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The Covid-19 Pathway
- 1. THE COVID-19 PATHWAY HYPOTHETICALMODEL oral-vascular-pulmonary route of infection and potential for poor oral health to mediate vascular transmission of SARS-COV-2 to the lungs D R . G R A H A M L L O Y D - J O N E S D R . S H E R V I N M O L A Y E M D R . C A R L A P O N T E S P R O F . I A I N C H A P P L E
- 2. RESEARCH GROUP Dr. Carla Cruvinel Pontes PhD,MsC, DDS. Periodontist, Researcher - Mouth-Body Research Institute, Cape Town, South Africa Dr. Graham Lloyd-Jones BA, MBBS, MRCP, FRCR. Consultant Radiologist, Salisbury District Hospital, United Kingdom. Director of Radiology Masterclass Dr. Shervin Molayem DDS. Periodontist, Director - Mouth-Body Research Institute, Los Angeles, California Prof. Iain Chapple PhD, BDS, FDSRCPS, FDSRCS, CCST (RCS). Periodontal Research Group, Institute of Clinical Sciences, College of Medical & Dental Sciences, The University of Birmingham, UK
- 3. PRESENTATION OVERVIEW INTRODUCTION – CURRENTCHALLENGES BIOLOGICAL RATIONALE - ORAL-PULMONARY HYPOTHESIS Oral cavity perspective Radiological perspective ANATOMICAL ROUTE – FROM ORAL CAVITY TO LUNGS CLINICAL SIGNIFICANCE RECOMMENDATIONS FINAL REMARKS
- 4. VACCINATIONS PER STATE CHALLENGES NEW VARIANTS LACK OF BIOMARKERS LACKOF PREDICTABLE TREATMENT LACK OF INFORMATION ON VIRAL INFECTION ROUTE
- 5. MEDICAL HYPOTHESIS Radiological evidence Primaryvascular pathological processes in the lung 1 Initial site Upper respiratory tract is understood as the primary site of infection 2 Viral reservoir Formation of a viral reservoir in oral cavity and saliva 3 Virus survival Survival within the sub-gingival biofilm 4 Virus translocation 5 Pulmonary vessels Direct vascular delivery of virus to pulmonary vessels 6 From saliva to gingival sulcus/periodontal pocket
- 6. VACCINATIONS PER STATE CHALLENGES RADIOLOGICAL PERSPECTIVE Image courtesyof Radiology Masterclass https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1 CHEST X-RAY - Patient with proven swab positive COVID-19 - Distribution of shadowing typical for COVID-19 lung disease (bilateral, symmetrical, peripheral, and basal) PATHOLOGICAL DISTRIBUTION OF THE DISEASE 1
- 7. VACCINATIONS PER STATE CHALLENGES RADIOLOGICAL PERSPECTIVE Image courtesyof Radiology Masterclass https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1 Computed tomography (CT) - Patient with proven swab positive COVID-19 - CT with typical ground-glass opacities seen in COVID- 19 lung disease - The peripheries of the lung bases are dominantly affected PATHOLOGICAL DISTRIBUTION OF THE DISEASE 1
- 8. VACCINATIONS PER STATE CHALLENGES RADIOLOGICAL PERSPECTIVE Image courtesyof Radiology Masterclass https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1 Computed tomography (CT) - Patient with proven swab positive COVID-19 - Vascular tree-in-bud opacification of pulmonary vessels - A specific sign of COVID-19 which is present in 64% of patients with the lung disease EVIDENCE OF PULMONARY VASCULAR PHENOMENA 2
- 9. RADIOLOGICAL PERSPECTIVE Image courtesyof Radiology Masterclass https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1 CT PULMONARY ANGIOGRAM (CTPA) - Thromboembolic disease in COVID-19 - Pulmonary arteries (blue arrows) highlighted by injection of contrast (white) - Areas not highlighted (filling defects) are due to thrombotic material (blood clots) in arteries (red arrows) DISTINCT PHENOTYPE OF THROMBOEMBOLIC DISEASE 3
- 10. VACCINATIONS PER STATE CHALLENGES RADIOLOGICAL PERSPECTIVE Image courtesyof Radiology Masterclass https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1 CT SCAN - Wedge-shaped opacities at lung’s edge - Similar to pulmonary thromboembolic disease - They are present in COVID-19 lung disease with or without visible filling defects in pulmonary arteries - Pulmonary infarcts are found at autopsy DISTINC PHENOTYPE OF THROMBOEMBOLIC DISEASE 3
- 11. RADIOLOGICAL PERSPECTIVE CORRELATION OFRADIOLOGICAL AND AUTOPSY FINDINGS 4 VASCULAR OBSTRUCTION Pulmonary infarcts and perfusion defects INFLAMMATION Endothelial cell damage and dysfunction MICROANGIOPATH Y Microthrombi in both arterioles/venules
- 12. VACCINATIONS PER STATE CHALLENGES ORAL CAVITY PERSPECTIVE LippiG et al. Clinical Chemistry and Laboratory Medicine 2020;58(9): 415-1422 ► Key elements for host cell infection ► Expressed in gingiva, salivary glands, tongue, saliva ► Cells from the sulcular epithelium express all molecules ► Gingival sulcus - target for infection ACE2, TMPRSS2, FURIN SEVERAL NICHES IN ORAL CAVITY CAN BECOME INFECTED ENTRY FACTORS FOR SARS-COV-2 IN ORAL AND GINGIVAL TISSUES 1
- 13. Huang et al.Medrxiv 2020 October 27, doi: 10.1101/2020.10.26.20219089 Fernandes Matuck et al. J Oral Microbiol 2021;13(1):1848135 Confirmed in vivo SARS-CoV-2 infection in salivary glands and oral mucosa COVID-19 AUTOPSY STUDY 1 Confirmed virus presence in periodontal tissues of 5 out of 7 deceased patients COVID-19 AUTOPSY STUDY 2 ORAL CAVITY PERSPECTIVE PRESENCE OF SARS-COV2 IN ORAL CAVITY AND PERIODONTAL TISSUES 2
- 14. Badran. Med Hypotheses2021;143:109907 Gupta et al. J Dent Res 2021;100:187–93. ORAL CAVITY PERSPECTIVE VIRAL RNA Detected in gingival crevicular fluid of approximately 64% of COVID-19 patients SULCUS/POCKET Favorable conditions for viral particles in the oral cavity SUBGINGIVAL PLAQUE Unique environment for the virus MICRO ULCERATIONS Can facilitate passage of virus to capillaries and systemic circulation VIRUSES IDENTIFIED IN SALIVA, GCF, SUBGINGIVAL PLAQUE, AND GINGIVAL TISSUES Human Immunodeficiency Virus Herpes simplex virus Epstein–Barr Virus Human Cytomegalovirus PERIODONTAL POCKETS AS RESERVOIR FOR VIRUSES 3
- 15. ORAL CAVITY PERSPECTIVE PERIODONTAL DISEASE Localinflammation Micro-ulcerations on pocket epithelium HIGHER RISK FOR TRANSLOCATION OF BACTERIA AND VIRUSES BACTERIEMIA INFECTIVE ENDOCARDITIS Oral bacteria can damage other organs in the body Higher risk with poor oral hygiene and periodontal inflammation ORAL CAVITY AS ENTRY POINT FOR MICROORGANISMS 4
- 16. ORAL CAVITY PERSPECTIVE PERIODONTITIS Pgcan reactivate EBV and HIV-1 viruses; EBV infection linked to periodontal inflammation CO-INFECTION Respiratory conditions often linked to viral–bacterial co-infections SARS-COV-2 Synergy can facilitate penetration of virus through pocket epithelium SYNERGY can help viruses evade immune response and enter systemic circulation VIRAL-BACTERIAL SYNERGY IN PERIODONTAL ENVIRONMENT 5
- 17. ORAL CAVITY PERSPECTIVE REGULATEHOST RESPONSE PERPETUATE INFLAMMATION Link between periodontal disease and systemic inflammation SEVERITY OF COVID-19 ALSO LINKED TO SYSTEMIC INFLAMMATION INNATE IMMUNITY ADAPTIVE IMMUNITY PMN MACROPHAGE TH1 TH2 TH17 TREGS IFN-γ, IL-4, IL-17, IL-10, TGF-β CYTOKINES CELLS HOST RESPONSE TNF-α, IL-1β, IL-6 PERIODONTAL INFLAMMATION NEUTROPHILS Of periodontitis patients are hyper- reactive (IL-1β, IL-8, IL-6, TNF-α) when FcγR and Toll-like R4 receptors are challenged Ling MR, Chapple ILC, Matthews JB. Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis. Innate Immun 2015;21(7):714–25 LOCAL AND SYSTEMIC INFLAMMATORY RESPONSE 6
- 18. - Reduce incidence/severityof pulmonary infection - Lower incidence of aspiration pneumonia in elderly patients in hospital and nursing homes - Decrease morbidity and mortality - Potential to mitigate COVID-19 lung complications ORAL CAVITY PERSPECTIVE 1 IN 10 DEATHS FROM PNEUMONIA IN NURSING HOMES CAN BE PREVENTED THROUGH ORAL HYGIENE MEASURES ADEQUATE ORAL HYGIENE Muller et al. J Dent Res 2015;94:14S-16S Sjogren et al. J Am Geriatr Soc 2008;56(11):2124-30. LINKS – PERIODONTITIS RESPIRATORY CONDITIONS 7
- 19. ORAL CAVITY PERSPECTIVE PERIODONTAL DISEASE PHYSICALDISABILITY, LEARNING DIFFICULTY SPECIFIC ETHNIC GROUPS TYPE-A BLOOD GROUP CHRONIC KIDNEY DISEASE DOWN SYNDROME DEMENTIA AGING MALE SEX DIABETES CARDIOVASCULAR DISEASE OBESITY COPD COVID-19 PERIODONTAL DISEASE SHARED RISK FACTORS - PERIODONTAL AND COVID-19 8
- 20. Marouf et al.J Clin Periodontol 2021;00;1-9. DOI: 10.1111/jcpe.13435 ORAL CAVITY PERSPECTIVE 3.67 4.57 3.54 8.81 0 2 4 6 8 10 All complications* Assisted ventilation ICU admission Death Odds ratio COVID-19 outcomes N = 568 patients Cases = patients with COVID-19 complications Controls = COVID-19 patients discharged without major complications Periodontal conditions assessed radiographically Associated with higher risk of COVID-19 complications and increased blood levels of biomarkers linked to worse disease outcomes PERIODONTITIS COVID-19 SEVERITY AND PERIODONTITIS 9 *After accounting for confounders including age, sex, smoking, BMI, diabetes and comorbidities
- 21.
- 22. IF THE HYPOTHESISIS CONFIRMED NEW APPROACHES To prevent or mitigate lung disease ORAL HYGIENE Importance of oral care and daily oral hygiene for COVID-19 MOUTHWASH PRODUCTS With virucidal properties may help COVID-19 infection EARLY MEASURES To decrease transmission from oral cavity to lungs
- 23. GOOD GENERAL ORAL HEALTHCARE POOR ORAL HYGIENE Dentalplaque can function as a viral reservoir Increases risk for pulmonary infections and potentially COVID-19 The importance of plaque control cannot be underestimated in the context of transmissibility, hospitalization, and mechanical intubation - Brush twice daily for at least 2 minutes - Use fluoride toothpaste - Manual or power tooth brush - Brush for at least 2 minutes* TOOTHBRUSHING INTERDENTAL CLEANING - Daily - Floss, interdental brushes, irrigators - Inflammation: inter- dental cleaning should be professionally taught to patients *For periodontitis patients 2 minutes is likely to be insufficient Chapple ILC, et al. Primary prevention of periodontitis: Managing gingivitis. Vol. 42, Journal of Clinical Periodontology. Blackwell Munksgaard; 2015. p. S71–6
- 24. ETHYL LAUROYL ARGINATE(ELA) 0.147% 20 ml for 30 seconds CETYLPYRIDINIUM CHLORIDE (CPC) 0.05%-0.1%, 30 seconds ORAL RINSES Mouthwash products Should not replace daily oral hygiene Should be used after toothbrushing for limited periods Should never be swallowed Should only be used in accordance with the manufacturer's instructions or on the advice of oral healthcare experts in the context of a population study or clinical trials Sanz M, et al. Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline J Clin Periodontol. 2020;47 Suppl 22(Suppl 22):4-60 POVIDONE-IODINE (PVP-I) 0.2, 0.4 or 0.5%, 30 seconds BASED ON IN VITRO DATA (In vivo data is awaited)
- 25. THANK YOU! DR. GRAHAMLLOYD-JONES graham.lloyd-jones@nhs.net https://www.radiologymasterclass.co.uk DR. SHERVIN MOLAYEM smolayem@gmail.com https://www.drmolayem.com DR. CARLA PONTES info@onequestscience.com https://www.onequestscience.com PROF. IAIN CHAPPLE I.L.C.CHAPPLE@bham.ac.uk https://www.birmingham.ac.uk
Editor's Notes
- #5 Despite combined efforts to implement vaccination, the disease remains a major healthcare challenge, as predictable treatment strategies are yet to be developed. Other ongoing concerns include the clinical variability of the disease, and the lack of effective biomarkers to identify individuals at risk for severe complications.1 The oral cavity is a key entry point for SARS-CoV-2, however, the viral infection route from the oral cavity to the lungs has not been clarified, with some authors suggesting aspiration of oral bacteria as a likely pathway.2 Pulmonary radiological findings from COVID-19 patients suggest against delivery of SARS-CoV2 to the lungs via the airways to the lower respiratory tract. Several lines of research suggest that from the oral cavity, the virus seems to be delivered to the lungs via the pulmonary arteries, which would be mediated by poor plaque control and periodontal inflammation.3 Initial studies suggest that poor oral hygiene and periodontitis increase the risk for severe COVID-19 infection.2,4–6 Understanding the role played by the oral cavity and the periodontal environment in COVID-19 can bring important insights that can potentially impact millions of lives.
- #6 This study aimed to present a medical hypothesis on the rationale behind the ORAL-pulmonary connection and the hematogenous viral pathway from the oral cavity to the pulmonary arteries. Our hypothesis is based upon: Radiological evidence for primary vascular pathological processes in the lungs; An understanding of the upper respiratory tract as the initial site of infection; The formation of a viral reservoir in the oral cavity (and saliva); Potential for translocation of the virus from saliva to the gingival sulcus/periodontal pocket, evading the oral mucosal immune response; Survival of the virus within the sub-gingival plaque biofilm, and; Subsequent direct vascular delivery to the pulmonary vessels. If proven correct, this hypothetical model may provide a rationale for understanding why some individuals develop COVID-19 lung disease and others do not. It would also fundamentally change the way COVID-19 is managed, providing a new line of exploration into treatments targeted at the source of the viral reservoir, the mouth.
- #7 Pulmonary radiological findings in COVID-19 do not align with a model of SARS-CoV-2 infection primarily causing disease of the airways of the lower respiratory tract; the initial and dominant pathological features demonstrated radiologically are focused on the blood vessels.4–6 The distribution of COVID-19 lung disease (bilateral, symmetrical, peripheral, basal, and posterior) is not typical for an inhaled pathogen. Rather, inhaled pathogens would be expected to present an even distribution to all areas of the lungs, perhaps dominantly in the mid or upper areas, and would not be expected to spare the perihilar or central areas.7,8 It has also been noted that many of the findings usually associated with respiratory pneumonia, for example bronchial wall thickening, mucous secretion, and the ‘respiratory tree-in-bud’ opacification of small airways, are not features of COVID-19.4,9 Furthermore if the airway findings commonly associated with respiratory pneumonia are present, they are considered inconsistent with the diagnosis of COVID-19.10
- #8 Conversely, there are numerous studies in the radiological literature describing the pathogenesis of COVID-19 lung disease as driven by vascular phenomena.4–6,9–14 Early in the pandemic period, the presence of ground-glass opacities was reported to be the hallmark sign of COVID-19 lung disease.15 However, these ground-glass opacities were acknowledged as a non-specific feature, and histological confirmation on their significance was needed, with edema or hemorrhage suggested as possible causes.16 Notably, the radiological literature now reports that these ground-glass opacities are accompanied by abnormally dilated blood vessels, which are thought to be responsible for the phenomenon of pulmonary arteriovenous vascular shunting and subsequent hypoxemia.4
- #9 A specific vascular feature known as the ‘vascular tree-in-bud’ sign (not to be confused with ‘respiratory tree-in-bud’ found in conventional respiratory pneumonia) is visible on computed tomography (CT) as a distinct entity in 64% of patients with COVID-19 lung disease. This sign is thought to be a marker for the pathological process of immunothrombosis (inflammatory mediated clotting) and can be visible without lung parenchymal changes in the form of ground-glass opacities.11 The presence of this sign correlates with the length of hospital stay.12 Further evidence of vascular disease comes from studies of Dual Energy CT (DECT) which describe perfusion defects in 100% of patients with COVID-19. These defects of blood flow are categorized by two distinct patterns: a wedge-shaped pattern - analogous to pulmonary embolism; and a mottled/amorphous pattern - analogous to chronic or idiopathic thromboembolic hypertension. Dilated blood vessels and hyperperfusion are also described proximal to areas of ground-glass opacification.13
- #10 There has been much interest regarding the high incidence of pulmonary thromboembolic disease in COVID-19 patients. When compared to conventional pulmonary thromboembolic disease, a different distribution is described in patients with COVID-19. In COVID-19, the filling defects visible within pulmonary arteries with CT pulmonary angiography (CTPA) are lower in volume and more peripheral. This difference is thought to be related to the pathological process of immunothrombosis.14 Indeed, immunothrombosis is the main driver of disease in the lungs,17 and can even be considered as an appropriate immune response, which acts by trapping the virus in situ in the affected area of tissue, thus preventing escape into the systemic circulation.18 This difference in the distribution of thromboembolic disease, with smaller and more peripheral filling defects visible on CTPA, is significant because it is known that smaller and more peripheral clots are more likely to result in pulmonary vascular occlusion when compared to larger central filling defects.19 Many peripherally-located areas of ground-glass opacification are morphologically identical to pulmonary wedge-shaped infarcts. These are visible regardless of the presence or absence of visible filling defects in adjacent pulmonary arteries.20
- #11 At the edges of the lungs, wedge-shaped areas of opacification visible with CT are a common feature of COVID-19 lung disease. These could indicate a process analogous to pulmonary infarction (obstruction of the lung vessels) which is a common feature of pulmonary thromboembolic disease. It has been noted that these wedge-shaped opacities are visible regardless of the presence or absence of the visible clots in the pulmonary arteries [Martini et al]. Importantly, pulmonary infarcts are found at autopsy in patients with COVID-19 [Lax et al], which supports the idea that these wedge-shaped opacities at the edge of the lungs could indeed be pulmonary infarcts. Source: https://www.radiologymasterclass.co.uk/tutorials/covid-19/covid-19-discussion-1#top_2nd_img
- #12 It is also important to note that both macroscopic and microscopic pulmonary vascular obstruction is universally found on autopsy and that pulmonary infarcts are indeed present in the majority of individuals dying with COVID-19 lung disease.21 Virus elements have been detected in endothelial cells in autopsy studies of those who have died with COVID-19, with evidence of endothelial cell inflammation and inflammatory cell death.22,23 Histologically, microangiopathy of lung vessels is described with microthrombi visible within both pulmonary arterioles and peripheral lung venules. Thus, there is thrombosis on both sides of the capillary bed of the pulmonary vasculature, proximal and distal to the alveolar capillaries.24 It is important to appreciate that this means that CTPA, the conventional imaging modality used to look for pulmonary thromboembolic disease, will underestimate the presence of thrombosis because some of the thrombosis is on the venous side which is not enhanced with intravenous contrast. This may be helpful in understanding the pathogenesis of some of the peripheral vasculitis mimics seen specifically in patients with COVID-19 lung disease which are thought to be mediated by microemboli arising from the venous side of the pulmonary vasculature (blood vessels returning to the heart) and disseminated systemically.25
- #13 The model of direct viral delivery from the oral cavity via venous drainage to the heart and then to the pulmonary arteries, compounded by poor oral hygiene and/or periodontal disease can be hugely significant. We will discuss the biological plausibility of the presented ORAL-pulmonary hypothesis for COVID-19. The invasion of host cells by SARS-CoV-2 is mediated by angiotensin-converting enzyme 2 (ACE2) receptors, furin, and transmembrane protease serine 2 (TMPRSS2). Viral spike proteins bind to ACE2 receptors on the surface of host cells, and TMPRSS2 mediates endocytosis. Furin mediates the release of new viral particles to the extracellular compartment.10 These molecules, which are key elements for infection of host cells, are expressed abundantly in the oral cavity, including gingival tissues, salivary glands, tongue, and saliva. While not all oral tissues express the three molecules that affect viral entry, cells from the sulcular epithelium express ACE2, TMPRSS2, and furin. This indicates the potential for the gingival sulcus to be a target for SARS-Cov-2 infection.11 Thus, several niches in the oral cavity can become infected by COVID-19, including the gingival sulcus.
- #15 Previous studies have reported the presence of human viruses in saliva, gingival crevicular fluid (GCF), subgingival plaque, and gingival tissues, including HIV, Herpes simplex virus (HSV), Epstein–Barr (EBV), and Human Cytomegalovirus (HCMV).15–19 In a recent SARS-CoV-2 study, viral RNA was detected in the GCF of nearly 64% of COVID-19 positive patients.12 It has been speculated that viral particles from the oral cavity can migrate into the gingival sulcus or periodontal pocket, where the conditions are favorable for replication. In the presence of inflammation, subgingival plaque can provide a unique environment for the virus, and the squamous epithelium can develop ulcerations that facilitate the passage of viral particles to the underlying connective tissue and gingival capillary complex, reaching the systemic circulation.4,5 Thus, periodontal pockets present favorable conditions for viral replication, infection, and spread to gingival capillaries.
- #16 In periodontitis patients, the risk for viral invasion is likely to increase due to potential disruption of the pocket epithelium resulting from local inflammation, which is the same principle that potentially explains bacterial entrance to the systemic circulation.121 Even in healthy patients, the permeable nature of the junctional epithelium can facilitate viral infection.122 The presence of oral bacteria in the systemic circulation has been reported previously in studies on bacteriemia and infective endocarditis of oral origin. These studies propose that oral bacteria can cause damage elsewhere in the body, with the risk being higher with poor oral hygiene and periodontal inflammation.123 As bacteria can pass into the systemic circulation via breakdown of the immune defenses of the mouth, then the same route could be open to viruses, including SARS-CoV-2, and facilitated by periodontal disease.
- #17 Thus, SARS-CoV-2 can possibly interact with periodontal bacteria, however, the nature, extent, and consequences of this interaction are currently unknown. In periodontitis patients, it can be speculated that: 1) a viral-bacterial synergy might facilitate penetration of SARS-CoV-2 through the pocket epithelium; 2) such an interaction can help viruses evade the immune response, thus enabling its entrance to gingival capillaries, the systemic circulation, and the lungs. Co-infection in COVID-19 is also a possibility, given that serious respiratory conditions are often associated with viral–bacterial co-infections.23 However, there is a scarcity of data on SARS-CoV-2 bacterial co-infection.24 It is also possible that periodontal inflammation can increase the risk for viral infection. A study on Epstein-Barr virus found that gingival epithelial cells were frequently infected, and the level of viral infection correlated to the level of periodontal inflammation.25 Previous studies report that Porphyromonas gingivalis, a well-known anaerobe involved in periodontitis, can facilitate the reactivation of latent Epstein-Barr and HIV-1 viruses.26,27 Hence, a synergistic relation between SARS-CoV-2 and periodontal bacteria cannot be excluded.
- #18 In periodontitis, the host response to microorganisms in the subgingival biofilm is mediated by the expression of pro-inflammatory cytokines, particularly tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6. These soluble proteins can change cellular functions to promote and perpetuate inflammation and tissue destruction in the periodontal tissues and elsewhere in the body.52,53 The link between chronic periodontitis and systemic diseases has been researched extensively in the last decade, and findings from multiple studies point to the significance of elevated levels of pro-inflammatory cytokines and acute-phase proteins.54–57 Periodontal treatment has been shown to positively affect systemic inflammation in healthy patients and in those who have chronic diseases, such as hypertension58, coronary heart disease, and atherosclerosis.59–62 Severity of COVID-19 has also been linked to systemic inflammation.63,64 In COVID-19 patients, the risk for respiratory failure was 22 times higher in patients who presented high IL-6 levels upon hospital admission.65 It can be speculated that the raised IL-6 level found in patients with COVID-19 is an indicator of the pre-existing inflammatory processes in the periodontium. To some extent, IL-6 could be a biological marker of periodontal disease and, thus, could be considered a marker of the risk of clinical deterioration in COVID-19. In the search for treatment of severely unwell COVID-19 patients, drugs that reduce inflammation such as dexamethasone and tocilizumab have shown some positive effects.66,67 It is possible that hidden sources of infection in the body that perpetuate inflammation, such as periodontitis, could contribute to systemic inflammation. However, it seems unlikely that inflammation external to the lungs could account entirely for triggering the lung disease, especially in view of the potential for direct endothelial viral-ACE2 interaction as described below.
- #19 There is evidence that oral hygiene measures lower the incidence of aspiration pneumonia in elderly patients in hospital and nursing homes, decreasing morbidity and mortality.84 In the systematic review from Sjögren et al. (2008), the authors estimate that one in ten cases of death from pneumonia in nursing home patients can be prevented through simple oral hygiene measures.85 Given that periodontitis and inadequate oral hygiene negatively impacts respiratory conditions and lung function, particularly in hospitalized patients, their potential to worsen lung complication in hospitalized COVID-19 patients should not be ignored. This also perhaps acts as an existing rationale for treating any patient with symptomatic COVID-19 by implementing oral hygiene measures.
- #20 Periodontitis and poor outcome in COVID-19 share many risk factors, such as aging86,87, male sex 88,89, diabetes90,91, cardiovascular disease92,93, obesity87,94, COPD95,96, Down syndrome97,98, specific ethnic groups99,100, type-A blood group101,102, chronic kidney disease103–105 , physical disability or learning diffiulty106,107, and dementia.108,109 Smoking is a recognized risk factor for periodontitis.110 In a recent meta-analysis, smoking was associated with increased risk for severe COVID-19,111 but not all studies confirm this association.112 It is notable that if COVID-19 lung disease was mediated by airways pathology, smoking would be considered a risk factor for poor outcome, as it is in influenza.113 Rather, there is counter-intuitive evidence about the role of smoking and the suggestion that nicotine may have a therapeutic role.114–116 The harmful effects of smoking on gingival tissues are mediated, in part by the vasoconstrictive biological action of nicotine,117 which leads to significantly reduced gingival bleeding and decreased diameter of gingival capillaries.118,119 Conceivably, the local vasoconstriction action of nicotine may limit the transfer of microorganisms across the mucosal membrane of the oral cavity and periodontal tissues to the venous drainage of the mouth.
- #23 From the oral cavity, if SARS-CoV-2 can reach the lungs through the blood, causing immunothrombosis-driven disease in the pulmonary vessels, then early measures to decrease transmission to the lungs in this way must be considered in the management of COVID-19. This concept could influence the development of new approaches with the aim of preventing or mitigating lung disease. This concept potentially highlights the importance of active oral healthcare and adequate daily oral hygiene measures in the management of COVID-19 infection.42 Importantly, it is noted that readily available mouth rinses containing cetylpyridinium chloride (CPC) or ethyl lauroyl arginate (ELA) can inactivate SARS-CoV-2 with high efficacy in vitro.135–138 Those containing povidone-iodine (PVP-I) have also been shown to be effective.137,139–145 These specific mouthwash products could play a role in mitigating development or worsening of the lung disease at any stage, from those who are swab positive and asymptomatic in the community to those who are hospitalized or even in intensive care. Media outlets have reported the adoption of mouthwashes in some countries, as advised by government officials, either officially or perhaps unofficially. In Japan, for example, the sales of mouthwash increased substantially after a governor advised the population to use a gargling solution.146 COVID-19 outcomes in Japan are significantly better than in other G20 countries, such as the UK and the US (as of February 19th, 2021 – data from the previous seven day period – 3.41 deaths per million (Japan), 33.28 deaths per million (USA), and 46.28 deaths per million in the UK).147 Although there are likely to be many confounding reasons for the lower mortality in Japan, this difference of approach is raised as a point of interest to be urgently researched by governmental and public health officials.
- #25 mouthwash products have shown potential to decrease the viral load in the oral cavity.149 Despite the scarcity of clinical evidence for in vivo viral inactivation, well-established mouthwashes, which inactivate SARS-CoV-2 in vitro, could potentially help mitigate transmission and decrease the risk of severe lung disease in COVID-19:136,137 0.2%, 0.4% or 0.5% Povidone-Iodine (PVP-I): 10 ml for 30 seconds twice a day. The use of PVP-I is supported by in vitro139–141 and in vivo studies.137,142–144 In one clinical trial, the use of 1% PVP-I mouth rinse resulted in temporary thyroid dysfunction in 42% of COVID-19 patients, suggesting that lower concentrations should be preferred.142Contraindications: allergy, hyperthyroidism, thyroid dysfunction, pregnancy, lactation, and treatment with radioactive iodine.150,151 0.05%-0.1% Cetylpyridinium Chloride (CPC): 15 ml for 30 seconds twice a day. In vitro and in vivo studies indicate that mouthwash products containing CPC are able to inactivate SARS-CoV-2.135–138 These products are generally considered to be safe, with staining of the tongue and teeth being rarely reported.152 0.147% Ethyl lauroyl arginate (ELA): 20 ml for 30 seconds twice a day. In vitro results suggest virucidal activity of ELA against SARS-CoV-2.136 The use of mouthwashes should not replace other daily oral hygiene measures. They should be used after toothbrushing for limited periods due to potential side effects. Mouthwashes should never be swallowed. In the context of the pandemic, it would seem logical to use mouthwash products both before and after social interactions, but clinical trials are required to answer the critical question of the potential effect of these products as a means of reducing the risk of transmission between individuals. Clinical trials are also required to specifically address the potential for oral rinses to mitigate the development of COVID-19 lung disease, and hence the severest form of the disease