key: cord-0876399-vrirb75a
authors: Kusiak, Aida; Cichońska, Dominika; Tubaja, Monika; Skorek, Andrzej; Jereczek-Fossa, Barbara Alicja; Corrao, Giulia; Marvaso, Giulia; Alterio, Daniela
title: COVID-19 manifestation in the oral cavity – a narrative literature review
date: 2021-09-14
journal: Acta Otorhinolaryngol Ital
DOI: 10.14639/0392-100x-n1584
sha: 6f8f9fd65e654c2b13d58a0b37e83e08edb95445
doc_id: 876399
cord_uid: vrirb75a

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently discovered coronavirus, which in 2020 led to a global pandemic. Clinical manifestations of COVID-19 are very diverse and symptoms range from mild to severe. Correlated symptoms might also manifest in the oral cavity, which is a potential pathway for viral infection, and therefore might be a potential pathway for SARS-CoV-2. In recent research among patients with SARS-CoV-2 infection, taste and olfactory disorders, dry mouth, drones and inflammation of mouth, bitter taste in mouth, difficulty in swallowing and burning sensations have been reported. There have been cases of oral mucosal lesions in patients diagnosed with COVID-19 disease. Some correlations between periodontitis and severity of COVID-19 disease have also been observed. Oral mucosa, due to occurrence of ACE2 receptors, is highly susceptible to SARS-CoV-2 infection. The occurrence of changes on oral mucosa should increase the alertness of dental practitioners. However, knowledge in this area is still limited and in the field of oral manifestations of COVID-19 more research and patient observations are required.

COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently discovered coronavirus. COVID-19 emerged in China and spread rapidly around the world, posing a huge threat to the human population, which led to a global pandemic declared in March 2020 by the World Health Organization (WHO) 1 . In Febru-ary 2021, COVID-19 was diagnosed in almost 104 million people and contributed to the death of more than 2 million patients, becoming the worst health challenge that our generation has had to face. Coronaviruses are a diversified class of RNA-viruses with zoonotic origin, characterised by high transmission in humans and respiratory infections. In 2002 and 2012, two highly pathogenic coronaviruses appeared in population, a severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), becoming the cause of deadly respiratory illness 2 . SARS-CoV-2 is significantly different from SARS-CoV and MERS-CoV in both its genome structure and spike protein structures. SARS-CoV-2 has higher affinity to the cellular receptor angiotensin-converting enzyme 2 (ACE2), which results in easier entrance to human cells than SARS-CoV and MERS-CoV, faster spread in humans and higher mortality rate 3, 4 . The infectivity of SARS-CoV-2 is strictly correlated with the ability of virus to enter human body cells with ACE2 as the primary receptor interacting with virus spike protein when entering the cell 5 . SARS-CoV-2 is characterised by high level of transmissibility and ability to spread from human to human by aerosol and contact 6 . This virus is viable in air for 3 hours and on plastic and stainless-steel surfaces for 72 hours 7 . The incubation period for the virus varies from 1 to 14 days. After symptoms are observed, a diagnosis can be achieved by real-time PCR (RT-PCR). SARS-CoV-2 can be detected in fluids from throat swabs, secretions of the lower respiratory tract and blood 7, 8 . The aim of this review is to summarise current knowledge about the oral manifestations of SARS-CoV-2, which could improve diagnosis of COVID-19.

COVID-19 is mainly associated with pneumonia, which in more severe cases can develop into acute respiratory distress syndrome (ARDS). The severity of infection can be assessed based on the results of a biochemical blood test including level of albumin, lactate dehydrogenase, C-reactive protein, lymphocytes and neutrophils 9 . Patients with COVID-19 disease present symptoms such as leukocytosis, leukopenia and lymphopenia, hypoalbuminaemia, an increase of lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, bilirubin and D-dimer 10 . To improve prognosis of COVID-19, patients should be provided with respiratory support at early stages of the disease 11 . Clinical manifestations of COVID-19 are very different and observed symptoms range from mild to severe. The most common symptoms are fever, cough, fatigue, com-plicated dyspnoea and pneumonia. Other less frequently reported symptoms include headache, haemoptysis, diarrhoea, runny nose and phlegm-producing cough 12 . In the most severe cases, symptoms rapidly progress to acute respiratory distress syndrome, respiratory failure and multiple organ failure, becoming the cause of death 7 . Patients with general comorbidities such as diabetes, cancer, cardiovascular diseases are more susceptible to develop complications of COVID-19 7, 8, 13 . Middle-aged and elderly patients with chronic diseases are also more susceptible to respiratory failure and have poorer prognoses 11 . In addition, patients with moderate and severe periodontitis are more susceptible to general health complications of COVID-19 14 . Although periodontitis is commonly correlated with other chronic inflammatory diseases as diabetes and hypertension, which are known risk factors of severe COVID-19 15, 16 , periodontitis has a significant impact on the severity of COVID-19 14 .

The influence of SARS-CoV-2 on the human body remains unknown, although there are also symptoms in the oral cavity, which may play a crucial role in the early diagnosis of COVID-19 17 .

A literature search for relevant papers in the literature from January 2020 to February 2021 was conducted using Pub-Med and Scopus databases. We included only studies on the oral manifestations of SARS-CoV-2 infection. Key words included: SARS-CoV-2 infection, SARS-CoV-2 symptoms, SARS-CoV-2 in oral cavity, COVID-19 symptoms, COVID-19 disease, SARS-CoV-2 in saliva, oral cavity, taste impairment, dry mouth, oral mucosa lesions.

The infectivity of SARS-CoV-2 is dependent on the ability of the virus to enter human cells and it has been shown that ACE2 is the primary receptor interacting with virus spike protein, which enables cell entry 5 . The oral cavity is one of the entry points to the body and a potential pathway for viral infection, and therefore might be a potential pathway for SARS-CoV-2 18 . There is also a possibility that oral mucosa might be a potential route of entry for SARS-CoV-2 into human cells 19 . The SARS-CoV-2 cellular entry receptor ACE2 is found in oral mucosal tissues including the tongue and floor of the mouth 20 . However, ACE2-positive cells are also observed in other oral mucosa tissues such as buccal and gingival epithelial cells 21 . The presence of ACE2 receptors in oral tissues suggests that the oral cavity can be perceived an initial site of entry for SARS-CoV-2 21 . Another potential reservoir for SARS-CoV-2 in the oral cavity might be gingival sulcus, which is a well-established ecosystem promoting colonisation of microorganisms 22, 23 . In both clinically healthy and pathological pockets, other viruses, such as herpes simplex virus and human papilloma virus have been discovered 24, 25 . SARS-CoV-2 RNA has also been identified in the ulcerated squamous cell carcinoma of the tongue. This finding could be of some interest as it emphasises the potential risk for pathologists handling samples from asymptomatic patients with unknown SARS-CoV-2 status 26 . Therefore, according to the study by Chen et al. SARS-CoV-2 can be detected in saliva. This might be correlated to the presence of ACE2 receptors and their tissue distribution 27 . In research by Liu et al., it was shown that salivary gland epithelial cells are characterised by high expression of ACE2 receptors 28 . It should be mentioned that ACE2 expression is higher in minor salivary glands than in lungs, which might lead to the possibility that salivary glands might be an important site for SARS-CoV-2. It has also been observed that the possibility of SARS-CoV-2 nucleic acids in saliva is higher among patients with more progressed infection 27 . Furthermore, dysfunction of salivary glands in late stage of COVID-19 infection was observed 27 . According to Xu et al., contaminated saliva secreted by infected salivary glands are probably a potential reservoir for SARS-CoV-2 and might be the main reason for the spread of COVID-19 through asymptomatic infection 18 .

The most frequently observed oral manifestations among patients with SARS-CoV-2 infection are taste and olfactory disorders, dry mouth, drones and inflammation of mouth, bitter taste in mouth, difficulty in swallowing and burning sensations in mouth (Tab. I).

In research by Chen et al., there was a questionnaire on the oral health status of patients with infection by SARS-CoV-2. The study included 108 patients, 52 males and 56 females. Oral manifestations of COVID-19 included loss of taste, dry mouth, dryness and inflammation of mouth. Loss of taste was reported in 47.2% cases (36.5% in males, 57.1% in females), dry mouth among 46.3% cases (46.2% in males, 46.4% in females) and dryness and inflammation of mouth among 11.1% of patients (13.5% in males, 8.9% in females). This study demonstrated that patients infected by SARS-CoV-2 generally present symptoms related to the oral cavity like loss of taste and dry mouth, which might be included in diagnostic criteria of COVID-19 27 . In a multicentre case series by Qiu et al., olfactory and/ or taste dysfunction were reported among patients with COVID-19. This study included 349 patients and in 41% of cases such symptoms were present. 10% of patients presented only olfactory or gustatory symptoms and 19% of patients presented olfactory and/or gustatory symptoms prior to any other COVID-19 symptoms. This study also suggested that loss of smell and taste among patients might be a screening criteria that is useful in early identifications of COVID-19 29 .

In a cross-sectional study on 59 patients hospitalised for COVID-19, cases of olfactory and taste disorders were observed, 33.9% of patients reported at least one taste or olfactory disorder and 18.6% reported both taste and olfactory disorder, 20.3% of patients observed those symptoms before hospitalisation and in 13.5% the symptoms appeared during hospitalisation. Smell and taste disorders were reported more often by females (52.6%) than males (25%) 30 . In an observational study by Sinjari et al. on a group of 20 SARS-CoV-2 positive hospitalised patients, oral manifestations such as dry mouth, taste disorders, burning sensations and difficulty in swallowing were observed. 30% of patients in this study developed xerostomia during hospitalisation, 25% of patients reported impaired taste, 15% burning sensation of the mouth and 20% difficulty in swallowing. It should be stressed that burning sensations were reported only by female patients. Considering sex and age of patients, no significant results were observed 31 . Although taste disorder in the most common oral mani- 32 . Taste disorder observed as an early symptom of COVID-19 before other symptoms may support the hypothesis that oral cavity mucosa might be an initial site of infection by SARS-CoV-2, especially taking into consideration the fact that taste receptors are widely distributed in tongue, where 96% of the oral ACE2-positive cells are observed 20, 21 .

It has been shown that ACE2-positive salivary gland epithelial cells are early targets of other coronaviruses, and that salivary gland functions may be affected at an early stage of the infection 28 . This might be a possible explanation for a dry mouth symptom reported by patients undergoing SARS-CoV-2, although this hypothesis requires further research 21 .

The presence of oral mucosa cells with high ACE2 receptor distribution might lead to inflammatory reactions in such organs and tissues as tongue and salivary glands 21 . According to Dziedzic et al., SARS-CoV-2 infection is the reason for diversified oral cavity disorders caused by both susceptible oral tissues and impairment of the immune system. Oral ulcerations, gingivitis, recurrent oral herpes simplex virus infections, opportunistic fungal infections and xerostomia caused by a decreased salivary flow have been observed among patients with COVID-19 33 . Rarely reported oral manifestations are presented in Table II . According to Carreras-Presaset et al., oral vesiculobullous lesions among patients with COVID-19 have also been reported. There were symptoms such as pain of palate, pain of tongue and many small ulcers on the palate with unilateral affection. Blisters on the internal lip mucosa and desquamative gingivitis has been observed. Patients presented ulcers or blisters, which commonly appear in other viral infections, such as hand, foot, and mouth disease and herpetic gingivostomatitis 34 . Soares et al. have also reported the occurrence of oral manifestations in a 42-year-old male diagnosed with COV-ID-19 35 . Intramural examination revealed the ulcerated lesion and multiple reddish macules of different sizes scattered along the hard palate, tongue and lips. Petechia-like and small vesicobullous lesions on skin were also observed. After 3 weeks observation, lesions on both the oral mucosa and skin subsided 35 .

Oral mucosa lesions have also been diagnosed in a 19-yearold SARS-CoV-2 positive patient 36 . Intraoral examination revealed erosions, ulcerations and blood crusts on the inner surface of the lips and palatal and gingival petechiae. Skin lesions were also observed. Both mucosal and skin lesions disappeared after 10 days 36 . In a case report by Amorim Dos Santos et al., oral mucosa changes in a patient with COVID-19 were observed. Oral manifestation included a persistent white plaque on the tongue dorsum refractory to antifungal therapy and multiple ulcers in the tongue dorsum resembling herpetic oral lesions 37 . In a report by Patel et al., necrotising periodontal disease was observed in a 35-year-old female suspicious for COV-ID-19. The patient presented with fever, submandibular lymphadenopathy and halitosis. Oral manifestations of the disease like painful, diffuse erythematous and edematous gingiva with necrosis of papillary areas were also observed. The oral lesions recovered after 5 days were diagnosed as necrotising periodontal disease due to bacterial coinfections along with COVID-19 38 .

The diverse impact of COVID-19 on oral health, including both subjective symptoms reported by patients and oral mucosa lesions undoubtedly require a proper dental care. Patients recovering from COVID-19, especially if hospitalised, should be provided with special oral health monitoring to ensure their full recovery 33 .

The changes observed on the oral mucosa related to COVID-19 are not pathognomonic, and their treatment is symptomatic and does not differ from the treatment of oral mucosa lesions resulting from other diseases or disorders. Treatment includes the use of drugs that accelerate healing and painkillers, a gentle diet, maintain proper oral hygiene and saliva substitutes in case of dry mouth symptoms [34] [35] [36] [37] [38] [39] . 35 Case report Ulcerated lesion and reddish macules on the hard palate, tongue and lips Ciccarese et al. (2020) 36 Case report Erosions, ulcerations and blood crusts on lips; palatal and gingival petechiae Amorim Dos Santos et al. (2020) 37 Case report Persistent white plaque and multiple ulcers on the tongue dorsum Patel et al. (2020) 38 Case report Necrotising periodontal disease COVID-19 has become the subject of research by many specialists from various fields of medicine, who, depending on the clinical situation, attempt to develop appropriate standards of management. This applies to treating the symptoms of SARS-CoV-2 infection as well as encouraging proper treatment of patients with chronic diseases in a new pandemic reality [40] [41] [42] .

Oral mucosa, due to the presence of ACE2 receptors, is highly susceptible to COVID-19 infection. Symptoms of COVID-19 related to the oral cavity such as taste impairment, dry mouth and burning mouth syndrome may appear in patients with SARS-CoV-2 infection, becoming crucial for identification of the disease. The occurrence of oral mucosa lesions related to SARS-CoV-2 infection should increase alertness among dental practitioners. However, knowledge in this area is still limited. More research and patient observations are required in the field of oral manifestations of COVID-19.

Olfactory and oral manifestations of covid-19: sex-related symptoms -a potential pathway to early diagnosis

History is repeating itself: probable zoonotic spillover as the cause of the 2019 novel Coronavirus epidemic

From SARS and MERS CoVs to SARS-CoV-2: moving toward more biased codon usage in viral structural and nonstructural genes

Identification of a novel coronavirus causing severe pneumonia in human: a descriptive study

Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2

Aerosol transmission of SARS-CoV-2? Evidence, prevention and control

Biological and social aspects of Coronavirus Disease 2019 (COVID-19) related to oral health

Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

Clinical, laboratory and imaging features of COVID-19: a systematic review and meta-analysis

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Association between periodontitis and severity of COVID-19 infection: a case-control study

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Is the oral cavity relevant in SARS-CoV-2 pandemic?

Salivary glands: potential reservoirs for covid-19 asymptomatic infection

Transmission routes of 2019-nCoV and controls in dental practice

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Dental care and oral health under the clouds of COVID-19

Periodontitis and respiratory diseases: a systematic review with meta-analysis

Periodontal pockets: a potential reservoir for SARS-CoV-2?

Periodontal disease and detection of human herpesviruses in saliva and gingival crevicular fluid of chronic kidney disease patients

Viruses in periodontal disease -a review

SARS-CoV-2 detection in formalin-fixed paraffin-embedded tissue specimens from surgical resection of tongue squamous cell carcinoma

Detection of SARS-CoV-2 in saliva and characterization of oral symptoms in COVID-19 patients

Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques

Olfactory and gustatory dysfuncion as an early identifier of COVID-19 in adults and children: an international multicenter study

Self-reported olfactory and taste disorders in patients with severe acute respiratory coronavirus 2 infection: a cross-sectional study

SARS-CoV-2 and oral manifestation: an observational, human study

Investigation of COVID-19-related symptoms based on factor analysis

The impact of coronavirus infectious disease 19 (COVID-19) on oral health

Oral vesiculobullous lesions associated with SARS-CoV-2 infection

Letter to Editor: Oral lesions in a patient with Covid-19

Oral erosions and petechiae during SARS-CoV-2 infection

Oral mucosal lesions in a COVID-19 patient: new signs or secondary manifestations?

Necrotizing periodontal disease: oral manifestation of COVID-19

Diagnosis and treatment of diseases of the oral mucosa

COVID-19 impact in radiotherapy practice in an oncology hub: a screenshot from Lombardy, Italy. Tumori

Head and neck radiotherapy amid the COVID-19 pandemic: practice recommendations of the Italian Association of Radiotherapy and Clinical Oncology (AIRO)

Head and neck cancer radiotherapy amid COVID-19 pandemic