furin, a proprotein convertase is involved in viral infection via the cleavage of viral envelope glycoproteins. There is a well-known Furin-cleavage site in the spike protein of SARS-CoV-2, possibly facilitating the virus-cell fusion, which may be an explanation for the viral transmission.[26] Available data suggest the expression of ACE2 with a variety of cells, including lung tissue cells, nasal tissue cells, and salivary gland cells, and a high expression of ACE2 was reported by cells from the oral cavity.[27] In addition to ACE2, oral epithelial cells (lip, gingiva, buccal mucosa, palate, and tongue) express Furin as well. Significant expression of Furin and ACE2 on oral epithelial cells may facilitate the efficiency of SARS-CoV-2 entry.[28,29] ACE2 is also reportedly expressed in gingival and periodontal ligament fibroblasts in rats, and human tissues and blockade of angiotensin II 1 receptor (AT1R) and renin could remarkably prevent periodontal bone loss in rats.[30]

SARS-CoV-2 was capable of infecting cells with the help of its S for binding to CD 147 on cell membranes and not essentially ACE2.[31] CD 147 is expressed in oral epithelial cells, constituting the buccal and subgingival components of PP cells, spindle-shaped periodontal ligament fibroblasts, and epithelial cells.[32] Moreover, CD 147 was increasingly expressed in the gingival epithelium in cells collected from patients suffering from PDs.[29,33] It was established that the blockage of CD 147 led to a significant decrease in osteoclasts, improvement of alveolar height, and trabecular microstructure in the interdental periodontium.[34] So, severe periodontitis is associated with an increased CD147 and an increased risk of infection by SARS-CoV-2.

Common inflammatory mediators in severe COVID-19 and PDs

Several markers were identified that are common between PDs and severe COVID-19. These include some Interleukins (IL), C-reactive protein (CRP), Endothelin-1 (ET-1), and Galectin-3 (Gal-3). Inflammatory cytokine storm elevates the severity of COVID-19 which could result in severe adverse effects and death. Tissue injury can be induced extensively by cytokine storms, particularly in the lungs’ connective tissue. Among the various cytokines, such as IL-1, 6, and 17 appear to be common between COVID-19 and PDs, described in detail in the following sections [Table 1].

Table 1.

Common inflammatory mediators in severe COVID-19 and PDs

Mediator	Effect	In PDs		In Covid-19 disease
		Author	Results	Author	Results
IL-6	Proinflammatory cytokine	Machado et al.[67]	Serum levels of IL-6 in transplanted patients with periodontitis were higher than transplanted patients without periodontitis	Yang et al.[68]	Peripheral blood IL-6 concentrations utilized as a factor to predict Covid-19 development
				Aziz et al.[58]	Elevations of IL-6 could predict prolong staying in ICU and mortality
		Cardoso et al.[41]	IL-6 levels increase in chronic periodontitis	Ulhaq and Soraya[69]	Significant increases in IL-6 concentrations in severe Covid-19 patients compared to those with non-severe condition
		Almehmadi and Alghamdi[70]	Il-6 can act as a diagnostic marker for areas of active periodontitis and is capable of bone resorption
		Corbella et al.[71]	High levels of IL-6 diminished by periodontal treatment
IL-17	proinflammatory cytokine	Batool et al.[72]	Salivary levels of IL-6 and IL-17 increased in chronic periodontitis patients and the progression of chronic periodontitis increases these levels	Pacha et al.[73]	Elevated serum levels IL-17 observed in cytokine storm
		Jayakumar Sunandhakumari et al.[74]	Plasma levels of IL-17 decreased following non-surgical periodontal therapy in chronic periodontitis patients	Huang et al.[75]	Levels of IL-17 increased in SARS-CoV-2 infection
IL-1	proinflammatory cytokine	Papathanasiou et al.[76]	IL-1 family contains the major signaling molecules which stimulate and perpetuate periodontal inflammation.	Van de Veerdon and Netea[77]	Highly upregulation of IL-1/IL-6 happen in patients with severe disease and blocking of IL-1 inhibit respiratory failure in Covid-19 patients
		Fu et al.[78]	IL-1 level expression increased in the periodontitis group and inhibiting IL1 and TNF-α pathways can suppress inflammation and alveolar bone loss in periodontitis.
CRP	acute inflammatory protein	Montenegro et al.[79]	Periodontal therapy can decrease IL-6, IL-8 and, CRP levels in cardiovascular patients with elevated CRP levels	Liu et al.[80]	Developing severe COVID19 was more probable in patients with CRP >41.8 mg/L
		Swaroop Chandy et al.[81]	Serum CRP levels in patients with chronic and aggressive periodontitis were higher than healthy controls	Tan et al.[82]	CRP was related to disease progression and predicted early severe Covid-19
ET-1	A vasoconstrictor and strong mediator of vascular inflammation	Isola et al.[83]	Salivary and serum ET-1 levels in patients with coronary heart disease (CHD) and periodontitis plus CHD were higher than patients with periodontitis and healthy controls.	Farhangrazi and Moghimi[49]	ET-1 levels can be a biomarker that predicts patients at high risk to develop the severe type of Covid-19
		Kadhim et al.[84]	The Serum level of ET-1 is considered as a biomarker that links between periodontitis and risk of endothelial dysfunction
				Badagliacca et al. [85]	Blocking of ET receptors affected SARS-CoV-2 pathogenesis in experimental models and ET-1 receptor antagonists is a treatment option in this disease
		Khalid et al.[50]	ET-1 levels in patients with chronic periodontitis were significantly higher than healthy controls
Gal-3	Proinflammatory protein	Velicovic et al.[86]	Possible role of Gal-3 in development of periodontal diseases by modulation of the key players in periodontitis pathogenesis	Caniglia et al.[87]	An important area in the S protein of Covid-19 is almost the same as the morphology of Gal-3
		Kara et al.[88]	Increased level of Gal-3 is associated with the severity of PDs

Neutrophil extracellular traps (NETs)

Neutrophil-intermediated defensive mechanisms, named NETs, putatively function to retain and kill bacterial, fungal, viral, and protozoan pathogens.[35] NETosis has been attributed to a possible function in the pathophysiology of PDs with mediators, including interferon alpha, involved in the induction of releasing NET, which is reportedly at greater concentrations in periodontitis patients. An abundance of NETs in pus exudate collected from PP in association with the PPs epithelium of chronic periodontitis patients was reported.[36] Viral stimulated NETs are capable of circulation uncontrollably, giving rise to an excessive bodily systemic response by producing immune complexes, chemokines, and cytokines and eventually in favor of inflammation.[37] NETs have been shown to increase bronchoalveolar lavage fluid in patients suffering from ARDS and those with acutely exacerbated chronic obstructive pulmonary disease (COPD).[35] Arcanjo et al. were the pioneers to demonstrate that SARS-CoV2 was actually capable of activating NETosis in human neutrophils. These data refer to elevated levels of NETs in patients with COVID-19 and periodontitis. It proposes that patients affected by PDs may be at a high risk of COVID-19 linked harmful consequences, which, following proper clinical confirmation, will likely add to the present record of situations that predispose to the development of severe types of diseases.[38,39]

Common risk factors between severe COVID-19 and PD

One of the things which can help examine the relationship between PDs and COVID-19 is through close common risk factors of these two diseases, some of which will be mentioned and discussed below. Studies have shown that diabetes and some other systemic diseases may alter oral biofilms associated with higher amounts of Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis and an increased rate of periodontitis. Periodontal pathogenic bacteria are found in the metagenome of patients with severe COVID-19 infection.[2]

Diabetes mellitus (DM)

DM is a hyper-inflammatory situation that appears to increase susceptibility to Covid-19 independently of other underlying diseases.[40] Several biological mechanisms have illustrated the association between periodontitis and DM. Periodontitis causes glycemic levels to get out of control, and poor glycemic control increases the risk of developing periodontitis.[41] Some reports showed that elderly patients with chronic diseases such as DM are at higher risk for severe COVID-19 and mortality.[42] Many biomarkers are common between PDs, DM, and COVID-19 such as IL-6, IL-1, and TNF-α. Elevated levels of these biomarkers are associated with poor glycemic control, the severity of COVID-19, and the extent of the severity of periodontitis, and also blocking them was suggested as a possible treatment option.[43,44] On the other hand, it showed that initial nonsurgical periodontal therapy could reduce the levels of the aforementioned biomarkers. Furthermore, DM is associated with increased lung ACE2 expression and in severe COVID-19 cases, ACE2 in the lung may also be affected.[45]

Aging

Aging creates destructive changes in individual cells which can lead to different autoimmune, infectious, and inflammatory diseases including periodontitis. The following are some of the causes which can increase periodontal problems in old age: loss of dexterity which leads to plaque accumulation, systemic effects of diseases, poor nutritional status, low number of teeth that exist in the mouth or edentulous which can lead to malnutrition, use of medication, and lack of timely dental visits. These can alter the subgingival plaque and cause periodontal problems.[45] For COVID-19, there are strong indications for age relation in an increased number of cases, the severity of disease, and mortality, so that subclinical infections over the age of 70 are rare.[46] In severe cases, COVID-19 can increase inflammation, compromise lung tissue integrity and function, and cause pneumonia.[47] The onset of pneumonia is related to the aspiration of some bacteria from oral and nasal cavities including periodontal bacteria. Aspiration pneumonia is especially common in the elderly. The oral cavity is a great reservoir for pulmonary pathogens, and dental plaque can provide nutrition for respiratory route pathogens mainly in bad plaque control.[48] A biomarker that may unite PDs and aging is endothelin.[14] Elevated ET-1 levels also may be used as a possible biomarker to identify people at high risk for severe COVID-19.[49] Also, elevated levels of ET-1 in the serum of patients with periodontitis are observed which reduces after periodontal therapy.[50]

Obesity

Obese people are more prone to have PDs than normal-weight people, and this relationship is independent of gender and age. Increased levels of obesity are associated with more extent and severity of periodontitis. Obesity alone can create a destructive pathway in oral health. It can change the microbial composition of the periodontium and increase periodontal pathogens.[51] Adipose tissue secretes low levels of cytokines, including TNF-α and IL-1, 6, and 8. These cytokines could lead to periodontitis by changing bacteria's status in the gingiva.[45,52]

Elevated inflammatory factors in obesity can exacerbate a patient's response and lead to severe COVID-19.[53] Adipose tissue significantly increases viral shedding in obese people with influenza infection, and there is a possibility of increased viral shedding in adipose tissue in obese people with COVID-19. Viral infection can intensify the preliminary response of cytokines in adipose tissue.[54,55,56] IL-6 is one of the most important of these cytokines and an independent predictor of COVID-19 mortality.[53,57,58] IL-6 inhibition is suggested as a treatment for COVID-19.[52] Also, periodontitis can exacerbate inflammatory status in COVID-19 by spreading microbial productions as a reservoir of inflammatory cytokines. Therefore, obese people with periodontitis may have an increased hazard for severe COVID-19.[45]

Gender

The prevalence and severity of periodontitis are more common in men than women. Various reasons were proposed to explain it, including immune system function and environmental and behavioral factors, which require more detailed and extensive studies to determine.[59]

Due to COVID-19, men have a greater gender distribution than women. Some studies attributed the difference in the prevalence and severity of COVID-19 to the male gender, and men can be associated with fatal outcomes in patients with severe forms of the disease.[60,61,62] Decreased susceptibility to viral infection in women likewise can be attributed to the protection of sex hormones and X chromosomes, which play a vital role in innate and acquired immunity.[63] On the other hand, the most probable entry point for SARS-COV-2 is ACE2 and the ACE2 encoding gene is located on the X chromosome.[64] Due to gene dosage, men suffer more from X-linked diseases. Men may suffer more from ACE2 related diseases than women probably because of more occurrences of ACE2 on the X chromosome.[65] Therefore, it seems that ACE2 expression is probably higher in men than women, and this gender difference might lead to an increase in morbidity and mortality due to Covid-19 in men than women.[66]

CONCLUSION

Presumably, PDs play a role in the exacerbation of the Covid-19 disease and even affec this disease's mortality rate. According to this study, there are at least three different connections between PDs and Covid-19. Firstly, the common microbiome and oral environment as a reservoir of SARS-CoV-2. Secondly, inflammatory mediators of PDs can aggravate the condition of COVID-19. Finally, similar risk factors make the underlying condition worse. Therefore, there is a need for further studies to determine the cause-and-effect relationship between these two diseases. By proving this relationship, the need to pay attention to oral hygiene education and pay special attention to PD treatment will become more apparent. On the other hand, considering the periodontal status may help physicians identify patients with a higher risk of disease progression and prompt timely invention and may decrease morbidity and mortality rates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.