COVID‐19‐related oral mucosa lesions among confirmed SARS‐CoV‐2 patients: a systematic review

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus that was observed initially as a cluster of cases with pneumonia in December 2019 in Wuhan, China.1 The fatality rate is reported as between 2% and 4% in all age groups, but it increases with advanced age and the presence of comorbid conditions.2 Erythema with vesicles or pustules (pseudo-chilblain) in acral areas, varicella-like vesicular eruptions, urticaria, maculopapular eruptions, livedo, and necrosis are among the skin manifestations seen in coronavirus disease 2019 (COVID-19) cases.3, 4 The pseudo-chilblain was usually associated with milder disease, whereas livedo and necrosis were associated with severe disease.5 In children, SARS-CoV-2 infection usually has a benign course; however, Kawasaki-like multisystem inflammatory syndrome may develop, with associated skin findings, in a subset of children.

Enanthema and oral lesions are among the typical manifestations of many viral diseases. When the diagnosis is uncertain, the presence of enanthema in oral mucosa assists in distinguishing the type of viral exanthema. Recently, we observed four confirmed COVID-19 patients with oral mucosa findings: three patients with erythema multiforme and accompanying oral ulcers and cracked lips, and one patient with a swollen red tongue (Figure 1). The erythema multiforme in these cases developed presumably due to a reactive response to COVID-19.

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SARS-CoV-2 confirmed cases with oral mucosa findings. (a) A 47-year-old woman with a maculopapular rash on admission developed erosions under the tongue and ulcers in the oral mucosa 3 days after diagnosing COVID-19. (b) A 78-year-old man developed herpetiform ulcers unresponsive to valacyclovir on the tongue 10 days after diagnosis. Herpes simplex type I IgM was negative, and IgG was positive with a low titer, and herpes simplex type II IgM and IgG were negative (c). A 53-year-old woman developed a red, edematous painful tongue 4 days after PCR and chest CT confirmation of COVID-19. (d) A 25-year-old woman with fever and a maculopapular rash developed cracked lips and erosions on the buccal mucosa. Herpes simplex type I and II antibodies were negative, and repeated SARS-CoV-2 PCR was positive on the 7th day of admission

High infectivity and fatality rates restricted oral cavity examinations for COVID-19 patients owing to safety concerns. Still, numerous published case reports and case series show that skin changes in oral mucosa may precede or accompany the disease. Furthermore, many publications have reported on the effect of altered health status in oral mucosa, including the effects of concurrent infections and related conditions, without focusing on the direct impact of viral infection. The concurrent infections considered included herpes simplex virus, candida, and mucormycosis, and concurrent non-infection conditions considered included drug use (antiplatelet, antibacterial drugs) in addition to other related factors.6 In this review, we searched the literature in detail for specific manifestations of COVID-19 in the oral mucosa to promote a comprehensive understanding of possible patterns and to provide up-to-date information for clinical practice.

Materials and Methods

This review was planned and conducted based on PRISMA guidelines. The inclusion criteria consisted of case reports and case series that reported the co-occurrence of COVID-19 and oral mucosal lesions. We performed a systematic literature search without language, publication time, or patient age, sex, or ethnicity restrictions in PubMed, Scopus, Google Scholar, and Medline for eligible records until April 07, 2021. We searched the electronic databases for relevant articles with the keywords “oral mucosa,” “oral lesions,” “mucocutaneous,” “gingiva,” “tongue,” “Kawasaki-like,” AND “SARS-CoV-2” or “Covid-19” or “Coronavirus 19.” An additional search across reference lists of included studies was performed. EndNote X9 was used to collect references and remove duplicates.7

Patients with molecular confirmation of SARS-CoV-2 with either reverse transcriptase-polymerase chain reaction or serologic confirmation of IgG/IgM antibodies against the virus were included. Oral mucosa lesions associated with the cases with concomitant infections (HSV, Candida albicans, or bacterial infections), reports related to mechanical trauma (intubation), reports related to possible drug reactions, studies only reporting taste disorders without mucocutaneous findings, and reports with inadequate investigations were excluded.

For the selection of studies, a two-phase process was applied. At first, two authors (NE and GE) independently screened the articles based on the titles and abstracts to select those appearing to meet the inclusion criteria. In the second phase, the full text of the articles retrieved in the initial literature research was reviewed by the same two authors independently. The third author (AB) was involved in resolving conflict and making the final decision. All papers selected for inclusion in the systematic review were subjected to critical appraisal using the Joanna Briggs Institute Critical Appraisal Tools for case reports and case series.8, 9

The risk of bias in the studies was assessed independently by three authors (GE, NE, and AB) using the appropriate checklist. Information for each included patient regarding gender, age, laboratory testing for SARS-CoV-2, medical history, concomitant symptoms including skin findings, histopathology, onset, treatment, and resolution time were collected and summarized. After collecting the initial data, results were recruited into one of three categories: ulcers, Kawasaki-like syndrome-associated mucosal lesions, and miscellaneous lesions. Statistical analysis was performed with SPSS version 26. Group comparisons were evaluated with Kruskal–Wallis, Pearson chi-square test, and Fisher’s exact test.

Results Study selection

The initial search yielded 5685 references (last updated on April 7, 2021). After removing duplicates, 2072 citations remained. Following title and abstract screening, 1944 reports were considered irrelevant since they did not meet our inclusion criteria. Consequently, 128 articles underwent a complete review. The full-text review resulted in the exclusion of 89 studies according to the predetermined eligibility criteria, and 39 articles remained for final analysis. A flowchart representing this process is presented in Figure 2.

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Article selection flow chart according to PRISMA guidelines

Summary of findings

The epidemiologic and clinical manifestations of the patients reported in the literature are summarized in Table 1. In the 39 studies reviewed, 59 eligible cases were reported, including 24 female and 35 male patients. Overall, patients were aged between 4 months and 83 years. The median age was 28. Among these 59 patients, 48 were diagnosed by SARS-CoV-2 RT-PCR, two had both SARS-CoV-2 IgM and IgG positivity, and nine had SARS-CoV-2 IgG positivity after the disease. Demographics of patients are summarized in Table 2.

TABLE 1. Characteristics of included studies Study Design Sample, n Gender Age, years Risk of biasa 1 Akca et al.10 CS 1, 3/4 cases excluded M 7 Low 2 Alnashri et al.11 CR 1 M 16 Low 3 Ansari et al.12 CR 2 F/M:1/1 56;75 Low 4 Bahrami et al.13 CR 1 F 5 Low 5 Balasubramanian et al.14 CR 1 M 8 Low 6 Bhaswati et al.15 CR 1 M 4 months Low 7 Blondiaux et al.16 CS 2, 2/4 cases excluded due to the absence of oral mucosal findings F/M:1/1 8;6 Low 8 Brandao et al.17 CS 8 F/M:3/5 81;71;83;72;32;35;29;28 Low 9 Chaux-Bodard et al.18 CR 1 F 45 Moderate 10 Chérif et al.19 CR 1 F 35 Low 11 Chiotos et al.20 CS 3, 3/6 cases excluded due to the absence of oral mucosal findings F/M:2/1 12;9;5 Low 12 Chiu et al.21 CR 1 M 10 Low 13 Ciccarese et al.22 CR 1 F 19 Low 14 Cruz Tapia et al.23 CS 4 F/M:3/1 41;51;55;42 Low 15 Demirbaş et al.24 CR 1 F 37 Low 16 De Paulis et al.25 CR 1 F 4 Low 17 Dominguez-Santas et al.26 CS 4 F/M:1/3 43;33;37;19 Low 18 Gabusi et al.27 CR 1 M 78 Moderate 19 Haena et al.28 CR 1 M 11 Low 20 Holcomb et al.29 CR 1 M 17 Moderate 21 Jones et al.30 CR 1 F 6 months Low 22 Cebeci-Kahraman et al.31 CR 1 M 51 Low 23 Lidder et al.32 CR 1 M 45 Low 24 Labé et al.33 CR 1 M 6 Moderate 25 McGoldrick et al.34 CR 1, 1/2 case excluded due to the absence of COVID-19 confirmation M 53 Moderate 26 Ng et al.35 CS 1, 2/3 cases excluded due to the absence of oral mucosal findings M 17 Low 27 Peterson et al.36 CR 1 F 2 Low 28 Rafiei Tabatabaei et al.37 CR 1 M 11 Low 29 Renganathan et al.38 CR 1 M 10 30 Rivera-Figueroa et al.39 CR 1 M 5 Low 31 Rodriguez et al.40 CS 1, 2/3 cases excluded as they were related to candidal infection F 43 Moderate 32 Shaigany et al.41 CR 1 M 45 Low 33 Soares et al.42 CR 1 M 42 Low 34 Soares et al.43 CR 1 F 23 Low 35 Sokolovsky et al.44 CR 1 F 36 Low 36 Spencer et al.45 CR 2 F/M:1/1 11; 7 Low 37 Taşkın et al.46 CR 1 F 61 Low 38 Tomo et al.47 CR 1 F 37 Low 39 Waltuch et al.48 CS 2, 1/3 case excluded due to the absence of oral mucosal findings M:2 5; 13 Low CR, case report, CS, case series, F, female, M, male, n, number of cases. a Risk of bias of each case is assessed by the Joanna Briggs Institute critical appraisal tools for case reports and prevalence studies. TABLE 2. Characteristics of COVID-19 patients with oral mucosa findings Age (Median) 28 (4 months–83 years) Sex Female 40.7% (n = 24) Male 59.3% (n = 35) SARS-CoV-2 detection SARS-CoV-2 RT-PCR (+) 81.4% (n = 48) SARS-CoV-2 IgM (+) IgG (+) 3.4% (n = 2) SARS-CoV-2 IgG (+) 15.2% (n = 9) Oral lesion type Cheilitis/cracked lips 43.9% (n = 29) Oral ulcer 36.3% (n = 24) Miscellaneous 19.6% (n = 13) Skin lesions 60.6% (n = 40) Dysgeusia 30.8% (n = 20) Fever 86.2% (n = 56) Onset of oral lesions in relation to other symptoms Before 10.1% (n = 6) Simultaneously 25.4% (n = 15) After 64.4% (n = 38)

The onset of oral lesions was synchronous with other symptoms and diagnosis in 15 patients (25.4%). Anosmia/dysgeusia accompanied oral mucosa lesions in 20 patients (30.8%). Additional skin lesions were detected in 40 patients (60.6%). Lesions developed after SARS-CoV-2 detection in 38 patients (64.4%). In six (10.1%) patients, oral lesions were present before molecular confirmation and the onset of other symptoms. The cases in the reports consisted of 48 hospitalized patients with severe disease and 11 patients with mild-moderate symptoms. The mean age was lower in patients with accompanying skin lesions (mean: 25 vs. 43; P = 0.001). Among hospitalized patients, the mean age was 31.1 (P = 0.068).

We categorized the reported oral mucosa findings into three subgroups: KWL: Kawasaki-like syndrome-associated oral mucosa findings (cracked lips, dry lips, cheilitis with/without erythema of oral mucosa; Table 3).11, 13-16, 19-21, 25, 28, 30, 32, 35-39, 41, 44, 45, 48, 49 OU: Ulcers in the oral mucosa (aphthous, herpetiform, multiple, single, necrotizing; Table 4).17, 18, 22, 24, 26, 27, 29, 33, 40, 42, 43, 46, 49, 50 M: Miscellaneous group (macular, papular, pustular, bullous, and overlapping cases; Table 5).22-24, 31, 33, 34, 42, 43, 47, 51 Seven patients in this group had accompanying oral ulcers to other mucosal findings and are also included in Table 4.22, 24, 33, 40, 42, 43, 49 TABLE 3. Characteristics of SARS-CoV-2 (+) Kawasaki-like systemic disease patients with oral mucosa findings Reference Type of KD Sex Age Systemic manifestions Skin Oral lesions Onset Hospitalization Treatment of oral lesions Akca et al. IC M 7 Fever, respiratory symptoms Yes Erosive hyperemia of oral mucosa N/A + IVIG, azithromycin, hydroxochloroquine, ritonavir, lopinavir, tocilizumab, mesenchymal stem cell treatment Alnashri et al. KL-MISC M 16 Fever Yes Fissured lips N/A + IVIG, tocilizumab Bahrami et al. KL-MISC F 5 Fever Yes Swelling and congestion of lips After SS + IVIG, acetylsalicylic acid Balasubramanian et al. KL-MISC M 8

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