The COVID-19 Pathway: A Proposed Oral-Vascular-Pulmonary Route of SARS-CoV-2 Infection and the Importance of Oral Healthcare Measures

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The COVID-19 Pathway: A Proposed Oral-Vascular-Pulmonary Route of SARS-CoV-2 Infection and the Importance of Oral Healthcare Measures

   

Graham Lloyd-Jones1*, Shervin Molayem2, Carla Cruvinel Pontes3, Iain Chapple4

1Consultant Radiologist, Salisbury District Hospital, United Kingdom, Director of Radiology Masterclass
2Periodontist, Director, Mouth-Body Research Institute, Los Angeles, California
3Periodontist, Researcher, Mouth-Body Research Institute, Cape Town, South Africa
4Professor, Periodontal Research Group, Institute of Clinical Sciences, College of Medical & Dental Sciences, The University of Birmingham & Birmingham Community Health Trust, Birmingham, United Kingdom

*Corresponding author: Graham Lloyd-Jones, Consultant Radiologist, Salisbury District Hospital, United Kingdom, Director of Radiology Masterclass.

Citation: Lloyd-Jones G, Molayem S, Pontes CC, Chapple I. (2021) The COVID-19 Pathway: A Proposed Oral-Vascular-Pulmonary Route of SARS-CoV-2 Infection and the Importance of Oral Healthcare Measures. J Oral Med and Dent Res. 2(1):1-25.

Received: April 09, 2021 | Published: April 20, 2021

Copyright© 2021 by Lloyd-Jones G, et al. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in late 2019, the world has faced a major healthcare challenge. There remains limited understanding of the reasons for clinical variability of coronavirus disease 2019 (COVID-19), and a lack of biomarkers to identify individuals at risk of developing severe lung disease. This article aims to present a hypothesis on a vascular route of transfer of SARS-CoV-2 from the oral cavity to the lungs. Saliva is a reservoir of SARS-CoV-2, thus any breach in the immune defenses of the mouth may facilitate entrance of the virus to the vasculature through the gingival sulcus or periodontal pocket. From the oral vasculature, the virus would pass through veins of the neck and chest, and reach the heart, being pumped into pulmonary arteries, and to the small vessels in the lung periphery. The binding of the virus to the angiotensin-converting enzyme 2 receptor (ACE2), present on the endothelial surface of lung vessels, inactivates ACE2 and increases angiotensin-II levels, leading to pulmonary vasoconstriction and immunothrombosis (inflammatory-mediated clotting). This leads to vascular congestion, proximal vasodilatation, and subsequent lung parenchymal damage mediated by endothelial dysfunction. The biological rationale for the oral-vasculo-pulmonary route of infection is discussed in detail in this article, including pertinent radiological and oral cavity scientific findings. We propose that dental plaque accumulation and periodontal inflammation would further intensify this pathway. Therefore, it is suggested that daily oral hygiene and oral healthcare should be prioritized as such measures could be potentially lifesaving for COVID-19 patients. If this proposed pathological pathway is verified, it would be hugely significant in terms of understanding disease management. Simple low-cost measures, such as use of specific mouthwashes, could decrease the salivary viral load, and help prevent or mitigate the development of lung disease and severe COVID-19.

Keywords

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Saliva; Periodontal inflammation; Oral healthcare; Mouthwash; Lung disease; Disease management; COVID-19 pneumonia

Introduction

Since the first cases of SARS-CoV-2 infection emerged in China, the world has faced a major ongoing healthcare challenge. Although there have been advances in treatments and vaccination in populations, there remains limited understanding of the reasons for clinical variability of the disease. There is a lack of effective biomarkers to identify individuals at risk of developing COVID-19 lung disease, or those who might progress to severe disease leading to intensive care admission, mechanical ventilation, or death [1]. In this article, we propose a novel understanding of SARS-CoV-2 transmission from the mouth to the lungs and the development of COVID-19 lung disease (Figure 1).

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;
  • Survival of the virus within the sub-gingival plaque biofilm, thus evading the oral mucosal immune response;
  • Subsequent direct vascular delivery to the pulmonary vessels;
  • A model of the biological processes associated with viral binding of the ACE2 receptor on the endothelium of pulmonary vessels and how subsequent processes correlate with the radiological features of a primary pulmonary vasculopathy.

If confirmed, 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.

Figure 1: The COVID-19 pathway: A hypothetical model for the oral-vascular-pulmonary route of infection.

Initial Upper Respiratory Tract Infection and Proposed Mechanism of Transmission to the Lungs via Blood Vessels

Based on knowledge of the intensity of expression of the main SARS-CoV-2 binding receptor – the ACE2 receptor – the upper airways are considered the initial site of infection for SARS-CoV-2, rather than the lower respiratory tract. Expression of the ACE2 receptor is reported to be between 200 to 700 times more intense in the nasal airways, specifically on the surface of the olfactory neuroepithelial cells, compared to the respiratory epithelial cells of the lower respiratory tract [1,2]. The conclusion from the study by Chen and Shen et al. [2] that the initial site of infection is the upper airway, challenges the notion that the SARS-CoV-2 virus is necessarily delivered to the lungs via the airways, where expression of ACE2 receptors on respiratory epithelial cells is low [3].

The concept that the upper airways may be the predominant initial site of infection for viral transmission to the lungs requires further scrutiny. Here we present radiological evidence that raises the important possibility of a vascular viral delivery route to the lungs rather than via the respiratory airways. The proposed model describes the oral cavity as the reservoir of SARS-CoV-2, specifically in saliva, with transmission to the lungs mediated by a breach of the mucosal immune defense barrier of the periodontal tissues or oral mucosa, with subsequent intravascular carriage. If proven to be correct, this hypothesis would have significant implications for the understanding of how the disease should be managed. Simple antimicrobial oral healthcare measures could be implemented not only with the aim of reducing the risk of transmission between individuals but also with the aim of providing benefit to individuals who are COVID-19 positive. Specifically, these measures could be a means of mitigating the risk of developing lung disease, and therefore the most severe form of the disease.

Radiological Perspective – COVID-19 Lung Disease

1. Pathological Distribution of Disease

Pulmonary radiological findings in COVID-19 do not align with a model of SARS-CoV-2infection primarily causing disease of the airways of the lungs; the initial and dominant pathological features demonstrated radiologically are vascular in nature [4-6].

The distribution of lung disease does not favor an inhaled pathogen. No known inhaled infective pathogen has preferential tropism for the periphery of the lung bases. Rather, inhaled pathogens would be expected to present a uniform distribution to other areas of the lungs, including 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 radiological findings typically 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 typically associated with respiratory pneumonia are present on computed tomography (CT), they are considered inconsistent with the diagnosis of COVID-19 [10].

2. Evidence of Pulmonary Vascular Phenomena

Conversely, there are numerous studies within 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” visible on CT 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 of their significance was required, 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].

Figure 2: CT images of patients with COVID-19 lung disease demonstrating ground-glass opacities (yellow arrows) accompanied by abnormally dilated blood vessels (green arrows).

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 CT as a distinct entity in 64% of patients with COVID-19 lung disease [11]. This sign is thought to be a marker of the pathological process of immunothrombosis and can be visible without lung parenchymal changes in the form of ground-glass opacities. 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 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].

3. Distinct Phenotype of Thromboembolic Disease

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 [15-17], and can even be considered as an appropriate immune response, serving to trap pathogens 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].