Introduction

One year after detecting the first cases of pneumonia puta tively attributed to the novel severe acute respiratory syn drome coronavirus 2 (SARS-CoV-2), much has been learned about the pathogenesis of the corresponding disease (i.e., co ronavirus disease 2019 [COVID-19]). However, little is known about the oral manifestations of COVID-19, and the oral tis sues involved in viral infection and transmission. This can, in part, be attributed to the restrictions placed on dentists to examine hospitalized patients, and the difficulties in exami ning infected individuals with mild symptoms and those who are asymptomatic. Nevertheless, the oral cavity has not been given sufficient attention in the context of COVID-19.

Since the 2003 SARS-CoV outbreak, it was determined that this coronavirus could replicate in cells of the salivary gland duct(s). However, due to rapid infection control, research has not progressed further¹. SARS-CoV-2 is transmitted by droplets or aerosols produced by speaking, coughing, or sneezing^2,3. Additionally, there is evidence supporting SARS-CoV-2 replication in the oral mucosa and salivary gland cells; however, research investigating the relationships between the oral mucosa, oral cavity, and the infection remains incipient.

The present article reviews some fundamental aspects of what has been observed in the oral cavity regarding the new coronavirus (i.e., SARS-CoV-2), and addresses two main li nes of investigation: first, the need for qualified training of healthcare providers and deepen knowledge regarding the role of the oral cavity in SARS-CoV-2 infection and transmis sion; and second, the pathogenesis of COVID-19 in the con text of oral manifestations.

Methodology

A literature search of the PubMed (MeSH), Scopus, SciELO and medRvix (Dentistry and Oral Medicine, Epidemiology, In fectious diseases) databases for articles published in English and Spanish from 2019 to date was performed. Search terms included: “SARS-CoV-2” and “mouth diseases”; “SARS-CoV-2” and “oral manifestations”; ““SARS-CoV-2” and “sa liva”; and “SARS-CoV-2” and “mouthwashes”. 108 duplicate studies were excluded from the articles retrieved. In the first step, two investigators independently reviewed the search results and screened both titles and abstracts, to remove the studies outside the scope of the review and 622 articles were excluded. Then, we obtained the full texts of all potentially eligible studies, which were further examined to exclude tho se not fulfilling inclusion criteria; in these step 187 citations were removed. Ultimately, 33 studies were included, and the extracted information was organized in a spreadsheet (Ex cel, Microsoft Corporation, Redmond, WA, USA) to facilitate analysis. A flow diagram of the literature search is presented in Figure 1.

Figure 1 Flowchart of the literature search and included studies. 

The inclusion criteria set for the selection of articles were study design: prospective/retrospective cohort study, case-control studies, systematic reviews, original articles with ex perimental studies in human, animal and in vitro, case reports and replies to these reports. The exclusion criteria were opi nion articles, editorials and articles published in languages other than English or Spanish.

Results

After identifying the virus and corresponding disease, it was reported that the primary receptor for SARS-CoV-2 is angio tensin-converting enzyme 2 (ACE2). This membrane ecto peptidase is well expressed in type I and II pneumocytes, en terocytes, cardiac cells, oral epithelial cells, ducts, and acinic salivary gland cells, among other cell types^4-6, which partially explains the pathogenesis of COVID-19.

ACE2 expression has recently been recognized in oral mu cosal cells using immunohistochemistry, polymerase chain reaction, and single-cell RNA sequencing techniques^7-10. In the oral cavity, ACE2 is expressed primarily in epithelial cells of the gingival sulcus, the dorsal surface of the tongue, taste buds, floor of the mouth, ducts, and acinic cells of the minor and major salivary glands^7-10. The presence of the ACE2 re ceptor varies according to anatomical location, and expres sion appears to be increased by inflammatory processes such as periodontal diseases^7-10.

Thus, it has been shown that SARS-CoV-2 infection and re plication in the oral cavity appear to occur in independent “niches”. Therefore, it is probable that, in addition to its role as the initial entry portal for SARS-CoV-2, the oral epithelia act as a bridge in viral spreading to other locations such as the lower respiratory airways and the gastrointestinal tract. Of significant concern is that the oral cavity mucosa parti cipates in person-to-person transmission¹⁰. Saliva is the pri mary vehicle for viral transmission from the oral cavity. There is also evidence that SARS-CoV-2 is found in desquamated epithelial cells; as such, these infected cells may participate in viral dissemination¹⁰.

Diagnosing SARS-CoV-2/COVID-19 from saliva samples has attracted much interest due to the possibility of using this bodily fluid to confirm infection in a minimally invasive man ner; moreover, several studies have shown that it is feasible. Detection from saliva yields results comparable to those obtained using nasopharyngeal swab methods^11-14. It is well known that saliva sample collection involves less risk, both to the operator and the patient, is easily and safely transported, and does not require highly trained personnel, thus resulting in cost reductions¹⁵.

Regarding oral manifestations, published case reports have mainly described erythematous, vesicular, and ulcerative lesions, together with vascular lesions. A thorough review published by Galván-Casas et al.¹⁶ regarding dermatological and oral cavity manifestations of COVID-19, mainly described enanthema, characterized by the appearance of erythema tous small dots or spots on the hard and soft palates, le sions traditionally associated with childhood viral infections. Among individuals with COVID-19, these lesions appear a fewdays after infection and are accompanied by odynophagia¹⁶.

Vesicular and ulcerative lesions are superficial and mostly only a few millimeters in diameter. They are, however, often painful, multiple, and have been described as varicelliform eruptions of the skin, similar to the lesions produced in oral herpes simplex virus (HSV) 1 and 2 infections^17-21. In some cases, the appearance of these lesions may be the first ma nifestation of SARS-CoV-2 infection or concomitant syste mic manifestation(s). Frequently, the evolution of COVID-19 complications may be accompanied by the development of oral lesions^16,17.

The pathogenesis of these vesicular and ulcerative lesions in the oral mucosa of patients infected with SARS-CoV-2 ap pears to be similar to that observed in HSV infections, which are cytopathic, causing loss of epithelial tissue integrity, lea ding to the formation of intraepithelial vesicles and loss of epithelial coverage progressing to ulcer formation. Although there is no direct evidence of the consequences of infection in cells of the oral cavity, it is known that SARS-CoV-2 indu ces a cytopathic effect on airway epithelial cultures with loss of intercellular adhesion and syncytia formation²².

Considering that this particular coronavirus replicates in the epithelial cells of the oral cavity, this could explain the oral manifestations described to date. The few reported cases have shown that oral mucosal lesions can be aggravated by secondary lesions appearing as a decrease in salivary se cretion, and the anti-inflammatory and immunosuppressive therapies that patients with COVID-19 undergo. Additionally, there is a fact that appears not to have been considered― namely, the risk for additional infection or inflammatory pro cesses in patients using oral-tracheal ventilation devices that impair oral hygiene, leading to endogenous microbiota alte ration (dysbiosis) and overgrowth of periodontopathogenic bacteria, or any of the typical members of the oral microbiota such as Candida species; for example, oral pseudomembra nous or erythematous candidiasis have been described ^23-24.

Severe caries or periodontal diseases sequelae are more se rious in those patients who overcome COVID-19²⁵. This pro blem has local implications in the mouth and wider systemic consequences due to the dissemination of infectious agents to the lower airways, complicating pneumonia, and contribu ting to the elevation of systemic markers, such as C-reactive protein and pro-inflammatory cytokines^26-28. Therefore, stu dies investigating possible two-way relationships between this local inflammatory process and COVID-19 are warranted.

The systematic review²⁹ about oral manifestations of SARS-CoV-2 infection on 10.228 patients, found a prevalence of 45% for taste alterations. The most frequent was dysgeu sia (38%), followed by hypogeusia (35%) and ageusia (24%) showing a positive association (OR=12.68), mainly with mild and moderate forms of COVID 19 disease. These symptoms could be due to direct infection of taste bud cells, although nerve alteration(s) should not be ruled out, such as those described for anosmia during COVID-19.

Other reported symptoms include burning mouth sensation and xerostomia (subjective manifestations of oral dryness). These manifestations could be attributed to a decrease in salivary secretion and indirectly to salivary gland ducts and acini infection; however, more evidence is required²⁹. On the other hand, in severe hospitalized patients the lack of oral food intake and lack of hygiene can decrease salivary secre tion stimuli contributing to additional manifestations.

Vascular lesions have, to a lesser extent, also been reported. These can appear as spots or nodules with dark red or pur ple coloration mainly on the palate. Endothelial injury and coagulation disorders with severe consequences have been well described in COVID-19³⁰. Endothelial cells express ACE2 and are susceptible to SARS-CoV-2 infection, thus leading to cell dysfunction, apoptosis, and perivascular inflammatory responses. Therefore, endothelial alterations may explain the appearance of vascular lesions in the oral cavity³¹.

Table 1 shows a summary of the main primary and secondary manifestations of SARS-CoV-2 infection in the oral cavity.

Table 1 Oral Primary and Secondary Manifestations of SARS-CoV-2 infection.