COVID-19: Current Overview on SARS-CoV-2 and the Dental Implications

Introduction

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported December 31, 2019, to the China Ministry of Health and the World Health Organization (WHO). It started in Wuhan, China, and is highly contagious. The spread was rapid, and it was declared a global emergency on January 30, 2020 and global pandemic on March 11, 2020. SARS-CoV-2 transmits via droplet, aerosol, oral-fecal routes,¹ as well as contact with contaminated surfaces and oral fluids.² Dentists and healthcare professionals are at risk of exposure to SARS-CoV-2 during daily patient care. Dental and medical offices are at risk for patient and healthcare provider cross infection.³ Thus, personal protective equipment (PPE) like masks, face shields, and gowns, as well as hand washing and pre-treatment mouth rinsing are adopted in the dental and medical facilities to curb the spread of COVID-19.⁴

Systemic consequences

COVID-19 clinical symptoms included fever, myalgia, fatigue, dry cough, sore throat, diarrhea,^5,6 and loss of taste;⁷ symptoms appear about 5.2 days after infection.⁸ Most clinical presentations are asymptomatic or mild; less than 5% develop multi-organ failure or acute respiratory distress syndrome (ARDS). In an epidemiologic study, 17% of COVID-19 patients were asymptomatic and COVID-19 transmission in asymptomatic and symptomatic patients was statistically similar.⁹ SARS-CoV-2 is highly contagious, colonizing nasal, oral and pharyngeal mucosa.¹⁰ Advanced age, hypertension, diabetes, heart disease, and obesity were risk factors for SARS-CoV-2 .^11-13 Severe complications included blood clots, septic shock, pneumonia, sepsis, and ARDS.¹⁴ Respiratory viral infections can increase susceptibility to inflammatory lung damage and bacterial superinfections.¹⁵ The likely cause of death were post-viral complications, like ARDS, rather than the initial viral infection.

Antibody response to SARS-CoV-2 peaks at 14-21 days after signs of infection.¹⁶ Exposure to SARS-CoV-2 appears to stimulate increased levels neutralizing secretory antibodies. Immunoglobulin A (IgA) dominates the initial mucosal immune response in the oral cavity.¹⁷ In mild COVID-19 infection, recovery is approximately 2 weeks. For severe infection, recovery could extend 3-6 weeks and can persist beyond 4 weeks to develop into long COVID.¹⁸ Long COVID or post-COVID-19 syndrome was highest in patients aged 24-36 years and in females. COVID-19-related systemic conditions involving multiple organs may persist during long COVID,¹⁹ increasing risks of encephalitis and strokes. These symptoms for COVID-19 and long COVID may manifest as fever, coughing, breathlessness, fatigue, brain fog, depression, psychosis, anxiety, myocarditis, arrhythmias, heart damage, and muscle and joint pain.^20,21 Smell and taste are frequently altered or impaired.²¹ Furthermore, the increased inflammatory cytokine activation triggered by SARS-CoV-2 can cause prolonged damage to the immune system.²² Seniors over 70 years have the highest morbidity and mortality,²³ while children have significantly less morbidity.²⁴ Immuno-senescence or age-related immunity effects may contribute to increased mortality in the older age group. Some of the effects of immuno-senescence on innate/adaptive immunity may include increased lymphocyte response impairment,²⁵ cytokine secretion,²⁶ failed antibody production, ineffective T-cell response, and severe organ dysfunction from inflammation,²⁷ increasing SARS-CoV-2 susceptibility and COVID-19 severity, and reducing vaccine responses.

Pathogenesis

SARS-CoV-2 is single stranded RNA with cell-surface spike glycoproteins enabling penetration and adherence to host cells.²⁸ (Fig. 1) The primary receptor for the SARS-CoV-2 spike glycoprotein is the angiotensin-converting enzyme 2 (ACE-2) receptor found in the lungs, myocardial cells, kidneys, tongue, and salivary glands.

Fig. 1

The disease progression can be described in 3 main stages:

Stage 1 Innate immunity activation
Stage 2 Adaptive immunity activation
Stage 3 Cytokine release syndrome (“cytokine storm”)²⁹

The hyper-responsive host produces an exaggerated cytokine release^30,31 resulting in a cytokine storm. (Fig. 2) This proinflammatory cytokine release is intensified by increased vascular permeability and effector cells infiltration, inducing excessive monocyte proliferation and lymphocyte apoptosis, possibly resulting in immunodeficiency states32 that manifest as shock, multiple organ dysfunction, hypercoagulation, and acute lung injury.²⁹ The dysregulation and elevated production of acute proinflammatory cytokines (including IFN-γ, IFN-γ-induced protein 10, IL-1, IL-6, IL-12, and monocyte chemoattractant protein36) can cause multi-organ failure, particularly kidneys and heart.33-35 The IL-6 levels in SARS-CoV-2 non-survivors were higher than in the survivors.³¹ IL-6 has also been associated with the severity of the SARS-CoV-2 infection,^37-41 and the increased mortality of older patients and patients with comorbidities.⁴²

Fig. 2

Periodontal inflammation and other chronic inflammatory diseases may influence susceptibility to COVID-19. (Fig. 3) Three different clinical responses of the periodontium to bacterial burden, designated as “high”, “low”, and “slow”, have been identified. The clinical responses to bacteria reflect clinical responses to SARS-CoV-2 virus challenges in the oral cavity. The “high” response group to microbial plaque has clinically high IL-1β levels in inflamed gingival tissues. High clinical gingival responses in gingiva may include patients who were previously referred to as “Aggressive or Early Onset Periodontitis” (now designated as Stage II, III, or IV Grade C Rapid Rate Periodontitis by the new American Academy of Periodontology – European Federation of Periodontology Classification).⁴³

Fig. 3

Low Clinical gingival responses to microbial plaque may include patients who may be relatively resistant clinically to accumulations of bacterial burden around the dentition and soft tissues (now designated as Stage I, Grade A slow rate).⁴³

Slow Clinical responses to microbial plaque may include patients who were previously designated as “Chronic or Adult” forms of Periodontitis (now designated as Stages I, II, or III, Grade A).⁴³

Although it may be argued that the gingiva responds differently to viral challenges as compared to bacterial challenges, varying degrees of inflammatory response for non-vaccinated SARS-CoV-2-infected patients may be at varying levels of risk, from hospitalizations to possible death.

COVID-19 vaccines

The ideal vaccine should be effective after 1-2 doses, protect for at least 6 months, and reduce viral transmission if infected. According to the US Food and Drug Administration (FDA), a vaccine should have at least 50% vaccine efficacy.⁴⁴ Randomized controlled trials for vaccine efficacy evaluated infection reduction, clinical disease severity reduction, and infectivity duration reduction.⁴⁵ Vaccine protection is proportional to infection reduction between vaccinated subjects and control. However, other factors may interfere with the data. These factors include socioeconomic conditions (conditions representing strata of social classes reflecting potential differences in access to dental care, personal oral health habits, and living conditions) (representing urban, rural, or other areas of the country), geographical settings, age differences, and herd immunity.

There are varied SARS-CoV-2 vaccine approaches,⁴⁶ including targeting nucleic acid/m-RNA, spike proteins (protein subunits), adenovirus carrier (viral vector), and inactivated (whole) virus, aiming at neutralizing the spike protein, mRNA, or inactivated virus.⁴⁷ Clinical trials for SARS-CoV-2 vaccines investigated the neutralizing antibody response for the following vaccines: mRNA,^48,49 adenoviral vector,^50,51 spike glycoprotein52 with adjuvants, and inactivated virus.^53,54 An effective vaccine should prevent infection, disease progression or transmission, with reduced mortality and disease severity the desired outcome. The major vaccines available worldwide are outlined in Table 1.

Diminishing immunologic memory and/or mutating antigenicity may decrease vaccine efficacy over time. Vaccine boosters (multiple vaccinations or multiple vaccine types) can prolong protection may induce robust and longer lasting immunity.^55,56 The CDC reported that vaccine effectiveness decreased in selected medically compromised groups, resulting in higher risks of COVID-19 breakthrough infections⁵⁷ and breakthrough infections in fully vaccinated patients.⁵⁸ Vaccines may reduce breakthrough infections significantly, and United Kingdom data⁵⁹ indicated that fully vaccinated patients were at a reduced risk for severe complications, breakthrough infections, and developing long-haul COVID.

Dental and oral implications

For cellular entry, the SARS-CoV-2 uses the ACE-2 receptors,⁶⁰ and its infectivity is dependent on its ability to penetrate the cell. ACE-2 receptors are found in oral mucosa at the floor of the mouth, buccal mucosa, gingiva, and the tongue.⁶¹ SARS-CoV-2 can target the ACE-2-positive taste organs on the tongue61 may, causing the commonly reported loss of taste .7,^61-63 Similarly, ACE-2-positive salivary glands may be targeted, causing salivary dysfunction,⁶⁴ dry mouth,⁷ and SARS-CoV-2 detectability in saliva.⁶⁵ There ae more ACE-2 receptors in salivary glands than in the lungs, and the salivary glands may harbor SARS-CoV-2 in asymptomatic patients.⁶⁶ ACE-2 receptors in chronic periodontitis fibroblasts with elevated protease levels⁶⁷ may increase the risk for viral entry.⁶⁸

SARS-CoV-2 fusion to the host cell requires S protein cleavage by transmembrane protease serine 2 (TMPRSS2) or furin,^69-71 available from oral pathogenic bacteria.⁷²

Oral health can affect overall health (73), and may be related to the increased/decreased COVID-19 risk.^61,66 A healthy oral cavity has a symbiotic balance of gram+ bacteria. Periodontal disease and poor oral hygiene promote dysbiotic biofilms that can trigger cytokine release which may have systemic repercussions, and may propagate pulmonary infections.⁷⁴ Furthermore, aspired oral pathogenic bacteria may exacerbate lung infections,⁷⁵ leading to inflammation and aggravation of COVID-19.⁷² Mortality in severely affected COVID-19 patients was due to secondary bacterial infection rather than SARS-CoV-2.¹² This is supported by the higher neutrophil to lymphocyte ratio detected in COVID-19 patients, indicative of a bacterial, rather than viral, superinfection.⁷⁶ This factor is significant in the elderly and medically-compromised, where the poor swallowing reflex may increase the risk of bacterial aspiration,⁷⁷ increasing COVID-19 severity.^78,79 Periodontal pathogens have been found in the lower respiratory tract and lungs of COVID-19 patients.⁸⁰

Periodontitis and poor oral hygiene increase periodontal pathogens, raising ACE-2 expression, increasing proinflammatory cytokine release, and degrading the SARS-CoV-2 S-protein. These pathogens upregulate ACE-2 transcription, induce alveolar epithelial cell IL-8 and IL-6 production,⁸¹ and degrade S protein by microbial proteases,^70,71 increasing SARS-CoV-2 infectivity and penetration. Prolonged COVID-19 hospitalization risks poor oral care access, increasing the risk of aspirated pathogenic oral bacteria causing lung inflammation. Thus, periodontitis and poor oral hygiene (increased oral pathogenic bacteria) may contribute to COVID-19 progression,⁷² and may increase morbidity. Periodontitis, when associated with comorbidities(diabetes mellitus, chronic obstructive pulmonary disease, hypertension, and cerebrovascular or cardiovascular disease), can worsen COVID-19 outcomes.⁸² Diabetes and cardiovascular disease were the most prevalent comorbidities in COVID-19 hospitalizations.⁸³ COVID-19 patients with periodontitis had a higher mortality risk than non-periodontitis patients.⁸⁴ In addition, periodontitis increased IL-1 and TNF cytokine release exacerbating the “cytokine storms“ in COVID-19 patients. Higher cytokine levels elevated COVID risk. The reduction of periodontitis-induced cytokines may lower the risk of SAR-CoV-2 mortality.

Meticulous daily oral hygiene maintenance and periodontitis treatment reduces gingival inflammation, ACE-2 expression, inflammatory cytokines, and aspiration pneumonia,⁸⁵ and may reduce COVID-19 susceptibility and aggravation.⁷² Periodontitis therapy and attention to oral health mitigates systemic diseases (diabetes, COPD),^86,87 and may reduce pneumonia and influenza mortality and complications.^88,89

Pre-procedural oral antiseptic rinses are effective in reducing bacterial cross-infection risk in aerosols.⁹⁰ Oral antiseptics reported antiviral activity in vitro.⁹¹ Oral antiseptics disrupt the viral lipid envelope interfering with viral integrity.⁹¹ Oral antiseptics active in viral cross-contamination prevention include: 0.05-0.10% cetylpyridinium chloride,⁹² 1% povidone-iodine,⁹³ 0.12% chlorhexidine,⁹⁴ beta-cyclodextrin with citrox,⁹⁵ 1% hydrogen peroxide,⁹⁶ and essential oil mouth rinses (e.g., eucalyptol, thymol, menthol, methyl salicylate).⁹⁷ Mouth rinse combination of 1% hydrogen peroxide and 0.2-0.3% chlorhexidine in sequence can also be beneficial,⁹⁸ reducing salivary viral load and decreasing SARS-CoV-2 transmission.⁹⁹

A randomized control clinical trial investigated antimicrobial mouth rinse viral load reduction in asymptomatic SAR-CoV-2 patients¹⁰⁰ with chlorhexidine (0.12%), povidone iodine (0.5%), and hydrogen peroxide (1%), with sterile saline as a control. All 4 mouth rinses and the saline control decreased viral load indicating that antimicrobial pre-rinsing may be effective in reducing salivary viral cross-contamination in the dental practice. The limitation: SARS-CoV-2 viral loads were investigated, excluding other respiratory viruses and oral bacteria.

Oral cavity bacterial/viral load in aerosol sprays generated from dental and hygiene procedures has long been of concern. This study suggests that povidone iodine and hydrogen peroxide, together with chlorohexidine may be an effective antiviral rinse. Another study suggests that povidone iodine, cetypyridinium chloride, and chlorohexidine have effective anti-SARS-CoV-2 activity.⁹⁶ However, long-term bioactivity and substantivity of these rinses must be considered. Antimicrobial mouthwashes or nasal sprays in symptomatic or asymptomatic COVID-19 patients may prevent viral cross-infection and protect healthcare professionals.¹⁰¹

Conclusions

Good periodontal health and optimal oral hygiene habits may contribute to increased survival with SARS-CoV-2. In addition, good systemic health and optimal oral health may contribute to the prevention of COVID-19 infections. Antimicrobial mouth rinses may be recognized as routine therapeutic agents to inhibit the transmission of COVID-19 in the dental office.

Oral Health welcomes this original article.

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About the Author

Miriam Ting, DMD (Temple University, magna cum laude), BDS (Singapore), Cert. Advanced Periodontology and MS (Craniofacial Biology) at USC. Diplomate, American Board of Periodontology and ICOI. Dr. Ting is founder and director, Think Dental Learning Institute and Magnifico Oral Health Foundation and practises at Think Oral Implants and Periodontics in Paoli, PA.

 

Jon B. Suzuki, DDS (Loyola), PhD (IIT) MBA (Pittsburgh), is the current Chairman, Food and Drug Administration, Dental Products Advisory Panel. He has Clinical Professorships at University of Maryland, University of Washington and Nova Southeastern University and was Dean, University of Pittsburgh, and Director, Graduate Periodontology and Oral Implantology, Temple University.

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