Revisiting the importance of oral health management based on the lessons learned from the COVID-19 pandemic

Abstract

The oral cavity is the starting point and an integral part of the respiratory system. Oral bacteria are deeply involved in the onset and aggravation of lower respiratory tract diseases, including aspiration pneumonia, influenza, and chronic obstructive pulmonary disease. Oral health conditions, such as periodontal disease, influence the severity of coronavirus disease 2019 (COVID-19). Oral bacteria can be detected in the respiratory organs of patients with COVID-19, and the composition of oral bacterial flora may be altered. Aspiration pneumonia is common among patients with COVID-19 who are advanced in age or have underlying diseases due to poor oral hygiene management, fever, and other issues. While findings from further studies are awaited, maintaining a healthy oral cavity can prevent COVID-19 onset and aggravation. In addition to routine management of oral microflora at home and maintenance of periodontal health in dentistry, medical-dental collaboration is crucial for a prompt response to future pandemics, as humans have just experienced in COVID-19.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic is in its fourth year, and humans have now adapted to the new normal with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Because the oral cavity serves as an important entry point for SARS-CoV-2 into the lower respiratory system, including the bronchi and lungs, where SARS-CoV-2 elicits inflammation, aspiration of oral bacteria can influence COVID-19 [1,2]. Increased severity and high mortality rates have been noted among patients with SARS-CoV-2 infection and other underlying diseases, such as chronic obstructive pulmonary disease (COPD) and diabetes mellitus [3,4,5], in which periodontal disease and oral bacteria are deeply involved [6].

The association of COVID-19 with the oral cavity and poor oral hygiene has been extensively reported. Because oral health management is an effective measure for preventing pneumonia, it is considered to be effective for preventing and ameliorating underlying diseases that aggravate COVID-19, thus impeding COVID-19 progression.

This review discusses the relationship between COVID-19 and oral health conditions based on published clinical and basic studies.

Association of COVID-19 with oral hygiene and periodontitis

Epidemiological studies have revealed considerable evidence on the relationship between oral hygiene and COVID-19. This review mainly discusses findings from case-control studies and meta-analyses (Table 1).

Marouf et al. analyzed electronic health records in Qatar and found an association between periodontitis and COVID-19 aggravation [7]. In the analysis, patients with COVID-19 were divided into patients with aggravated COVID-19 (who died, were admitted to intensive care unit [ICU] or required a ventilator; the case group) and those discharged with no COVID-19 aggravation (the control group). The analysis revealed that 258 of 568 patients with COVID-19 had periodontitis (stages II-IV). Among the 258 patients with COVID-19 and periodontitis, 33 became severely ill because of COVID-19, whereas 7 of 310 patients with COVID-19 and without periodontitis became severely ill; thus, the odds ratio for aggravation in patients with periodontitis was 3.67. Further detailed analysis of patients with severe COVID-19 showed odds ratios for risks of mortality, ICU admission, and mechanical ventilation in patients with periodontitis as 8.81, 3.54, and 4.57, respectively. Furthermore, blood test data showed that the white blood cell (WBC) count and C-reactive protein (CRP) levels were elevated in those who died of COVID-19. Both the WBC count and CRP levels in patients with COVID-19 and periodontitis were higher than those in patients with COVID-19 and without periodontitis. Thus, the authors concluded that the poor prognoses of patients with COVID-19 and periodontitis may be attributable to systemic inflammation originating from periodontitis, highlighting an association between periodontitis and COVID-19 aggravation.

Gupta et al. examined 82 patients diagnosed with COVID-19 in India for periodontal disease and divided the patients into those with gingivitis, those with periodontitis (stages I-IV), and those with a healthy oral cavity [8]. Analysis of these patients showed that the odds ratios for mortality, COVID-19 pneumonia, hospitalization, and ventilation risks in patients with COVID-19 and severe periodontitis (stages II-IV) versus patients with COVID-19 and healthy oral cavity, gingivitis, or stage I periodontitis were 14.58, 4.42, 36.52, and 7.45, respectively. The results indicated an association between severe periodontitis and COVID-19 prognosis.

Anand et al. conducted oral cavity examinations to assess oral hygiene and periodontal disease in India to test their association with the development of COVID-19 [9]. Among 150 individuals who visited an outpatient clinic specializing in COVID-19, 71 with negative polymerase chain reaction (PCR) test results and 79 with positive PCR test results were analyzed as the control and case groups, respectively. The control participants underwent oral cavity examinations after PCR tests confirmed that they were negative, whereas the case patients underwent oral cavity examinations after they completed treatments and were then confirmed to be positive for COVID-19. The analysis showed that the odds ratio for testing positive for COVID-19 was 7.01 in those with a plaque index (PlI) ≥1, 17.65 in those with periodontitis, 8.46 in those with a clinical attachment level (CAL) ≥2 mm, and 11.75 in those with severe periodontitis. These results indicate that poor oral hygiene and periodontitis increase the risk of COVID-19 infection.

Using the UK Biobank, which collects health/medical information from people in the UK, Larvin et al. studied the effects of periodontal disease on hospitalization and mortality rates in 13,253 people who were tested for COVID-19 during the COVID-19 pandemic in 2020 [10]. Although the data on oral health conditions (bleeding gums, painful gums, and loose teeth) were based on self-reporting, the analysis showed that those with gingival pain or bleeding had a mortality odds ratio of 1.71 and did not have an increased hospitalization risk. This study may have underestimated periodontal disease because self-reported periodontal disease statuses were used. Nevertheless, periodontal disease stood out as a risk factor for COVID-19 mortality even in the analysis of such data.

Recently, meta-analyses were performed on the relationship between periodontitis and COVID-19 based on the integrated analysis of these results [11,12]. A 2022 meta-analysis reported that periodontitis was associated with ventilation (odds ratio: 6.24) and mortality (odds ratio: 2.26) [11]. A 2023 meta-analysis reported periodontitis was associated with severe COVID-19 symptoms (odds ratio: 6.95), ICU admissions (odds ratio: 3.15), and mortality (odds ratio: 1.92) [12]. Therefore, based on these reports, periodontitis could be involved in the aggravation of COVID-19.

Table 1 Representative studies of oral health and COVID-19

First author, year [Ref.]	Country	Study design	Sample size	Results
Marouf, 2021 [7]	Qatar	case-control study	total: n = 568 case: n = 40 control: n = 528	Periodontitis was associated with COVID-19 complications (death, ICU admission, need for assisted ventilation): Odds ratio (OR) = 3.67 (95% confidence interval [CI]: 1.46-9.27)
Gupta, 2022 [8]	India	cross-sectional study	total: n = 82	Severe periodontitis was associated with death: OR = 14.58 (95% CI: 1.69-125.33), COVID-19 pneumonia: OR = 4.42 (95% CI: 1.57-12.45), hospital admission: OR = 36.52 (95% CI: 4.62-288.64), and requiring ventilation: OR = 7.45 (95% CI: 2.71-20.45)
Anand, 2022 [9]	India	case-control study	total: n = 150 case: n = 79 control: n = 71	Associations of COVID-19 with mean plaque score ≥1: OR = 7.01 (95% CI: 1.83-26.94), gingivitis: OR = 17.65 (95% CI: 5.95-52.37), clinical attachment level ≥ 2 mm: OR = 8.46 (95% CI: 3.47-20.63), and severe periodontitis: OR = 11.75 (95% CI: 3.89-35.49)
Larvin, 2020 [10]	UK	cross-sectional study	total: n = 13,253	Association of COVID-19 with painful or bleeding gums: OR = 1.71 (1.05-2.72)
Molina, 2023 [11]		meta-analysis		Periodontitis was associated with the need for assisted ventilation: OR = 6.24 (2.78-13.99) and COVID-19-related mortality: OR = 2.26 (1.36-3.77)
Al-Maweri, 2023 [12]		meta-analysis		Periodontitis was associated with severe COVID-19 symptoms: OR = 6.95 (2.24-21.56), ICU admissions: OR = 3.15 (2.07-4.79), and mortality: OR = 1.92 (0.70-5.32)

Effects of COVID-19 on oral microbiome and cytokine expression

Numerous studies have analyzed the association between microbiome within the oral cavity and cytokine production with the onset and aggravation of COVID-19.

A research group in China analyzed the microbiome using bronchoalveolar lavage fluid samples collected from patients with COVID-19 (n = 8), patients with community-acquired pneumonia (n = 25), and healthy individuals (n = 20) [13]. The analysis showed that the microbiome of patients with COVID-19 was similar to that of patients with community-acquired pneumonia and was characterized by an increased population of resident bacteria in the oral cavity and upper airway. Investigators in Italy used mouth rinse samples to analyze microbiome [14]. Microbial species diversity in the oral cavity was inversely correlated with COVID-19 severity, i.e., the diversity of microorganisms decreased with an increase in disease severity. Moreover, patients with COVID-19 were characterized by increases in bacteria associated with poor oral hygiene and periodontal disease (Prevotella spp., Lactobacillus spp., Capnocytophaga spp., Porphyromonas spp., Abiotrophia spp., Aggregatibacter spp., and Atopobium spp.) compared with those in healthy individuals. Furthermore, the oral microbiome of patients with COVID-19 had low bacterial species richness and high fungal species diversity. In particular, while most oral fungal species in healthy participants belonged to the genera Candida (47%) and Saccharomyces (52%), patients with COVID-19 showed the presence of Aspergillus spp. (4%), Nakaseomyces spp. (3%), and Malassezia spp. (<1%) as well as Candida spp. and Saccharomyces spp., highlighting an increased fungal diversity. The study also analyzed viruses in the oral cavity. In healthy individuals, viruses accounted for only 0.07% of the whole microbiome; however, the number of viruses increased to 1.12% in patients with COVID-19. In addition, although herpes simplex virus type 1 and Epstein-Barr (EB) virus, viruses belonging to the family Herpesviridae, were detected in both healthy individuals and patients with COVID-19, EB virus reactivation was noted in 30% of patients with COVID-19 in contrast to the reactivation observed in only 5% of healthy individuals. This may be a contributing factor to the increased number of viruses in the oral cavity. Furthermore, the number of bacteriophages, viruses that infect bacteria, was increased in the oral cavity of patients with COVID-19. Because cytokine storms, excessive release of inflammatory cytokines, such as IL-6, IL-17, and TNF-α, are characteristically observed in severe cases of COVID-19, cytokine levels in mouth rinse samples were measured. The results revealed that the IL-6 and IL-17 levels in samples from patients with COVID-19 were higher than those in samples from healthy individuals. Moreover, the TNF-α and GM-CSF levels in samples from symptomatic patients with COVID-19 were higher than those from healthy individuals.

Investigators in PR China used pharyngeal swabs to analyze microbiome [15]. They also showed that the diversity of oral microbial species in patients with COVID-19 was decreased compared with that in healthy individuals and that the oral microbial diversity in patients with severe COVID-19 was further decreased than that in patients with nonsevere COVID-19. Bacteria associated with periodontitis (Veillonella spp., Campylobacter spp., Rothia mucilaginosai, Granulicatella spp., Kingella spp., and Filifactor spp.) were relatively increased in patients with COVID-19. Moreover, Neisseria spp., resident bacteria in the oral cavity, markedly decreased in patients with COVID-19, and functional analysis of oral microbiome revealed that vital metabolic pathways, including the tricarboxylic acid cycle, were suppressed in the oral microbiome of patients with COVID-19.

While the above studies reported the decreased diversity of oral microorganisms in patients with COVID-19, there is also a report that revealed no changes in the diversity. Investigators in the United States used saliva samples to investigate oral microbiomes [16]. They found no significant differences in the oral microbial diversity between healthy people and patients with COVID-19. However, salivary microbiome in patients with COVID-19 differed depending on whether SARS-CoV-2 was detected in saliva.

Some studies have analyzed cytokines and oral microbiome in the oral cavity. Microbiome analysis using oral swab samples revealed that Prevotella salivae and Veillonella infantium were predominantly detected in samples from patients with COVID-19, whereas Neisseria perflava and Rhothia mucilaginosa were predominant in samples from healthy individuals [17]. In addition, cytokine measurements in the same swab samples showed increased IL-6 levels in patients with COVID-19 and IL-12p70 levels in healthy individuals.

A study focusing on the detection levels of periodontopathic Fusobacterium nucleatum (F. nucleatum) in the pharynx showed an increased number of F. nucleatum in patients with COVID-19 than that in healthy individuals, indicating that the SARS-CoV-2 infection risk increases with the F. nucleatum level in the pharynx [18].

These reports have demonstrated substantial changes in oral microbiome compositions, particularly increased periodontal disease-associated bacteria in patients with COVID-19, strongly indicating a link between COVID-19 and periodontal disease.

Bacteria colonizing dentures have been studied in Iran [19]. The authors cultured bacteria that colonized the complete dentures of COVID-19 patients and those of healthy individuals for identification. Consequently, Streptococcus spp. and Klebsiella pneumoniae were detected at higher rates in the dentures of patients with COVID-19 than in those of healthy individuals. These bacteria may contribute to the aggravation of COVID-19 symptoms because they can cause respiratory infections.

Oral cavity has a close connection to SARS-CoV-2/COVID-19

The relationship between SARS-CoV-2 infection, and oral bacteria and poor oral hygiene is an important research area necessitating advancement. It was previously reported that the culture supernatant of periodontopathic F. nucleatum induced the expression of angiotensin-converting enzyme 2 (ACE2), the host cell receptor for SARS-CoV-2, at the protein and gene levels [20].

Although they did not use the gingivae of patients with COVID-19, Ohnishi et al. analyzed the expression levels of transmembrane serine protease 2 (TMPRSS2) – a host protease responsible for cleavage of the SARS-CoV-2 spike protein, a step required for the establishment of infection – in the gingivae of patients with periodontitis but not with COVID-19 and of the periodontally healthy corresponding individuals. They have reported a significantly higher expression of TMPRSS2 in the gingivae of patients with periodontitis [21]. However, there were no detectable differences in the expression of ACE2 or furin, which also cleaves the spike protein, like TMPRSS2.

Other relevant reported findings include higher ACE2 and TMPRSS2 expression levels in oral epithelial cells from older individuals than in those from young individuals and the effect of smoking on increased ACE2 and TMPRSS2 expression levels in gingival epithelial cells [22].

These findings suggest the direct involvement of periodontitis, periodontopathic bacteria, and smoking in local SARS-CoV-2 infection of the periodontal tissue.

Even if they have no direct involvement, oral bacteria may aggravate lower airway inflammation, thereby contributing to COVID-19 aggravation (Fig. 1). When aspirating periodontopathic bacteria and other oral bacteria that have grown because of poor oral hygiene, in addition to the aforementioned increase in ACE2 expression, increased expression of platelet-activating factor receptor, a receptor for causative bacteria of pneumonia [23], and production of inflammatory cytokines are induced [24]. Moreover, periodontopathic bacteria can cause mucin overproduction and a deterioration in respiratory function [25]. They can disrupt alveolar and airway epithelial barriers and facilitate viral invasion [26,27]. In addition, inflammatory substances in the oral cavity affect tissues in the whole body, including the lungs, through blood circulation (chronic systemic inflammation due to periodontal disease), and aspirated oral bacteria disrupt the composition of bacterial flora of the lungs (dysbiosis). These mechanisms may involve oral bacteria in the pathogenesis and progression of respiratory diseases.

Fig. 1 Oral cavity is closely associated with SARS-CoV-2/COVID-19

The relationships between underlying diseases associated with COVID-19 aggravation (such as diabetes mellitus and chronic obstructive pulmonary disease) and periodontitis are well known. Thus, the aggravation of periodontitis and poor oral hygiene may be involved indirectly in COVID-19 aggravation. Meanwhile, periodontitis and periodontopathic bacteria may promote SARS-CoV-2 infection or directly contribute to COVID-19 aggravation through inflammatory cytokine induction. In addition, aspiration of periodontopathic bacteria may induce excessive production of mucin and destruction of the epithelial barrier in the lower respiratory tract, resulting in decreased respiratory function. Dental professionals must take the current pandemic as an opportunity to reconsider the role of the oral cavity in the progression of infectious diseases and the importance of oral hygiene management.

Importance of measures against aspiration pneumonia during the COVID-19 pandemic

Measures against COVID-19 in older individuals are crucial in countries with hyper-aged populations, such as Japan. Multiple vaccinations have prevented severe COVID-19 cases to some extent; however, the number of older patients with COVID-19 dying from aspiration pneumonia has increased since the Omicron outbreak (Fig. 2) [28]. People infected with SARS-CoV-2 often lack adequate oral hygiene management because of fever and malaise. Moreover, infected individuals have decreased swallowing function and are prone to aspirate oral bacteria that can cause pneumonia. Patients with COVID-19 and such problems may contract viral and bacterial pneumonia (either coinfection or secondary infection), which can be lethal for older patients. Many people acquiring aspiration pneumonia and SARS-CoV-2 infection may overwhelm the emergency outpatient unit and other units of hospitals. Maintaining a healthy oral cavity is important for avoiding such situations. Oral healthcare and periodontal disease treatment prevent the onset and aggravation of pneumonia and COPD [1]. From this perspective, the Clinical Management of Patients with COVID-19: A Guide for Front-Line Healthcare Workers Version 10.1 (published in April 2024) in Japan has a section on managing older adults, focusing on the prevention of bacterial pneumonia and aspiration pneumonia [Ministry of Health, Labour and Welfare, 2024]. Because oral care can prevent aspiration pneumonia, maintaining a healthy oral cavity is important to avoid such an adverse effect (Fig. 2).

Fig. 2 Oral health management can prevent COVID-19 aggravation

Older adults and medically compromised patients experience a negative cycle as follows: SARS-CoV-2 infection → fever and decreased swallowing function → aspiration of oral bacteria → viral + bacterial pneumonia → increased mortality or overwhelmed hospitals. Consequently, oral health management has attracted attention as a means to break such a negative cycle.

Future insights/directions

Maintaining oral hygiene by lowering the number of oral bacteria has a positive impact on people. Conversely, respiratory viruses other than SARS-CoV-2, such as influenza viruses, are also closely related to oral hygiene and oral bacteria. For example, poor oral hygiene itself increases the risk of influenza [29], but professional oral health management reduces this risk [30]. Using its own secreted sialidase, Streptococcus oralis, a predominant constituent of human oral microflora, promotes the release of progeny influenza virus [31]. In addition, secondary bacterial infections exacerbate respiratory viral infections. This was the leading cause of death in previous influenza pandemics [32,33,34]. As mentioned above, aspiration pneumonia became the leading cause of death after the outbreak of the Omicron variants, and these findings indicate that oral bacteria contribute to the severity of respiratory viral infections.

The influenza virus and SARS-CoV, along with SARS-CoV-2 [35], are speculated to be potential pathogens of the next pandemic. Based on this speculation, it appears necessary to widely share among healthcare professionals the possibility that oral health management can prevent infection and reduce the severity of the next pandemic caused by these respiratory viruses.

Apart from viral infectious diseases such as COVID-19, a prolonged stay in evacuation shelters because of disasters such as severe earthquakes and floods can also be associated with inadequate oral health management and increased deaths from aspiration pneumonia, posing a social problem. In addition, maintaining good oral hygiene may help decrease the use of antibacterial/antiviral agents; therefore, it may help reduce medical costs and prevent bacteria and viruses from acquiring antimicrobial resistance.

There is an increasing understanding of the link between poor oral hygiene and COVID-19. Although humans have adapted to the new normal with SARS-CoV-2, new variants may still become rampant. Accumulation of evidence through large-scale clinical randomized controlled trials related to oral health management and COVID-19 and the promotion of further basic research can lead to a broad understanding of the benefits of oral health management, which in turn will contribute to an increase in healthy life expectancy. In addition, to prepare for future outbreaks of respiratory viral pandemics, it is important to be aware of the possibility that oral health management can prevent the next pandemic – the outbreak of the respiratory viral pandemic – and the need to establish a system that allows for smooth medical-dental collaboration on a daily basis.

Abbreviations

ACE2: angiotensin-converting enzyme 2; COPD: chronic obstructive pulmonary disease; COVID-19: coronavirus disease 2019; CRP: C-reactive protein; EB virus: Epstein-Barr virus; PCR: polymerase chain reaction; SARS-CoV-2: severe acute respiratory syndrome coronavirus; TMPRSS2: transmembrane serine protease 2

Conflicts of Interest

The authors declare that there is no conflict of interest in regard to this article.

Funding

This work was supported by JSPS KAKENHI Grant Numbers JP21K10265 and JP23H03120, Uemura Fund, Nihon University School of Dentistry (UEMURA-2023-3), a grant from the Dental Research Center, Nihon University School of Dentistry (DRC(A)-2023-4) and a Nihon University Multidisciplinary Research Grant for 2021.

Author Contributions

NK: conceptualization, literature paper selection, funding acquisition, writing – original draft, and writing – review and editing; MT: literature paper selection and writing – review and editing; SO: literature paper selection and writing – review and editing; KS: literature paper selection and writing – review and editing; MC: writing – review and editing; HT: literature paper selection and writing – review and editing; KI: conceptualization, literature paper selection, funding acquisition, and writing – review and editing. All authors read and approved the final version of the manuscript.

ORCID iD

NK*: [e-mail], https://orcid.org/0000-0002-5639-3902

MT: [e-mail], https://orcid.org/0000-0002-8637-1579

SO: [e-mail], https://orcid.org/0009-0008-2243-5140

KS: [e-mail], NA

MC: [e-mail], https://orcid.org/0000-0002-6275-2676

HT: [e-mail], NA

KI*: [e-mail], https://orcid.org/0000-0003-0985-4267

Data Availability Statements

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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