key: cord-0821357-pb6r098o
authors: Reis, Vanessa Paiva; Bezerra, Adriana Raymundo; Maia, Adriane Batista Pires; Marques, Letícia Côgo; Conde, Danielle Castex
title: An integrative review of oral manifestations in patients with COVID‐19: signs directly related to SARS‐CoV‐2 infection or secondary findings?
date: 2021-09-19
journal: Int J Dermatol
DOI: 10.1111/ijd.15881
sha: 68a1a1d1d65db60db83b99bb1de38d331d5a7bc9
doc_id: 821357
cord_uid: pb6r098o

We conducted an integrative review on oral manifestations in patients with COVID‐19 based on the current available literature evidence. A bibliographic search was carried out on March 11, 2021, among published studies in the years 2019–2021 in the PubMed database and based on the search strategy (“COVID‐19” AND “oral lesions” OR “oral mucositis” OR “oral manifestation”). After applying the inclusion and exclusion criteria, 29 articles were considered suitable for this review. A total of 110 cases of patients with COVID‐19 who had oral manifestations were reported. The presence of ulcerated lesions was the most common finding, having a herpetiform and aphthous clinical pattern observed in most cases. Macules, petechiae, hemorrhagic blisters, pustular enanthem, mucositis, and halitosis were also among the most frequently described oral manifestations. The tongue was the most commonly affected site, followed by the palate and lip. Most of the reported cases were diagnosed only by the clinical aspect of the lesion associated with a positive SARS‐CoV‐2 test or the presence of other COVID‐19 symptoms. Current scientific evidence still could not affirm that most of the oral lesions observed in patients with COVID‐19 are related to the virus's direct or indirect action on the oral mucosa. To confirm this association, prospective and longitudinal studies are further needed, together with a larger number of patients, complemented by histopathological examination of these lesions. Additionally, molecular techniques, such as immunohistochemistry and in situ hybridization, may be necessary to perform the differential diagnosis with other oral lesions.

Introduction headache, anosmia, taste disorders, sore throat, nasal congestion, nausea, vomiting, and diarrhea. 1 As the COVID-19 pandemic progresses, knowledge about the disease also evolves with the availability of new scientific evidence. Several reports of dermatological changes in patients with COVID-19 have been published, including symptoms such as erythematous rash, urticaria, vesicles, petechiae, and livedo reticularis. [2] [3] [4] [5] Changes in the oral mucosa have also been highlighted in some studies, although it is still impossible to be sure that the virus induces them.

The entry of the SARS-CoV-2 virus into the host cell, enabling infection, occurs through the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein that functions as a virus receptor. This protein is expressed in high concentrations in the lungs, esophagus, ileum and colon, cholangiocytes, myocardial cells, renal tubular cells, and the bladder urothelial cells. 27 The presence of the virus is also found in oral cavity epithelium, with high expression in tongue and salivary glands duct epithelium. 28 Thus, these previous findings indicate that oral cavity may be a target for the SARS-CoV-2. 6, 27 The distribution and expression of ACE2 in the oral cavity explain findings such as the presence of virus in the saliva of infected patients, 29 since contaminated salivary glands can act as a reservoir for eliminating the virus in saliva and also the high incidence of gustatory impairment since taste buds are mostly concentrated on the dorsal tongue surface. 30 A recent systematic review showed that almost half of patients with COVID-19 (i.e., 49.8%) had presented taste disorders. 31 This integrative review was designed to analyze current evidence pertaining to oral manifestations in patients with COVID- 19 and pointing to some gaps in knowledge that still need to be filled with new studies about the disease.

The question that moved the study carried out in this integrative review was: are there any other oral manifestations besides the taste disorders associated with COVID-19? The methodology for the integrative review followed the phases: (i) establishment of the research question; (ii) search of relevant studies; (iii) selection of studies based on pre-established inclusion criteria; (iv) data analysis and preparation; and (v) summary and communication of information. 32 The search was carried out on March 11, 2021 , in the PubMed database. The search strategy employed included:

("COVID-19" AND "oral lesions" OR "oral mucositis" OR "oral manifestation"). Publications from 2019 to 2021 were retrieved, and no geographical restriction was imposed. The search was carried out based on the title, abstract, and keywords. The documents were then included or excluded according to the following criteria: (i) inclusion: publications that presented reports of oral manifestations, in addition to taste disorders, in suspected or confirmed cases of COVID-19. (ii) exclusion: studies that exclusively discussed cases reported by other authors, publications that only addressed issues related to the treatment, diagnosis, or prognosis of COVID-19, and publications not available in English, Portuguese, or Spanish.

Based on the adopted search strategy, 266 studies were identified. Of these studies, 34 were excluded as they were found duplicated. The remaining 232 articles had their abstracts read by two reviewers. When an abstract indicated that the document may fit the inclusion criteria, it was retrieved in full to confirm its eligibility for inclusion. When an abstract was read and it was unclear whether the study should be included, the respective full article was also obtained and read in full. After applying the exclusion criteria, 23 publications were selected.

To expand the scope of analysis of this review, the bibliographical references of the selected articles were searched to identify any other studies that may fit the inclusion criteria, which resulted in the inclusion of six other articles, bringing the final total to 29 studies.

Increasing evidences of skin manifestations related to COVID-19 and high expression of ACE2 in oral epithelium, raised the question whether the SARS-CoV-2 could cause other oral manifestations besides taste impairment. Table 1 allows verifying the articles identified in this review according to the author, age and sex of the patient, test for diagnostic confirmation of SARS-CoV-2 infection, observed oral manifestations, anatomical location, latency, management of oral lesions, and presence of associated cutaneous manifestations.

Oral manifestations were reported in 110 patients of this review. Lesions were found to be more prevalent in women (n = 68/61.8%). 6-26 Three cases did not mention patient's sex. 33 Patient age was specified in 26 articles (mean age of 42.5 years). SARS-CoV-2 infection was confirmed in 94.5% cases by polymerase chain reaction (PCR) (n = 104), [6] [7] [8] [9] [10] [11] [12] [13] 15, [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [33] [34] [35] [36] [37] [38] in three (2.7%) cases by antibody measurement (IgG), 16, 39, 40 and not investigated in the remaining three (2.7%) cases because of the patient's mild symptoms. 11, 14 In the three cases in which the infection's diagnostic confirmation was not performed, one of the patients had systemic symptoms of COVID-19 (e.g., fever, asthenia, hyposmia, and dysgeusia), and the second was asymptomatic, but the wife had a confirmed infection. 11 The third had only systemic symptoms (e.g., fever and cervical lymphadenopathy), which the necrotizing ulcerative gingivitis presented by the patient could justify those symptoms. 14 In the three cases in which the diagnosis was confirmed by antibody measurement (positive IgG), one of the patients had the IgM test performed during the symptoms and the IgG test two weeks before the oral lesions appeared 40 ; the other performed only three weeks before the oral lesions appeared 16 ; and the last one did not mention when the test was performed. 39 However, since these antibodies are produced later during the It is estimated that more than 70% of the population aged 25 years old has already been exposed to HSV, and this rate may be even higher in developing countries. The to diffuse, painful erosions and ulcers with irregular borders, and with associated necrosis. The formation of hemorrhagic crusts on lips is common. Associated skin lesions may be present, usually macules or erythematous papules, which develop into a concentric erythematous pattern (target lesions). 52 This review included only two (1.8%) cases with an erythema multiforme-like presentation. 11, 38 One patient used several medications such as antibiotics, lopinavir-ritonavir, hydroxychloroquine, and corticosteroids during hospitalization for the treatment of COVID-19, developing, after hospital discharge, an erythematous rash on the trunk and genital region, blisters on the mucosa of the lower lip, desquamative gingivitis, and crusts on the vermilion portion of the lower lip. 11 Oral manifestations

were observed approximately 30 days after the onset of COVID-19 symptoms. 11 Only the skin lesion was biopsied,

showing nonspecific findings with some viral rash criteria and urticarial dermatitis with slight blood extravasation. Based on the time elapsed between the diagnosis of COVID-19 and oral manifestations, it is more likely that those injuries were because of a drug reaction. 11 The other patient, 5 days after the first symptoms (cough, headache, myalgia, and fever), was hospitalized, and physical examination found ulcers of the mouth and glans, and erythematous conjunctivitis, and these findings were consistent with erythema multiforme major. 38 Swabs of the mouth ulcers, glans, and conjunctiva were negative for herpes simplex virus, varicella-zoster virus, and COVID-19. 38 Human immunodeficiency virus antigen and antibodies were negative, cytomegalovirus and Epstein-Barr virus serologies only found IgG, and mycoplasma pneumoniae nasopharyngeal polymerase chain reaction was negative. 38 These findings suggest mucosal damages were more likely to result from deleterious immune responses towards self-tissues rather than a cytopathic effect directly caused by the virus. 38 The presence of macules, petechiae, hemorrhagic blisters, pustular enanthem, and mucositis was reported in 33 (30.0%) patients in this review. 6, 9, 10, 13, 16, 19, 26, 33, 36, 40 We found that 42.4% of these patients also had associated skin lesions (n = 14), 9, 10, 13, 16, 33, 36 signaling the possibility that these changes represent a viral enanthema. In some cases, the presence of low platelet count and/or elevation of the D-dimer was highlighted. 10, 13 The pathophysiology by which COVID-19 causes thrombocytopenia is not yet completely understood, but, it is believed to be associated with the interference in hematopoiesis, excessive destruction of platelets by antibodies, and platelet consumption because of hypercoagulability. 53 In three studies of this review, the authors performed a histopathological examination of the lesions and observed microscopic characteristics of hemorrhages and thrombi formation in the small vessels. 19, 22, 36 These findings have similarities with cutaneous vasculitis and thrombotic complications reported in cutaneous biopsies of patients with COVID-19. 53 In two of these studies, the authors complemented the histopathological analysis with immunohistochemical exam for HSV-1, HSV-2, cytomegalovirus (CMV), Treponema pallidum, and in situ hybridization for Epstein-Barr virus (EBV) with a negative result for all reactions. 22, 36 In one of these studies, based on clinical characteristics, histopathological and immunohistochemical findings suggested that patients' lesions were a direct result of SARS-CoV-2 infection. 36 In the other study, immunohistochemistry for spike SARS-CoV-2 protein was positive in endothelial cells, keratinocytes, acinar and ductal cells of the minor salivary glands, which proved the presence of virus at the time of lesions. 22 Halitosis or "bad breath" is a condition that is characterized by an unpleasant odor coming from the mouth. About 80-85% of all halitosis cases are of intraoral origins, such as gingival and periodontal diseases (e.g., acute necrotizing ulcerative gingivitis, herpetic gingivitis, periodontitis, pericoronitis, and periodontal abscess), deep caries lesions, exposed necrotic pulp, poorly adapted dentures and orthodontic appliances, biofilm on the tongue, and candidiasis, among others. 54 Riad et al. 24 reported that 18 patients diagnosed with COVID-19, confirmed by PCR and without any relevant medical history, presented halitosis during the course of infection. The authors also

reported that most of the study participants had oral hygiene at a "reasonable" level, and only one participant had intraoral ulcers associated with halitosis. 24 The halimeter examination showed that all patients had physiological halitosis. 24 The authors suggested that SARS-CoV-2 may cause possible epithelial changes on the dorsal tongue surface because of ACE2 receptors, which are deeply located in abundance in this site. 24 This hypothesis was reinforced by the study of Watanabe, 55 which found that the severity of halitosis was strongly associated with epithelial changes in the keratinized mucosa of the tongue. The other halitosis case was described in a patient who also had edema and gingival erythema, necrosis of the interdental papillae, and bleeding from the gingival sulcus. 14 The presence of candidiasis was reported in five (4.5%) patients in this review. 16, 21, 23, 34 Candidiasis is the most common fungal infection in the oral cavity, and it is associated, among other factors, with the patient's immune status and the oral mucosa microenvironment. 56 In the cases reported in this review, there was a recent history of antibiotic therapy, 16 who had severe thrombocytopenia. 13 Finally, the case of a patient who had asymptomatic COVID-19, diagnosed through a positive IgG test performed three weeks earlier, developed a pigmented lesion on the gums. 16 As happens with any scientific study, our integrative review had some limitations. One of them was because of the reviewed articles' methodological weaknesses since most of the publications analyzed were case reports. In three of the patients, there was no laboratory confirmation for COVID-19 using PCR testing, and in three cases, 16, 39, 40 there was confirmation of past infection through serology. In addition, because of the suspension of in-office appointments, many patients were followed up through telemedicine, which made it difficult to obtain further investigation for better characterization of oral lesions. Thus, there is a need for prospective longitudinal studies with many more patients to assess the incidence of oral manifestations in these cases. Additional studies should be associated with histopathologiy, immunohistochemistry, and molecular techniques for a better understanding of these lesions. The low number of publications correlating COVID-19

to oral manifestations may be because of these manifestations' rarity or underreporting because of the lack of an adequate oral clinical examination. Many of the cases reported in this review were of critically ill hospitalized patients, supporting the importance of including an oral surgeon in the multidisciplinary hospital team. As we are dealing with a new virus, we expect that new publications will further point to new evidence that will help us to understand the presentation spectrum of this disease.

Based on current scientific evidence, it was not possible to state that the oral lesions seen in patients with COVID-19 were induced by the virus or were secondary to the deterioration of systemic health and the drugs used in treatment of the disease.

Healthcare professionals should be aware of COVID-19-related oral symptoms, and, whenever possible, patients with COVID-19 should undergo an intraoral examination.

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