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.
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.
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.
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.
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).
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.
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
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,
was confirmed in a recent meta-analysis.
The SNP -1363 was only evaluated in two studies,
which reported a positive association with periodontitis.
Two studies investigated IL-6 SNP -
597, from which one found an association with periodontitis.
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.
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
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.
Additional in vitro studies have revealed that upregulation of matrix metalloproteinases
(MMPs) is one of the mechanisms by which IL-6 causes periodontal destruction.
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-
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.
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.
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.
Interestingly, in a clinical study from Almaghlouth and
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.
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
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.
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
• 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
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
Fewer remaining teeth, higher loss of attachment and higher levels of
inflammatory mediators in the GCF were reported in COPD patients.
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
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 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
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
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
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
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.
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
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.
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.
In vitro experiments have shown that Porphyromonas gingivalis was able to successfully
withstand stomach acids and colonize the colon, leading to functional changes.
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.
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.
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.
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.
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.
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,
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.
In nursing homes and ICUs, oral hygiene and professional oral health have been shown to
reduce the rate of pneumonia and mortality.
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.
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.
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
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
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.
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.
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.
the fact that periodontitis is multifactorial and associated with multiple cytokines,
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
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
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.
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.
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.
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
• 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.
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
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.
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:
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:
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.
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-
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.
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:
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:
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.
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:
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.
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:
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:
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:
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:
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-
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-
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-
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:
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-
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:
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-
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:
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:
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-
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:
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:
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:
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-
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:
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:
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:
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:
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.