The Mouth-COVID Connection

Published online ahead of print July 30, 2020. Set for publication in the October Issue of Journal of California Dent. Association

The Mouth-COVID Connection: Il-6 Levels in

Periodontal Disease — Potential Role in

COVID-19-Related Respiratory Complications

Shervin Molayem, DDS, and Carla Cruvinel Pontes, DDS, MsC, PhD

Molayem S, Pontes CC. The Mouth-COVID Connection: Il-6 Levels in Periodontal Disease — Potential Role in

COVID-19-Related Respiratory Complications [published online ahead of print July 30, 2020]. J Calif Dent

Assoc doi: 10.35481/jcda-48-10-01.

Disclaimer: This article has been peer reviewed and accepted for publication in the Journal of the California Dental Association and is posted online before publication

in October 2020. This article may contain statements, opinions and information that have errors in facts, figures or interpretation.

Abstract

Researchers are combining efforts to better understand SARS-CoV-2 and recent

findings point to the importance of cytokine storms. Elevated IL-6 levels can predict COVID-19

pulmonary complications. Dental professionals play a significant role, since periodontitis can

increase IL-6 levels locally and systemically. Periodontal treatment have positive effects in

systemic inflammation and the importance of oral hygiene and periodontal health for

respiratory conditions and COVID-19 should not be underestimated.

Authors

Shervin Molayem, DDS, earned his Doctor of Dental Surgery at the University of California, Los

Angeles, School of Dentistry and completed a specialty program in periodontics at the Herman

Ostrow School of Dentistry of USC. He is a periodontist in private practice in Los Angeles.

Conflict of Interest Disclosure: None reported.

Carla Cruvinel Pontes, DDS, MsC, PhD is a Brazilian dentist and researcher with an MSc degree

in periodontology from the University of Sao Paulo and a PhD in health sciences from the

University of Copenhagen, Denmark. She works as an independent dental researcher and

writer in Cape Town, South Africa

Conflict of Interest Disclosure: None reported.

Abstract

Researchers around the world are combining efforts to increase our understanding on SARS-

CoV-2, and recent findings point to the potential role of cytokine storms in the severity of this

viral infection. High IL-6 levels have been linked to significantly higher risk for pulmonary

complications and increased need for mechanical ventilation in COVID-19 patients. As dental

professionals try to establish a new normal in their practices, they play a significant role in

decreasing transmission of the coronavirus disease and decreasing inflammation and IL-6 levels

because periodontitis has been shown to increase cytokine levels locally and systemically.

Periodontitis has been previously associated with increased risk for respiratory conditions, such

as chronic obstructive pulmonary disease (COPD), pneumonia and lung function, hence there is

biological plausibility for a link between periodontitis, IL-6 levels and COVID-19-related

pulmonary problems. The potential mechanisms behind this association include systemic

inflammation, bacterial load, gut dysbiosis and endothelial function. Genetic variations in the

IL-6 gene can also be a relevant risk factor for exacerbated inflammatory response. Findings

from pneumonia studies showing lower rates of infection and mortality associated with plaque

control suggest that dental care can have a major impact in the coronavirus disease course.

Furthermore, for systemically healthy patients and for those who have systemic conditions,

periodontal treatment can decrease the burden of systemic inflammation, thus decreasing the

risk for pulmonary complication due to COVID-19. Despite the lack of studies on this topic, the

importance of oral hygiene and periodontal health for respiratory conditions and COVID-19

infections should not be underestimated. Dentists should promote screening, plaque control

and periodontal treatment because a healthy periodontium can help decrease the severity and

complications related to COVID-19.

Introduction

The global COVID-19 outbreak has caused a public health emergency crisis, as declared by the

World Health Organization in January 2020.

While up to 80% of patients infected by SARS-

CoV-2 recover after mild cold-like symptoms with no major complications, 20% can develop

serious respiratory complications that can develop into acute respiratory distress syndrome due to the

virus’ ability to infect human respiratory epithelial cells. Around 5% of COVID-19

patients require intensive care and mechanical ventilation.

As researchers from different countries try to shed light on potential treatments and vaccines

against the coronavirus, recent findings point to the potential role of cytokine storms in this

viral infection, particularly interleukin-6 (IL-6).

3–5

A recent study from Germany suggested that

high IL-6 levels can be a powerful predictor of respiratory failure and need for mechanical

ventilation in hospitalized COVID-19 patients.

Dental professionals have suffered the impact of COVID-19 in profound ways, which is directly

related to the importance of the oral cavity as a transmission route, the potential for salivary

glands to function as reservoirs for COVID-19, the infectivity of saliva and occupational health

issues due to the nature of dental treatments. With the reopening of dental practices during the

pandemic, dental professionals are faced with challenges that range from strict infection control

measures to a decrease in the number of patients willing to undergo dental treatments.

In these extraordinary times, dental professionals might need to shift their focus to a general

health and systemic inflammation approach. In this context, periodontitis has been linked to

increased levels of proinflammatory cytokines, including IL-6, which is a recognized mediator

in the periodontal destruction process.

The ability of nonsurgical periodontal treatment to

lower cytokine levels has been highlighted in the dental literature.

8,9

Thus, lower IL-6 levels and

inflammation resulting from periodontal treatment can potentially protect COVID-19 patients

against life-threatening respiratory complications.

In fact, previous studies have linked periodontitis to respiratory conditions, with increased risk

for complications and higher mortality rate in hospitalized patients.

The impact of a

connection between periodontal treatment, IL-6 levels, respiratory conditions and COVID-19

can be powerful considering the high prevalence of periodontal disease in adults, the high

transmission rate of SARS-CoV-2, the limited access to periodontal treatment during the

pandemic and the shortage of health care resources related to hospitalized COVID-19 patients

who require mechanical ventilation.

The proposed biological mechanisms behind the link between periodontitis and increased risk

for COVID-19 complications are presented in the FIGURE. In this review, the current state of

knowledge on the scientific foundation for the connection between IL-6 levels and periodontitis,

COVID-19 and respiratory diseases is presented, including the importance of this cytokine for

periodontitis, viral infections and COVID19, the effect of periodontal treatment in IL-6 levels,

the biological link between periodontitis, respiratory problems and coronavirus disease. The

clinical importance of this review lies in the awareness that dental professionals can have a

major impact on the COVID-19 pandemic through promotion of periodontal health, considering

the benefits of prevention and treatment of periodontal disease on overall health, including the

prevention of complications resulting from the coronavirus disease.

IL-6 in Relation to Periodontitis

Periodontitis is characterized by an inflammatory process that results in destruction of the

periodontium triggered by mediators derived from the adaptive and innate immune response

to microorganisms in the biofilm.

Cytokines are soluble proteins that attach to cell surfaces

through specific receptors, regulating cell function and mediating complex cell interactions

involved in periodontal destruction. In periodontitis, cytokines cause intracellular cascades and

phenotypic changes that regulate the amplitude and severity of the host response with

interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 being the most extensively

investigated.

IL-6 is a well-known proinflammatory cytokine secreted by a multitude of cells, including

monocytes, macrophages, endothelial cells, epithelial cells, B and T cells. In periodontitis, IL-6 is

crucial for regulation of the host response to infection, injury and alveolar bone resorption.

The participation of IL-6 in periodontal inflammation has been well described in the literature

through genetic studies on IL-6 polymorphisms and studies evaluating IL-6 expression levels in

serum, saliva, gingival crevicular fluid (GCF) and gingival tissues. Each of these categories is

discussed below.

Genetic Studies: IL-6 Polymorphisms and Risk for Periodontitis

Polymorphisms deriving from one base change in the genome are known as single nucleotide

polymorphisms (SNPs), resulting in different gene versions or alleles. Cytokine SNPs can

influence risk and outcomes for certain diseases, such as periodontitis, by influencing secretion

of these mediators, immune and inflammatory responses.

The diversity in the clinical

presentation of periodontitis have been partly attributed to genetic nucleotide variations in the

IL-6 gene, localized in chromosome 7.

In 2003, the first study associating an IL-6

polymorphism (-174) to periodontitis was published and a protective effect for allele C against

periodontitis was reported in a sample from Brazil.

The role of IL-6 polymorphisms in the susceptibility to periodontitis has been explored in

several other studies, with different SNPs being investigated (-174, -572, -597, -373, -190, -1363, -

6106, -1480, +874). A summary of published studies on IL-6 gene polymorphisms in patients

with periodontitis is presented in the TABLE. For the IL-6 gene, SNP -174 (promoter region) and

-572 (regulatory region) have been the most investigated, and the majority of studies have

found an association between these polymorphisms and the risk for periodontitis,

17–28

which

was confirmed in a recent meta-analysis.

The SNP -1363 was only evaluated in two studies,

which reported a positive association with periodontitis.

20,30

Two studies investigated IL-6 SNP -

597, from which one found an association with periodontitis.

31,32

The remaining IL-6

polymorphisms have been investigated to a lesser degree with varying results (TABLE).

Data on IL-6 gene variants suggest that SNP -174 allele C can protect against chronic and

aggressive periodontitis, while allele G increases the risk. Likewise, for SNP -572, allele C seems

to have a protective effect for chronic and aggressive periodontitis. The majority of these studies

report on data from European, Asian and Brazilian participants, hence further studies on

different ethnic groups are warranted. The protective effect of the polymorphisms has been

linked to lower serum IL-6 levels.

32,33

The other IL-6 SNPs have been studied to a lesser degree,

reasons why their association to periodontitis needs to be further explored.

In Vitro Studies on IL-6 Expression in Periodontitis

High expression of IL-6 has been reported in inflamed gingival tissues, and human gingival

fibroblasts are able to produce elevated IL-6 levels when exposed to polysaccharides (LPS) or

IL-1.

34,35

The role of IL-6 on periodontal bone destruction has been investigated through in vitro

studies, which suggest that this cytokine is involved in osteoclastogenesis, a crucial process in

alveolar bone destruction. IL-6 stimulates osteoclast formation and increases expression of

receptor activator of nuclear factor-κB ligand (RANKL) in osteoblasts, being an essential

mediator for osteoclast function and possibly osteoblast function.

36,37

Additional in vitro studies have revealed that upregulation of matrix metalloproteinases

(MMPs) is one of the mechanisms by which IL-6 causes periodontal destruction.

IL-6

stimulates the production of MMP-1 in human gingival fibroblasts, which is a key protease in

the process of tissue destruction due its ability to degrade collagen and activate the fibrinolytic

protease cascade.

When CD4+ T-cells from gingival tissue and peripheral blood from periodontitis patients were

exposed to Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, upregulation of

IL-6 levels was observed in comparison to healthy subjects.

Similar responses were found in

studies exposing monocytes or whole blood cells from periodontitis patients to LPS and/or

periodontal pathogens, where increased levels of IL-6 were consistently observed in cells from

periodontitis patients compared to periodontally health patients. The main cellular sources for

IL-6 secretion in the periodontium have been identified as macrophages, epithelial cells and T-

cells.

40,4

Collectively, data from in vitro studies have shown that T-cells, gingival fibroblasts, monocytes,

and peripheral mononuclear cells from gingiva and blood produce elevated IL-6 levels when

stimulated by pathogens, LPS or other cytokines. Cells from periodontitis patients can express a

different phenotype, characterized by higher IL-6 expression when compared to cells from

periodontally healthy subjects. Once secreted, IL-6 mediates periodontal destruction through

upregulation of MMPs and osteoclastogenesis.

IL-6 levels in Gingival Crevicular Fluid (GCF), Saliva, Gingival Tissues and Serum

As soluble proteins, cytokines produced in periodontal tissues can be detected in the GCF. A

variety of studies have measured IL-6 levels in GCF, and despite some conflicting results, IL-6

levels seem to be higher in the GCF of periodontitis patients when compared to subjects with a

healthy periodontium according to a comprehensive meta-analysis.

Doubled IL-6 levels have

been reported in sites with refractory periodontitis when compared to stable periodontal sites.

As another potential source for biomarkers, saliva has also been investigated for IL-6 levels,

given the higher volume and easier access for sampling in comparison to GCF.

Despite the fact

that IL-6 salivary levels seem to be low in periodontal health and periodontitis, few studies have

detected an increase in salivary IL-6 levels in the presence of periodontitis.

45,46

In a recent clinical

study by Batool and co-workers, IL-6 salivary levels increased with increasing severity of

chronic periodontitis.

However, several other studies have failed to detect differences in

salivary IL-6 levels of periodontitis, suggesting that IL-6 might not be a strong biomarker for

periodontitis in saliva.

48,49

When compared to healthy gingival tissues, inflamed gingival tissues have shown higher IL-6

concentration through immunohistochemistry methods.

In addition, increased IL-6 mRNA

and protein expression have been observed in periodontitis patients when compared to

periodontally healthy patients.

A recent study on periodontitis patients reported gingival IL-6

levels ranging from 3 to 13 pg/ml, with one patient presenting levels as high as 53.1 pg/ml.

Serum levels of IL-6 In patients with periodontitis have been reported to be significantly higher

than those for patients with a healthy periodontium, with values ranging from 0.25 pg/ml to

41.2 pg/ml in periodontitis.

Similar results have been confirmed by other investigations on

chronic and aggressive periodontitis.

54,55

Interestingly, in a clinical study from Almaghlouth and

co-workers,

the maximum serum IL-6 levels found in the periodontitis group was 216.3 pg/ml.

Impact of Periodontal Treatment on IL-6 Levels

D’Aiuto and co-workers (2004) investigated the effect of nonsurgical periodontal treatment in

serum inflammatory markers in 94 systemically health participants presenting severe

generalized periodontitis. A significant decrease in serum IL-6 (median decrease 0.2 ng/L) and

CRP (median decrease 0.5 mg/L) was observed six months after treatment.

These findings

were confirmed by other investigations, where serum levels of IL-6 were significantly reduced

after conventional nonsurgical periodontal treatment in chronic periodontitis patients.

53,58,59

Interestingly, Lobao et al. (2019) noted an average IL-6 reduction of 12 ng/ml three months after

conventional periodontal treatment. In this study, even participants subjected to supragingival

scaling and polishing (control group) presented significant serum IL-6 comparable to the test

group, which received supra and subgingival scaling and root planing.

In another study from D’Aiuto et al. (2006), conventional nonsurgical periodontal treatment was

compared to intensive periodontal treatment in 40 systemically healthy participants. Intensive

therapy, which included local antimicrobial agents, resulted in greater reductions of serum IL-6

and CRP after two and six months.

A recent systematic review and meta-analysis evaluated the effect of periodontal therapy on IL-

6 levels in patients with diabetes. When obese participants were excluded, the majority of

studies reported a significant decrease in serum IL-6 levels in diabetics after periodontal

treatment.

Conventional periodontal therapy has also been shown to decrease IL-6 levels in

patients with other systemic conditions, such as hypertension, metabolic syndrome,

atherosclerosis and coronary heart disease.

9,63,64

Altogether, these findings support a beneficial effect of periodontal therapy in serum IL-6 levels

and in systemic inflammatory activity. The improvement in circulating IL-6 levels has been

reported for systemically healthy patients and for patients with systemic conditions.

Summary: IL-6 Significance for Oral Diseases and Periodontitis

There is strong evidence on the key role played by IL-6 in the immune and inflammatory

response and bone resorption in periodontitis based on the following findings:

• Genetic studies confirm that IL-6 polymorphisms can increase susceptibility to

periodontitis.

• In vitro studies confirm that IL-6 can be produced by a variety of cells in the

periodontium, being a mediator for inflammation, host response and bone destruction.

• IL-6 levels are upregulated locally in periodontal tissues, GCF and potentially in saliva

in periodontitis patients with the potential to spread to the systemic circulation as

confirmed by elevated serum levels of IL-6 in periodontitis patients.

• Periodontal treatment can contribute to a decrease in local and circulating IL-6 levels in

healthy individuals and in those who present systemic conditions.

• Pulpitis and periapical lesions can be linked to increased expression of IL-6 as well as

oral squamous cell carcinoma; however, these associations have been investigated to a

lesser degree compared to periodontitis.

Respiratory Diseases, Pulmonary Function and Periodontitis

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory condition

affecting nearly 24 million Americans. It is among the leading causes of the death in the U.S.,

being characterized by compromised pulmonary function, limited airflow and breathing

problems.

Observational studies have linked COPD to periodontitis and the association was

supported by results from a meta-analysis by Zeng et al. (2012). In total, 14 studies and nearly

4,000 COPD patients were included, and the results showed a robust association between

COPD and periodontitis with OR = 2.08 (1.48–2.91). The authors concluded that periodontitis is

an independent risk factor for COPD.

More recent data show increased prevalence of periodontitis in COPD patients who require

hospitalization.

Fewer remaining teeth, higher loss of attachment and higher levels of

inflammatory mediators in the GCF were reported in COPD patients.

Pneumonia

Pneumonia is the infection of the pulmonary parenchyma, which can be caused by bacteria and

viruses. It presents high mortality rates worldwide and often affects individuals with impaired

immune systems, being usually classified as community-acquired or hospital-acquired

(nosocomial).

In a systematic review from Scannapieco et al. (2003) including nine randomized

controlled trial (RCT) and 11 case-control studies, there was a significant association between

nosocomial pneumonia and poor oral hygiene.

In another systematic review, Azarpazhooh and Leake (2006) investigated the association

between oral health and respiratory diseases. Based on findings from 19 studies, the authors

found good evidence to support a link between antimicrobial oral hygiene interventions and

decreased incidence of pneumonia in nursing home patients.

Data from several RCT published since 2010 provide further evidence on the impact of poor

oral hygiene and periodontitis in the incidence of nosocomial pneumonia in adults.

intensive care patients, oral swabbing with 0.2% chlorhexidine (CHX) decreased the rate of

nosocomial infection.

In patients scheduled for surgery for esophageal cancer, pre-operative

toothbrushing alone reduced the rate of postoperative pneumonia.

In contrast, a study on

nursing home patients failed to find reduction in pneumonia rates as a result of oral hygiene

care interventions.

Very interesting results were reported in one RCT, where comprehensive professional dental

care provided by a dental surgeon in the intensive care unit was compared to routine oral

hygiene offered by nurses. Dental treatment to intensive care patients (toothbrushing, tongue

scraping, atraumatic caries treatment, removal of calculus and extractions) resulted in a

dramatic reduction in the incidence of respiratory infections and ventilator-associated

pneumonia. These results suggest that in hospitalized patients, intense dental therapy can help

prevent respiratory infections.

Pulmonary Function

In a case-control study from Peter et al. (2013), worse periodontal status was observed in COPD

patients and associated with increased lung obstruction measured as forced expiratory volume

in one second (FEV1).

Another study investigated lung function in systemically healthy

patients as part of the Study of Health in Pomerania, which included 1,463 subjects. Periodontal

disease and number of missing teeth were positively associated with airflow limitation and

reduced lung volume.

Similar findings were reported in a recent large study based on the

NHANES III data, where poorer pulmonary function was associated with increased severity of

periodontitis in systemically healthy participants.

In one interventional study on the effect of periodontal therapy on lung function, the authors

compared three treatment groups (scaling and root planing, supragingival scaling and oral

hygiene instructions alone) and concluded that the two therapy groups resulted in improved

lung function, measured as FEV.

A lack of correlation between pulmonary function and

periodontitis has also been reported in one study.

Asthma

Asthma is a prevalent chronic condition that can affect adults and children, characterized by

alterations in the airways, bronchoconstriction and inflammation. Currently there are

contradictory results regarding a potential association of periodontitis and asthma.

Two recent

systematic reviews have addressed this association. The systematic review from Moraschini et

al. (2017) included 21 studies on adults and children and the results showed increased gingival

inflammation in asthmatic subjects in relation to systemically healthy individuals, which can be

related to the use of inhalers, mouth breathing and decreased salivary production.

The other

systematic review focused on adults with asthma (Ferreira et al. 2019) and, based on results

from 11 studies, the authors concluded that there was increased prevalence of periodontal

disease, particularly gingivitis, in adults with asthma.

In a case-control study by Soledade-Marques and co-workers (2017), severe asthma was

associated with periodontitis with adjusted OR = 3.01-3.25. Prevalence of periodontitis was

higher in patients with severe asthma (46.6%) in comparison to systemically healthy controls

(22.3%) and periodontitis patients had a threefold increased risk of having severe asthma.

Altogether, findings from most published studies on respiratory conditions and oral health

suggest an association between periodontitis and COPD, pneumonia, worse lung function and

potentially asthma. Oral hygiene interventions, dental and periodontal treatment are crucial to

decrease the risk for nosocomial pneumonia and other respiratory conditions.

IL-6, Viral Infections and COVID-19

The coronavirus disease is caused by a new coronavirus, known as severe acute respiratory

syndrome coronavirus 2 (SARS-CoV-2), and due to high transmission rates, it has spread

catastrophically in most countries, including the U.S. The pandemic caused by the virus is

unprecedented according to the WHO and has put strain on primary health care systems

around the world.

Although most cases have been described as mild to moderate with self-limiting cold-like

symptoms or no symptoms, around 20% of patients can develop more severe complications that

require hospitalization, from which approximately 5% need intensive care and mechanical

ventilation. Mortality rates range from 0.25% to 3.0% on average, being higher for vulnerable

subjects presenting certain risk factors such as age over 70, respiratory disease, diabetes,

cardiovascular disease and cancer. The most frequent cause of mortality is COVID-19-related

pneumonia and acute respiratory distress syndrome (ARDS), with some patients also

presenting severe cardiovascular damage. In severe cases, mortality rates can be as high as

60.5%.

8 6

The virus infects host cells through the angiotensin converting enzyme 2 (ACE2) receptor,

which is highly expressed in several organs, including salivary glands.

Studies on the

coronavirus disease suggest that there is a massive activation of mononuclear macrophages and

T lymphocytes and release of inflammatory mediators such as IL-6. In SARS-CoV-2, IL-6 seems

to bind to target cells, inducing increased cytokine production that perpetuates inflammation in

the pulmonary tissues and in other organs.

Some studies have investigated the potential role of upregulated levels of IL-6 in the

exacerbation of viral diseases before the pandemic, suggesting that IL-6 has the potential to

promote worsening of clinical symptoms and facilitate virus survival.

Of interest, IL-6 has been

suggested to contribute to viral persistence, with serum upregulation of IL-6 being linked to

other viral infections in humans, including influenza virus and human immunodeficiency

virus.

During infection, together with IL-1β and TNF-α, IL-6 is a crucial mediator.

The potential

biological mechanisms for increased IL-6 production during viral infection include the potential

ability of some viruses to evade the immune response and increase IL-6 levels as viral loads

increase, and the presence of genetic IL-6 polymorphisms leading to overproduction of IL-6

during the infection.

Furthermore, studies on COVID19 suggest that higher IL-6 levels can

worsen alveolar capillary blood gas exchange in the lungs and oxygen diffusion, potentially

contributing to fibrosis and pulmonary failure.

Recently, a study on IL-6 levels in hospitalized COVID19 patients suggested an important role

of this cytokine in predicting the need for mechanical ventilation.

Forty hospitalized COVID-19

patients were included, from which 32.5% deteriorated and required mechanical ventilation.

There was a strong association between the need for ventilation and IL-6 serum levels above 80

pg/ml. High IL-6 levels accurately predicted respiratory failure, with 22 times higher risk for

respiratory complications. The authors highlighted that the accuracy of the cutoff value needs to

be further assessed due to the small sample size.

In a recent meta-analysis, severe COVID19

cases presented a 2.9 fold increase in IL-6 levels when compared to mild to moderate cases

without complications.

With the current shortage of health care resources due to the high

number of infections, identification of patients who have increased risk for respiratory

complications can be crucial for resource allocation.

The importance of IL-6 for COVID19-related pulmonary complications has been confirmed by a

small study in China, where tocilizumab was given to 20 hospitalized patients who had severe

coronavirus disease. The drug had excellent results, with 90.5% of patients recovering after an

average of 13.5 days.

Tocilizumab is a humanized IL-6 receptor monoclonal antibody, which

has high affinity for IL-6 receptors. It binds to these receptors, preventing IL-6 from altering

cellular behavior and ultimately improving inflammation. Currently, two RCTs are underway

to further investigate the effect of IL-6 receptor antagonists in severe COVID19 cases

(NCT04310228 and NCT04315298).

Further confirmation on the importance of an intense inflammatory reaction in critically ill

COVID-19 patients comes from a recent report from the RECOVERY Trial. This RCT from the

U.K. included 2,100 participants in the dexamethasone arm (6mg/day for 10 days) and 4,300

participants in the standard care arm. Preliminary results show that in COVID-19 patients who

were on ventilators, dexamethasone decreased mortality by one-third. Previous studies show

that dexamethasone inhibit T-cell activation and downregulates IL-6 and other

proinflammatory cytokines, promoting a shift towards an anti-inflammatory direction.

Another line of treatment currently being investigated is the use of inhaled steroids, with

ongoing studies taking place in the U.S., France and England. Inhaled steroids are thought to

reduce virus replication and inflammation in the airways, leading to less immunosuppression

than systemic steroids.

Findings from COVID-19 studies and the current treatment options under investigation suggest

a pivotal role of cytokine storms in the mortality associated with COVID-19 complications,

hence mitigating sources of inflammation is prudent.

Biological Mechanisms Behind the Connection Between Periodontal Disease

and Pulmonary Conditions, Including COVID-19-Related Respiratory

Complications

Systemic Inflammation

In the presence of inflammation in the periodontium, several host cells can increase production

of IL-6, which can diffuse into the systemic circulation together with other cytokines. Elevated

IL-6 levels have been reported in periodontal tissues, saliva, GCF and serum in periodontitis

patients, as discussed previously in this review. Once in the blood, IL-6 and other mediators

have the potential to affect distant organs and tissues, such as the lungs, through the activation

of circulating immune cells and endothelial cells, which induces further release of inflammatory

mediators and potentially contributes to inflammation in the respiratory tissues.

Entrance of oral pathogens into the systemic circulation is another potential mechanism that can

result in upregulated production of inflammatory mediators in the body. Endothelial cells and

leukocytes respond to circulating bacterial antigens with secretion of proinflammatory

mediators. Continuous systemic exposure to bacterial antigens cause formation of immune

complexes that further promote production of TNF-α, IL-6 and IL-1β. Moreover, in

periodontitis patients, peripheral blood neutrophils present a hyperactive profile characterized

by increased production of proinflammatory cytokines and reactive oxygen species.

Bacterial Load

Approximately 100 million bacteria are present in every cubic millimeter of oral biofilm, which

can function as a reservoir for periodontal and respiratory pathogens.

According to

Scannapieco et al., there are four possible ways through which oral pathogens can contribute to

respiratory diseases.

The first is the aspiration of secretions from the oropharynx into the

upper and lower airways. They can adhere to the respiratory epithelium and initiate/exacerbate

infection indirectly through the release of LPS or directly through signal transduction via

adhesion receptors. Second, enzymes produced in periodontal disease can alter the surface of

the respiratory epithelium and facilitate adherence of respiratory pathogens. Third, hydrolytic

enzymes produced in periodontal disease can deteriorate salivary proteins on bacterial surfaces,

facilitating their adherence to mucosa. Lastly, cytokines can modulate bacterial adhesion of

pathogens to the pulmonary epithelium.

Elimination of aspirated bacteria by the immune system is impaired in patients with impaired

saliva production, swallowing disorders and poor cough reflex, putting these patients at higher

risk for lung infections. For intensive care patients, intubation and mechanical ventilation

decreases clearance of oral secretions leading to increased oral bacterial load and risk for

pneumonia.

In support of these findings, studies have reported cultures of oral facultative and

anaerobe species from infected lung fluids, such as Porphyromonas gingivalis, Eikenella corrodens,

Fusobacterium nucleatum, Aggregatibacter actinomycetemcomitans and Peptostreptococci.

100

Studies have suggested that bacteria and/or bacterial products of oral origin are able to induce

secretion of cytokines from pulmonary epithelial cells, leading to recruitment of inflammatory

cells. The inflamed respiratory epithelium can in turn become more susceptible to infection due

to epithelial inflammation.

Some oral pathogens are able to stimulate epithelial cells to

produce proinflammatory cytokines to a similar degree to that observed for respiratory

pathogens.

101

Gut Dysbiosis

Gut dysbiosis has been suggested as a potential novel pathogenic mechanism linked to changes

in immunity, systemic inflammation and development of respiratory disease.

102

New research

suggests that periodontal pathogens can contribute to gut dysbiosis, given that oral bacteria are

frequently swallowed through saliva. Thus, periodontal pathogens can reach the intestines,

alter the local microbiota, increase gut permeability and the risk for endotoxemia, which is

defined as the entrance of LPS in the blood circulation and promotes systemic inflammation.

103

In vitro experiments have shown that Porphyromonas gingivalis was able to successfully

withstand stomach acids and colonize the colon, leading to functional changes.

104

In health, oral

microorganisms are poor colonizers of the gastrointestinal tract; however, when systemic

conditions such as viral infections are present, higher numbers of oral bacteria have been

identified in the intestines.

105

Despite the early stages of research on gut dysbiosis in periodontitis patients, this can become

an additional biological mechanism to explain the proinflammatory effect of periodontitis in the

systemic environment and the lungs.

Endothelial Dysfunction

Endothelial dysfunction encompasses changes in endothelial physiology, representing an early

step in atherosclerosis. It is mainly characterized by reduced production of nitric oxide and

impaired endothelium-dependent vasodilatation. Periodontitis has been linked to endothelial

dysfunction in healthy patients and in patients with hypertension.

106

Accordingly, periodontal

treatment was able to improve acetylcholine-induced vasodilation in hypertensive and normal

patients, suggesting a positive effect on endothelial dysfunction irrespective of the patient’s

general condition.

107,108

To conclude, there are several biological pathways for the link between periodontitis and

COVID-19. The oral bacterial load and systemic inflammation resulting from periodontal

disease can affect the lung endothelium and the gut microbiome. Aspiration of oral bacteria is

another potential mechanism through which oral pathogens can reach the respiratory tract and

potentially interact with the SARS-CoV-2 virus to increase severity and mortality. In the lungs,

circulating bacteria and cytokines such as IL-6 can alter the respiratory tissues, leading to

decreased lung function, increased risk for infection and other complications, particularly in

patients with COVID-19 (FIGURE). Changes in the lungs have been reported even in

systemically healthy patients as a consequence of periodontitis, suggesting that periodontal and

dental treatment are essential for both healthy subjects and for those who have lung diseases or

other chronic diseases, such as hypertension, diabetes and atherosclerosis. Directly, through

high IL-6 levels or indirectly, through alterations in the lung endothelium and gut microbiome,

periodontitis can increase the risk for COVID-19 severity and complications, potentially

affecting the course of the disease. Of note, chronic psychological stress has also been linked to

elevated circulating IL-6 levels.

109

Considering the widespread psychological and financial stress

brought by the pandemic, it can be a significant contributor to periodontal and systemic

inflammation, further increasing IL-6 levels and the risk for COVID-19 related complications.

Periodontal Screening and Treatment as Preventive Tool Against COVID-19

Considering the potential impact of poor oral hygiene and periodontitis on respiratory

infections and COVID-19, periodontal interventions are important to reduce the burden of oral

bacteria and potentially decrease systemic inflammation.

57,60,61

As dental offices remained closed

for elective procedures during lockdown, millions of dental cleaning appointments were

postponed, suggesting a possible increase in the rates of gingivitis and periodontitis, with

consequent elevation of systemic inflammation. Given the high transmission rate of the virus

and the 22 times higher risk for COVID-19 respiratory issues linked to high IL-6 levels,

every

attempt to decrease this inflammatory mediator should be prioritized. Furthermore,

periodontitis is considered as a risk factor for cardiovascular disease, hypertension and

diabetes, which are comorbidities associated with increased mortality rate for COVID-19.

110

In nursing homes and ICUs, oral hygiene and professional oral health have been shown to

reduce the rate of pneumonia and mortality.

111

In Brazil, hospitals that have a dentist presented

a reduction in aspiration pneumonia and hospital infections, decreased need for antibiotics,

shorter hospitalization time, lower costs, reduced mortality and improved general well-being.

112

Based on these findings, a national law was approved in 2016 requiring the presence of a dentist

in private and public hospitals that have an ICU in Brazil.

112

The Centers for Disease Control and Prevention (CDC) has estimated that up to 30% of COVID-

19 cases in the U.S. require hospitalization. With the evidence that dental care, including topical

application of CHX, can be effective in the prevention of respiratory infections, it is tempting to

wonder if hospital dentistry or dental care delivered by hospital nurses could make a difference

in the disease course of thousands of hospitalized COVID-19 patients.

Because the throat seems to be crucial for virus replication early after infection with COVID-19,

oral rinses can potentially alter the viral lipid envelope, reducing the viral load and the risk of

transmission.

113

Despite the lack of human studies on the effect of mouthwashes on SARS-CoV-

2, the American Dental Association (ADA) recommends the following agents to help reduce

transmission of the virus: 1% hydrogen peroxide and 0.2–0.5% povidone.

The current recommendations for use of oral rinses include preoperative for all patients during

the pandemic (ADA). Challacombe et al. (2020) suggest the use of povidone 0.5% every two to

three hours (up to four times daily) for dentists and dental assistants to reduce their risk of

infection.

114

Despite the fact that CHX can reduce risk of pneumonia in hospitalized patients undergoing

mechanical ventilation, few in vitro studies suggest less effectiveness against viruses when

compared to povidone and hydrogen peroxide. A study from England suggests mouthwashes

containing 21%–27% ethanol combined with essential oils can be effective against viruses;

however, they require further clinical studies.

113

IL-6 Genetic Testing

Findings from studies on the -174 IL-6 genetic polymorphism suggest that the G/G genotype

increases the risk for severe periodontitis due to exacerbated inflammatory response

characterized by elevated IL-6 levels.

19,24

According to data from 12,000 salivary tests performed

by OralDNA Labs (Eden Prairie, Minn.) for the -174 IL-6 polymorphism, 45.2% of periodontitis

patients have the high risk genotype (G/G), 41.0% have intermediate risk (C/G) and 13.8% have

low risk (C/C) (unpublished data). In the study from Trevilatto et al. (2003), 71% of severe

periodontitis and 50% of moderate periodontitis patients presented the G/G genotype.

Despite

the fact that periodontitis is multifactorial and associated with multiple cytokines,

103

recent

findings on the pivotal role of IL-6 in cytokine storms in hospitalized COVID-19 patients make

it a promising choice for genetic testing.

Currently, there are no studies on the role of -174 IL-6 polymorphism in coronavirus disease. In the

near future, IL-6 genetic testing for COVID-19 patients could help identify those at risk for

cytokine storms and guide treatment to decrease complications and mortality. It will be

interesting to investigate if the high-risk G/G genotype that predisposes to severe periodontitis

is also linked to the severity of coronavirus disease.

Solutions Section

Based on the scientific evidence provided in this review and on guidelines from the ADA, the

following solutions are recommended for the oral team during these unprecedented times.

Promotion of Oral Hygiene To Decrease the Burden of Bacteria and Screening for

Untreated Periodontitis

Good personal hygiene has never been so crucial, including optimal daily oral hygiene.

Bacterial plaque can harbor respiratory and periodontal pathogens, which can reach the

systemic circulation and invade host cells. Keeping the burden of oral bacteria as low as

possible can reduce the risk of aspiration to the respiratory tract. Patients should be encouraged

to brush their teeth twice per day for a minimum of two minutes with fluoridated toothpaste

and perform interproximal cleaning. In a recent meta-analysis, interdental brushes and water-

jets showed the highest reduction in gingival bleeding, while unsupervised flossing was not

effective.

115

For management of gingivitis, the consensus from the 11th European Workshop in

Periodontology suggests that flossing should only take place when there is no space for an

interdental brush. For periodontitis patients, two minutes of toothbrushing might not be

enough, hence instructions for periodontitis patients need to be customized. Early identification

of patients with periodontitis is very important for timely treatment and reduction of the

inflammatory response.

Professional Teeth Cleaning and Periodontal Treatment To Decrease the Burden of Inflammation

Not all patients have motivation and/or fine motor skills to maintain optimal plaque control.

The consensus from the 11th European Workshop is in support of professional plaque control

as a way to improve gingival inflammation, decrease plaque and reinforce oral hygiene

habits.

116

As discussed previously, it is imperative for periodontitis patients to undergo comprehensive

treatment to control alveolar bone loss and decrease systemic inflammation and IL-6 levels. For

advanced cases, systemic antibiotics can be considered as an adjunct to periodontal treatment

for better clinical and microbiological effects, taking into consideration both local and systemic

health. Successful control of periodontal inflammation can be beneficial to the lungs, possibly

decreasing severity and risk of COVID-19 respiratory problems.

Genetic IL-6 Testing To Provide Risk Assessment for Periodontitis

The G alleles in the IL-6 polymorphism in the -174 promoter region have been linked to

increased risk for severe periodontitis.

17–19

IL-6 genetic testing can be a useful tool to provide

information on the risk for severe periodontitis and guide treatment, as more aggressive

approaches may be required in patients that carry the G allele in order to diminish the

inflammatory response. Currently there are no studies evaluating genetic variations in this

position of the IL-6 gene in COVID-19 patients.

Infection Control Measures To Decrease the Spread of SARS-CoV-2

The ADA (ADA COVID-19 Center) and the CDC have provided comprehensive

recommendations to mitigate the spread of SARS-CoV-2 in dental practices regarding patient

management, personnel, facility and equipment considerations, administrative and engineering

controls, infection control, personal protective equipment (PPE) and hygiene.

117

As mentioned previously, hydrogen peroxide has been recommended as a preprocedural rinse

with the potential to decrease the transmission of SARS-CoV-2 because it is vulnerable to

oxidation. Although it has not been tested in clinical trials, in vitro studies report that it can

inhibit virus replication in epithelial cells.

As discussed earlier, hospitalized patients are unable to maintain oral hygiene, resulting in

plaque build-up that can provide a niche for respiratory pathogens and a source for aspiration

of oral pathogens. This increases the risk for pneumonia and respiratory problems and can have

a negative impact in COVID-19 related respiratory complications, although there is currently no

studies on this topic. Based on data from pneumonia studies, it can be speculated if use of

hydrogen peroxide or chlorhexidine could have positive affect the course of the coronavirus

disease in hospitalized patients.

Virtual Dental Consultations and Monitoring and Mobile Dentistry for Patients Who Want To

Avoid Leaving Their Homes

With the high transmission rate of SARS-CoV-2, it is understandable that patients want to avoid

potential exposure to the virus, particularly those with comorbidities. Teledentistry can be a

solution, as several platforms have emerged to offer dentists complete solutions to provide

virtual dental consultations. Even though professional cleaning and periodontal treatment

require in-office visits, triaging for dental emergencies and oral hygiene reinforcement can be

done virtually. In addition, mobile dentistry can become a necessary solution in the future to

offer treatment in the comfort of the patient’s home or workplace.

118

Take-Home Message

• The coronavirus disease can dysregulate the host immune response and elevate IL-6

levels. High IL-6 levels increase the risk for mechanical ventilation in hospitalized

patients by 22 times, being a predictor for COVID-19-related respiratory complications.

IL-6 receptor antagonists and dexamethasone have the potential to improve disease

severity in hospitalized patients through changes in the inflammatory response,

however, results from robust trials need to confirm safety and effectiveness for this

treatment.

• Oral diseases, particularly periodontitis, can contribute to a systemic inflammatory

response with high circulating IL-6 levels. Certain genetic variations of the IL-6 gene can

increase the risk to severe periodontitis through an exacerbated IL-6 response. Genetic

testing can be useful to identify patients at high risk and guide treatment. High IL-6

levels in periodontitis patients can contribute to COVID-19 respiratory complications.

• Oral bacteria can be aspirated and affect lung function, increasing the risk for

pneumonia, COPD and potentially COVID-19-related pulmonary complications.

• Oral hygiene interventions, periodontal and dental treatment have the potential to

decrease the oral bacterial burden and the systemic inflammatory response. Thus, is it

essential to treat periodontitis and promote good plaque control for general health and

decrease the risk to COVID-19 problems.

• Periodontal treatment is beneficial for systemically healthy patients and for those with

pulmonary conditions, as it can decrease IL-6 levels and decreased inflammation.

Periodontal health can help prevent severe COVID-19 respiratory complications.

• Prevention of COVID-19-related pulmonary complications can have a huge impact on

health care systems with the potential to decrease the need to intensive care and

mechanical ventilation and decrease mortality rates.

Conclusion

There are several biological reasons to consider periodontitis as a risk factor for respiratory

diseases, and as such, it can contribute to the development of respiratory complications in

COVID-19 patients. Several mechanisms are proposed as possible explanations for the link

between the oral environment and the lungs, including systemic inflammation, bacterial load,

gut dysbiosis and endothelial function. High serum IL-6 levels can predict COVID-19-related

respiratory complications and the need for mechanical ventilation, hence dentists should focus

on eliminating underlying conditions that promote systemic inflammation, such as

periodontitis and other oral conditions. Despite the current lack of studies on this topic, the

potential of oral hygiene and periodontal interventions to decrease the burden of oral bacteria

and inflammation, improve general health and protect against severe complications from

coronavirus disease should not be underestimated.

FIGURE 1. Proposed biological mechanisms behind the link between periodontitis and

increased risk for COVID-19 complications. Local inflammation in the periodontium can affect

the body through three main pathways: spill over of locally produced inflammatory mediators

to the systemic circulation, leading to systemic inflammation; entrance of bacteria or bacterial

products to the systemic circulation through the gingival sulcus (bacteriemia); and aspiration of

oral bacteria, which can reach the upper and lower respiratory tract. Stress can further

contribute to local and systemic inflammation. Combined, these pathways can enhance

endothelial dysfunction, gut dysbiosis, potentially predisposing to changes in the lungs. Gut

dysbiosis and endothelial dysfunction can affect several organs and systems, including the

lungs. Circulating cytokines and bacteria can alter the respiratory epithelium, predisposing to

infection, inflammation and potential pulmonary complications. The elevated levels of

cytokines in periodontitis patients, particularly IL-6, has the potential to directly increase the

risk for COVID-19 pulmonary complications. Changes in the lung tissues can constitute an

indirect pathway through which periodontitis can influence the course of the coronavirus

disease.

Acknowledgments

We would like to express our appreciation to Dr. Joan Otomo-Corgel for her valuable and

constructive suggestions during the development of this research work.

References

1. Sohrabi C, et al. World Health Organization declares global emergency: A review of the 2019

novel coronavirus (COVID-19). Int J Surg 2020;76:71–76. doi: 10.1016/j.ijsu.2020.02.034.

2. Zhou F, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19

in Wuhan, China: A retrospective cohort study. Lancet 2020;395(10229):P1054–1062. doi:

10.1016/S0140-6736(20)30566-3.

3. Velazquez-Salinas L, Verdugo-Rodriguez A, Rodriguez LL, Borca M V. The Role of

Interleukin 6 During Viral Infections. Front Microbiol 2019;10:1057. doi:

10.3389/fmicb.2019.01057.

4. Herold T, et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-

19 patients. J Allergy Clin Immunol 2020;146(1):128–136.e4. doi: 10.1016/j.jaci.2020.05.008.

5. Mehta P, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression.

Lancet 2020;395(10229):P1033–1034. doi:10.1016/S0140-6736(20)30628-0.

6. Coulthard P. Dentistry and coronavirus (COVID-19) — moral decision-making. Br Dent J

2020;228(7):503–505. doi:10.1038/s41415-020-1482-1.

7. Irwin C, Myrillas T. The role of IL-6 in the pathogenesis of periodontal disease. Oral Dis

2008;4(1):43–47. doi:10.1111/j.1601-0825.1998.tb00255.x.

8. Reis C, et al. Clinical improvement following therapy for periodontitis: Association with a

decrease in IL-1 and IL-6. Exp Ther Med 2014;8(1):323–327. doi:10.3892/etm.2014.1724.

9. Zhou SY, Duan XQ, Hu R, Ouyang XY. Effect of nonsurgical periodontal therapy on serum

levels of TNF-a, IL-6 and C-reactive protein in periodontitis subjects with stable coronary heart

disease. Chin J Dent Res 2013;16(2):145–151.

10. Hobbins S, Chapple I, Sapey E, Stockley R. Is periodontitis a comorbidity of COPD or can

associations be explained by shared risk factors/behaviors? Int J Chron Obstruct Pulmon Dis 2017;

12:1339–1349. doi:10.2147/COPD.S127802.

11. White DB, Lo B. A framework for rationing ventilators and critical care beds during the

COVID-19 pandemic. JAMA 2020;323(18):1773–1774. doi:10.1001/jama.2020.5046.

12. Kramer CD, Genco CA. Microbiota, immune subversion and chronic inflammation. Front

Immunol 2017;8:255. doi:10.3389/fimmu.2017.00255.

13. Gemmell E, Marshall RI, Seymour GJ. Cytokines and prostaglandins in immune homeostasis

and tissue destruction in periodontal disease. Periodontol 2000 1997;14(1):112–143.

doi:10.1111/j.1600-0757.1997.tb00194.x.

14. Pan W, Wang Q, Chen Q. The cytokine network involved in the host immune response to

periodontitis. Int J Oral Sci 2019;11(3):1–13. doi:10.1038/s41368-019-0064-z.

15. Scapoli L, et al. Interleukin-6 gene polymorphism modulates the risk of periodontal diseases.

J Biol Regul Homeost Agents Jul–Sep 2015;29(3 Suppl 1):111–116.

16. Farhat SB, et al. Complete physical mapping of IL6 reveals a new marker associated with

chronic periodontitis. J Periodontal Res 2017;52(2):255–261. doi:10.1111/jre.12389.

17. Trevilatto P, Scarel-Caminaga RM, de Brito RB Jr, de Souza AP, Line SR. Polymorphism at

position –174 of IL-6 gene is associated with susceptibility to chronic periodontitis in a

Caucasian Brazilian population. J Clin Periodontol 2003;30(5):438–442. doi:10.1034/j.1600-

051x.2003.20016.x.

18. Toker H, Görgün EP, Korkmaz EM. Analysis of IL-6, IL-10 and NF-ΚB gene polymorphisms

in aggressive and chronic periodontitis. Cent Eur J Public Health 2017;25(2):157–162.

doi:10.21101/cejph.a4656.

19. Pirim Gorgun E, Toker H, Korkmaz EM, Poyraz O. IL-6 and IL-10 gene polymorphisms in

patients with aggressive periodontitis: Effects on GCF, serum and clinic parameters. Braz Oral

Res 2017;31:e12. doi:10.1590/1807-3107BOR-2017.vol31.0012.

20. Nibali L, et al. Association between interleukin-6 promoter haplotypes and aggressive

periodontitis. J Clin Periodontol 2008;35(3):193–198. doi:10.1111/j.1600-051X.2007.01188.x.

21. Shi D. Interleukin-6-572C/G polymorphism is associated with the risk of chronic

periodontitis. Biomed Res 2017;28(15):6637–6639.

22. Jingjin L, Zemin G, Xin M, et al. Correlation Between an interleukin-6 -572C/G

polymorphism and chronic periodontitis. Int J Periodontics Restorative Dent 2010;30(3):301–305.

23. Holla LI, Fassmann A, Stejskalová A, Znojil V, Vaněk J, Vacha J. Analysis of the interleukin-6

gene promoter polymorphisms in Czech patients with chronic periodontitis. J Periodontol

2004;75(1):30–36. doi:10.1902/jop.2004.75.1.30.

24. Kavitha L, Vijayshree Priyadharshini J, Sivapathasundharam B. Association among

interleukin-6 gene polymorphisms, Type 2 diabetes mellitus and chronic periodontitis: A pilot

study. J Investig Clin Dent 2017;8(3). doi:10.1111/jicd.12230.

25. Teixeira G, Mendonça SA, Menezes Oliveira K, et al. Interleukin-6 c.-174G>C polymorphism

and periodontitis in a Brazilian population. Mol Biol Int 2014;2014:490308. doi:

10.1155/2014/490308.

26. Tervonen T, Raunio T, Knuuttila M, Karttunen R. Polymorphisms in the CD14 and IL-6

genes associated with periodontal disease. J Clin Periodontol 2007;34(5):377–383. doi:

10.1111/j.1600-

051X.2007.01067.x.

27. Babel N, Cherepnev G, Babel D, et al. Analysis of tumor necrosis factor-alpha, transforming

growth factor-beta, interleukin-10, IL-6 and interferon-gamma gene polymorphisms in patients

with chronic periodontitis. J Periodontol 2006;77(12):1978–1983. doi:10.1902/jop.2006.050315.

28. Brett P, Zygogianni P, Griffiths G, Tomaz M, Parkar M, Tonetti M. Functional gene

polymorphisms in aggressive and chronic periodontitis. J Dent Res 2005;84(12):1149–1153.

doi:10.1177/154405910508401211.

29. Zhu J, et al. Interleukin-6-174G/C polymorphism contributes to periodontitis susceptibility:

An updated meta-analysis of 21 case-control studies. Dis Markers 2016;2016:9612421. doi:

10.1155/2016/9612421 34.

30. Zhang HY, Feng L, Wu H, Xie XD. The association of IL-6 and IL-6R gene polymorphisms

with chronic periodontitis in a Chinese population. Oral Dis 2014;20(1):69–75. doi:

10.1111/odi.12075.

31. Sharma N, Joseph R, Arun R, Chandni R, Srinivas K, Banerjee M. Cytokine gene

polymorphism (interleukin-1β +3954, interleukin-6 [-597/-174] and tumor necrosis factor-α-308)

in chronic periodontitis with and without Type 2 diabetes mellitus. Indian J Dent Res

2014;25(3):375–380. doi:10.4103/0970-9290.138343.

32. Komatsu Y, et al. Interleukin-6 (IL-6) — 373 A9T11 allele is associated with reduced

susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level.

Tissue Antigens 2005;65(1):110–114. doi:10.1111/j.1399-0039.2005.00347.x.

33. Raunio T, Nixdorf M, Knuuttila M, Karttunen R, Vainio O, Tervonen T. The extent of

periodontal disease and the IL-6 −174 genotype as determinants of

serum IL-6 level. J Clin

Periodontol 2007;34(12):1025–1030. doi: 10.1111/j.1600-051X.2007.01151.x.

34. Dongari-Bagtzoglou AI, Ebersole JL. Production of inflammatory mediators and cytokines

by human gingival fibroblasts following bacterial challenge. J Periodontal Res 1996;31(2):90–98.

doi:10.1111/j.1600-0765.1996.tb00469.x.

35. Naruishi K, Nagata T. Biological effects of interleukin-6 on gingival fibroblasts: Cytokine

regulation in periodontitis. J Cell Physiol 2018;233(9):6393–6400. doi:10.1002/jcp.26521.

36. Bakker AD, Kulkarni RN, Klein-Nulend J, Lems WF. IL-6 alters osteocyte signaling toward

osteoblasts but not osteoclasts. J Dent Res 2014;93(4):394–399. doi: 10.1177/0022034514522485.

37. Wu Q, Zhou X, Huang D, JI Y, Kang F. IL-6 Enhances osteocyte-mediated osteoclastogenesis

by promoting JAK2 and RANKL activity. Cell Physiol Biochem 2017;41(4):1360–1369. doi:

10.1159/000465455.

38. Irwin CR, Myrillas TT, Traynor P, Leadbetter N, Cawston TE. The role of soluble interleukin

(IL)-6 receptor in mediating the effects of IL-6 on matrix metalloproteinase-1 and tissue inhibitor

of metalloproteinase-1 expression by gingival fibroblasts. J Periodontol 2002;73(7):741–747. doi:

10.1902/jop.2002.73.7.741.

39. Cheng W, et al. Periodontitis-associated pathogens P. gingivalis and A.

actinomycetemcomitans activate human CD14 + monocytes leading to enhanced Th17/IL-17

responses. Eur J Immunol 2016;46(9):2211–2221. doi:10.1002/eji.201545871.

40. Nakamura T, Nitta H, Ishikawa I. Effect of low dose Actinobacillus actinomycetemcomitans

lipopolysaccharide pretreatment on cytokine production by human whole blood. J Periodontal

Res 2004;39(2):129–135. doi:10.1111/j.1600-0765.2004.00717.x.

41. Nagasawa T, Kobayashi H, Aramaki M, Kiji M, Oda S, Izumi Y. Expression of CD14, CD16

and CD45RA on monocytes from periodontitis patients. J Periodontal Res 2004;39(1):72–78. doi:

10.1111/j.1600-0765.2004.00713.x.

42. Stadler AF, Angst PDM, Arce RM, Gomes SC, Oppermann RV, Susin C. Gingival crevicular

fluid levels of cytokines/chemokines in chronic periodontitis: A meta-analysis. J Clin Periodontol

2016;43(9):727–745. doi: 10.1111/jcpe.12557.

43. Reinhardt RA, et al. Gingival fluid IL-1 and IL-6 levels in refractory periodontitis. J Clin

Periodontol 1993;20(3):225–231. doi: 10.1111/j.1600-051X.1993.tb00348.x.

44. Jaedicke KM, Preshaw PM, Taylor JJ. Salivary cytokines as biomarkers of periodontal

diseases. Periodontol 2000 2016;70(1):164–183. doi: 10.1111/prd.12117.

45. Costa PP, et al. Salivary interleukin-6, matrix metalloproteinase-8 and osteoprotegerin in

patients with periodontitis and diabetes. J Periodontol 2010;81(3):384–391. doi:

10.1902/jop.2009.090510.

46. Ebersole JL, et al. Patterns of salivary analytes provide diagnostic capacity for distinguishing

chronic adult periodontitis from health. J Clin Immunol 2013;33(1):271–279. doi: 10.1007/s10875-

012-9771-3.

47. Batool H, Nadeem A, Kashif M, Shahzad F, Tahir R, Afzal N. Salivary levels of IL-6 and IL-

17 could be an indicator of disease severity in patients with calculus associated chronic

periodontitis. Biomed Res Int 2018; 8531961. doi:10.1155/2018/8531961.

48. Scannapieco FA, et al. Salivary biomarkers associated with alveolar bone loss. Ann N Y Acad

Sci 2007;1098:496–497. doi: 10.1196/annals.1384.034.

49. Gursoy UK, et al. Salivary interleukin-1β concentration and the presence of multiple

pathogens in periodontitis. J Clin Periodontol 2009;36(11):922–927. doi: 10.1111/j.1600-

051X.2009.01480.x

50. Bartold PM, Haynes DR. Interleukin-6 production by human gingival fibroblasts. J

Periodontal Res 1991;26(4):339–345. doi: 10.1111/j.1600-0765.1991.tb02072.x.

51. Ross JH, Hardy DC, Schuyler CA, Slate EH, Mize TW, Huang Y. Expression of periodontal

interleukin-6 protein is increased across patients with neither periodontal disease nor diabetes,

patients with periodontal disease alone and patients with both diseases. J Periodontal Res

2010;45(5):688–694. doi: 10.1111/j.1600-0765.2010.01286.x.

52. Noh MK, et al. Assessment of IL-6, IL-8 and TNF-α levels in the gingival tissue of patients

with periodontitis. Exp Ther Med 2013;6(3):847–851. doi: 10.3892/etm.2013.1222.

53. Marcaccini AM, et al. Circulating interleukin-6 and high-sensitivity c-reactive protein

decrease after periodontal therapy in otherwise healthy subjects. J Periodontol 2009;80(4):594–

602. doi: 10.1902/jop.2009.080561.

54. Sun XJ, et al. Elevation of C-reactive protein and interleukin-6 in plasma of patients with

aggressive periodontitis. J Periodontal Res 2009;44(3):311–316. doi:1 0.1111/j.1600-

0765.2008.01131.x.

55. Leira Y, et al. Periodontitis and systemic markers of neurodegeneration: A case–control

study. J Clin Periodontol 2020;47(5). doi: 10.1111/jcpe.13267.

56. Almaghlouth AA, et al. Effect of periodontal treatment on peak serum levels of

inflammatory markers. Clin Oral Investig 2014;18(9):2113–2121. doi: 10.1007/s00784-014-1187-4.

57. D’Aiuto F, et al. Periodontitis and systemic inflammation: Control of the local infection is

associated with a reduction in serum inflammatory markers. J Dent Res 2004;83(2):156–160. doi:

10.1177/154405910408300214.

58. de Moura Leite SA, et al. The effect of nonsurgical periodontal therapy on hepcidin and on

inflammatory and iron marker levels. Braz Oral Res 2019;33:e055. doi: 10.1590/1807-3107bor-

2019.vol33.0055.

59. Shimada Y, Komatsu Y, Ikezawa-Suzuki I, Tai H, Sugita N, Yoshie H. The effect of

periodontal treatment on serum leptin, interleukin-6, and C-reactive protein. J Periodontol

2010;81(8):1118–1123. doi: 10.1902/jop.2010.090741.

60. Lobão WJM, et al. Relationship between periodontal outcomes and serum biomarkers

changes after nonsurgical periodontal therapy. An Acad Bras Cienc 2019;91(2):e20170652. doi:

10.1590/0001-3765201920170652.

61. D’Aiuto F, Parkar M, Nibali L, Suvan J, Lessem J, Tonetti MS. Periodontal infections cause

changes in traditional and novel cardiovascular risk factors: Results from a randomized

controlled clinical trial. Am Heart J 2006;151(5):977–984. doi: 10.1016/j.ahj.2005.06.018.

62. Lima R, et al. Effect of periodontal therapy on serum levels of IL-6 in Type 2 diabetics: A

systematic review. Int J Periodontics Restorative Dent 2019;39(1):e1–e10. doi: 10.11607/prd.3866.

63. Montenegro MM, et al. Randomized controlled trial of the effect of periodontal treatment on

cardiovascular risk biomarkers in patients with stable coronary artery disease: Preliminary

findings of 3 months. J Clin Periodontol 2019;46(3):321–331. doi: 10.1111/jcpe.13085.

64. Torumtay G, Kırzıoğlu FY, Öztürk Tonguç M, Kale B, Calapoğlu M, Orhan H. Effects of

periodontal treatment on inflammation and oxidative stress markers in patients with metabolic

syndrome. J Periodontal Res 2016;51(4):489–498. doi: 10.1111/jre.12328.

65. Vos T, et al. Global, regional, and national incidence, prevalence, and years lived with

disability for 328 diseases and injuries for 195 countries, 1990-2016: A systematic analysis for the

Global Burden of Disease Study 2016. Lancet 2017;390(10100):1211-1259. doi: 10.1016/S0140-

6736(17)32154-2.

66. Zeng XT, Tu ML, Liu DY, Zheng D, Zhang J, Leng WD. Periodontal disease and risk of

chronic obstructive pulmonary disease: A meta-analysis of observational studies. PLoS One

2012;7(10). doi: 10.1371/journal.pone.0046508.

67. Shen TC, et al. Risk of periodontal diseases in patients with chronic obstructive pulmonary

disease a nationwide population-based cohort study. Medicine (Baltimore) 2015;94(46):e2047. doi:

10.1097/MD.0000000000002047.

68. Öztekin G, et al. The association between periodontal disease and chronic obstructive

pulmonary disease: A case control study. J Chronic Obstr Pulm Dis 2014;11(4):424–430. doi:

10.3109/15412555.2013.858316.

69. Raghavendran K, Mylotte JM, Scannapieco FA. Nursing home-associated pneumonia,

hospital-acquired pneumonia and ventilator-associated pneumonia: The contribution of dental

biofilms and periodontal inflammation. Periodontol 2000 2007;44(1):164–177. doi: 10.1111/j.1600-

0757.2006.00206.x.

70. Scannapieco FA, Bush RB, Paju S. Associations between periodontal disease and risk for

nosocomial bacterial pneumonia and chronic obstructive pulmonary disease. A systematic

review. Ann Periodontol 2003;8:54-69. doi: 10.1902/annals.2003.8.1.54.

71. Azarpazhooh A, Leake JL. Systematic review of the association between respiratory diseases

and oral health. J Periodontol 2006;77(9):1465-1482. doi: 10.1902/jop.2006.060010.

72. Sabharwal A, Gomes-Filho IS, Stellrecht E, Scannapieco FA. Role of periodontal therapy in

management of common complex systemic diseases and conditions: An update. Periodontol 2000

2018;78(1):212-226. doi: 10.1111/prd.12226.

73. Ćabov T, et al. The impact of oral health and 0.2% chlorhexidine oral gel on the prevalence

of nosocomial infections in surgical intensive-care patients: A randomized placebo-controlled

study. Wien Klin Wochenschr 2010;122(13-14):397-404. doi:10.1007/s00508-010-1397-y.

74. Akutsu Y, et al. Pre-operative dental brushing can reduce the risk of postoperative

pneumonia in esophageal cancer patients. Surgery 2010;147(4):497-502. doi:

10.1016/j.surg.2009.10.048.

75. Hollaar VRY, Van Der Putten GJ, Van Der Maarel-Wierink CD, Bronkhorst EM, De Swart

BJM, Creugers NHJ. The effect of a daily application of a 0.05% chlorhexidine oral rinse solution

on the incidence of aspiration pneumonia in nursing home residents: A multicenter study. BMC

Geriatr 2017;17(1):128. doi: 10.1186/s12877-017-0519-z.

76. Bellissimo-Rodrigues WT, et al. Effectiveness of a dental care intervention in the prevention

of lower respiratory tract nosocomial infections among intensive care patients: A randomized

clinical trial. Infect Control Hosp Epidemiol 2014;35(11):1342-1348. doi: 10.1086/678427.

77. Peter KP, Mute BR, Doiphode SS, Bardapurkar SJ, Borkar MS, Raje DV. Association between

periodontal disease and chronic obstructive pulmonary disease: A reality or just a dogma? J

Periodontol 2013;84(12):1717-1723. doi: 10.1902/jop.2013.120347.

78. Holtfreter B, Richter S, Kocher T, et al. Periodontitis is related to lung volumes and airflow

limitation: A cross-sectional study. Eur Respir J 2013;42(6):1524-1535. doi:

10.1183/09031936.00109112.

79. Lee W, et al. Association between periodontitis and pulmonary function based on the Third

National Health and Nutrition Examination Survey (NHANES III). J Clin Periodontol

2020:47(7);788-795. doi: 10.1111/jcpe.13303.

80. Zhou X, Han J, Liu Z, Song Y, Wang Z, Sun Z. Effects of periodontal treatment on lung

function and exacerbation frequency in patients with chronic obstructive pulmonary disease

and chronic periodontitis: A 2-year pilot randomized controlled trial. J Clin Periodontol

2014;41(6):564-572. doi: 10.1111/jcpe.12247.

81. Lee E, Lee SW. Prevalence of periodontitis and its association with reduced pulmonary

function: Results from the Korean national health and nutrition examination survey. Medicine

(Kaunas) 2019;55(9):581. doi: 10.3390/medicina55090581.

82. Moraschini V, de Albuquerque Calasans-Maia J, Diuana Calasans-Maia M. Association

between asthma and periodontal disease: A systematic review and meta-analysis. J Periodontol

2017;89(4):1-20. doi: 10.1902/jop.2017.170363.

83. Ferreira MKM, et al. Is there an association between asthma and periodontal disease among

adults? Systematic review and meta-analysis. Life Sci 2019;223:74-87. doi:

10.1016/j.lfs.2019.03.005.

84. Soledade-Marques KR, et al. Association between periodontitis and severe asthma in adults:

A case-control study. Oral Dis 2017:1-7. doi:10.1111/odi.12737.

85. Spinelli A, Pellino G. COVID-19 pandemic: perspectives on an unfolding crisis. Br J Surg

2020;107(7):785-787. doi: 10.1002/bjs.11627.

86. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-

CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study.

Lancet Respir Med 2020;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5.

87. Xu J, Li Y, Gan F, Du Y, Yao Y. Salivary glands: Potential reservoirs for COVID-19

asymptomatic infection. J Dent Res 2020 99(8):989. doi: 10.1177/0022034520918518.

88. Fu B, Xu X, Wei H. Why tocilizumab could be an effective treatment for severe COVID-19? J

Transl Med 2020;18(1):164. Published 2020 Apr 14. doi: 10.1186/s12967-020-02339-3.

89. Borges ÁH, O'Connor JL, Phillips AN, et al. Factors associated with plasma IL-6 levels

during HIV infection. J Infect Dis 2015;212(4):585-595. doi: 10.1093/infdis/jiv123.

90. Dienz O, Rincon M. The effects of IL-6 on CD4 T cell responses. Clin Immunol 2009;130(1):27-

33. doi: 10.1016/j.clim.2008.08.018.

91. Lan T, Chang L, Wu L, Yuan Y-F. IL-6 plays a crucial role in HBV infection. J Clin Transl

Hepatol 2015;3(4):271-276. doi: 10.14218/JCTH.2015.00024.

92. Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-

analysis. MedRxiv 2020:20048058. doi:10.1101/2020.03.30.20048058.

93. Xu X, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad

Sci U S A 2020;117(20):10970-10975. doi: 10.1073/pnas.2005615117.

94. Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives.

Nature 2020;582(7813):469. doi: 10.1038/d41586-020-01824-5.

95. Armitage LC, Brettell R. Inhaled corticosteroids: A rapid review of the evidence for

treatment or prevention of COVID-19. Cent Evidence-Based Med Univ Oxford 2020.

96. Dias IHK, Matthews JB, Chapple ILC, Wright HJ, Dunston CR, Griffiths HR. Activation of

the neutrophil respiratory burst by plasma from periodontitis patients is mediated by

proinflammatory cytokines. J Clin Periodontol 2011;38(1):1-7. doi: 10.1111/j.1600-

051X.2010.01628.x

97. Thoden van Velzen SK, Abraham-Inpijn L, Moorer WR. Plaque and systemic disease: A

reappraisal of the focal infection concept. J Clin Periodontol 1984;11(4):209-220. doi:

10.1111/j.1600-051X.1984.tb02211.x.

98. Scannapieco FA. Role of oral bacteria in respiratory infection. J Periodontol 1999;70(7):793-

802. doi: 10.1902/jop.1999.70.7.793.

99. Munro CL, Grap MJ, Elswick RK, McKinney J, Sessler CN, Hummel RS. Oral health status

and development of ventilator-associated pneumonia: A descriptive study. Am J Crit Care

2006;15(5):453-460. doi: 10.4037/ajcc2006.15.5.453.

100. Chen AC, Liu CC, Yao WJ, Chen CT, Wang JY. Actinobacillus actinomycetemcomitans

pneumonia with chest wall and subphrenic abscess. Scand J Infect Dis 1995;27(3):289-290. doi:

10.3109/00365549509019023.

101. Scannapieco FA, Wang B, Shiau HJ. Oral bacteria and respiratory infection: Effects on

respiratory pathogen adhesion and epithelial cell proinflammatory cytokine production. Ann

Periodontol 2001;6(1):78-86. doi: 10.1902/annals.2001.6.1.78.

102. Budden KF, et al. Emerging pathogenic links between microbiota and the gut-lung axis. Nat

Rev Microbiol 2017;15(1):55-63. doi: 10.1038/nrmicro.2016.142.

103. Hajishengallis G. Periodontitis: From microbial immune subversion to systemic

inflammation. Nat Rev Immunol 2015;15(1):30-44. doi: 10.1038/nri3785.

104. Walker MY, Pratap S, Southerland JH, Farmer-Dixon CM, Lakshmyya K, Gangula PR. Role

of oral and gut microbiome in nitric oxide-mediated colon motility. Nitric Oxide 2018;73:81-88.

doi: 10.1016/j.niox.2017.06.003.

105. Seedorf H, Griffin NW, Ridaura VK, et al. Bacteria from diverse habitats colonize and

compete in the mouse gut. Cell 2014;159(2):253-266. doi: 10.1016/j.cell.2014.09.008.

106. Moura MF, et al. Periodontitis and endothelial dysfunction: Periodontal clinical parameters

and levels of salivary markers interleukin-1β, tumor necrosis factor-α, matrix

metalloproteinase-2, tissue inhibitor of metalloproteinases-2 complex and nitric oxide. J

Periodontol 2017;88(8):778-787. doi: 10.1902/jop.2017.170023.

107. Orlandi M, et al. Association between periodontal disease and its treatment, flow-mediated

dilatation and carotid intima-media thickness: A systematic review and meta-analysis.

Atherosclerosis 2014;236(1). doi: 10.1016/j.atherosclerosis.2014.06.002.

108. Higashi Y, et al. Periodontal infection is associated with endothelial dysfunction in healthy

subjects and hypertensive patients. Hypertension 2008;51:446-453. doi:

10.1161/HYPERTENSIONAHA.107.101535.

109. Rohleder N, Aringer M, Boentert M. Role of interleukin-6 in stress, sleep and fatigue. Ann

N Y Acad Sci 2012;1261(1):88-96. doi: 10.1111/j.1749-6632.2012.06634.x.

110. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus

disease 2019 (COVID-19) outbreak in China: Summary of a report of 72,314 cases from the

Chinese Center for Disease Control and Prevention. JAMA 2020;323(13):1239-1242. doi:

10.1001/jama.2020.2648.

111. 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(1). doi: 10.3390/ijerph17010356.

112. Santaella N, Santos P, De Souza IS, Santaella NG, Sérgio P, Santos S. The practice of

hospital dentistry in Brazil: An integrative literature review. Rev Bras Odontol 2017;74(3):232-241.

doi: 10.18363/rbo.v74n3.p.232.

113. O’Donnell VB, et al. Potential role of oral rinses targeting the viral lipid envelope in SARS-

CoV-2 infection. Function 2020;1(1). doi: 10.1093/function/zqaa002.

114. Challacombe SJ, Kirk-Bayley J, Sunkaraneni VS, Combes J. Povidone iodine. Br Dent J

2020;228(9):656-657. doi: 10.1038/s41415-020-1589-4.

115. Kotsakis GA, Lian Q, Ioannou AL, Michalowicz BS, John MT, Chu H. A network meta-

analysis of interproximal oral hygiene methods in the reduction of clinical indices of

inflammation. J Periodontol 2018;89(5):558-570. doi: 10.1002/JPER.17-0368.

116. Chapple ILC, Van Der Weijden F, Doerfer C, et al. Primary prevention of periodontitis:

Managing gingivitis. J Clin Periodontol 2015;42(S16):S71-S76. doi:10.1111/jcpe.12366.

117. CDC. Center for Disease Control. www.cdc.gov/coronavirus/2019-ncov/cases-

updates/hospitalizations-forecasts.html. Published 2020.

118. Carvajal P, Gómez M, Gomes S, et al. Prevalence, severity, and risk indicators of gingival

inflammation in a multi-center study on South American adults: A cross sectional study. J Appl

Oral Sci 2016;24(5):524. doi: 10.1590/1678-775720160178.

The corresponding author, Dr. Shervin Molayem, DDS, can be reached at smolayem@gmail.com.