SARS-COV 2 Associated Oral Lesions-A Review

Introduction: COVID-19 disease is caused by SARS-CoV-2 virus and it was declared pandemic by World Health Organization (WHO) on March 11,2020. The coronavirus infection has an affinity for ACE2 receptors and by attaching to them, the virus enters the host cells. Along with many body organs like lungs, kidney, liver, upper respiratory tract, nervous system, skeletal muscles, ACE2 concentration is also found in abundance in epithelial cells of tongue and salivary glands. Materials and Methods: Recent studies, researches, documents and case reports published in the world medical literature in the year 2020-2021 were searched and documented in our study. The search engines used were PUBMED, google scholar, WEB OF SCIENCE etc. Results: Dysgeusia, xerostomia, sore throat, aphthous and herpetiform ulcers, candidiasis, enanthema, Kawasaki like lesions were the most common among various oral manifestations. Others includes plaque like changes, gingival inflammation, necrotizing gingivitis, erythema multiforme, angina-bullosa like lesions, Melkersson-Rosenthal Syndrome, Oral mucormycosis etc.The sites of infection mainly include tongue, gingiva, hard and soft palate, buccal and labial mucosa etc. Review Article Moumalini et al.; JPRI, 33(47B): 431-468, 2021; Article no.JPRI.75411 432 Conclusion: The etiopathogenesis of such lesions cannot be directly corelated with COVID-19 and factors such as stress, immunosuppression, co-infections, secondary lesions, opportunistic infections, systemic diseases, poor oral hygiene etc. must be considered. Management of stress is an important factor. In this review article various oral lesions are discussed in COVID-19 infection states in detail. The importance of earliest diagnosis of oral lesions is to be kept in mind to prevent further complications.


INTRODUCTION
Coronavirus disease  is caused by newly discovered novel coronavirus Severe Acute Respiratory Syndrome Coronavirus 2(SARS-CoV-2). The WHO declared the disease as global pandemic last year on March 11,2020 [1] and potentially a life-threatening respiratory disease. It was identified in December 2019 after its outbreak in China (Wuhan) [1,2].
It presents as a lot of symptoms among whom fever, sneezing, dry cough, shortness of breath, taste alteration, anosmia, fatigue are characteristic [3,4]. It may worsen to fulminant pneumonia and severe respiratory distress if not treated early in many cases [5]. Mostly present as mild, some are moderate and severe and a little percentage as critically ill, even some are asymptomatic also [4,6]. Surprisingly, the features are different for every other person and the course of the disease depends majorly on the immunity of the patient affected. It can spread from an infected patient via droplets mainly through oral, nasal and eye mucous secretions [2]. It has an incubation period of 1 to 14 days, mostly between (3-7) days [2].
RT-PCR (Reverse Transcriptase Polymerase Chain Reaction) test from oropharynx is considered an effective method for detection of SARS-CoV-2 from human saliva and its sensitivity is higher than nasopharyngeal test [7].
There is a higher incidence of SARS-CoV-2 virus's nucleic acid in oropharyngeal swabs of infected patients [1]. The coronavirus enters the cells of human through receptor angiotensinconverting enzyme 2(ACE2) indicated by singlecell RNA-seq data analysis [1,6]. ACE2 is found in cell membranes of lungs, kidney, liver, upper respiratory tract, nervous system, skeletal muscles etc. It has been found that oral cavity presents ACE2 expression particularly in epithelial cells of tongue and salivary glands, and naturally it becomes prone or becomes the target cells for SARS-CoV-2 infection [1,3,6].
The coronavirus disease results in various oral/oropharyngeal manifestations which may be either a direct effect of the disease or may be secondary to any underlying disease, immune status following COVID-19 infection, or any drugs used for treatment of the same [6].
The most common intraoral sites of infection are the various parts of tongue, gingiva, hard and soft palate, buccal and labial mucosa, oropharynx, tonsillar pillar etc. and each one has different presentation.
Patients suffering from coronavirus disease suffer from stress and therefore oral hygiene maintenance is sometimes neglected. Many bacteria, virus, fungus may be found alongside normal commensals like Streptococci, Fusobacterium, Treponema, Prevotella intermedia, Candida species etc. [10] Therefore, bacterial co-infection, stress, lack of oral hygiene, immunosuppression, co-morbidities must also be considered.
Oral lesion presentation due to the virus is a broad classification and must not be neglected [7]. More clinical evidence and research are needed to establish the co-relation between SARS-CoV-2 and intraoral manifestations [3].  The aim of this study is a review of maximum of the oral lesion presentation associated with COVID-19 previously described and explained by many authors and a collection and overview of the same for better understanding and knowledge in depth.
We have searched recent studies published from previous year and this year (2020,2021) in search engines like PubMed, Google Scholar etc. We have typed the keywords like oral lesions, COVID-19, SARS-CoV-2, oral mucosa, manifestations. (Table1,2,3)

COVID 19 AND ALLIED ORAL LESIONS
Angiotensin Converting Enzyme 2(ACE2) receptor is a membranous protein presented by oral epithelium specially the salivary gland and the tongue [11]. It is found in abundance in oral tissues [12]. The virus SARS-CoV-2 has an invasive ability and special affinity for receptors for ACE2. Naturally the oral epithelium becomes the host cells or the target organ for infection and an easy route for entry for the virus, causing inflammatory response in salivary gland and tongue mucosa epithelium [12,6]. Studies have also indicated that salivary glands carry the most RNA linked to protein than tongue mucosa, buccal mucosa, palate, tonsils for the attack of the virus. ACE2 receptor and an enzyme called TMPRSS (transmembrane protease, serine 2) are included under them. They help the virus in fusing its membrane with cells of the host and thus gains entry [12]. Therefore, saliva is a major reservoir for SARS-CoV-2 infection as per reports [1]. SARS-CoV-2 interaction with ACE2 can also result in dysgeusia by impairment of taste buds [6]. Due to this pathogenesis, the oral signs and symptoms related to this virus may be taken into account and studied further.

Dysgeusia
The most important feature among all may be the altered taste or dysgeusia associated with loss of smell that is noticed in patients infected with COVID-19. Thus, they are one of the earliest indicators. The cranial nerves 1,7, 9,10 may be affected by SARS-CoV-2 and also the cells supporting their transmission. Again, ACE2 receptors are present in huge numbers in tongue mucosa which helps the virus to infect and attack the cells because of their affinity for ACE2 receptors [12] through dopamine and serotonin synthesis pathway coregulation [6].
SARS-CoV-2 can bind with sialic acid (essential salivary mucin component) thus altering gustatory sensation. Also, ACE inhibitors and ACE2 blockers used in COVID-19 treatment causes taste disorders by G protein-coupled and sodium channel inactivation. After recovery from COVID-19 and their discontinuation taste sensation becomes normal [6].

Xerostomia
Xerostomia is the 2 nd most common characteristic oral sign associated with COVID-19 infection. Due to the presence of ACE2 receptor in salivary glands as stated above, the virus gets entry into the salivary gland's epithelial cells and the quality and quantity of saliva produced is interrupted. Another cause can be the mouth breathing due to continual use of mask which results in dryness of mouth if not hydrated frequently. Xerostomia can affect oral cavity in caries prevalence and fungal infections due to Candida [12].

Sore throat
Sore throat is also a common finding in many patients with COVID-19 infection. It has been suggested by many authors [2].

Oral ulcers
Oral ulcers are considered to be the most common among all oral lesions characterized in COVID-19 infection. We can divide them into Aphthous-like and Herpetiform-like oral ulcers.

Aphthous ulcers
According to many studies, they presented as multiple shallow ulcers and circular with a whitish center and surrounded by an erythematous halo, ranging from 3 to 4 mm, or, (0.5-1)cm may be covered by an fibrinopurulent membrane or with a whitish pseudomembrane. Some present as several painful small ulcers, with irregular margins, in red and non-hemorrhagic background. They may occur in clusters or single [4,13,14].
Increased level of tumour necrosis factor (TNF)-α in COVID -19 patients may result in chemotaxis of neutrophils to oral mucosa and and develop these lesions [6]. They can also develop by cytokine storm due to COVID-19, stress, immunosuppression. Maximum of them present in tongue, others seen in gingiva, palate, buccal mucosa, labial mucosa, mucogingival junction, tonsillar pillar [4,13,14].

Herpetiform ulcers
They present as painful multiple small, pinpoint, yellowish or orange ulcers unilaterally with an erythematous halo, some with burning, itching sensation, irregular, shallow, round to oval in shape ulcer(0.5mm×0.5mm, well-circumscribed. Some are covered with mucopurulent membrane, some with hemorrhagic ulcerations with necrosis. They are most prevalent in tongue, labial mucosa followed by buccal mucosa and palate [4,15,3,16,17,18].

Ulcer and erosion
They appeared as painful lesions, some as multiple reddish macules of different sizes. Location as per studies can be buccal mucosa, hard palate, tongue, lip and in gingiva also [5,8]. They can be seen in moderate cases of COVID-19 in maximum number [8,5].
Early and late ulcerative lesions are due to SARS-COV-2 related lesions and treatment related lesions respectively. Lesions related to poor oral hygiene leads to ulcero-necrotic gingivitis [5]. Thrombotic vasculopathy secondary to COVID-19 may be another cause [8].

CANDIDIASIS
Candidiasis is seen in some cases and manifested mainly in tongue, and also in lip, palate, gingiva. Pain and burning symptoms were seen. Lesions presented as white plaque/whitish areas. Red forms mainly located in tongue with median rhomboid glossitis like appearance, while in palate white forms were more frequent, the first type(white forms) present more in moderate form of COVID-19 and second type(red forms) in intubated patients (severe and critically-ill). Pseudomembranous and mild oral candidiasis were noted, in 1 case it was associated with herpetic recurrent oral lesions [3,5,19,9]. Immunosuppression, stress, secondary lesions, COVID-19 treatment related lesions, lack of oral hygiene can be the probable cause [3,5,19,9].

Gingival Inflammation/Swelling
One of the important signs reported are bleeding and gingival inflammation in COVID-19 infection. Generalized increase in inflammation due to increased cytokine and interleukin level by SARS-CoV-2 virus can be a major cause. Immune imbalance can also be considered vital factor in this disease, resulting in cytokine storm specially by interleukin-6, which worsens in presence of periodontal disease [12].

Enanthema
Enanthema is mainly reported by 2 authors. Typical presentations were on hard and soft palate and oropharynx. The signs were inability to taste, sore throat, largely erythematous surface, a few petechiae in the midline and numerous pustular enanthema, more prominent on the left side,1-3 mm in diameter. Also in another case macule, petechiae were noticed.
Probable reason described by the authors were infection by SARS-CoV-2 virus in oral cavity due to COVID-19 [20,21].

Necrotizing Gingivitis
Covid-19 infection is also associated with necrotizing periodontal disease. Signs and symptoms included severe halitosis, with generalized erythematous and edematous gingivae. Necrotic interdental papillae and bleeding gums were noted. Bilateral submandibular lymphadenopathy was associated. They are also seen mostly in severe and critical cases of COVID-19 [5,10].

Hyperplasia of Papilla
It was always seen in patients with dysgeusia and characterized by red enlargement of papilla on dorsum and sides of tongue. Moderate form of COVID-19 cases showed a high number of hyperplasia of papilla. They may have an association with COVID-19 [5].

Oral Mucormycosis
It was described by one author in the context of COVID-19 and seen in current yeari.e.2021. It was presented by a female patient(50yrs), having a painful, deep ulcerated lesion located at the center of the hard palate. The lesion measured around 2 cm with exposed bone and was surrounded by an erythematous halo and had lobulated borders and swollen focal areas. Incisional biopsy was done and medications were advised.

Geographic and Fissured Tongue
They were found in 2 studies. In 1 study, the lesions were asymptomatic and were pre-existing conditions [5]. In another study, presented as atrophic areas surrounded by elevated yellowwhite halo which was associated with fissured tongue. This severe geographic tongue was classified as moderate after recovery from COVID-19. They were thought to be due to secondary lesions as a result of degradation of systemic health or treatments for COVID-19 infection [3].

Strawberry Tongue and Cracking of Lips
These lesions presented as swelling, redness, cracking of labial mucosa. Red strawberry tongue appeared as hyperplastic papilla against an erythematous dorsal tongue. White strawberry tongue presented as hyperplastic papilla against a white coating of the dorsal tongue [25].
The authors concluded that lesions were due to post-viral inflammatory reaction and these oral changes presented were early indicators of Multisystem Inflammatory Syndrome in Children (MIS-C) with COVID-19 infection [25].

Angina-Bullosa Like Lesions
They generally presented in the hard and soft palate, tongue or buccal mucosa as brown-black single multiple bullae with associated petechiae. They were mainly treatment related lesions (patients on anticoagulant medications) and seen mostly in moderate cases of COVID-19. In another study, these angina-bullosa like lesions presented as non-bleeding, asymptomatic lesions and appeared as purple, erythematous bullae (6-8) mm of soft consistency. These lesions were associated with COVID-19 infection [11,5].
The authors stated that these oral lesions were due to Kawasaki disease with concurrent COVID-19 infection or may be due to disordered immunological response following infection by SARS-CoV-2 virus. These oral lesions characterized may not be having direct effect by the virus [7,23,26,27,28,29,30,31].

Melkersson-Rosenthal Syndrome
One case was reported of a 51yrs old women having a medical history of Melkersson-Rosenthal Syndrome with a positive report of COVID-19. She presented with unilateral lip swelling, malaise, orofacial oedema, facial paralysis, fissured tongue, affecting her right side of face. The signs were coincident with COVID-19 infection.
There may be co-existence between COVID- 19 and Melkersson-Rosenthal Syndrome and that may have caused its recurrence [32].

STRESS AS AN IMPORTANT FACTOR IN DEVELOPMENT OF ORAL LESIONS
Due to highly contagious and sudden outbreak of COVID-19 as a pandemic, anxiety, depression and other stress related reactions among people are inevitable [32]. As a result of halt in the daily activities and social interactions because of lockdown for unknown period of time, people develop depressions and may lose confidence in life which affect their mental health [33]. This kind of panic of the public in psychology is called PSYCHOLOGICAL STRESS. Here COVID-19 become the stressor of public panic. The uncertainty and lack of knowledge of COVID-19, its fast transmission speed and infectious nature and its outcomes in human lives, SARS-CoV-2 virus is responsible for making public nervous and highly stressful [33]. According to WHO, the current death rate due to COVID-19 worldwide is 36.9 lakhs. Many people have negative thoughts in their minds and some may lose their hopes after watching and reading news channels, newspapers and seeing the death rates or number of infected rates, hospitalization news, shortage of beds and treatment in proper time, and it becomes a continuous hammer to their brain. One author reported that females are more prone than males to develop these anxiety, stress and nervousness and that 40yrs or below aged people faces these problems more than those of above 40yrs [33].
Stress response activates autonomic nervous system, mainly sympathetic, via hypothalamicpituitary-adrenal (HPA) axis, which secretes corticotropin-releasing factor (CRF) and arginine-vasopressin (AVP). Adrenocorticotrophic hormone (ACTH), enkephalins, and endorphins are released as a result of this. Thus, the stress-response function acts by a positive, bidirectional feedback loop. Various other factors released in response to stress are angiotensin II, various cytokines, and lipid mediators of inflammation. They act on different components of HPA axis and intensifies the action [34].
COVID-19 is also seen more in people having comorbidities such as obesity, hypertension, diabetes and cardiovascular disease and periodontitis [35].
Smoking or tobacco consumption in any form for deleting effect of stress imposes an additional risk by contributing to poor oral health status. COVID-19 infection induces oxidative stress, activates unregulated cytokine offering (cytokine storm) and inflammation. The receptor of SARS-CoV-2 is Angiotensin-converting enzyme 2(ACE2) regulates vascular function by modulating nitric oxide (NO) release and oxidative stress [35].
Psychosomatic reasons with oral diseases are there from long ago and they impose a threat for the development and progression of oral lesions [36]. Various oral manifestations include xerostomia, dysgeusia, aphthous ulcers, herpetiform ulcers, candidiasis, necrotizing periodontitis, erythema multiforme etc. which have a very close relation with stress [34]. A possible mechanism of ACE-2 and reactive oxygen species (ROS) activation by COVID-19 and the repressing of NRF2(nuclear factor erythroid 2-related factor-2) manifests oral symptoms and Acute Respiratory Distress Syndrome (ARDS) in lungs, inflammations and oxidative stress in multiple organs [35].
Reactive oxygen species (ROS) and free radicals are physiologically produced during cellular metabolism. When their balance is disrupted in favour of ROS, a condition called oxidative stress occurs. Uric acid is the main antioxidant in saliva and has role in managing oxidative stress. Inflammatory infections of oral cavity by bacteria in gingiva is initiated which triggers the activation of host defence systems. Thus, production of ROS is increased to disturb pathogenic microorganisms. ROS does not distinguish between pathogenic bacteria (having antioxidant defences) and host structures and destroys the tissue of the organism that has produced them as a 'defence weapon'. ROS action is highly increased in patients with periodontal disease having weak antioxidant defence system. Recurrent aphthous stomatitis (RAS) causes include local trauma, systematic, genetic, immunological, microbial factors, use of immunosuppressive drugs etc. Oxidantantioxidant equilibrium is thus disturbed and increases production of free radicals. There is compromise of immune system by oxidative stress situation. Cell damage occurs after getting trigger from an increase in free radicals. The enzymatic antioxidant defence system is damaged in RAS having active lesion and has an important role in its pathogenesis [37].
People as a general basis must stay away from the media as far as possible, discuss about positive news, can do free hand exercise or jogging, practice meditation or breathing exercises, indulge themselves in any type of productive works or can have music therapy to keep their mind fresh and stress-free. Vaccination against COVID-19 among all age groups must be encouraged as fast as possible. This also ensures people to fight the pandemic and hoping for better days to come.

CONCLUSION
COVID-19 disease started in Wuhan, China, gradually affected all other countries including India and soon it became a global crisis and became a pandemic. The respiratory system is the target of SARS-CoV-2 virus and alongside it also impairs other body organs. It directly or indirectly affects the oral mucosa mainly due to the presence ACE2 receptor, to which the virus attaches and finds its entry.
Dysgeusia, xerostomia, sore throat, oral ulcers including aphthous and herpetiform, candidiasis, swelling of gingiva, enanthema, oral lesions of Kawasaki-like disease are the most common oral lesions manifested. We have also found 1 case of oral mucormycosis related to COVID-19 disease. We cannot fully corelate the etiopathogenesis of such lesions with COVID-19 or justify its exclusiveness. Several other factors which seem to be worth mentioning includes stress, immunosuppression, underlying systemic disorder, co-infections, secondary lesions, opportunistic infections, older age, slight female predilection, poor oral hygiene, severity of COVID-19 infection, vascular compromise, treatment related lesions, hyper inflammatory response secondary to COVID-19. Hence, we can conclude that there are some lesions having direct association with SARS-CoV-2 virus and in some it has a great contributory effect with other etiopathogenesis keeping in mind.
Stress or emotional distress playing a major part in development of oral lesions must not be neglected in the era of COVID-19. So, its high time for all the generations to keep their mind free from any negative thoughts, have healthy food and music therapy, have social contact, meditation and exercising, and discussing positive news.
Oral health management is also necessary and regular follow up and a visit to the dentist can help decrease most of these oral lesion's progress by early detection.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.