COVID-19 discussion pages:
Oro-Vasculo-Pulmonary route - update

Key hypothesis points

  • The first site of SARS-CoV-2 infection is the nasal airways
  • Saliva contains the virus
  • High salivary viral load is associated with severe disease and death
  • Gum disease is independently associated with poor outcome (ITU, ventilation, death)
  • The risk factors for gum disease (periodontitis) are very similar to those for severe COVID-19
  • COVID-19 lung disease is primarily and dominantly a disease of pulmonary blood vessels rather than the respiratory airways
  • There is a potential intravascular/haematogenous route for the virus to get from the mouth to the lungs not previously considered
  • Microorganisims causing other infections diseases follow the same path to the heart (endocarditis) or the lungs (Lemierre syndrome)
  • SARS-CoV-2 could be taking the same anatomical path
  • If this concept is proven, then oral healthcare may become paramount in managing the disease
  • It is proposed that the converging and main risk factor for severe COVID-19 could be gum disease
  • If proven correct, this concept could have wide-reaching public health implications

The vascular anatomical pathway between the mouth and the pulmonary blood vessels:

A potential causal link between poor oral health and increased risk of severe COVID-19

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Dr Graham Lloyd-Jones FRCR, Director of Radiology Masterclass, presents a hypothetical novel understanding of the link between poor oral health and poor outcome in COVID-19.

First published - February 20, 2021.

Revised version published - April 26, 2021.

This theory has now been published formally in The Journal of Oral Medicine and Dental Research, April 20th 2021. 

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.

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IMPORTANT: Please note that the concept presented here remains a theory which is unproven and will require further investigation. It is submitted here for the interest of researchers investigating the role of nasal and oral healthcare in the context of prevention of the spread of SARS-CoV-2 and the management of COVID-19.

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Proposed vascular anatomical route of transmission of SARS-CoV-2 from the mouth to the lungs

Figure 1.

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Figure 1. Proposed vascular route of infection

  • The mouth acts as a reservoir of SARS-CoV-2 which is present in saliva
  • If virus particles were able to cross the immune defence barrier of the mouth, the oral mucosa and the gums, then it could reach the veins of the mouth
  • The virus would then pass into the veins of the neck and chest, and would be pumped by the heart into the lungs via the pulmonary arteries (major arteries of the lungs)
  • It is proposed here that this is the primary route the virus takes to infect the lungs
  • In those with poor oral health or poor oral hygiene this pathway would be permanently open during the course of illness with COVID-19
  • Those with good oral health or good oral hygiene could be relatively protected from the passage of the virus to the lungs by this route

The COVID-19 Pathway:

A Proposed Oral-Vascular-Pulmonary Route of SARS-CoV-2 Infection and the Importance of Oral Healthcare Measures.

Note: For ease of reading the following introduction is not referenced. Below is a detailed and referenced explanation.

Hypothesis introduction

We need to understand how the SARS-CoV-2 virus enters the body and causes disease. Without this understanding we cannot aim treatments optimally.

Here it is proposed that the virus does not predominantly cause disease by being breathed deeply into the lungs. Rather, it is proposed that the virus escapes the mouth through the protective layer of the gums and enters blood vessels of the mouth. From here blood drains into the veins of the neck and chest, and is pumped by the heart into the pulmonary arteries (large blood vessels which carry deoxygenated blood to the lungs). The virus could be transferred from the mouth to the lungs via this route, referred to on this page as the oro-vasculo-pulmonary route (mouth to blood vessels to lungs).

It is now thought that the nasal passage is the first site in the body to be infected. Specifically, the cells responsible for the sense of smell are targeted (olfactory neuroepithelial cells). Evidence from computed tomography (CT) scans shows us that the airways of the lungs are not affected initially and that the dominant disease processes affect the blood vessels. In this way COVID-19 should perhaps not be considered a 'respiratory pneumonia' but rather is better termed a 'pulmonary vasculopathy' (a disease of the lung blood vessels).

In view of the lack of CT evidence for the lung disease being mediated by airways inflammation, the hypothetical oro-vasculo-pulmonary route of infection would explain why the lungs are most severely affected in comparison to other organs of the body. Viral interaction with the ACE2 receptor on the inner lining of blood vessels (endothelium) results in increase of the hormone angiotensin-II. This hormone acts on blood vessels, causing them to narrow, become inflamed, and clot. The main disease process in the lungs is understood to be that of immunothrombosis (blood clotting mediated by inflammation) which can be explained by viral interaction with the ACE2 receptor of endothelial cells (cells lining the inside of blood vessels) and subsequent deregulated angiotensin-II. Immunothrombosis can be seen as an immune defence mechanism serving to trap pathogens in affected tissue but at the expense of reduced blood supply. If the virus was delivered to the lungs via the oro-vasculo-pulmonary route, then the lungs would be the first organ of the body it would reach. In this way it is proposed that the lungs are dominantly affected by SARS-CoV-2 infection in an attempt to prevent the virus from passing to the rest of the body.

Saliva contains the SARS-CoV-2 virus in patients with COVID-19. Not only so, but the higher the viral load in the saliva the more likely an individual with COVID-19 is to develop severe disease or die. This requires an explanation.

Importantly, gum disease is strongly associated with COVID-19 severity and death. This too is yet to be explained satisfactorily.

With the above in mind, it can be explained how the virus gets to the lungs and causes disease.

The lining of the mouth is in contact with the outside world. The gums act as a defence barrier, stopping pathogens passing into the body. If this defence barrier is damaged because of gum disease, then the virus present in saliva may be able to pass into the circulation. It would then pass to the lungs via the blood vessels. There is no further anatomical barrier. We know this route of infection is found in some bacterial infections, so it is at least plausible that it could be occurring with SARS-CoV-2.

This concept is proposed as the main anatomical route the virus takes to the lungs. The oro-vasculo-pulmonary route would explain why some individuals get lung disease and some do not. If this pathway remains open during the course of illness with COVID-19 because of gum disease or poor oral hygiene, then further damage to the lungs could continue until the defence mechanism of the lungs is overwhelmed. Then the virus may be permitted to pass more freely into the rest of the body via the systemic circulation.

It seems likely, therefore, that measures to care for the gums and to inactivate the virus in the mouth, should be investigated as a matter of urgency.

This anatomical infection route is currently theoretical, but is offered here as a rational explanation for several phenomena as yet not fully understood.

It is noted that many of the risk factors for periodontitis (gum disease) are shared risk factors for severe COVID-19. These include – patient age, male sex, specific ethnic groups, non-O ABO blood group, obesity, diabetes, cardiovascular disease, and for those who have difficulty caring for their gums because of dementia, physical disability or learning difficulties. It is proposed that gum disease is not merely another associated risk factor for severe COVID-19, but that it could be the converging and main risk factor for poor outcome.

This concept is shared here for the urgent attention of researchers investigating oral healthcare measures in the context of preventing SARS-CoV-2 transmission. It is suggested that use of mouthwashes containing specific ingredients known to inactivate the virus in vitro (those containing CPC, ELA, or PVP-I) should be explored in the context of population studies or clinical trials and on the advice of oral healthcare experts, as a simple, cheap, and non-invasive preventative measure, or indeed as a potential treatment for individuals positive for COVID-19.

The concept is also brought to the urgent attention of officials who have influence over public health messages. Attention is drawn to the difference in outcome between those countries who it seems have given advice about oral healthcare measures and those that have not. It is suggested that similar oral healthcare measures should be considered in addition to social distancing and vaccination programmes.

Below is a more detailed and fully referenced explanation.

Disclaimer: Radiology Masterclass can offer no advice regarding the use of mouthwashes or other oral healthcare measures. This advice must come from those specialised in the field of oral medicine, from researchers in the context of population studies or approved clinical trials, or from central governmental scientific advisers. No responsibility will be taken by Radiology Masterclass for the inappropriate use of mouthwashes.

Anatomy

The anatomical pathway between the mouth and the pulmonary vessels (lung blood vessels) is an established route for certain infectious diseases. Endocarditis is a rare condition of bacterial growth on the heart valves. Individuals with heart valve problems have an increased risk of this disease and require protection with antiobiotics whenever undergoing dental procedures to reduce the risk of spread of bacteria from the mouth to the heart valves [Carinci et al].

Lemierre syndrome, another rare condition, is caused by mouth and throat infection which is complicated by thrombophlebitis (inflamed and clotted blood vessel) of one of the jugular veins (major veins in the neck) with delivery of infected emboli (blood clots) to the lungs which then cause lung abscesses [Harper et al].

If this anatomical pathway is open to bacteria, then conceivably it could be a route for SARS-CoV-2 to pass from the mouth to the lungs.

Poor oral health and poor outcome in COVID-19

Poor oral health has been linked with poor outcome in patients with COVID-19 [Sampson et al]. Specifically, periodontitis, a common form of gum disease, has been shown to be linked with poor outcome. Although it is important to recognise that this link may be associative rather than causative, it is striking that both conditions (periodontitis and severe COVID-19) share many of the same risk factors – patient age [Darby v Mahase], male sex [Ioannidou v Peckham et al], non-O ABO blood group [Prakesh et al v Zhao et al], specific ethnicities [Albandar and Rams v CDC website], physical disability and learning difficulties [Ameer et al v Louapre et al, and PHE website], diabetes mellitus [Preshaw et al v Apicella et al], cardiovascular diseaes [Dhadse et al v Nishiga et al], and obesity [Martinez-Herrera et al v Mahase]. Smoking is another risk factor for periodontitis which has a complex relationship with COVID-19 and is discussed separately below.

After adjusting for possible confounders (such as age, sex, smoking, body mass index, diabetes, and comorbidities) the multivariable analysis presented by Marouf et al showed that periodontitis was associated with an overall odds ratio (OR) of 3.67 for poor outcome in patients with COVID-19, defined as admission to intensive care (OR 3.54), need for mechanical ventilation (OR 4.57), and death (OR 8.81) [Marouf et al].

It has been suggested that this association between periodontitis and poor outcome in COVID-19 is related to the increased risk of bacterial co-infection with contamination of the airways or the lungs due to inhalation of bacteria [Sampson et al]. However, the number of bacterial co-infections with COVID-19 is unknown and considered to be much lower than in severe influenza [Huttner et al]. Also, it has been shown that co-existing lower respiratory bacterial infections were not identified in sputum or blood samples obtained in the early clinical course of intensive care admissions [Bhatraju et al]. Although numbers of those with bacterial co-infection can be high in intensive care patients, there is no difference between survivors and non-survivors [Pandolfi et al]. Significantly, autopsy studies do not show high incidence of secondary bacterial infection in the lungs of those who die of COVID-19. Rather, a lack of secondary bacterial infection is described at autopsy [Fox et al].

There is also evidence from radiology that aspiration (inhalation of fluid from the mouth) is not a key feature of COVID-19 lung disease. Indeed, the presence of airways secretion visible on CT scans is considered an atypical feature of COVID-19, or even inconsistent with the diagnosis [Ufuk and Savas].

If proven correct, the concept of the direct anatomical vascular route from the mouth and the pulmonary vessels, as described on this page, would mean that this link between gum disease and severe COVID-19 is not associative, but rather directly causative.

If the oro-vasculo-pulmonary pathway for transfer of SARS-CoV-2 from the mouth to the lungs is in action (Figure 1), then further evaluation of what is known about the pathological processes in the lungs which might support this case is required. Below, evidence from the radiology is presented and knowledge of the development of COVID-19 from a pathological perspective is discussed.

Radiological evidence: A pulmonary vasculopathy

It has long been of interest to radiologists (experts in medical imaging) that some of the key features usually associated with viral pneumonias are missing in the setting of COVID-19 [Lang et al - Radiology:Cardiothoracic imaging]. A key feature of other viral pneumonias such as influenza, known as respiratory tree-in-bud opacification of bronchioles (smallest airways visible on CT scans), is absent in COVID-19 lung disease [Lou et al].

Imaging appearances of COVID-19

The distribution of COVID-19 lung disease (bilateral, symmetrical, peripheral, basal, and posterior) is not typical for an inhaled pathogen. This distribution would suggest a distribution of disease mediated by distribution to the pulmonary vessels (blood vessels of the lungs) [Nemac et al] which are the parts of the lungs with the greatest blood supply due to gravity [Powers and Dhamoon, and Patwa and Shah].

Figure 2. Chest X-ray image

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Figure 2. Chest X-ray image

  • Patient with proven swab positive COVID-19
  • The distribution of shadowing visible on this chest X-ray is typical for COVID-19 lung disease – bilateral, symmetrical, peripheral (towards the edges), and basal (towards the lower lungs)
  • Note that the upper parts of the lungs remain normal (black)
  • See examples of normal chest X-ray appearances - Normal chest X-ray

CT appearances of COVID-19

Descriptions of the computed tomography (CT) scan appearances of COVID-19 lung disease show that so-called 'ground-glass' opacities (Fgirue 3) are the hallmark feature [Tamar et al, and Bernheim et al]. These were reported in the earliest descriptions of the disease from China when throat swab tests were not available. At that time, no autopsy studies had been performed. Although it was suspected that the virus might be located in the airways of the lungs, it was pointed out that, until autopsy studies could be performed, these lung opacities may be caused by other disease processes. Both oedema (fluid) and haemorrhage (bleeding) were proposed as possible causes [Shi et al].

Figure 3. CT showing ground-glass opacities

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Figure 3. CT showing ground-glass opacities

  • Patient with proven swab positive COVID-19
  • The typical ground-glass opacities seen in COVID-19 lung disease
  • The back and edges of the lung bases are dominantly affected in COVID-19

Abnormal blood vessels on CT in COVID-19

If not primarily due to airways inflammation, then other causes of the lung opacities need to be explored. The presence of dilated (widened) blood vessels (Figure 4) within the areas of lung opacification has been widely reported in descriptions of CT and Dual-Energy CT (DECT) scans. These dilated vessels are present both with or without lung opacities and are thought to result in shunting of blood from the arteries to the veins of the lungs [Lang et al - Lancet]. This leads to blood returning to the heart without efficient exchange of oxygen or carbon dioxide which is thought to account for the low blood oxygen levels in patients with COVID-19 [Lang et al -Radiology:Cardiothoracic imaging].

Figure 4. CT images - dilated blood vessels

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Figure 4. CT images - dilated blood vessels

  • Patients with COVID-19
  • Areas of ground-glass opacification are supplied by dilated blood vessels
  • The pulmonary arteries and veins are dilated

A specific vascular feature seen on CT scans of patients with COVID-19 is the phenomenon known as vascular tree-in-bud opacification (Figure 5). (This should not be confused with the respiratory tree-in-bud opacification which is seen in other viral pneumonias but which is not a feature of COVID-19). This feature is thought to indicate a distinct vascular process, likely a manifestation of a pulmonary thrombotic angiopathy (clotting disease in blood vessels of the lungs) or immunothrombosis (in situ clotting driven by inflammation). This vascular tree-in-bud opacification is a specific sign seen in 64% of patients with COVID-19 lung disease and has been linked to length of hospital stay [Eddy and Sin, Patel et al].

Figure 5. CT image

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Figure 5. CT image

  • Patient with proven swab positive COVID-19
  • Vascular tree-in-bud opacification of small pulmonary vessels

Thrombosis (clotting) in COVID-19 lung disease

It is generally understood that COVID-19 is associated with a higher incidence of pulmonary thromboembolic disease (clots of the lung arteries) visible with CT pulmonary angiogram (CTPA) (Figure 6). This is reported in 50% of intensive care patients [Bombard et al]. However, the pattern of clotting is different in patients with COVID-19 when compared with patients who have a conventional pulmonary embolus (from deep vein thrombosis). In COVID-19 the clots are located more towards the edges of the lungs and are smaller. This pattern is thought to be due to a combination of pulmonary thromboembolic disease and immunothrombosis [Van Dam et al]. It is important to be aware that small clots at the edge of the lungs are more likely to result in pulmonary artery occlusion and subsequent pulmonary infarction than even massive central clots [Kirchner et al].

Figure 6. Coronal plane CTPA image

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Figure 6. Coronal plane CTPA image

  • Pulmonary thromboembolic disease in COVID-19 lung disease as seen on CTPA
  • The pulmonary arteries (PA – blue arrows) are highlighted by injection of contrast material (white) given via a vein in the arm at the time of the scan
  • The areas not highlighted by contrast material (filling defects) are due to the presence of thrombotic material (blood clots) within the pulmonary arteries (red arrows)

At the edges of the lungs, wedge-shaped areas of opacification visible with CT are a common feature of COVID-19 lung disease (Figure 7). These could indicate a process analogous to pulmonary infarction (obstruction of the lung blood vessels) which is a feature of pulmonary thromboembolic disease. It has been noted that these wedge-shaped opacities are visible regardless of the presence or absence of visible clots in the pulmonary arteries [Martini et al].

Figure 7. CTPA scans

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Figure 7. CTPA scans

  • CTPA scans in patients with COVID-19
  • Wedge-shaped opacities resembling pulmonary infarcts are seen at the edge of the lungs
  • These are thought to represent a disease process similar to pulmonary thromboembolic disease
  • They are present in COVID-19 lung disease with or without visible filling defects in the pulmonary arteries

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. It is important to know that thrombi (clots) are visible at autopsy both in the arterioles (small arteries) and in the venules (small veins) of the pulmonary vascular system [Fox et al]. It is also important to appreciate that clots within the pulmonary veins cannot be detected with CTPA scans which only assesses the pulmonary arteries.

Evidence from studies of Dual-Energy CT scans, performed at Imperial College - London, shows that COVID-19 lung disease is characterised by perfusion defects, indicating reduced blood supply to areas of the lungs. These perfusion defects were found in 100% of scans performed, irrespective of the presence or absence of pulmonary emboli, with distinct patterns described. One pattern is wedge-shaped and thought to be analogous to appearances seen in pulmonary thromboembolic disease. The other pattern is amorphous or mottled, as is found in chronic or idiopathic thromboembolic hypertension [Ridge et al]. These features are further evidence of a vascular-driven pathology in COVID-19 lung disease.

Summary of radiological features of COVID-19 lung disease

In view of the radiological evidence for a process primarily driven by disease of the blood vessels in COVID-19 lung disease, and in view of the lack of radiological evidence of disease of the airways, the term ‘COVID-19 pneumonia’ is perhaps unhelpful. The categorisation of the lung disease in COVID-19 as a ‘pneumonia’ has possibly led the world of academic medicine to investigate treatment pathways which are not based on a complete understanding, and so possibly have missed the opportunity to investigate treatments at an earlier stage of disease development. The presence of vascular phenomena in the lungs should perhaps not be considered a ‘complication’ of COVID-19 lung disease, but rather the initial step in development of the lung disease.

Hypothesis for a direct (anatomical) link between mouth disease and COVID-19 lung disease

In this model, the mouth is likened to a reservoir of the virus. The blood vessels of the mouth, neck, and chest are likened to drainpipe conduits, the heart a pump, and the lungs acting as a sump, mopping up the virus and preventing spread to the rest of the body.

The nose: a virus inlet

The initial site of infection with SARS-CoV-2 is the upper respiratory tract (nasal airways) rather than the lower respiratory tract (airways supplying the lungs). Work by Chen and Shen et al reports that the angiotensin converting enzyme 2 receptor (ACE2 - the virus binding receptor) is expressed between 200-700 more intensely in the nasal airways than in the airways of the lower respiratory tract (the airways of the lungs) [Chen and Shen et al].

The mouth: a virus reservoir

Saliva contains SARS-CoV-2 and persists for up to ten days after infection [Wyllie et al]. The study by Huang et al shows that some symptomatic individuals can be positive for the virus in their saliva for >2 months, and asymptomatic individuals for as long as 3.5 weeks [Huang et al].

It is also known that the viral load in saliva (the number of viruses in saliva) can significantly predict disease severity and mortality. The salivary viral load is higher in men, it predicts outcome more significantly than age, and it is also a better predictor than the viral load found in the nasopharynx (where the back of the nose meets the upper throat) [Silva et al].

The blood vessels and heart: drainpipes and pump

As the upper airway is the initial seat of viral infection, with high levels of SARS-CoV-2 in the saliva, if there is breakdown of the immune barrier of the mouth, compounded in those with poor oral health, such as gum disease, then the virus could be delivered via the venous drainage of the mouth and neck, into the superior vena cava, through the right side of the heart, and into the pulmonary arteries. This route, shared by other micro-organisms (as described above), would explain the vascular distribution of COVID-19 lung disease.

The lungs: a virus sump

On arrival in the small vessels in the lungs, SARS-CoV-2 could interact with the angiotensin-II receptor (ACE2) found on the surface of endothelial cells (cells lining the blood vessels). Viral interaction with the ACE2 receptor would lead to raised levels of the hormone angiotensin-II.

The hormone has multiple biological functions. As indicated by the name of the hormone, angiotensin-II causes vasoconstriction (angio=blood vessel, tensin=tension). A scientific paper written in 2016 [Senchenkova et al] also indicates the biological effects of angiotensin-II as both pro-inflammatory (causing inflammation) and pro-thrombotic (causing clotting in blood vessels). Thus, unregulated increase of angiotensin-II in an affected blood vessel has the potential biological effect of blocking off the blood supply to that vessel. This has been proposed as a possible biological process involved in the development of immunothrombosis in COVID-19 lung disease [Lloyd-Jones and Oudkerk]. This process could be considered harmful to the area of lung affected as it stops blood passing through the fine capillary network where gas exchange occurs. Subsequent vascular congestion would cause blood to return to the heart without coming into close contact with air and without transfer of the blood gases, namely oxygen and carbon dioxide. This would account for the low level of oxygen in the blood in patients with COVID-19 [Lang et al (Radiology:Cardiothoracic imaging)]

In this way, deregulated increased levels of angiotensin-II in a blood vessel of the lungs could be the trigger for the process of immunothrombosis (inflammatory driven thrombosis), which is now considered as a key pathological step in deterioration to acute respiratory distress syndrome (ARDS) and the widely reported systemic hypercoagulable state (tendency to form blood clots) seen in COVID-19 [Nicolai et al].

Although the ACE2 receptor is said to be expressed on pneumocytes in the epithelium of the respiratory side of the gas exchange unit (the air side), it is expressed at much lower levels than in the nasal passages [Chen and Shen et al and Sungnak et al], and some have questioned its presence at all in the normal respiratory tract [Hikmet et al]. ACE2 is expressed in the endothelial cells on the inner surface of vessels (the blood side) [Ackermann et al]. This autopsy study by Ackermann et al showed a change in endothelial cell shape as well as the presence of the virus itself in endothelial cells. This suggests a central role for endothelial cells in COVID-19 and was consistent with other autopsy studies which found viral elements, evidence of endothelial cell inflammation, and inflammatory cell death [Huertas et al and Varga et al]. Thus, although also likely mediated by other complex biological pathways, the role of viral/ACE2 receptor interactions in the lung vessels is further implicated as a process which triggers immunothrombosis and endothelial dysfunction in the development of COVID-19 lung disease.

The process of immunothrombosis is considered an appropriate immune response which traps pathogens in affected tissues and prevents systemic distribution [Nakazawa et al]. In the context of COVID-19, the closure of the blood supply to small blood vessels of the lungs would trap the SARS-CoV-2 virus and prevent it escaping to the rest of the body via the heart and systemic blood vessels. This may go some way to explain the lack of systemic viraemia (virus in the blood) in the early phase of the disease [Wolfel et al] and why increased viraemia is associated with poor outcome in critically ill patients [Bermejo-Marton et al]. Hypothetically, this viraemia of late disease could be due to the immune responses in the lungs become overwhelmed as more areas of lungs are damaged. It is speculated here that another explanation for viremia being more detectable late in the disease is that venous blood samples taken from patients in intensive care would usually be obtained from central lines and so would be taken along the oral-vascular-pulmonary route, namely from the jugular vein or superior vena cava, rather than from a peripheral vein. According to the model proposed, the virus may be present in these central veins but not peripherally. Biological studies, as described below, will be required to confirm or refute this proposal.

Immunothrombosis in the lungs has also been proposed as a potential mechanism of some of the processes in the body which mimic vasculitis, such as the so-called COVID toe, due to delivery of microembolic material (small blood clots) originating from the small veins of the lungs via the systemic circulation to the rest of the body [McGonagle et al].

The conundrum of smoking

It is especially intriguing that one risk factor for poor oral health, as listed above, is not clearly shared as a risk factor for severe COVID-19. Smoking is identified as a risk factor for development of periodontitis [Gautum et al]. However, some investigators have not identified smoking as a risk factor for development of severe COVID-19 [Rossato et al]. This is a particular conundrum because smoking would usually be considered a risk factor for poor outcome in patients with a conventional viral pneumonia, such as influenza [Wong et al].

However, the harmful effect of smoking in the context of gum disease is not related to smoke inhalation, but rather is associated with the biological effects of nicotine on the blood vessels in the mouth. Nicotine causes vasoconstriction (narrowing of blood vessels) and dysfunction of the endothelial cells (cells on the inner surface of blood vessels) in the gums [Gatum et al]. It is of interest that the biological effects of nicotine, both vasoconstriction and endothelial dysfunction, are reversed within 24 hours following cessation of smoking [Morena et al]. So, unlike the associated risk factors listed above which are shared by poor oral health and poor outcome in COVID-19, smoking is a factor the patient has control over. It could be that smoking cessation on becoming unwell with COVID-19 symptoms means that any associated harmful effect of nicotine on the gums is rapidly reversed and the defences of the gums are somewhat restored. It is also the only risk factor for periodontitis which would not be a factor in the hospital setting, should a patient be unwell enough to be admitted. Indeed, smoking is not permitted in hospitals. However, the function of nicotine in the context of COVID-19 is complex. Other biological effects of nicotine may also be at play in the lungs themselves, particularly if the lung disease is mediated by powerful pathological processes involving dysregulation of vasodilation and vasoconstriction. Nicotine is itself linked to the biological effects of the ACE2 – angiotensin II pathway [Oakes et al]. Indeed, it has been proposed that nicotine could be beneficial to patients with COVID-19 and research into its effect as a drug are ongoing [Clinical Trials Website].

A large population study showed increased symptoms of COVID-19 in smokers. It seems likely, therefore, that smoking should be considered yet another risk factor shared between development of gum disease and worse outcome in COVID-19 [Hopkinson et al].

Conclusion

Above is presented a theoretical explanation for the link between poor oral health and poor outcome in COVID-19. It is suggested, yet to be proven, that this association could be caused by a direct anatomical pathway between the mouth and the blood vessels of the lungs. In this sense, the presence of poor oral health in patients infected with SARS-CoV-2 could be an independent causative risk factor for the development of lung disease, severity of disease, and death. The risks, although perhaps associative rather than causative, shared between periodontitis and poor outcome in COVID-19 are striking. It is even possible that poor oral health is established as the single greatest risk factor for developing severe COVID-19.

Proof of this concept is required urgently. In the meantime, this theory is presented for the particular attention of those researchers investigating the use of nasal and oral cleansing regimes in the context of COVID-19. Oral disease may not be completely treatable but greater emphasis on oral care in community and hospitalised patients could be beneficial.

It is noted that certain mouthcare products containing specific ingredients are already known to rapidly inactivate the SARS-CoV-2 in vitro with high efficacy. These specific mouthwash ingredients include: cetylpyridinium chloride (CPC), ethyl lauroyl arginate (ELA), or povidone-iodine (PVP-I) [Statkute]. But, importantly, if the theory presented above is correct, it is vital that patients and medical professionals follow agreed regimes as advised by experts in this field of research, once results are available.

This concept is also presented for the urgent attention of those who influence public health policy, both in the UK and globally. During the pandemic, measures to preserve oral health or treat oral disease have been given different emphasis in different countries. Where mouthcare has been advised, either officiially or unofficiatlly, such as in Japan where a governor recommended use of mouthwash resulting in panic buying of products in August 2020 [Reuters], outcome has been considerably better. Although the better outcome in Japan is likely multifactoral the use of mouthwash products may have contributed to some extent. As of February 19th, 2021 – 3.41 deaths per million (Japan), 33.28 deaths per million (USA), and 46.28 deaths per million in the UK [Statista website].

Final word

This theory is submitted in hope that increased scientific study is focused on the proposed route of infection, from the oral cavity to the arteries of the lungs, via damaged gums, the veins of the mouth, neck, and chest, the heart, and the pulmonary arteries. It is hoped that results of such research may lead to better outcomes for all those who are infected with SARS-CoV-2, and for the COVID-19 pandemic to come under greater control.

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Dr Graham Lloyd-Jones. BA MBBS MRCP FRCR. Director of Radiology Masterclass.

First published February 20th, 2021.

Revised version published April 26th, 2021. Link to video animation added. Comment regarding jugular vein sampling from central lines in late stage disease added.

Revised version updated April 29th, 2021. Hopkinson et al and Huang et al references.

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Note from author

This is a work in progress. Further updates will be available shortly.

Peer review is invited and will be acknowledged as appropriate. Please contact Radiology Masterclass if you are involved with research in this field or a public health official via the contact page. Thank you.

Dr Graham Lloyd-Jones FRCR

Director of Radiology Masterclass. February 20th 2021.

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Work yet to be completed

Further illustrations to be added

Acknowledgements to be compiled

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Disclaimer: Radiology Masterclass can offer no advice regarding the use of mouthwashes or other oral healthcare measures. This advice must come from those specialised in the field of oral medicine, from researchers in the context of population studies or approved clinical trials, or from central governmental scientific advisers. No responsibility will be taken by Radiology Masterclass for the inappropriate use of mouthwashes.

REFERENCES

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Last reviewed: May 2021