COVID-19: Oro-Pulmonary route

Key points

  • The first site of SARS-CoV-2 infection is now known to be the nasal passage
  • Saliva contains the virus in those with COVID-19
  • The more virus in the saliva the higher the risk of 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 of severe COVID-19
  • The lung disease of COVID-19 does not affect the airways - the respiratory tract
  • COVID-19 lung disease is a disease of the lung blood vessels
  • There is a potential route for the virus to get from the mouth to the lungs not previously considered
  • 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 is proven to be the case, then oral healthcare becomes paramount in managing the disease
  • Here it is proposed that the main risk factor for severe COVID-19 could be gum disease
  • If proven correct, this concept could have wide-reaching public health implications

The 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 rationale for a novel understanding of the link between poor oral hygiene and poor outcome in COVID-19.

First published February 20, 2021.

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

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

Figure 1.

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Figure 1.

  • The mouth acts as a reservoir of SARS-CoV-2 which is present in saliva
  • If the virus is able to cross the immune defence barrier of the mouth, the gums, then it would be taken up by 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 hygiene this pathway would be permanently open during the course of illness with COVID-19
  • Those with good oral hygiene could be relatively protected from passage of the virus to the lungs in this way

Introduction

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

Here it is proposed that the virus does not enter the body by being breathed into the lungs. Rather, it is proposed that it escapes the mouth through the protective layer of the gums and enters the blood. From here blood drains into the veins of the neck and chest. Then blood is pumped by the heart and into the pulmonary arteries (large blood vessels which carry deoxygenated blood to the lungs). The virus could be transferred to the lungs along this route.

This 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 in the lungs results in increase of the hormone angiotensin-II. This hormone acts on the surrounding blood vessel, causing it to narrow, become inflamed, and clot. The main disease process in the lungs is also understood to be that of inflammatory clotting (immunothrombosis) which can be explained by this process. Immunothrombosis can be seen as an immune defence mechanism, it traps the virus in the lungs but at the expense of blood vessel circulation to the area affected. In this way the lungs are dominantly affected 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 more virus in the saliva the more likely someone with COVID-19 is to get severe disease or die. This is yet to be explained.

Also, very importantly, gum disease is strongly associated with disease severity and death. This too is yet to be explained satisfactorily.

We now know that SARS-CoV-2 binds to the nasal passage 200 to 700-fold more powerfully than the airways of the lungs. This indicates that the nasal passage is the first area to be infected and explains the loss of smell in many patients. We also know from CT scans that the airways of the lungs are not affected initially and that the dominant disease processes affect the blood vessels. In this way the disease should not be considered a respiratory pneumonia but is better termed as a pulmonary vasculopathy, or, in simple terms, a disease of the lung blood vessels.

With all 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 substances pass into the body. If this defence barrier is damaged, for example because of gum disease, then the virus, which is in the saliva, will be allowed to pass into the circulation system. It will then pass to the lungs. There is no further barrier.

This concept is proposed as the anatomical route the virus takes to the lungs. It explains why some get lung disease and some do not. If this pathway remains open during the course of infection then further damage to the lungs could continue until the defence mechanism of the lungs is overwhelmed. Then the virus would be permitted to pass more freely into the rest of the body.

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

This pathway is, as yet, theoretical but is offered as a rational explanation of many as yet understood phenomena.

It is noted that all of the irreversible risks of periodontitis (a severe form of gum disease) are shared with the risk factors for severe COVID-19. These are – age, male sex, certain ethnic groups (for example Black, Hispanic, certain Asian groups), non-O ABO blood group, obesity, diabetes, cardiovascular disease, and for those who have difficulty caring for their gums because of physical disability or learning difficulties. It is proposed that these are not associated risks but that they point to the single main risk factor, that of gum disease.

This concept is shared for the urgent attention of those researchers investigating oral healthcare measures in the context of preventing SARS-CoV-2 transmission or, indeed, in the treatment of COVID-19. It is suggested that the mouthwashes known to kill the virus in vitro (those containing CPC, ELA, or PVP-I) should be trialled as a simple and non-invasive preventative and treatment measure.

The concept is also brought to the urgent attention of officials who have influence over public health measures. Attention is drawn to the difference in outcome between those countries who have included oral healthcare measures as part of their public campaign (for example Japan). It is suggested that similar oral healthcare measures should be adopted in addition to social distancing and vaccination programmes.

Below is a more detailed and references 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 dentistry and oral health.

Anatomy

The anatomical pathway between the mouth and the pulmonary arteries (lung blood vessels) is an established route for certain infectious diseases to pass from the mouth to the chest, via the veins.

Endocarditis is a rare condition of bacterial growth on the heart valves. There is a known increased risk for those with poor oral hygiene in this condition in which bacteria from the mouth can spread via the veins of the mouth and neck 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 [Harper].

If this pathway is open to bacteria, then why not consider this as a possible route for SARS-CoV-2 to pass from the mouth to the lungs?

Viral load in saliva is associated with poor outcome in COVID-19

It is known that saliva contains SARS-CoV-2 and persists for up to ten days after infection [Wyllie et al]. It is also known that the amount of virus found in the saliva (the viral load) can significantly predict disease severity and mortality. The viral load in saliva is higher in men with COVID-19. The viral load predicts outcome more significantly than age. 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].

Poor oral hygiene and poor outcome in COVID-19

Poor oral hygiene 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 – 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, but not for severe COVID-19, which is discussed separately below.

After adjusting for possible confounders (such as age, sex, smoking and comorbidities) the multivariable analysis presented by Marouf et al showed that periodontitis was associated with an 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].

In the dental literature 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 of 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 [Furkan and Savas].

If proven correct, the concept of the direct anatomical link between the mouth and the pulmonary vessels, as described on this page, would mean that this link is not associative, but rather directly causative.

Here the mouth is likened to a reservoir of the virus with the lungs acting as a sump, mopping up the virus and preventing spread to the rest of the body, but at the expense of tissue damage in the lungs.

The mouth: a virus reservoir

It is now known that 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 viral copy number is 200 to 700-fold higher in nasal swabs compared to samples taken from airways of the lungs [Chen and Shen et al].

In this sense, the mouth can be considered a reservoir of the virus.

The lungs: a virus sump

If the above anatomical pathway for transfer of SARS-CoV-2 from the mouth to the lungs is correct (Figure 1), then what evidence is there from what is known about the pathological processes in the lungs which might suuport this case? Below, evidence from the radiology is presented and knowledge of the development of COVID-19 from a pathological perspective is discussed (histology and pathophysiology).

Radiological evidence for 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, the so-called tree-in-bud opacification of bronchioles (smallest airways visible on CT scans) which is common to other respiratory pneumonias, such as influenza, is absent in COVID-19 lung disease [Lou et al].

Chest X-ray 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.

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Figure 2.

  • 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)

CT appearances of COVID-19

Descriptions of the CT scan appearances of COVID-19 lung disease show that so-called ground-glass opacities 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 had been 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.

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Figure 3.

  • Patient with proven swab positive COVID-19
  • CT with typical ground-glass opacities seen in COVID-19

So, if not primarily due to airways inflammation, what else could be the cause of the lung opacities?

The presence of dilated (widened) blood vessels within the areas of lung opacification has been widely reported in descriptions of CT and Dual Energy CT (DECT) scans. These dilated vessels are thought to result in the formation of shunts between the arteries and veins of the lungs [Lang et al (Lancet)] which leads to blood returning to the heart. This phenomenon could account for the low blood oxygen levels in patients presenting with COVID-19.

An unusual CT finding which is reported in 64% of CT scans of patients with COVID-19 is the phenomenon known as vascular tree-in-bud opacification. (This should not be confused with the respiratory tree-in-bud opacification which is not a feature of COVID-19). This feature is thought to indicate a primary vascular process, likely a manifestation of a pulmonary microangiopathy (disease of the small 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 4.

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Figure 4.

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

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). 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. In COVID-19 the distribution of the clots is more towards the edges of the lungs and is lower in volume. This pattern is thought to be due to a combination of pulmonary thromboembolic disease and immunothrombosis [Van Dam et al].

Figure 5.

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Figure 5.

  • 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 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) (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. 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].

Figure 6.

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Figure 6.

  • CT scans in COVID-19.
  • Wedge-shaped opacities are seen at the edge of the lungs.
  • These are thought to represent a disease process similar to pulmonary thromboembolic disease.

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 in the venules (small veins) of the pulmonary vascular system [Fox et al - figure 3 in this paper]. 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 performed at Imperial College, London, which have analysed findings on DECT scans, shows that X-ray is characterised by perfusion defects, indicating reduced blood supply to the lungs. Particular patterns of perfusion defects are 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], which is further evidence of a vascular driven pathology in patients with COVID-19.

In view of the radiological evidence for a process in the lungs, which is primarily driven by disease of the blood vessels of the lungs in X-ray, and in view of the lack of radiological evidence of disease of the airways, the term ‘X-ray 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 process of developing the lung disease.

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

As the upper airway is the initial seat of viral infection and replication, with high levels of SARS-CoV-2 in the saliva, if there is breakdown of the immune barrier of the mouth, which is compounded in those with poor oral hygiene, then the virus could be delivered via 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 lung disease.

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 in tissues) 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 – accepted correspondence for publication Lancet Rheumatology]. This process could be considered harmful to the area of lung affected as it stops blood travelling through the fine capillary network where gas exchange occurs. Upstream there would be obstruction to the passage of blood through vessels of the lungs which would then return to the heart without coming into close contact with air and without transfer of the blood gases, namely oxygen and carbon dioxide.

In this way, unregulated levels of angiotensin-II in a blood vessel of the lungs could be the mechanism for triggering 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 hypercoagulopathy (tendency to form blood clots) seen in COVID-19 [Nicolai et al].

Although the ACE2 receptor is found on the surface of pneumocytes in the epithelium of cells on the respiratory side of the gas exchange unit (the air side), it is also widely expressed in the endothelial cells on the inner surface of blood vessels. Virus elements are detectable in endothelial cells in autopsy studies of those who have died with COVID-19, and there is evidence of endothelial cell inflammation and inflammatory cell death [Huertas et al and Varga et al]. Thus, although 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 in the development of COVID-19 lung disease.

As some have suggested, it is logical that this shutting down of blood vessels by the process of immunothrombosis in the lungs acts as an appropriate immune response. This closure of the blood supply to small lung vessels would trap the virus and prevent escape to the rest of the body via the heart and systemic blood vessels [Nakazawa et al]. This may go some way to explain the lack of systemic viraemia (virus in the blood) in the early phase [Wolfel et al] and why increased viraemia is associated with poor outcome in critically ill patients [Bermejo-Marton et al]. Hypothetically, this could be because the immune responses in the lungs become overwhelmed as more areas of lungs are damaged. The mechanism of immunothrombosis 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 shared as a risk factor for severe COVID-19. Smoking is identified as a risk factor for development of periodontitis [Gautum et al]. But, perhaps surprisingly, it has not been identified 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 (inner blood vessels cells) 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 hygiene 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 that 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].

Conclusion

Above is presented a theoretical explanation for the link between poor oral hygiene 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 hygiene is established as the single greatest risk factor for developing severe COVID-19, but further investigation will be needed.

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 are already known to rapidly kill SARS-CoV-2 in vitro, such as those containing 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. Measures to preserve oral health or treat oral disease is given different emphasis in different countries. Where mouthcare has been advised as an integral part of these national measures, such as in Japan [Reuters], outcome has been considerably better – 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.

Updated February 25th 2021. Introduction added.

Updated February 26th 2021. References added.

Updated February 27th 2021. Reference links added.

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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 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

Introduction to be re-worded

Further investigation regarding role of nicotine

Detail word edit

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 dentistry and oral health.

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Last reviewed: February 2021