INTRODUCTION:

COVID-19 declared as the ‘Public Health Emergency’ by the World Health Organisation due to its rapid spread globally. It was created by the Novel Corona Virus, which is a single chain RNA virus, basically comes under the Coronaviridae family^1,2,3,4. The word “corona” means “crown” whose outer layers are covered with spike-protein ⁵. It is a surface protein, bind to the ACE2 receptor of human cells of lung, heart, kidney etc^6,7. The single stranded RNA of this virus is interconnected with the nucleoprotein which is present within the capsid incorporated of matrix protein and the envelop carry glycoprotein with club shaped projections. In human corona virus, one of this two serotypes, OC43-like and 229E-like, is present. This mRNAs mould a peculiar “nested set” sharing a similar 3’ end and the host cell membranes germinate new virions^{1, 8}.

The first confirmed human covid-19 case was reported in Wuhan city, China by the Wuhan city officials on 31^st December, 2019. First outbreak of SARS was in 2003 and ended in a year duration. The COVID-19 is similar to that which caused in 2003 SARS outbreak, but this one spread faster and farther. It spreads majorly through the droplets specially during coughing or sneezing.

Incubation period is 2-14 days of exposure to the virus. The infected person remains infected for 10-20 days depending upon the severity and immune system of their illness^9,10.On the 11^th March, 2020, WHO declared covid-19 as pandemic on seeing of its rapid spread globally. According to WHO, the top three affected countries are USA, INDIA, BRAZIL¹¹. Till now India noticed 2 peaks of covid-19, first one was on mid-2020, while second one was on March 2021 and now measures are being taken to prepare for the third wave. In first peak it mostly affected the comorbid elderly peoples and in second peak it affected elderly as well as middle age population^12,13. The main reason of second peak of covid -19 was the different variants of the virus. According to WHO, Alpha (B.1.1.7), Beta (B.1.351, B.1.351.2, B.1.351.3), Gamma (P.1, P.1.1, P.1.2), Delta (B.1.617.2), Omicron (B.1.1.529) variants are comes under the ‘Variants of concern’ and ‘Variants of Interest’ are Lambda (C.37) and Mu (B1.621) variants ¹⁴. According to ICMR, Delta (B.1.617.2) variant spread badly in India as it became “double mutant” and in few cases third mutation is also seen. In India as of now, in January 2022, Omicron (B.1.1.351) spreads more rapidly than other variants although it has least mortality rate then other variants. According to WHO, covid-19 affected patients show typical symptoms are like fever, nonproductive cough, aches, fatigue, pain, pharyngitis, diarrhoea, conjunctivitis, loss of taste and smell sensation; and other serious symptoms are like air hunger due to decreased oxygen saturation, chest pain or pressure, loss of speech or movement¹⁵. As covid-19 virus transmitted most commonly through the oral and nasal routes¹⁶, thereafter it is necessary to give importance to maintain proper hygiene of the oral cavity and should try to avoid emerging predisposing factors causing covid-19. This article enumerates major oral lesions linked with SARS-CoV-2 infection.

Oral mucosa and pathogenesis of SARS-COV-2 in oral mucosa:

In the oral cavity, there is the specialized outer covering layer of mucous called oral mucosa that comprises of lamina propria and stratified squamous epithelium. Although oral mucosa has common functions like protection, regionally it is also specified to form certain functions such as gustatory perception, sensitive observation, secretion and mastication. Oral epithelial cells have several structural and functional specs to counter act physical and chemical attacks within oral cavity. Squamous epithelial cells hold anatomical characteristics like stratification and cornification of the keratinocytes and distinct intercommunication between cells to prolong their barricade. The metabolically active epithelial cells are able to react to outer stimulation by incorporating a number of cytokines, adhesion molecules, growth factors and chemokines. Over the time, oral cavity constantly changing its ecosystem in various ways which impact the arrangement of oral microbiome group. Within the oral microbiome group, some common commensals can interchange in the opportunistic pathogens if the host shows compromised immunity. These pathogenic or opportunistic species including either of bacteria, fungi or viruses are creating gingivitis, periodontitis, caries, candidiasis and other viral infections in the mucosa of oral cavity. Viral infections which are commonly registered in dental clinics, is frequently linked with various mucosal lesions in oral cavity. Painful oral ulcers are associated with some viruses like Herpes virus (herpes simplex virus 1–8), HIV virus, Zika virus which are able to infect as well as replicate in the mucosal cells of oral cavity. In salivary glands, there is sign of presence of viruses such as paramyxovirus, HIV, cytomegalovirus and Epstein-Barr virus (EBV) and they also reproduce within the gland and alter the salivary gland’s normal function. In recent time many studies have given the statistics of oral manifestations in relation with covid-19 infection.

Several studies show, remarkable appearance of ACE-2 receptors in dorsum part of tongue and hard palate where keratinized epithelial cells are identified and comparably low in the buccal and gingival tissue cells. As a key receptor, this ACE-2 receptor manages blood pressure homeostasis in the human body by balancing the renin–angiotensin–aldosterone system where it switches angiotensin I in to angiotensin II to control blood pressure and sodium-water retention. In covid-19 infected person, corona virus enters a human body by invading the host cells through the ACE-2 receptor membrane; as a result, structural changes and break down of the S protein takes place from virion, and let out the nucleocapsid within the cell cytoplasm. Lysosomal protease, cathepsin L and serine protease, transmembrane protease serine 2 proteolytically break this S protein. On the other hand, this virus has the power to incite tissue necrosis factor-α-converting enzyme (TACE) in the shedding of the ACE2 ectodomain in association with TNF-α making. Inflammatory cytokine TNF-α is produced during acute inflammation by macrophages/monocytes. This TNF-α conduct a varied range of events within cells which results necrosis or apoptosis of cells. Studies also say that the interlinkage between corona virus and ACE-2 receptor trigger the cellular signals during the viral penetration and steer to the tissue destruction. There is the presence of high-rise of ACE2 receptor cells in the alveolar tissues, mucous cells of oropharynx, GI tract, kidneys and endothelial cells including oral tissues, which indicate these sites should be believed likely the great exposure sites for covid-19 virus^17,18.

Oral manifestations associated with SARS-CoV-2

According to WHO bulletin, SARS-CoV-2 infected persons shows symptoms like dry cough, headache, fever, body aches, sore throat, loss of taste and smell sensation¹⁵. Oral lesions are spread nearly equal in both male and female patients. Suggested diagnosis of Covid-19 oral lesions such as ulcers, erosions, necrotizing periodontal diseases, white and red plaque, petechiae, herpetiform lesion, mucositis, acute parotitis and other gingival changes etc. These oral lesions are briefly described below.

Ulcers and erosion:

Ulcer can be described as a discontinuation of epithelium caused by molecular necrosis. The characteristic features are usually redness, burning sensation and/or pain. Based on the duration of persistence, ulcers can be mainly classified into acute or short-term ulcer and chronic or long-term ulcer. Aphthous ulcers, herpetic ulcers, traumatic ulcers and chancres are acute type of ulcers and persist about three weeks and regress spontaneously. Chronic type of ulcers continues for few weeks or few months like major aphthous ulcers, ulcers associated with odontogenic infection, malignant ulcers, gummas, ulcers associated with crippling systemic diseases and some traumatic ulcers¹⁹.

Erosion is a disorder commonly terms as tooth wear. Etiological factors such as the alteration of tooth structure, altered physiologic properties of saliva, internal acidic sources like GERD, too much consumption of acid containing soft drinks and some lifestyle changes. The degree of concentration of encircling solution is determined by the pH of solution and calcium-phosphate concentrations and these changes generate the demineralisation of the hard tissue structure in oral cavity. Erosion of teeth starts through the initial demineralisation of the enamel surface and there after volume reduction with a softened layer holding on the remaining tissue surface²⁰. Ulcers and erosion appear painful in covid-19 effected patients. Commonly involved oral sites are the tongue, hard palate, labial mucosa²¹. There was a various clinical manifestations of oral ulcers, starting from aphthous stomatitis to extensive ulcerations amalgamated with necrosis or hard outer covering. Maximum lesions appeared one or more punched-out ulcerations enveloped by yellowish membrane which encircled with an erythematous halo²². The pathogenic process of COVID-19 virus may also be connected with the gradual evolution of oral ulcers. As there is the sign of presence of ACE2 receptor in the oral epithelial cells, the disturbance of these cells may arise during the spread of covid-19 virus in to these oral epithelial cells. However, in COVID-19 patients, another common symptom xerostomia or dry mouth likely play a vital character in producing oral ulcers. As the saliva loss its defencing and lubricating function, it can readily induce trauma to the mucosa and localized infection due to microorganisms²². It becomes painful after latency period of 4-7 days and recovered after 5-12 days²¹.

Necrotizing periodontal disease:

Necrotizing gingivitis (NG) or necrotising ulcerative gingivitis (NUG) is basically a type periodontal disease presents as an acute opportunistic gingival infection due to bacterial plaque. Generally, it appears more in malnourished children and young adults as well as patients with impaired immunity. Pathological factors cover an important role in NUG, such as psychological stress, immunodeficiency, poor diet maintenance, poor oral hygiene etc. which can alter the functions of polymorphonuclear leukocytes and lymphocytes, increased histamine concentration and capillary permeability of gingiva and ultimately leads to reduced PMN leukocyte chemotaxis²³. The disease is clinically diagnosed by pain, bleeding and papillary necrosis with tendency to relapse²⁴. The major etiological bacteria for several acute periodontal lesions are P. intermedia along with Fusobacterium as well as Treponema species which comprises of wide range of the microbes appear in necrotizing periodontal disease. Involuntarily in a close aspect, covid‐19 diseases can lead each patient to necrotizing periodontal diseases as a result of bacterial co‐infection procreated by P. intermedia²⁵. Patel et al. reported that painful, diffuse erythematous and oedematous gingiva associated with necrosis of interpapillary areas²¹. After taking 400mg metronidazole three times a day for 5 days along with 0.12% chlorhexidine mouthwash two times a day for 10 days, these lesions recovered^21,25.

White and red plaque:

White lesions can appear clinically within the oral cavity. In the oral cavity, lesions exists as white because of uniform reflection of light spectrum by the unusual keratin and also due to the ceaseless dipping of the hyperkeratotic tissue in saliva, which can be comparable with appearance of palms and soles after submerged in water for longer duration. White lesions in the oral cavity may appear as benign, pre-malignant or malignant lesion²⁶. White and red patches clinically appeared on the dorsum part of tongue, gingiva, palate in a covid-19 confirmed or suspected patients²¹. Candidiasis as a result of prolonged antibiotic coverage, collapsing of general status and poor oral care may be the reason for appearance of white and red patches or plaques^27,28,29.

Petechiae:

Petechiae is pinpoint non-blanching purple, red or brown spots on the skin, which is less than 2 mm in size. It mainly affects the skin as well as mucosa. Haemorrhagic areas in the dermis layer of skin may help in creating petechial rashes. Aberration in the normal haemostasis may create petechiae as well as various clinical finding. The main pathophysiologic reasons of petechiae and purpura are like low platelet level, platelet dysfunction, coagulation disorders and loss of vascular integrity³⁰. In studies, petechiae reported on lower lip, palate, oropharyngeal mucosa. Thrombocytopenia due to covid-19 or the prescribed drug for the treatment of covid-19 infection may be the possible cause of it²¹.

Olfactory dysfunction:

According to study of Biadsee et al. 67% patients reported olfactory dysfunctions. 52% reported altered taste sensation, 54% reported dryness of mouth, 26% reported facial pain and 11% reported masticatory muscle pain. He also said that more than 50% patients had confirmed case of dysgeusia and xerostomia. In another report, according to Kaye et al. 25% patients reported anosmia as 1^st symptom³¹.

Herpetiform/zosteriform lesion:

Herpetiform lesions diagnosed as unilateral, painful, multiple round yellowish-grey ulcer. On both keratinized and non-keratinized mucosae, it had an erythematous rim. According to Behzad et al. geographic tongue developed after recovery from Herpetiform lesions. The main cause for appearance of secondary herpetic gingivostomatitis was stress and immunosuppression associated with COVID-19²¹.

Non-specific lesions (mucositis):

In oral cavity, mucositis is a severely debilitating condition. Radiation therapy in the head and neck region, high-dose chemotherapeutic agents, hematopoietic stem cell transplantation (HSCT) are few causative factors of oral mucositis. It diagnoses as the erythema, oedema, and ulcerations within the oral mucosa and produce pain during the oral intake and makes it difficult. In severe cases, this may even force to take nutrition parenterally. Also, these lesions weaken the skin barrier and leads to the local or systemic infection³². Several studies reported that lip mucosa, tongue, hard palate and oropharynx shows the evidence of presence of erythematous-violaceous macules, patches, papules and plaques. In covid-19 patient inflamed blood vessels, covid-19 associated hypersensitivity, thrombotic vasculopathy could be the causes of mucositis²¹.

Melkersson-rosenthal syndrome:

Melkersson–Rosenthal syndrome is a rare, clinal, neuro-mucocutaneous syndrome. Etiology of melkersson-rosenthal syndrome is unknown. It is diagnosed by two or more of the triad symptoms such as orofacial oedema, recurrent facial palsy and fissure tongue or lingua plicata. Age of onset varies from early childhood to late adulthood³³.

Taşlıdere et.al. reported that a 51 year old woman complaints of discomfort and unilateral lip swelling, fissured tongue and paralysis of right side of face. She also gave a previous history of Melkersson-Rosenthal syndrome diagnosed 4 years ago and it was voluntarily restored without deterioration. Laboratory finding indicated an elevated level of C-reactive protein and computed tomography scan showed ground-glass opacity appeared in both lungs. After the successful treatment of COVID-19 disease, patients with melkersson Rosenthal syndrome cured completely^21,34.

Acute parotitis:

Capaccio et al. first reported parotitis in these circumstances of COVID-19 pandemic. He presented a case report of a 26 years old COVID-19 patient who gave history of pain in parotid gland with swelling in the left side but no purulent exudate from the gland during the massage. Remarkably, the first clinically present sign of COVID-19 was acute parotitis. Other following symptoms are like fever, muscle pain, partial or complete loss of taste and smell sensations. Serological tests report gave absence of cytomegalovirus and paramyxovirus antibodies. On the basis of clinical, serological and ultrasonographic findings, in relation to COVID-19 acute nonsuppurative parotitis was investigated^35,36.

Herpes simplex 1 (hsv 1) reactivation:

Herpes simplex virus type-1 (HSV-1) is a linear double-stranded DNA virus, is a member of the Alpha Herpesviridae subfamily which can reach up to the brain without any evidence of clinical symptoms. HSV-1 is the reason for forming initial and recurrent vesicular eruptions, chiefly in the orolabial and genital mucosa. The course of herpes simplex virus infection can be restricted through the antiviral therapy³⁷.

Hedou et al. reported Herpes Simplex virus reactivated in a patient out of 103 covid-19 patients present in ICU during documenting of cutaneous manifestations. Although these cutaneous manifestations dissipated within an average of 48 hours, but resolution of Herpes simplex virus was uncertain. Other study also revealed presence of many minute yellow ulcers on the dorsum of the tongue resembling to late phase of herpetic recurrent infection accompanying geographical tongue. Study of these two cases were established in Covid-19 patients^38, ³⁹.

Changes of gingiva:

The changes which are noticed in gingiva, are like generalized erythematous and oedematous gingiva, bleeding from gingival-periodontal region, necrosis of interdental papillae and desquamative gingivitis. These are diagnosed in patients with serious illness and compromised oral hygiene. In the Covid-19 suspected cases, these symptoms faded completely in 10 days after starting the use of antibiotics and topical antiseptic mouthwash^25,38,40,41.

Macroglossia:

Macroglossia generally is a painless enlargement of the tongue in a long duration. The term macroglossia can be described as the protrusion of tongue beyond the alveolar ridge or teeth, when it is in resting position. It is basically a rare anatomical anomaly which indicate a sign of an underlying condition. Diagnosis of the primary reason of macroglossia should be done and treated cautiously. Medications, surgery, radiation and sometimes orthodontic treatment are the various modalities that can be used for the treatment of macroglossia⁴². COVID-19 patients who are in prone-position in the ventilation for prolong duration, are especially in great possibilities. There are no proper instructions for handling patients with failed standard lingual compressive therapy. Patient may present various sizes of macroglossia, with or without various complexity like keratinised lingual plaques or infection. There are varying responses of patients to the management options such as corticosteroids, bite blocks and compressive therapy due to its heterogeneity. Uniform compression of tongue opposed to gravity can be more effective to make easier drainage as compared to uneven tongue compression not against gravity⁴³.

Post covid-19 complication:

In current scenario, most common post-covid-19 complication is Mucormycosis, previously known as Zygomycosis. It is a serious but rare fungal infection which is caused by Rhizopus and Mucor species, affecting patients with weakened immune system. These group of moulds live throughout the environment. They live in soil and in decaying organic matter, such as leaves, compost piles, or rotten wood. Rhinocerebral, Pulmonary, Gastrointestinal, Cutaneous and Disseminated, these come under different types of Mucormycosis. A classic clinical sign of it is the rapid onset of tissue necrosis with or without fever. The rhinocerebral (sinus and brain) type mucormycosis consists symptoms of fever, unilateral swelling of face, headache, nasal congestion, sinus blockage, blackish lesions on the nasal bridge or in the upper part of mouth which may turn into severe shortly. In pulmonary (lung) type mucormycosis, signs of fever, cough, chest pain, dyspnea can be seen. In the cutaneous mucormycosis, there can be appearance of blisters or ulcers along with black infected area. Other features comprise pain, warmth, excessive redness or swelling around the wound. Gastrointestinal mucormycosis presents symptoms of pain in abdomen, vomiting, nausea, gastrointestinal bleeding. Early recognition, diagnosis and proper treatment with antifungal drugs are important for improvement of the patient with Mucormycosis. Healthcare person should perform a tissue biopsy under microscope or in a culture medium, in which a small sample of tissue is collected from the affected site to analyse for evidence of mucormycosis in the laboratory. Imaging tests like CT scan of lungs, sinuses or other parts of body may require for diagnostic purpose where infection is suspected⁴⁴. South Asian country like India is one of the most Mucormycosis affected countries. Other post covid-19 complications are like fatigue, a most common musculoskeletal problem with reduce exercise capacity, anxiety and depression are most common mental health problems and these are mostly seen among ICU survivors^45,46,47. In acute post-COVID syndrome most common symptoms reported were fatigue and sleep disturbance. In chronic post-COVID syndrome fatigue, anxiety and dyspnoea were the most common clinically presented symptoms⁴⁸.

Future perspectives in relation with the oral health profession:

The ADA (American Dental Association) has proposed instructions to attend the patient during this COVID-19 pandemic. Based on the need of treatment, treatments can be divided in two, the emergency dental care and routine check-ups. In emergency situations, there may need of urgent medical attention incorporates deadly situations such as uncontrolled bleeding, swelling and fractures which may create obstruction of airway. Emergency dental treatment should always prioritize on minimal of pain, diminish or limit infection, which indirectly decrease the load on the emergency care units. The non-urgent procedures are basically routine dental care such as initial dental care, scaling, preventive and restorative therapies, aesthetic corrections, asymptomatic and hopeless teeth extraction, orthodontic procedures etc. The supreme intention is to keep away needless exposure and reduce the contiguity for prevention of farther transmission of the virus in the dental clinics. Patients having hidden comorbidities like diabetics, hypertension, malignancy, coronary artery diseases are in greater risk to develop COVID-19, requires certain consciousness. Researchers are currently focusing on developing biomarkers which can detect the virus in the early stage, so that proper therapeutics and precautions of COVID-19 will be taken easily. In the oral cavity, saliva and mucosal epithelial cells are excellent contender for cultivation of the biomarkers for identification of the asymptomatic carriers. In the oral cavity, there is the presence of the higher viral loads, it is crucial to use personal protective equipment (PPE) along with eye protective goggles, face shields, face masks, hand gloves and also these should be disposed of or correctly sterilized between attending every patient. Salivary aerosols and blood are the good carrier of the covid-19 virus and need to be protected from getting spread of the infection. Good ventilation of dental clinic, use of alcohol or chlorine orderly along with careful surface decontamination prior and after attending each patient and correctly manipulation of saliva and blood contaminating waste are important to prevent the outspread of COVID-19. New studies show some evidence of reduction of viral load in the oral cavity after mouth rinsing. Marui et al. stated that before starting the dental procedure mouth rinses may remarkably turn down the microbial load in the air-rotor generated aerosols. It is too first to forecast the post-pandemic outcomes of COVID-19. It is a rocky road for dental health professionals as the pandemic may impact their mental wellbeing, which can be deleterious for their overall efficiency⁴⁹. There is also a need to studied further for the use of corticosteroids, antivirals and antibiotics in treatment of mucosal lesions associated with COVID-19 in oral cavity by using large samples in different geographical society. So, scientifically the knowledge we achieved from this pandemic will be fruitful in mapping public healthcare guideline to turn future pandemics and vaccines away, and therapeutic treatment research will be crucial during patient care in any virulent coronavirus infections^50,51.

CONCLUSION:

This pandemic has given rise to a lot of changes in the social archetype. This pandemic has also given chances for use of technologies in medical care and also change the attitude of people towards health concern. Thus, it can be concluded that oral lesions appear first in covid-19 disease and adequate knowledge of these lesions will help the dentists and paramedical staffs to take proper preventive action. In such patients should be referred for further investigations immediately with proper medical attention otherwise lesions may precede the typical respiratory syndrome within few days and worsening of this oral lesion leads to more severe situation.

ACKNOWLEDGEMENT:

I wish to acknowledge the entire faculty members of my college for their all-time encouragement and specially thanks to Dr. Koushik Bhattacharya, for his mentorship to complete this work.

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Received on 21.02.2022 Modified on 01.05.2022

Research J. Pharm. and Tech 2023; 16(5):2565-2571.

DOI: 10.52711/0974-360X.2023.00421