Oral manifestations of COVID-19: A review

1.1Structure and classification

The word “coronavirus” comes from the Latin word CORONA, which means “Crown,” because, when viewed under an electron microscope, it has a structure that resembles a Crown with Multiple Spikes [4]. The first coronaviruses were found in poultry in the early 1930 s [5], and the first human coronaviruses were found in the 1960 s [6]. With a genome size of roughly 26 to 32 kilobases and multiple spikes on its surface, the new coronavirus, known as SARS CoV 2, is an enveloped, positive sense single stranded RNA virus that belongs to the beta coronavirus genus. SARS CoV 2 is a zoonotic coronavirus that is similar to the coronaviruses that cause SARS and MERS. The most likely natural reservoir is the Chinese horseshoe bat (Rhinolophus sinicus), and its genome is very similar to the coronavirus of bat origin RaTG13 [7, 8]. SARS CoV (SARS S) primarily uses endosomal membrane fusion or plasma membrane fusion to enter host target cells. In the binding of receptors, membrane fusion, and virus entry, the S protein (a glycoprotein) of the SARS CoV plays a minor role [9]. The S protein binds to the cellular receptor angiotensin converting enzyme 2 (ACE2) to start the SARS CoV entry [10]. Additionally, the cellular serine protease 2 TMPRSS2 is used for S protein priming (Fig. 1). Another isoform of CoV, namely CoV 2, has been identified as the primary virulent form in the current outbreak. According to a recent study, ACE2 and TMPRSS2 are required for SARS CoV 2 (SARS S 2) cell entry [10, 11]. In conclusion, SARS CoV 2 uses the ACE2 SARS CoV receptor ACE2 for entry in the host cell and TMPRSS2 primes the spike protein of SARS–CoV–2 [12]. A study was done to determine whether SARS-CoV2 and viruses that cause MERS and H1N1 influenza are related. Additional research was also conducted to comprehend the mutations that take place in the SARS-CoV2 sequences throughout the propagation of the disease and connected them to the functional domains of proteins. The resulting phylogenetic tree showed that the H1N1 and MERS viruses are distantly related, but SARS-CoV2 is closely related to both. The mutation study of six of the ten SARS-CoV2 proteins reveals that there were more than 50-point mutations in the sequences from 34 different countries. It’s interesting to note that during the analysis, four proteins remained unchanged. Therefore, when developing the diagnostics or treatments for this disease, these four proteins may be taken into account [13].

Fig. 1

Detail structure of coronavirus detailed coronavirus structure (a) SARS-CoV-2 transmission via aerosols and respiratory droplets (b). Spike glycoproteins are bound by Angiotensin-converting Enzyme-2 (ACE2) to initiate SARS-CoV-2 entry into host target cells. Additionally, spike proteins are primed with serine protease (c and d). Relationship between RBD and ACE2 (d). Oral SARS-CoV-2 Manifestations (all or none may occur separately or simultaneously) (e).

1.2Transmission of SARS CoV–2

It is believed that SARS CoV 2 is first transmitted from bats to humans in or near Wuhan, China, and then from one person to another. Direct person-to-person transmission happens when an infected person coughs or sneezes and creates respiratory droplets that are inadvertently inhaled by another person. Within a 6-foot radius, this kind of transfer happens between the closed contacts. Another way to spread the virus is by touching contaminated surfaces with your hands and then putting your mouth, nose, or eyes close afterward [14]. Viral particles created during coughing or sneezing settle to the surface and cause contamination. According to research by Kampf et al., the human coronavirus can survive for up to 9 days at room temperature on inanimate objects like metal, glass, or plastic. Additionally, self-inoculation from contaminated dry surfaces results in further transmission to the mouth, eye, and nose [15, 16]. Recent studies have found the virus in faecal samples and suggest that the virus can also be transmitted through the faecal oral route [17, 18]. The typical method of transmission is through direct contact with the symptomatic patient, but asymptomatic people can also spread the disease. A few authors have proposed that the SARS CoV 2 can also spread through the air [19].

1.3Clinical manifestations of COVID–19

The COVID 19 symptoms were divided into three general categories by WHO. Fever, a dry cough, and fatigue are the most typical signs. Body aches and pains, a sore throat, diarrhoea, conjunctivitis, headaches, loss of taste or smell, a skin rash, and discoloration of the fingers and toes are less common symptoms. Breathing problems or shortness of breath, chest pressure or pain, and loss of speech or movement are the severe symptoms [1, 20]. Clinical symptoms can range from being completely asymptomatic to experiencing mild flu-like symptoms to having a severe respiratory illness. People with comorbid conditions like diabetes, hypertension, and ischemic heart disease experience more severe symptoms. The pathogenesis and pathophysiology of COVID 19 infection are greatly influenced by ACE2. ACE inhibitors are some antihypertensive medications, and this causes an increased risk of infection by SARS–CoV–2 [21].

1.4Effect of SARS–CoV–2 on blood cells

In COVID-19 patients, increased estimated blood viscosity (EBV), which is calculated from haematocrit and globulins, is linked to thrombotic problems, organ failure, and higher mortality. EBV does not consider fibrinogen or cellular connections, despite being instructive. Use in vitro blood samples from patients to examine whether they have altered whole blood viscosity (WBV) when assessed at both high and low shear rates. A cross-sectional study of 58 patients has concluded that acute and convalescent patients, hyperviscosity offers a potential explanation for the thrombotic risk. Important ramifications for thromboprophylaxis result from these findings [22]. There is mounting evidence that COVID-19 also affects the endothelium system in addition to the lungs. Recent research has demonstrated that this can result in impaired microcirculation and, as a result, functional issues with all inner organs. Endothelial dysfunction, widespread inflammation, and complement components may all work together to contribute to the overall pro-coagulative condition seen in COVID-19 individuals, which can result in both venular and arteriolar occlusions [23].

1.5Effect of SARS–CoV–2 on haemostasis

In a study, dynamic changes in coagulation, haematological, and biochemical markers were examined for their relationships to COVID-19 patient mortality. It involved all COVID-19 patients who had severe respiratory failure and were critically sick. It was found that in critically ill COVID-19 patients, monitoring anomalies in coagulation, haematological, and biochemical markers as well as their dynamical changes may help with care and mortality prediction [24]. The coagulation profile of COVID-19 patients who had an acute stroke and its relationship to patients’ outcomes were reported in a study. The baseline D-dimer value and its peak value during hospitalisation were significantly greater in patients who had a poor outcome, demonstrating that the D-dimer can be a predictor of death in COVID-19 patients with acute stroke [25].

1.6Effect of SARS–CoV–2 on thrombotic processes in the whole body together with microcirculatory disorders

Contrast enhanced sonography (CEUS), in the hands of skilled examiners, provides the opportunity to study dynamic microcirculatory abnormalities in real time dynamically without any risk for the thyroid gland or kidneys, even in severe progressive disease bedside. The first experiences with abdominal CEUS tests are given based on severe COVID-19 infections. A narrowing of the organ-supplying arteries, as well as a delayed capillary filling of vessels close to the capsule, a regional reduced parenchymal perfusion, or an inflammatory hyperemia with capillary hypercirculation, can all be seen on CEUS in the stage of an imminent organ failure with significantly reduced kidney and liver function. It is feasible to dynamically monitor the arterial and venous blood flow in the mesentery and rapidly rule out organ infarction [26]. Use of contrast enhanced ultrasound (CEUS) was also done in severe cases of COVID-19 infection to assess pulmonary changes near the pleura. CEUS opens up new possibilities for bedside monitoring of pleural reactive inflammatory or peripheral thrombus embolism in severe cases of COVID-19 infection [27].

A poorly understood thrombotic consequence of COVID-19 are abdominal thromboses. A study was done to present abdominal multimodality ultrasound imaging results for the evaluation of thrombotic lesions in hospitalised COVID-19 patients. It showed that hospitalised COVID-19 patients can experience thromboembolic consequences. The early and precise diagnosis of these issues can be achieved with multimodality ultrasound tests [28].

With traditional B-mode and elastography, the small intestinal morphology was described. Additionally, utilising CEUS and color-coded perfusion parameters, the dynamic impacts of small bowel micro vascularization related to COVID-19 were assessed. Investigations were conducted on 13 patients who had severe acute respiratory distress syndrome (ARDS) caused by COVID-19. In conclusion, it was demonstrated that the small bowel may also be a critical interaction location in COVID-19 [29].

1.7Oral manifestations of COVID-19

An ulcer, erosion, bulla, vesicle, pustule, fissured or depapillated tongue, macule, papule, plaque, pigmentation, halitosis, whitish areas, hemorrhagic crust, necrosis, petechiae, swelling, erythema, and spontaneous bleeding were among the oral manifestations. The tongue (38 %), labial mucosa (26 %), palate (22%), gingiva (8 %), buccal mucosa (5 %), oropharynx (4 %), and tonsil were the most frequently affected areas (1%). Aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, mucositis, drug eruption, necrotizing periodontal disease, angina bullosa-like, angular cheilitis, atypical sweet syndrome, and Melkerson-Rosenthal syndrome were suggested diagnoses for the lesions. In 68 % of cases, oral lesions were symptomatic—painful, burning, or pruritic. Both genders had nearly equal rates of oral lesions (49 % female, 51 % male) The interval between the onset of systemic symptoms and the onset of oral lesions ranged from 4 days before to 12 weeks after. Systemic symptoms first appeared in three cases before oral lesions, and in four cases, oral and systemic symptoms simultaneously manifested. Kawasaki-like lesions had the longest latency period. Oral lesions usually disappeared 3 to 28 days after they first appeared. Depending on the aetiology, various treatments such as artificial saliva, chlorohexidine mouthwash, nystatin, oral fluconazole, topical or systemic corticosteroids, systemic antibiotics, systemic acyclovir, and photo biomodulation therapy (PBMT) were recommended for oral lesions [30].

1.8Aphthous-like lesions

shallow ulcers with erythematous halos and yellow-white pseudo membranes. In one patient, oral lesions and systemic symptoms both developed at the same time, and in other patients, the latency period ranged from 2 to 10 days. Two patients had positive PCR results for the herpes simplex virus, and one patient had a positive history of recurrent aphthous stomatitis (RAS) (HSV). Younger patients with mild infections frequently had aphthous-like lesions without necrosis, whereas older patients with immunosuppression and severe infections frequently had aphthous-like lesions with necrosis and hemorrhagic crusts. After 5 to 15 days, lesions were healed [31]. The improvement of the systemic disease coincided with the regression of oral lesions. Increased levels of tumour necrosis factor (TNF)- can cause neutrophils to migrate to the oral mucosa and form lesions that resemble aphthous. Other potential causes for the development of such lesions in COVID-19 patients include stress and immunosuppression brought on by the infection [30, 32].

1.9Herpetiform/zosteriform lesions

Multiple painful, unilateral, round, yellowish-gray ulcers with an erythematous rim on the keratinized and nonkeratinized mucosae were the initial symptoms of herpetiform lesions. These lesions showed up before, at the same time as, or after systemic symptoms. After healing from herpetiform lesions, geographic tongue manifested in one instance. The development of secondary herpetic gingivostomatitis has been attributed to stress and immunosuppression brought on by COVID-19 [30].

1.10Ulcer and erosion

On the tongue, hard palate, and labial mucosa, ulcerative or erosive lesions manifested as painful lesions with irregular borders. Lesions started to appear 4 to 7 days after the onset of systemic symptoms in some cases, and they recovered 5 to 21 days later in others. HSV-1 and HSV-2 PCR tests were negative in two instances. Different causes for the development of ulcerative and erosive lesions have been proposed, including drug eruption (to an NSAID in one case), vasculitis, or secondary thrombotic vasculopathy to COVID-19 [33–37].

1.11White/red plaques

On the dorsum of the tongue, gingiva, and palate of patients with confirmed or suspected COVID-19, white and red patches or plaques have been reported. White or red patches or plaques may be caused by candidiasis as a result of prolonged antibiotic therapy, a decline in general health, or a failure to practise good oral hygiene [30, 32].

1.12EM-like lesions

In patients with cutaneous target lesions in the extremities, EM-like lesions manifested as blisters, desquamative gingivitis, erythematous macules, erosions, and painful cheilitis with haemorrhagic crust. Lesions developed 7–24 days after the onset of systemic symptoms and disappeared in 2–4 weeks [30].

1.13Angina bullosa-like lesions

In two confirmed cases of COVID-19, angina bullosa-like lesions on the tongue and hard palate appeared as asymptomatic erythematous purple blisters without spontaneous bleeding [38].

1.14Melkerson-Rosenthal syndrome

A 51-year-old woman was described as presenting with malaise, unilateral lip swelling, a fissured tongue, and right facial paralysis. She had previously experienced spontaneous healing of her Melkersson-Rosenthal syndrome four years prior, with no relapse. Computed tomography (CT) scan results revealed ground-glass opacities in both lungs, and laboratory oratory data indicated an elevated level of CRP. After receiving treatment for COVID-19 disease, the patient was fully recovered [39].

1.15Atypical sweet syndrome

A 61-year-old woman was reported to have come in with symptoms including fever, fatigue, arthralgia, myalgia, several erythematous nodules on the scalp, trunk, and extremities, as well as minor aphthous ulcers on the hard palate and buccal mucosa. COVID-19 RT-PCR results were positive. An erythema nodosum-like sweet syndrome was supported by the results of a skin biopsy, which revealed diffuse neutrophilic infiltration in the upper dermis along with granulomatous infiltration in the lower dermis and subcutaneous area [40].

1.16Kawasaki-like disease

Patients with COVID-19 who had Kawasaki-like disease developed oral lesions such as cheilitis, glossitis, and an erythematous and swollen tongue (red strawberry tongue) (Kawa-COVID). In contrast to the direct effects of the virus on the skin and oral mucosa, the prolonged latency between the onset of systemic symptoms (respiratory or gastrointestinal) and the onset of oral or cutaneous symptoms may be caused by a delayed immune system hyperactivation response and a secondary release of acute inflammatory cytokines [30].

1.17Necrotizing periodontal disease

A 35-year-old woman who had oral lesions, submandibular lymphadenopathy, halitosis, and fever was reported to be suspect for COVID-19. A painful, diffusely erythematous, oedematous gingiva with necrosis of inter-papillary areas was among the oral lesions. The suggested diagnosis was COVID 19 and bacterial coinfections, particularly prevotella intermedia, which caused necrotizing periodontal disease. After 5 days, the lesions healed [41].

1.18Vesicles and pustules

9-year-old women who had diarrhoea, abdominal pain, weakness, and an erythematous papular exanthema in her mouth and on her acromion has been reported. Vesicular eruptions and erosions on the tongue and buccal mucosa were among the oral lesions. A COVID-19 PCR test came out positive. After one week, lesions healed. Another case described a 51-year-old man who had a fever, dry cough, lethargy, dysgeusia, anosmia, and a positive COVID-19 serology. After 10 days, the oropharynx and hard palate both developed extensive erythema, along with petechiae and pustules on the border of the soft palate. Enanthema caused by COVID-19 was the indicated diagnosis, and the lesions cleared up within a few days [42].

1.19Petechiae

A few studies have noted Petechiae on the oropharynx, palate, and lower lip mucosa. Patients with petechiae had shorter latency times than those with petechiae and macular lesions combined. Possible causes of petechiae have included thrombocytopenia brought on by COVID-19 infection or the prescribed medication [30].

1.20Nonspecific lesions (mucositis)

Several studies have described erythematous-violaceous macules, patches, papules, and plaques on the tongue, lip mucosa, hard palate, and oropharynx. Mucositis in COVID-19 patients may be brought on by thrombotic vasculopathy, vasculitis, or hypersensitivity related to the virus. The potential causes of mucositis in COVID-19 include vasculitis, thrombotic vasculopathy, and mucosal hypersensitivity secondary to COVID-19 [30].

1.21Post inflammatory pigmentation

A 40-year-old woman was reported to have pigmentation in her attached and interpapillary gingiva. Post-inflammatory pigmentations are caused by elevated levels of inflammatory cytokines, such as interleukin-1 [IL-1], tumour necrosis factor [TNF]-, and arachidonic acid metabolites (prostaglandins), which are produced as a byproduct of stem cell factor (SCF) and basic-fibroblast growth factor from basal layer keratinocytes [43].

1.22Loose teeth

In some patients, symptoms like tooth loss, sensitive gums, or grey or brittle teeth may be present. It might occur as a result of the SARS-ability CoV-2’s to irritate the gums and cause a sudden tooth loss [44].

1.23Taste disorders

In COVID-19, taste disorders are frequent. Taste disorders were more common in Europe, North America, and the Middle East among COVID-19 positive patients and less common in Asia. Taste disorders are now accepted as a diagnostic criterion for COVID-19 in the majority of regions due to their high incidence and some degree of presentation in the early stages of the disease. The inability to accurately perceive chemical stimuli, such as taste and spiciness, is known as a taste disorder. The three main categories of taste disorders are: total loss of taste (ageusia), diminished intensity of taste (hypogeusia), and distorted taste (dysgeusia). A relatively easy-to-use but subjective questionnaire can be used to diagnose taste disorders. Alternative methods include chemical gustometry. Patients with COVID-19 and those Alternative methods include chemical gustometry. Both COVID-19 patients and those with the acute cold can have taste disorders, but those with the disease have a difficulty telling the difference between bitter and sweet flavors while those with the acute cold have a similar ability to tell the difference between sour and salty flavors. We can distinguish COVID-19 patients from people with the acute cold using taste strips as well [3].

1.24Macroglossia disease

The incidence of macroglossia is relatively small. One (0.5 percent) of 210 patients with severe COVID-19 who were admitted to intensive care units in 14 clinical studies later developed macroglossia, according to a review of the patients. Macroglossia is a clinical diagnosis with a complex etiology. Before the COVID-19 outbreak, there had been a few reports of macroglossia cases. The natural extension of the tongue past the tooth or alveolar crest is the clinical definition of macroglossia. True macroglossia and relative macroglossia are two different pathological subtypes of macroglossia. True macroglossia has clear histopathological abnormalities, whereas relative macroglossia may have corresponding clinical symptoms but has a normal histological structure. Infection or keratinized tongue plaques are two problems that some patients with macroglossia may have. Congenital lingual vein malformation or lymphatic vascular malformation, which are more prevalent in young children, are the most common causes of macroglossia in non-COVID-19 patients, whereas macroglossia caused by COVID-19 is more prevalent in adults, the majority of patients have been on ventilators [3].