How to deal with coronavirus disease 2019: A comprehensive narrative review about oral involvement of the disease

Abstract Objectives The aim of this narrative review was to collect all findings from literature about oral signs and symptoms of COVID‐19, in order to draw a picture of oral involvement of this challenging viral infection, to help oral professionals in a better triage and early diagnosis. Material and methods The search for international literature was made including articles written in English and reporting about oral manifestations in patients with a diagnosis of COVID‐19. The publication time was limited to 2019 and 2020, up to May 20, 2020. A narrative review was performed. Results Twenty‐three articles were included in this review. Three different oral manifestations were found: taste alteration, oral blister and ulcers, and oral lesions associated with Kawasaki‐like diseases (erythema, bleeding of lips, “strawberry tongue”). The higher expression of Angiotensin‐converting enzyme 2 in the oral cavity and in endothelial cells might be responsible for oral manifestation and the major report of signs and symptoms in the occidental countries. Conclusions Detecting oral signs and symptoms of COVID‐19 could be useful to perform a better preliminary triage in dental setting, and in recognizing possible early manifestations of the disease. However, considering the outbreak of COVID‐19 and the consequent difficulty of undergoing oral examinations, the oral manifestations might be misdiagnosed; then, we would encourage oral professionals to perform other studies about this topic.

This disease had high virulence with the human-to-human transmission, with an incubation period ranged from 2 to 14 days (Jiang et al., 2020).
Lung appears to be the target organ and common clinical features of this virus infection were fever, respiratory involvement, dry cough and diarrhea (Jiang et al., 2020). However, the exponential diffusion of the COVID-19 infection around the world showed some new clinical signs of the disease (e.g., cutaneous [Tang et al., 2020], gastrointestinal [Lee, Huo, & Huang, 2020] manifestations). It was reported that atypical manifestations could be in some cases the first and/or the only manifestations of this disease (Daruich, Martin, & Bremond-Gignac, 2020;Wang, Wang, Chen, Tao, & Zeng, 2020); therefore, in this context, all specialists can contribute to early diagnosis, then to control outbreaks, identifying early signs and symptoms of  to speed-up self-isolation procedures.
Rapid detection of COVID-19 is crucial to control outbreaks: only by means of an early identification of manifestations and consequent early diagnosis, it is possible an effective and rapid isolation of cases and the appropriate contact tracing.
Indeed, the literature reported that case isolation was more effective when the delay from symptom onset to isolation was short (Hellewell et al., 2020).
The aim of this brief narrative review was to outline the oral signs and symptoms observed in patients diagnosed with  reported in the literature, in order and to better profile the role of oral professionals and what they may have to know. Other studies and reports about this topic are surely required.

| METHODS
Two of the authors (CG, NR) independently performed a literature search on PUBMED and PMC. At the beginning, the following search strategy was uploaded, combining free words and MESH terms: (oral manifestation) AND (COVID19 OR Coronavirus Disease 2019 OR SARS-CoV-2). Therewith, in this literature research, studies describing cutaneous manifestation were included, because these are often associated with oral manifestations, as described for some disease (Capocasale et al., 2017;Zotti et al., 2020), and therefore reported by dermatologists.
Considering the timing of the spread of the disease, the publication time was limited to 2019 and 2020, up to May 20, 2020. We had included all types of studies regarding the oral manifestations observed in patients diagnosed with COVID-19, only literature reviews were excluded. Other exclusion criteria were: articles for which full text was not available, articles were not in English or were grey literature.
Duplicate articles were eliminated and the first evaluation was performed reading only the title and abstract of the studies. Later, all studies considered eligible were included for full-text evaluation and only studies considered eligible by both authors were included in the review.
From those retrieved during the search, additional references were identified by a manual search among the cited references.

| RESULTS
From the first search resulted in 515 works, 508 resulted after checking of duplicates. By searching in references resulted, 17 were retrieved. Finally, according to inclusion and exclusion criteria, 23 were included for the narrative review. The literature selection process was reported in the diagram (Table 1).
Results were synthesized in Table 2: name of the first author and year, country of the diagnosed cases, oral sign or symptom reported, sample size, patients' age, gender and studies design were inserted. In addition, crucial information found in these studies were also presented. Given that the studies were published between December 2019 and May 20, 2020, results were set in the table in alphabetical order, by the surnames of the first authors, and divided considering the oral signs or symptoms described.
In the sections below, oral manifestations observed were described.

| Taste alteration
A pool of 5,399 patients diagnosed with COVID-19 resulted from studies selected, from those 1,581 subjects (29.28%) reported taste alteration as a symptom.
Taste alteration was found to be the most reported and thus described oral manifestation during the COVID-19 with a range of prevalence between 5.6% (Mao et al., 2020) and 92.64% (Bénézit et al., 2020). Studies analyzed outlined a varied picture of taste alterations, such as ageusia, hypogeusia and dysgeusia. Also, Jang et al. (2020) brought to the attention of scientific community a case of a 42-year-old male who reported both loss of taste and smell and but also having a metallic taste. He was only this manifestation of the disease, and he screened for COVID-19 only because he reported to had proximity with a COVID-19 positive subject. Paderno et al. (2020) reported that in 11% of cases patients mentioned the taste alteration as the first symptom of COVID-19 infection occurred, whereas other authors even described taste alteration as the only one symptom detected of this infection (Hjelmesaeth & Skaare, 2020;Jang et al., 2020;Villalba et al., 2020).

| Kawasaki-like disease
One of the issues of interest during the COVID outbreak was found to be the potential association between Kawasaki disease (KD) and the Coronavirus infection.
An Italian observational study by Verdoni et al. (2020) showed that, during the COVID-19 outbreak, KD had a monthly incidence at least 30 times higher than the monthly incidence of the previous

| DISCUSSION
A wide spectrum of signs and symptoms were reported in association with novel COVID-19, however, few studies highlighted oral clinical manifestations observed in patients diagnosed with this disease.
One of the most described oral symptoms was the taste alteration; indeed, a recent review of literature noted the 43.93% (95% CI, 20.46-68.95%) prevalence of gustatory dysfunction (Tong, Wong, Zhu, Fastenberg, & Tham, 2020). In this work, prevalence was reported ranged between 5.6% (Mao et al., 2020) and 92.64% (Bénézit et al., 2020), and in some case taste alteration was the first symptom However, these results deserve to be more carefully evaluated due to some critical issues, considering that this is a very subjective symptom and it is difficult to diagnose. Primarily, it should be considered that several studies documented symptoms based on selfreported and it could lead to an underestimation of them. Among all studies selected in our review, only the work by Lechien et al. (2020) assessed taste alteration using a validated questionnaire, the taste and smell disorders component of the National Health and Nutrition Examination Survey (NHANES). However, Vaira, Salzano, Deiana, and De Riu (2020) tested these alterations by means of different solutions (sweet, salted, acid and sour solutions) and they scored results. These three studies were found to be similar in terms of incidence of taste alteration, indicating values of 88.8, 73.6 and 51.5% respectively.
Other studies that assessed this symptom based on self-reporting resulted in a lower percentage of incidence (Wee et al., 2020).
In detail, Vaira supported this finding with three different studies assessing the taste alteration of COVID-19 patients. In the first (Vaira, Salzano, Fois, Piombino, & De Riu, 2020), the symptom was tested using self-reporting and the incidence was found to be of 19.4%, in the others (Vaira, Salzano, Petrocelli, et al., 2020) a test was used and the incidence was reported to be 73.6 and 51.5%.
With regard to the association between age and reported taste alteration, clarification is a duty. It is well known how altered taste perception is related with age and, in details, this association could be due to a decrease in saliva, drugs assumption, diabetes, malnutrition, neurological and oral mucosa disorders (Doty, 2018), all affections often associated with advanced age. This could lead to believe that the elders did not recognize the symptom during COVID-19 infection.
Furthermore, the resulted correlation between female gender and taste alteration could be explained by the gender difference in terms of inflammatory reactions (Lechien et al., 2020), highly expressed in females or, more simply, by the physiological influence of hormones in taste perception (Di Fede, Majorana, Manfredi, Pentenero, & Giuliani, 2014).
Several authors of studies selected reported positive associations between COVID-19 infection and smell and taste disorders (Bénézit et al., 2020;Lechien et al., 2020). However, some of them did not differentiate between the two symptoms (Beltrán-Corbellini et al., 2020; Lee, Min, et al., 2020;Roland et al., 2020), therefore data about taste could be underestimated (Tong et al., 2020). Most authors indicate the presence of these symptoms in absence of rhinitis or nasal obstruction (Tong et al., 2020;Vaira, Salzano, Petrocelli, et al., 2020), leading to hypothesize a direct action of the virus in determining this symptom.
According to some scholars, a possible cause of taste alteration could be the presence in oral mucosa of ACE2 receptors, identified as the cellular receptors for SARS CoV-2.
In detail, a work by  noticed the higher expression of ACE2 on tongue compared to other sites of oral mucosa. This could explain the findings reported and gives the reason for the independence of this particular symptom from smell alterations. Furthermore, ACE2 expression in epithelial cell of salivary glands, highlighted by (Xu, Li, Gan, Du, & Yao, 2020), is even higher than in the lung cells, indicating that salivary glands might be a potential target for COVID-19. The glands and their ducts may be further damaged and therefore a healing process of healing acted by fibroblasts with a fibrous connective tissue formation may follow. This mechanism, according to  could be the basis of early manifestations of COVID-19 such as acute sialadenitis accompanied by pain and tumor in parotid and submandibular glands. This process could be followed by chronic sialadenitis due to a decrease in the secretion of saliva responsible for potential infections and stones in salivary ducts.
These changes in secretion of saliva deserve to be taken into account during the early diagnosis process, they could be responsible for taste alteration and oral complication due to hyposcialia (e.g., oral candidiasis, burning mouth [Campisi et al., 2008]).
In addition, in several studies reporting cutaneous changes, information about the location of lesions was not provided (Tang et al., 2020). Likewise, Erythema multiforme was largely reported in the literature in association with viral infections, for example, Adenoviruses, Enteroviruses, Herpes Viruses, with an occurrence of oral manifestations in 70% of cases, especially represented by blisters and ulcers located on lips or non-keratinized mucosa (Scully & Bagan, 2008).
Considering these findings, it is possible that this virus provokes exanthematous lesions as other viral processes that we are used to diagnose in the dental practice. There are some limitations to this review, due to the design of the studies included, that were case reports/series, or cross-sectional or retrospective studies, therefore their scientific contribution could seem limited. This is an issue considered by authors, however, the current socio-economic and medical matters required to deeply investigate and discover as much as possible about this severe infection: with this in mind, also weak studies were included in the review.
To conclude, we observed that oral signs and symptoms of COVID-19 are not frequently recognized and reported by patients, together with the fact that they could be non-specific of this disease.
In this context, differential diagnosis with other chronic conditions is advisable, always deeply defining a correct and complete anamnesis of the patient.
In this regard, it could be actually useful that oral professionals evaluate and categorize all oral involvements of Coronavirus infection: this important action would allow to not underestimate and misdiagnose oral sign and symptom. With these findings in mind, we suggest that all specialists involved in oral health, especially dentists and dermatologists, could perform the oral examination in patients suspected or affected by SARS-CoV-2.
Furthermore, it is important to report the presence of any oral manifestations, especially until little is known. Indeed, the knowledge of oral signs and symptoms could be important in the dental setting for performing a more accurate triage of patients and for early diagnosis. For example, dental practitioners should include "recent onset of taste disturbance" or "oral ulcers" as questions of routinely anamnestic questionnaire and filtering out those who are at higher risk from attending primary healthcare environment.
The oral professionals must be conscious of COVID-19 (Bizzoca, Campisi, & Muzio, 2020) and their valuable role in controlling outbreaks. Health care professionals, indeed, could apply up-date triage before dental procedures and clinically identify early oral signs and symptoms of COVID-19, they also refer the patients for further investigation to speed-up self-isolation procedures.

ACKNOWLEDGMENTS
No financial support available for this study.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.