key: cord-0768387-4pv5i46x
authors: Santana, Lucas Alves da Mota; Vieira, Walbert de Andrade; Gonçalo, Rani Iani Costa; Lima dos Santos, Marcos Antônio; Takeshita, Wilton Mitsunari; Miguita, Lucyene
title: Oral mucosa lesions in confirmed and non-vaccinated cases for COVID-19: a systematic review
date: 2022-05-10
journal: J Stomatol Oral Maxillofac Surg
DOI: 10.1016/j.jormas.2022.05.005
sha: 0769ac3d38205214fb3952fc318ef3f1c96a354a
doc_id: 768387
cord_uid: 4pv5i46x

This systematic review purposed to investigate reports of oral lesions in confirmed COVID-19 patients summarizing clinical characteristics, histological findings, treatment and correlation of oral lesions and COVID-19 severity. Electronic search was conducted on November 2021 using seven databases to identify case reports/series describing lesions in oral mucosa in COVID-19 confirmed cases. A total of 5,179 studies were found, being 39 eligible from 19 countries, totalling 116 cases. It was observed only COVID-19 non-vaccinated cases and no sex or age predilection. The oral lesions presentation was mostly single location (69.8%), commonly in the tongue, lips, and palate, being ulcer the main clinical presentation. According to severity index for COVID-19, the reports were more frequent in patients with mild and moderate symptoms, being 75.8% in acute phase. The oral lesion appearance in post-acute COVID-19 were described after 14 to two months after patient recovery. Histologically, keratinocytes with perinuclear vacuolization, thrombosis and mononuclear inflammatory infiltrate were also described with the presence of the virus in keratinocytes, endothelial cells, and minor salivary glands. In conclusion, health care professionals should consider COVID-19 association when patient present ulcerated oral lesions and mild to moderate symptoms for COVID-19 or had acute-COVID-19.

The Coronavirus Disease-19 caused by SARS-CoV-2 virus, was firstly reported to WHO in 2019 New Year's Eve, as several cases of pneumonia of unknown cause in Wuhan City. The virus was identified on 7 th January 2020 by Chinese researchers and since than spread rapidly worldwide infecting more than 432 million individuals and causing 6.206 .609 deaths until 20 th April 2022 (https://arcg.is/0fHmTX).

Clinically, a variety of signs and symptoms are reported including oral lesions and oral disorders as dysgeusia (taste disorder) and dysphagia (difficulty swallowing). Since the first case series of oral lesion found in COVID-19 patients 1 , some cases were in patients based on COVID-19 symptoms and not confirmed by SARS-CoV-2 testing. Moreover, studies have demonstrated high correlation of loss of taste and COVID-19 2,3 , however, it is not yet clear whether oral lesions, are indeed related to SARS-CoV-2 infection 1,4 and its severity, or is associated with other factors. 5, 6 To better understand the relationship between COVID-19 infection and oral lesions, this study aimed to summarize the clinical characteristics, histological findings and the treatment of the oral lesions in SARS-CoV-2 positive patients and observe if there is any correlation with the severity of the COVID-19.

This systematic review was performed according to the guidelines of the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocol), 7, 8 , and registered in the PROSPERO (International prospective register of systematic reviews) platform under number CRD42020222737.

An electronic search was carried on November 21 st , 2021, using the Embase, LILACS, PubMed, SciELO, Scopus, LIVIVO and Web of Science databases. The following terms were used in the search strategies: "COVID-19", "SARS-COV-2", "2019 novel coronavirus disease", "2019-nCoV infection", "Oral Cavity", "Mouth", "Mucosal", "Lesion", "Infection", "Injuries", and "Injury". Boolean operators (AND and OR) were used to combine descriptors and improve the search strategy employing different combinations. The search strategies were adapted to each database respecting their rules of syntax (Supplementary File 1). A manual search was additionally performed on February 3 rd , 2022

Records were exported to the Mendeley software and to Rayyan QCRI software (Qatar Computing Research Institute, Doha, Qatar). Then 

Inclusion criteria was defined as case reports/series describing oral lesion in patients with positive results for COVID-19 by RT-PCR test and complete epidemiological data (participants' age, sex, COVID-19 severity, lesion location), reports presented as letters to the editor were also included. There were no limitations on publication year. Animal studies, in vitro studies, literature reviews, clinical trials, studies that were not case reports or case series, and case reports with different outcome or that did not present a confirmed COVID-19 test were excluded of present study. Only studies published in English language were considered.

The Joanna Briggs Institute (JBI) Critical Appraisal Tools for use in Systematic Reviews for case reports and for case series were used to assess the risk of bias and the individual quality of the studies selected. 10 Each question of the checklists could be answered as "yes", if the study did not present bias regarding the domain evaluated by the question; "no", if the study presented bias regarding the domain assessed by the question; "unclear", if the study did not provide sufficient information to evaluate the bias in the question; or "not applicable" if the question was not suitable for the study.

The risk of bias would be rated as high when the study reached up to 49% score "yes", moderate when it reached 50% to 69% score "yes", and low when it reached more than 70% score "yes".

All numerical data are presented as absolute values and percentage calculated using Microsoft Excel version 2202 (Microsoft). The

Pearson's chi-squared test was used to observe the association between COVID-19 severity and age or sex or oral lesion. P < 0.05 was considered statistically significant.

A total of 5,179 manuscripts were retrieved after the electronic databases search. There was 2596 duplicates and 2,533 references excluded in the first screening. Among full-text excluded studies, there were COVID-19 case reports or case series of oral lesions that did not report RT-PCR test for COVID-19 diagnosis or those describing confirmed COVID-19 cases that did not present oral lesions, remaining 27 articles for the assessment of the eligibility criteria. Another twelve records were identified through hand-searching, resulting in 39 eligible articles (Supplementary File 2). A flowchart depicting the selection process is provided in Figure 1 .

The majority of selected studies scored low risk of bias (33/39; 84.6%), while 12.8% (5/39) were moderate risk, and only one study shows high risk of bias (1/39; 2.6%).

The main shortcomings in the case reports studies were related to the insufficient description of the patients' clinical history and some case series studies presented scarce information about outcomes or follow up, and unclear reporting of the oral lesion site(s)/clinical aspects and demographic information. The risk of bias evaluation of all eligible articles is present in Supplementary File 3 and 4.

The selected articles comprise case reports (30/39; 76.9%) and case series (9/39;23.1%) published between April/2020 and October/2021, all of them written in English language. Studies were conducted in nineteen different countries from four continents, eighteen of them located in Europe, eleven in America, eight in Asia and two in Africa.

A total of 116 patients, between 6 and 83 years-old, with COVID-19 confirmed by RT-PCR test. There was no report about vaccinated patients for COVID-19. The proportion male/female investigated was of 1:1.1, with slight predilection for female sex (43/116; 53.4%). Most lesion occurred during acute phase of COVID-19 (88/116; 75.8%), while 28 reports were in post-acute COVID-19 cases, occurring at 14 to two months after the recovery of patient.

The most common comorbidities were diabetes and hypertension, and only 20.6% (24/116) of the cases had hospitalization history. All patients profile, medical history, COVID-19 symptomatology and severity, oral lesion characteristics and localization are presented in Table 1 . 

The selected studies presented a reduced number of COVID-19 patients with oral lesions that presented taste alterations (dysgeusia/ageusia, 12/116; 10.3%) or difficulty to swallowing (dysphasia, 5/116; 4.3%).

Regarding the clinical aspect of oral lesions ( Figure 2B ), ulcerative lesions (57/116; 49.1%) was the most frequent clinical presentation with varied sizes, being local or multiple, sometimes with haemorrhagic areas, crust and necrosis. Among ulcerative lesions (n=57), most of them there were no specific cause (44/57; 77.2 %), others were correlated with herps simplex virus (HSV) co-infection (5/57; 8.7%), [11] [12] [13] or Enterococcus faecalis and/or Pseudomonas aeruginosa bacteria (2/57; 3.5%) 14 or associated with fungi as candidiasis (6/57; 10.5%) [15] [16] [17] [18] and mucormycosis (23/116; 19.5%). [19] [20] [21] The other lesions reported were diffuse erythema diagnosed as mucositis (14/116; 12%); 6, 22 angina bullosa haemorrhagic-like and associated vascular disorder (5/116; 4.3%) 23 ; petechiae (2/116; 1.7%) 24,25 white plaque reported as candidiasis (5/116; 4.3%). 16, 17 Tumoral lesion (2/116; 1.7%) 26, 27 were also reported, being one case related to a Melkersson-Rosenthal syndrome 27 , which is characterized by recurrent orofacial edema, fissures in the tongue and peripheric facial paralysis and commissural fissures on lips.

The COVID-19 severity was evaluated according to the National Health Institute (NIH) clinical spectrum of SARS-CoV-2 infection criteria, (https://www.covid19treatmentguidelines.nih.gov/) with the majority of the patients presenting mild (43/116; 37.2%) and moderate (38/116; 32.7%) symptoms, followed by severe cases (33/116; 28.4%), one critical case (1/116; 0.8%) 15 , and one asymptomatic case (1/116; 0.8%). 18 The univariate analysis of the association between COVID-19 severity and age or sex presented no statistically significant difference (p=0.0954 and 0.5937, respectively), while ulcer occurrence presented significance (p=0.0002). (Table 2) 

Only eight studies investigated histological features in oral lesions using haematoxylin and eosin staining (H&E) and immunohistochemistry (IHC) techniques.

In general, the haematoxylin and eosin staining showed focal exocytosis and paranuclear keratinocytes vacuolization in epithelium. The lamina propria presents mononuclear inflammatory infiltrate, vascular thrombosis, and can present haemorrhagic and necrotic focal areas.

According to Soares et al. (2020) 28 The spike-protein immunoreactivity was used to identify SARS-CoV-2 virus in ulcerated tissues of the hard palate, tongue, buccal mucosa, and lips. Positive reaction for spike-protein was found in endothelial cells, keratinocytes, acinar and ductal cells of the minor salivary glands. 29 Serological technique was applied to investigate antibodies against Herpes Simplex Virus (HSV) type-1 and type-2 in small ulcers for differentiating the diagnostic. The authors had negative results for both HSV types and suggested that the ulcerative lesions can be potentially 

The oral lesions were treated with different pharmacological protocols: with 0.12% chlorhexidine mouthwash, steroidal antiinflammatories, antibiotics, Photobiomodulation therapy, antifungal, retroviral or herbal treatment. Specific details of treatment applied by each oral lesion are shown in Table 1 .

The COVID-19 is a complex disease, capable of causing a wide spectrum of severity classified as asymptomatic; mild, presenting fever, dry cough, anosmia, dysgeusia, and fatigue; moderate, when the patient starts to present hypoxia; severe illness when present oxygen saturation under 94%, dyspnoea; critical illness, respiratory failure, septic shock, and/or multiple organ dysfunction or failure, that can culminate in death. 32 Most of these severe/critical symptoms are more frequent in elderly individuals, males, and patients with obesity, cardiac and metabolic disorder, and chronic diseases and seems to be due to an immunopathological process that causes exceeded production of cytokines. 33 In the present study, the ulcer was the lesion more commonly reported and tongue the main anatomical area described by authors. Previous review 34 found a slight predisposition to the appearance of ulcers in patients with COVID-19, suggesting as a potential pathognomonic sign for early diagnosis of the disease.

According to the selected literature in our study, it was found a slight predominance of oral lesions in women, but no statistical significance. Some studies have demonstrated that is not possible to suggest any predictable profile for oral mucosa lesions occurrence in COVID-19 patients since both genders are equally affected. 4, 6 On the other hand, higher dysfunction of the gustatory system in female patients with COVID-19 were suggested to be related to an exacerbated hormonal modulation and immune innate response to viral infection in those patients. 35 Despite, the limitation of the study to find a greater number of reports describing confirmed cases of COVID-19 with complete information about patients' clinical aspect, and oral lesions details, it was possible to observe that most of the cases reported showed mild and moderate severity for COVID-19, and there was statistical significance in ulcer occurrence in those patients.

In general, it was observed a diversified clinical aspect of oral mucosal lesions in COVID-19 patients, such as vesicles, macules, plaques, blisters, erythema, petechia and ulcers. Interestingly, vascular alterations in oral cavity were also reported in COVID-19 patients. 23 Recent publications have supported the association of oral mucosa lesions related to COVID-19 with complications for thrombocytopenia, anticoagulant therapy, disseminated intravascular coagulation, and systemic inflammation. 22, 23, 29 Histopathological analysis have demonstrated that early oral lesions also present thrombosis of small and middle size vessels was always noticed with necrosis of superficial tissues. 36 These features are not exclusive to oral cavity, several studies demonstrates the predispose of COVID-19 patients to develop hematologic diseases that may result in thrombosis, especially, as consequence of vasculitis. 37, 38 Considering the period of oral lesions appearance, most cases reported their occurrence in COVID-19 patients during acute phase. On the other hand, fewer cases occurred during post-acute COVID-19 infection. 21, 30, 31 There still little evidence about the real cause of these oral lesions related to post-acute COVID-19. Ulceration 21,30 , erosion and a verrucous leucoplakia 31 were described, and authors suggested as a probable hypothesis the SARS-CoV-2 capacity in leading to reactivation of viruses like the herpes virus' family. 30, 31 Despite evidence about the presence of SARS-CoV-2 in oral tissue 29 , more studies are still needed to understand the pathogenesis of oral lesions related to COVID-19 and secondary causes cannot be excluded.

The oral health can also interfere in patients' recovery and COVID-19 severity. It was observed in a cross-sectional study observing protein C-reactive (PCR) levels in COVID-19 patients, their oral health and disease evolution. 39 They observed that the fast recovery period was present in 82% of the patients with good oral health and high PCR levels were related to poor oral health and severe cases, respectively. 39 Therefore, critical attention should be given to providing efficient oral hygiene to ill COVID-19 patients, especially in severe cases.

Interestingly, to date, although more than 10 billion doses of vaccine have been already administered around the world, (https://arcg.is/0fHmTX) we could not find any reports of oral lesions in patients infected with SARS-CoV-2 after receiving the vaccination.

Curiously, evidence about oral lesions as side effects after vaccination already exists 40 and are similar to the oral findings' characteristics in infected patients with SARS-CoV-2. The most prevalent oral side effect are vesicles, bleeding gingiva, halitosis, oral paraesthesia, swollen mucosa, and ulcers, emerging within the first week after vaccination in more than 75% of the cases 40 , similarly to the frequency of oral findings in acute-COVID-19 presented in our study.

In conclusion, COVID-19 patients seem to present more frequently oral ulcerations in mild and moderate illnesses, independent of age or sex. A detail oral examination is recommended in suspected and diagnosed cases of COVID-19 patients. The multidisciplinary approach in which dental health care professionals should be aware of infectious and vascular diseases associated with COVID-19 is for the better of patients' premature diagnostic and prognostic. 

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We would like to acknowledge the Coordination for the Improvement of Higher Education Personnel (CAPES) for fellow support L.M.[grant number 88882.315591/2019-01].

All authors declare there is no financial interest to report, confirming that there is no potential conflict of interest.

Patient permission/consent not applicable.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.