Oral manifestations detected in COVID-19 patients: an integrative review

The aim of this integrative review consisted of verifying whether the oral manifestations detected in patients diagnosed with COVID-19 are useful in diagnosing the disease, whether they are a manifestation resulting from the disease, or whether there is evidence that there is no correlation between the pathologies. Therefore, articles in the PubMed, Lilacs, Scopus, Science Direct, Web of Science and Embase databases were searched, in addition to the search in gray literature. The terms used in the search were: “COVID-19” or “Sars-Cov-2” or “coronavirus” and “oral conditions” or “oral health” or “oral manifestations” and “diagnosis/complications” or “symptoms”. Thus, 1.305 articles were selected, of which 61 were selected to compose this review. Most of the included studies considered oral symptoms as taste changes, xerostomia and ulcerative lesions in the oral and labial mucosa. All symptoms related to this pathology still need further studies and investigations so that all mechanisms and manifestations related to it are completely elucidated.


Introduction
On March 11, 2020, Coronavirus Disease (COVID-19) was declared a pandemic situation by the World Health Organization (WHO) (Osseni, 2020). It is a disease caused by SARs-CoV-2, discovered in 2019 in China with the occurrence of the first cases of the disease. It has had a fast progression throughout the years 2020 and 2021 with more than 203 million infected people around the world, spread over 215 countries . On August 2021, the main countries affected is: the United States of America (35.824.366 confirmed cases), India (240.842 confirmed cases), Brazil (20.177.757 confirmed cases) and the Russian Federation (11.012 confirmed cases) (WHO, 2021). To date, the profile of viral action and pathogenesis has not been fully elucidated, but it is known that the main signs and symptoms manifest themselves in the form of acute respiratory conditions (Ali & Alharbi, 2020). However, new characteristics emerge from time to time, and the lack of complete knowledge of the disease's etiopathogenesis associated with its potential risk of death and high probability of contagion form the set that characterizes COVID-19 as perhaps the greatest health crisis of the current century (Alvi et al., 2020;Lai et al., 2020;Osseni, 2020).
The epidemiological profile so far is the prevalence of symptom onset in men, with a mean age of 56 years , with the onset of symptoms within 8 days (which may vary from 5 to 13) after contact with the virus (Guan et al., 2020), and increased risk of death associated with older adults over 80 years of age (Wilson et al., 2020). Several comorbidities are associated with an unfavorable prognosis for the course of the disease, the main ones being cardiovascular diseases, hypertension, diabetes, chronic inflammatory diseases and the abusive habit of smoking (Ejaz et al., 2020).
The predominant form of contagion is direct contact, which can also happen indirectly and through the air when contaminated by aerosols (Umakanthan et al., 2020). Most of the symptoms presented are nonspecific (such as fever, cough and myalgia), and the course of the disease can follow a mild to moderate route (with and without pneumonia), severe (presence of dyspnea and respiratory distress) or critical (failure respiratory and even multiple organ failure), with rapid evolution and in many cases unpredictable (Raoult et al., 2020).
Even though acute pneumonia and respiratory manifestations were the first sign of the disease's challenge , today other systemic manifestations are directly associated with COVID-19 (Lai et al., 2020;Wiersinga et al., 2020).
Cardiac, gastrointestinal, hepatic, renal, neurological, olfactory and taste, ocular, cutaneous, hematological and immunological conditions and/or sequelae are already mentioned (Lai et al., 2020;Yang et al., 2020). They are cited as uncommon occurrences, but not rare in patients who went through the hospitalization process, coagulopathies, thromboembolic accidents, heart disease, hemodynamic instability and encephalopathies (Hendren et al., 2020;Long et al., 2020;Mao et al., 2020;Middeldorp et al., 2020;Wiersinga et al., 2020). In this context, it is important to emphasize the systemic inflammatory favoritism, directly associated with COVID-19, in which pre-existing chronic inflammatory conditions find room for acute and more intense manifestations, as well as the manifestation of more severe forms of COVID-19 itself .
In addition to systemic manifestations, some oral manifestations have also been reported .
Not restricted only to olfactory disorders and taste disorders, already directly associated with COVID-19, others involving oral mucosa, glossitis and gingival inflammation are reported, mainly in hospitalized patients (Amorim dos .
However, despite the reports, there is still no clinical consensus on which mechanisms are responsible for the manifestations, whether they are causes directly linked to the course of COVID-19 or events secondary to it, and even whether they can serve as a form of diagnosis (Iranmanesh et al., 2021a). The presence of bullous lesions, ulcerations, erosions, plaques and macules was noticed in different regions of the mucosa and under different clinical presentations (Amorim dos  such as transient lingual papillitis, mucositis, glossitis, aphthous stomatitis, burning sensation in the mouth, among others (Iranmanesh et al., 2021a;Nuno-Gonzalez et al., 2021;. Due to the existence of gaps in the literature regarding the understanding of this relationship between COVID-19 and oral health, and regarding the role of the dentist in monitoring these manifestations and the clinical evolution of patients, this review finds space and justification for its realization.
To assess, through an integrative literature review, whether the oral manifestations detected in patients diagnosed with COVID-19 are useful in the diagnosis of the disease, whether they are a manifestation resulting from the disease, or whether there are signs of no correlation between the pathologies.

Study design and eligibility criteria
This is an integrative review, carried out in accordance with the PRISMA checklist (Page et al., 2021), and registered within PROSPERO (CRD42021253256). The review guiding question is "Is COVID-19 cause or consequence of changes in the pattern of oral health?", and based on that, the PICO strategy is specified in Table 1, with the eligibility criteria. The inclusion criteria were defined via the PICO strategy and consisted of randomized control trials (RCTs), observational cohort studies (prospective or retrospective), literature reviews (narrative, integrative or systematic), clinical reports, case-control studies, or case series that included adult participants with COVID-19 infection and oral manifestations were included. There was no language restriction, and the papers that could not be accessed in the full-text version were excluded. Therefore, the literature search was conducted using a single search engine through PubMed, Lilacs, Scopus, Science Direct, Web of Science, and Embase databases. An additional search in the gray literature was performed, including Google Scholar. The search included all articles published until March 24, 2021, across all databases. To identify eligible articles, using the Medical subject headings (MeSH) "COVID-19" or "Sars-Cov-2" or "coronavirus" and "oral conditions" or "oral health" or "oral manifestations" and "diagnosis/complications" or "symptoms", using Boolean operators. The publication time was limited to 2019 onward, to assess the pandemic time course.
A free-web tool for review management (Rayyan QCRI®) (Ouzzani et al., 2016) was used to collect references and remove duplicate articles. The same search strategies will be run on every update.

Domain
Inclusion criteria Exclusion criteria

Interventions
Intraoral exam and test or clinical evaluation to assess the confirmation for SARS-CoV-2 presence and/or the COVID-19.
Non-realization of intraoral exam, absence of test or clinical evaluation to diagnose the COVID-19.
Research, Society andDevelopment, v. 10, n. 14, e594101422516, 2021 (CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i14.22516 4 Initially, broad screening was conducted according to the title and abstracts under the use of the tool Rayyan (Ouzzani et al., 2016). In the end, all potentially included articles were retrieved for a full assessment and those that could be accessed were reviewed in full length to be verified if they were answering the eligibility criteria. Translation of included papers from Chinese to English was conducted with the use of Google Chrome's built-in translation tool.

Data Extraction
Two reviewers (XX and XX) separately assessed the potentially included papers to verify eligibility. Discrepancies were resolved by a third reviewer (XX). Those three reviewers were supported by a fourth (XX) to accomplish the data extraction.
The main information to be extracted was related to the clinical conditions of the COVID-19 course, and any oral manifestations reported (ulceration, erosion, plaque, macules, bullous lesions, dysgeusia, mucositis, glossitis, burning mouth sensation, and others). This data extraction was based on information about the incidence and prevalence of oral manifestations detected on patients confirmed for COVID-19, in a way that all percentages and samples sizes, clinical states reported, the severity of the disease, moment of evaluation, and other relevant clinical data was also important to be summarized. All data extracted from the papers were tabulated on a unique sheet on Google Docs, simultaneously fed by the reviewers, seeking out the favoring of the qualitative synthesis.

Results
The literature search resulted in 1305 hits. After the removal of the duplicates, broad screening by title and abstract, retrieval of those selected for appraisal and critical evaluation by eligibility criteria in full-text version, and assessment in full length of them, 61 papers composed the sample of this review, for qualitative synthesis (Supplementary Table 1). The PRISMA flow diagram detailing the steps of identification, screening, and inclusion is available in Figure 1.

Discussion
More than 206.757 patients were considered in this review and there was a wide variation in the audience analyzed, probably due to the large variability of studies included, from case reports (Amorim Dos Santos et al., 2021;Amorim dos Santos et al., 2020a;Cebeci Kahraman, Özen, et al., 2020;Cherif et al., 2020;Chern et al., 2020;Cirillo et al., 2021b;Cruz Tapia et al., 2020;Eghbali Zarch & Hosseinzadeh, 2021b;Kitakawa et al., 2020b;Moreira et al., 2020b;Ramires et al., 2021) to clinical studies (Karadas et al., 2020;Marouf et al., 2021). There were no restrictions regarding the gender investigated by the studies, nor were there any discrepancies regarding this information to the course of the disease, clinical manifestations or even the severity of the outcome found. Age was also a factor considered in some investigations, although it did not interfere in the course of COVID either (Bao et al., 2020;Cebeci Kahraman, Özen, et al., 2020;Cirillo et al., 2021b;Coke et al., 2021b;Larvin et al., 2020b).
The aim and conduct of each study also varied a lot, which diversifies the findings and how each one was carried out.
Furthermore, the manifestations of infection in skeletal muscle can occur due to contamination of isolated muscle cells or due to the link between pro-inflammatory cytokines with ACE2 (Karadas et al., 2020;Pedrosa et al., 2020).
Another important finding in COVID-19 positive patients is xerostomia. It has been proved that salivary glands act as a reservoir of the virus, leading to contamination by saliva droplets and affecting salivary flow (Biadsee et al., 2020;. Even more, some included studies suggest that xerostomia has been associated with taste sensorial complaints, common in positive COVID-19 patients, not only by the role that saliva plays during chewing but also by the predilection of the virus for nervous tissues that affects gustatory papillae (Fantozzi et al., 2020;Karadas et al., 2020;Pedrosa et al., 2020). It's also well known how the low rate of saliva affects oral health and, because of it, how coronavirus might have influence, even temporarily, on oral affections and functions by the patient directly or indirectly (Coke et al., 2021a).
The presence of painful ulcerated or necrotic oral lesions is also described as a possible manifestation of coronavirus.
The location, size and characteristics of the lesions vary in the included studies, been reported aphthous-like ulcers in the upper and lower lip mucosa as well as the anterior dorsal tongue (Brandao et al., 2021;Chérif et al., 2020) and small hemorrhagic blisters and ulcerations affecting the upper and lower lips, as well as focal areas of shallow necrosis on the anterior dorsal tongue (Drago et al., 2021). Other studies also describe painful hemorrhagic ulcers along the upper and lower lips, leading to a thickcrusted hemorrhagic necrosis covering the lips entirely (Cebeci Kahraman, Ozen, et al., 2020;Coke et al., 2021a;Cruz Tapia et al., 2020;Fathi et al., 2021;Hockova et al., 2021;Karadas et al., 2020;Kitakawa et al., 2020a) (ST1). Therefore, these lesions should be considered during the patient's complaints and oral examination as a possible manifestation of COVID-19.
The scientific literature describes how periodontal disease, oral infections and the lack of oral hygiene can affect cases of intubated patients, inducing aspiration pneumonia (Marouf et al., 2021). Conversely, included studies in this review also reported gingival bleeding, necrotizing gingivitis and worsening of periodontal disease in positive COVID-19 patients (Brandini et al., 2021;Coke et al., 2021a;Drago et al., 2021;Eghbali Zarch & Hosseinzadeh, 2021a;Elibol, 2021;Larvin et al., 2020a;Maciel et al., 2020;Manzalawi et al., 2020;Marouf et al., 2021;Pitak-Arnnop et al., 2021). Although the interference mechanisms for COVID-19 in periodontal disease are not very sedimented yet, the occurrences might indicate a two-way path for these conditions to be explored in future studies where periodontitis can lead to aspiration pneumonia and the infection by COVID-19 can worst cases of gingivitis and periodontitis.
Minor reports and other oral conditions related to coronavirus were also reported in included studies of this review (ST1). In general, all reported oral manifestations and symptoms derived from COVID-19 are still under investigation by the international scientific community and future studies might show new interactions and mechanisms between the coronavirus and its influence in the stomatognathic system. Still there, the clinician needs to understand the possible manifestations of the disease to help in its diagnosis and treatment.
For the oral manifestations, most of the studies have not informed the therapy applied. It leads to the guesswork that they were not treated separately from the suggested therapy for COVID-19. However, some interesting reports were observed.
Two cases of phototherapy were reported: Ramires et al. (2021) have used photodynamic therapy for 2 days to treat crusted ulcers in the upper lip, that healed in 4 days; and Brandao et al. (2021) have used photobiomodulation associated with acyclovir daily, with complete resolution of aphthous-like ulcers in 11 days. Similarly, Cebeci Kahraman, Ozen, et al. (2020) has used Triticumvulgare extract, four times a day, with Subcutaneous low-molecular-weight heparin to treat hemorrhagic necrosis covering the lips, which was resolved in 10 days.
Most importantly, all suggested therapies were successful, with few exceptions. It highlights the efficiency of the suggested therapies and the high chances of spontaneous healing of COVID-19 and the associated oral manifestations. Just three studies have reported some non-fully recovered patients in the follow-up (Coke et al., 2021a;Marouf et al., 2021;Tanasa et al., 2020), and with a non-expressive n. Some of those reports of non-recovering were also related to committed patients, with one or more comorbidities (Coke et al., 2021a). Long-lasting or persistent symptoms were also reported: gingival hyperpigmentation (Eghbali Zarch & Hosseinzadeh, 2021a), olfactory and taste disorder (Tham et al., 2020), and burning mouth sensation (Cruz Tapia et al., 2020).

Conclusion
In conclusion, despite the large number of studies located in the literature on the subject, the diversity of methodologies, populations, objectives and approaches makes it difficult to conclude on it. However, it is well established that prevention is the best approach in these cases, when there is a failure in this objective, the early diagnosis is of great value for a better prognosis.
Thus, although it is still early to establish a direct relationship between oral manifestations and COVID-19, dental surgeons must recognize the symptoms related to this condition in their offices and make the appropriate referrals. Finally, more studies are needed to establish the link between COVID-19 and Dentistry in the future.