Oral manifestations of COVID-19 in unvaccinated patients: a cross-sectional study

The term “oral manifestations” has not yet been conclusively associated with pathognomonic features of COVID-19. Sarasati et al. [16]. found inconsistencies and the absence of pathognomonic features in previous studies on oral lesions in COVID-19 patients. Soares et al. [17]. suggest a potential causality due to angiotensin-converting enzyme 2 (ACE-2) in oral epithelial tissue. ACE-2 is suspected to serve as the initial receptor for developing oral lesions in SARS-CoV-2-infected patients. With ACE2 expression, oral tissues could facilitate direct SARS-CoV-2 invasion, contributing to its pathogenesis and potentially enhancing human-to-human transmission rates [6, 16]. Limongelli et al. [18]. present evidence that SARS-CoV-2 may persist in the oral epithelium/mucosa beyond the acute phase, potentially leading to lesions. However, the underlying pathogenetic mechanism requires further clarification. This disparity raises questions about whether these oral lesions directly result from SARS-CoV-2 (with identifiable specific cause and effect or pathognomonic features) or are merely coincidental.

In this study, xerostomia and dysgeusia/ageusia were the most frequent oral manifestations in symptomatic participants regardless of the molecular confirmation of COVID-19. These results were similar to those of another study conducted with 128 nonhospitalized patients with COVID-19 confirmed by rRT-PCR, where 56% of patients reported xerostomia as the most frequent oral manifestation, followed by gustatory dysfunction (32.8%) [19].

Gingivitis and halitosis were more frequent in the rRT-PCR-positive group than in the rRT-PCR-negative group. Both oral findings could be associated with a lack of oral hygiene, stress, or immunosuppression, which might be some of the most important predisposing factors for the onset of oral lesions in COVID-19 [12]. Gingivitis is a mild periodontal disease characterized by inflammation of the gums and is mainly caused by poor oral hygiene [20]. Periodontal disease is caused by poor oral hygiene, which results in bacteria in dental plaque. The presence of these bacteria causes a local inflammatory reaction and the emergence of neutrophils and other inflammation-promoting cells that receive the mediation of proinflammatory cytokines [21].

Furthermore, evidence suggests that the worsening of SARS-CoV-2 infection in the lung region may be caused by the aspiration of periodontal pathogens, increasing the secretion of inflammatory cytokines such as IL-6 [22]. Our findings are consistent with those reported by Manzalawi et al. [23]., who also observed gingivitis in patients with COVID-19. This association suggests that the debilitating effects of COVID-19 may lead to a neglect of proper oral hygiene measures, contributing to the development of gingivitis. Gingivitis in COVID-19 patients highlights the importance of promoting oral health awareness and emphasizing the significance of maintaining good oral hygiene practices, especially during illness and vulnerability.

In the symptomatic rRT-PCR-negative group, mouth ulcers were self-reported in 12 participants (14.6%) but observed in only three participants (3.7%) during the oral examination. In contrast, only five participants (10.0%) reported mouth ulcers in the rRT-PCR-positive group, with none presenting with such lesions during the clinical oral examination. According to a Spanish study [11], vesicular eruptions (1.6%) were observed in a minority of patients and appeared within the first few days of illness onset. This finding may suggest that vesicular eruptions in the Spanish study and mouth ulcers in our study could be more frequent in the early prodromal phase of the disease.

Glossitis was observed in both groups in our study, with similar relative frequencies. A Spanish study of 666 hospitalized COVID-19 patients presented several oral cavity findings, including transient lingual papillitis (11.5%), aphthous stomatitis (6.9%), and glossitis with lateral indentations (6.6%) [11]. They suggested that these alterations could also be due to specific procedures in hospitalized patients, including wearing ventilation masks. The present study did not observe papillitis; however, isolated glossitis and glossitis with lateral indentations were associated with tongue coating.

Glossitis with lateral indentations (teeth marks on the sides) was described as tongue depapillation with bilateral atrophy of the tongue’s surface in the lateral sides, recently coined “COVID tongue”. Both oral manifestations are related to a particular state of immunosuppression, and stress may play an essential role in the appearance of these oral conditions [12, 24].

Tongue coating (yellow color) was found in four participants (7.4%) in the rRT-PCR-positive group and only two participants (2.4%) in the symptomatic negative group, with no statistically significant difference between the groups. In addition, tongue coating and glossitis with indentations appeared together in some patients and were observed in both groups. According to a retrospective cross-sectional study of tongue features in 1043 patients with COVID-19 [25], with disease progression, the proportion of critically ill patients with yellow tongue coating increased to 62.5%. The authors agreed that fever and infection might cause it to turn yellow. Furthermore, the degree of yellow coating was positively correlated with the degree of lung infection and disease severity. In addition, tongue color change could be attributed to difficulties complying with meticulous oral hygiene measures as the severity of the disease increases and deteriorates [26].

Petechiae were found in the rRT-PCR-positive group (n = 4; 7.4%) and the symptomatic negative group (n = 3; 3.7%). These findings are consistent with previous studies that reported petechiae on the palate, lower lip, and oropharyngeal mucosa during COVID-19 [27, 28]. These authors suggested that oral lesions were associated with COVID-19. In our study, petechiae were found in the soft palate of seven patients. However, the direct effect of SARS-COV-2 on these lesions remains uncertain because conditions other than viral infection, such as adverse drug reactions, may be related to these findings [27].

The findings of oral manifestations in both groups were relatively similar, although it was not possible to detect SARS-CoV-2 using rRT-PCR in all participants. Recent studies suggest that rRT-PCR for SARS-CoV-2 detection should be performed between the third and seventh days of symptom onset to reduce false negative results [29]. Although the participants in our study underwent the rRT-PCR test an average of 4.68 days after the onset of signs and symptoms, the range was from one to 16 days, leading to potential false negative results. Another explanation for false-negative results is the sensitivity (86%) and specificity (96%) of the PCR test used for diagnosis. Therefore, a second sample collection is recommended when the first evaluation is negative to improve the probability of confirming the diagnosis using this molecular technique [30].

Our study has limitations that cannot be generalized to all COVID-19 patients. First, we evaluated only patients with mild-to-moderate disease and not hospitalized patients with more severe forms of COVID-19. Second, we did not analyze the use of medications to treat preexisting diseases, which may have influenced tongue findings and xerostomia. Third, as previously discussed, a second sample was only systematically collected from some symptomatic patients with negative rRT-PCR results.

COVID-19 has a high infectivity rate, mainly because of its spread through respiratory droplets. In addition to studying the role of saliva in the transmission of the virus and as an alternative fluid for diagnosis, one must carefully ensure the identification of saliva quality and the presence of xerostomia. A thorough oral clinical examination can indicate the presence of oral manifestations related to COVID-19 and thus establish immediate measures to reduce the transmission and pathogenicity of SARS-CoV-2.