Journal of Dental Sciences 16 (2021) 1066e1073

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Review article

Review of oral ulcerative lesions in COVID-19

patients: A comprehensive study of 51 cases
Yu-Hsueh Wu a,by, Yang-Che Wu c,dy, Ming-Jane Lang e,
Yi-Pang Lee e, Ying-Tai Jin f,g**, Chun-Pin Chiang e,h,i*

a
Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National
Cheng Kung University, Tainan, Taiwan
b
Institute of Oral Medicine, School of Dentistry, National Cheng Kung University, Tainan, Taiwan
c
School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
d
Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, Ministry of Health and
Welfare, New Taipei City, Taiwan
e
Department of Dentistry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien,
Taiwan
f
Department of Pathology, Taiwan Adventist Hospital, Taipei, Taiwan
g
Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
h
Department of Dentistry, National Taiwan University Hospital, College of Medicine, National Taiwan
University, Taipei, Taiwan
i
Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, Taipei, Taiwan

Received 6 July 2021

Available online 15 July 2021

KEYWORDS Abstract Numerous oral manifestations of COVID-19 have been reported in the literatures.
COVID-19; Common oral lesions in COVID-19 patients included ulcerations, xerostomia, dysgeusia, gingival
SARS-CoV-2; inflammation, and erythema. Among them, oral ulceration is the most frequent finding and is
Oral manifestation; present as various but distinct patterns. Thus, we conducted a comprehensive review of 51
Oral ulcerative COVID-19 patients with oral ulcerative lesions to further analyze the various oral ulcerative le-
lesions; sions in COVID-19 patients. There were a median age of 41.4 years and a slight female predi-
Recurrent aphthous lection in these patients. Most oral lesions manifested as an aphtha-like ulceration but lack of
stomatitis an evidence of recurrent aphthous stomatitis. Some of them were present as herpetiform ul-
cerations without HSV infection. Widespread ulcerations accompanied with necrosis were
observed in the more severe and immunosuppressed older patients. Although some reported
patients were asymptomatic, most of them had systemic symptoms concurring or slightly pre-
ceding the oral ulcerative lesions and the latency from the onset of systemic symptoms to oral
ulcerative lesions were under 10 days, suggesting that oral ulceration was one of the early

* Corresponding author. Department of Dentistry, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 707, Section 3,
Chung-Yang Road, Hualien 970, Taiwan.
** Corresponding author. Department of Pathology, Taiwan Adventist Hospital, No. 424, Section 2, Bade Road, Taipei 10556, Taiwan.
E-mail addresses: yingtaijin@[Link] (Y.-T. Jin), cpchiang@[Link] (C.-P. Chiang).
y
These two authors contributed equally to this work.

[Link]
1991-7902/ª 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V. This is an open access article under
the CC BY-NC-ND license ([Link]
 Journal of Dental Sciences 16 (2021) 1066e1073

symptoms of COVID-19. Therefore, the oral ulcerative lesions may be considered as oral
markers for early diagnosis of the underlying COVID-19 infection in the asymptomatic patients.
ª 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier
B.V. This is an open access article under the CC BY-NC-ND license ([Link]
org/licenses/by-nc-nd/4.0/).

Introduction involved site, while there were 6 cases with involvement of

more than one site in their oral cavities. The common sites
In the end of 2019, an acute respiratory illness appeared of involvement in descending order were lip and labial
abruptly and soon spread worldwide, which was officially mucosa (28.6%), tongue (25%), palate (16.4%), buccal mu-
named coronavirus disease-19 (COVID-19), and the virus cosa (16.4%), gingiva (8.9%), and tonsil (3.6%). The lesion
responsible for this disease was named as severe acute sizes were measured from 1 mm to 17 mm in the 27 re-
respiratory syndrome coronavirus 2 (SARS-CoV-2) by World ported cases and 88.9% of these lesions were under 1 cm in
Health Organization (WHO). The common clinical pre- greatest dimension. Pain was mentioned in 40 of 41 cases
sentations of COVID-19 included fever, cough, sore throat, and the remaining 10 cases did not report the pain
runny nose, myalgia, fatigue, and dyspnea. Less frequently, symptom.
sputum production, headache, and diarrhea were also The clinical presentations of the oral ulcerations were
observed.1 Wang et al.2 reported the hematological and various, from aphthous stomatitis-like lesions to wide-
radiographic alterations in the patients infected by SARS- spread ulcerations with necrosis or crusting. Like aphthous
CoV-2 in their study. Lymphopenia is found in 70.3% pa- stomatitis, most of the lesions showed solitary or multiple
tients, and prolonged prothrombin time occurs in 58% pa- punched-out ulcerations, which were covered by a
tients. Chest computed tomography shows patchy opacities yellowish membrane and surrounded by an erythematous
or “ground-glass” pattern in lungs. The median age of the halo (case 1e25, 37, 38, 41, 43, and 45).9e13,17 Some of
diagnosed patients is 56 years, while the patients treated in these lesions (case 31, 32, 40 and 42) showed herpetiform
the intensive care unit (ICU) are even older. About one pattern, with resemblance to herpes infection, but
fourth patients are transferred to the ICU due to compli- rendered a negative result to the test for herpes simplex
cations, such as acute respiratory distress syndrome or virus (HSV).13,14 Patients in case 34, 35, and 50 showed the
shock.2 lesions resembling recurrent herpetic infection but all of
Localized involvements of COVID-19, like skin rash, sore them did not have any previous history of herpetic infec-
throat, hyposmia, anosmia, and oral lesions, have also been tion.15,16 Although the lesions looked like aphthous ulcer-
mentioned in some literatures.3,4 The common oral lesions ations, patients in these reported cases usually lacked the
of COVID-19 include ulcerations, xerostomia, dysgeusia, history of recurrent aphthous stomatitis (RAS), oral in-
gingival inflammation, and erythema.4e6 According to the flammatory diseases, or allergy.10,13,18 Besides, some
associated studies, the most frequent oral finding was oral possible etiologic conditions of RAS, such as deficiencies of
ulceration, and there were distinct clinical patterns vitamin B12, folate, and iron were also excluded.13
observed in different case studies.7e17 Despite growing The 71-year-old-female in case 26 and the 81-year-old
literatures investigating oral presentations in COVID-19 male in case 28 possessed severe clinical presentations of
patients, few of them provide deep insight into oral ul- COVID-19 and were admitted to intensive care unit (ICU).
cerative lesions, the most frequent but diverse one. The Their oral examination showed multiple oral ulcerations
detailed clinical features, histological findings, immune with focal necrosis and crusting, and HSV-1 was detected in
profile, and the possible underlying pathogenetic mecha- the saliva sample by performing PCR.10 The patient in case
nism of the oral ulcerative lesions are still lacking. There- 33 was also admitted to the ICU and underwent invasive
fore, we conducted a comprehensive review of 51 COVID-19 mechanical ventilation. Multiple ulcerations over his oral
patients with oral ulcerative lesions to further analyze the mucosa were positive for HSV-1 DNA, and HSV-1 reac-
various oral ulcerative lesions in COVID-19 patients. tivation was also proved by the serum tests before and after
inpatient care.18 The patient in case 47 had a past medical
history of kidney transplant and took immunosuppressants
Clinical features of 51 COVID-19 patients with regularly. He was admitted to ICU for supplemental O2, and
oral ulcerative lesions his oral lesions exhibited herpes-like ulcers on the dorsal
tongue as well as candidiasis. However, no HSV test was
Age, sex, locations, and other clinical descriptions of the 51 performed to confirm the herpes infection.19 These exten-
COVID-19 patients with oral ulcerative lesions reported in sive ulcerations with necrosis, or co-infection of other
the literature are shown in Table 1. The age of the 51 pa- pathogens were almost observed in the immunocompro-
tients ranged from 16 years to 83 years with a mean age of mised or older individuals, and usually accompanied with
41.4 years. A slight female predilection was observed in the more severe clinical symptoms.
reported cases with a female-to-male ratio of 1.22:1 (28 The patients in case 2, 3, 6, 8, 11, 16, 18, 20 and 38
females, 23 males). The sites of the lesion were not re- showed oral ulcerations, independent of any systemic
ported in two cases. There were 43 cases with single symptoms. However, most reported cases showed systemic

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Table 1 Summary of 51 reported cases of oral ulcerative lesions in COVID-19 patients.

Case References Age Sex Lesion site Clinical features Lesion Pain General symptoms Onset Confirmation
No. (Year of size (day) of COVID-19
publication)
1 Riad et al.9 16 F Upper lip Solitary ulcerative 1 mm þ Cough 0 þ
(2021) white halos with
well-defined
erythematous
margins
2 Riad et al.9 17 F Buccal Same as above 1 mm þ Asymptomatic 0 þ
(2021) mucosa
3 Riad et al.9 19 M Buccal Same as above 1 mm þ Asymptomatic 0 þ
(2021) mucosa
4 Riad et al.9 20 M Palate Same as above 2 mm þ Anosmia 0 þ
(2021)
5 Riad et al.9 20 F Buccal Same as above 2 mm þ Anosmia 0 þ
(2021) mucosa
6 Riad et al.9 24 F Tongue Same as above 1 mm þ Asymptomatic 0 þ
(2021)
7 Riad et al.9 25 F Upper Same as above 2 mm þ Anosmia 0 þ
(2021) gingiva
8 Riad et al.9 26 F Buccal Same as above 2 mm þ Asymptomatic 0 þ
(2021) mucosa
9 Riad et al.9 27 F Upper lip Same as above 2 mm þ Cough 0 þ
(2021)
10 Riad et al.9 27 F Palate Same as above 2 mm þ NR 0 þ
(2021)
11 Riad et al.9 31 M Lower lip Same as above 2 mm þ Asymptomatic 0 þ
(2021)
12 Riad et al.9 31 F Tongue Same as above 2 mm þ NR 0 þ
(2021)
13 Riad et al.9 36 F Palate, Same as above 4 mm þ Anosmia, fever, cough 0 þ
(2021) upper and
lower
gingiva
14 Riad et al.9 37 M Buccal Same as above 2 mm þ Anosmia 1 þ
(2021) mucosa
15 Riad et al.9 38 F Buccal Same as above 1 mm þ Fever 0 þ
(2021) mucosa
16 Riad et al.9 38 F Tongue Same as above 1 mm þ Asymptomatic 0 þ
(2021)
17 Riad et al.9 39 F Upper lip Same as above 4 mm þ Cough 0 þ
(2021)
18 Riad et al.9 42 F Lower lip Same as above 3 mm þ Asymptomatic 0 þ
(2021)
19 Riad et al.9 46 F Upper Same as above 2 mm þ Fever 1 þ
(2021) gingiva
20 Riad et al.9 48 F Lower lip Same as above 2 mm þ Asymptomatic 0 þ
(2021)
21 Riad et al.9 56 F Buccal Same as above 2 mm þ Cough 0 þ
(2021) mucosa
22 Brandão 28 M Upper and Aphtha-like NR NR Anosmia, cough, fever, 8 þ
et al.10 lower ulcerations headache, myalgia, chills
(2021) labial
mucosa,
tongue
23 Brandão 29 M Tongue Same as above 10 mm þ Anosmia, fever, cough, 8 þ
et al.10 headache, dyspnea on
(2021) exertion, malaise
24 Brandão 32 F Tongue Same as above 3e4 mm NR Anosmia, fever, cough, 10 þ

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Table 1 (continued )
Case References Age Sex Lesion site Clinical features Lesion Pain General symptoms Onset Confirmation
No. (Year of size (day) of COVID-19
publication)
et al.10 headache
(2021)
25 Brandão 35 M Tonsillar Same as above 5 mm NR Hyposmia, fever, cough, sore 6 þ
et al.10 pillar throat, malaise
(2021)
26 Brandão 71 F Upper and Oral ulceration with NR þ Cough, dysgeusia, fever, mild 4 þ
et al.10 lower lips, focal necrosis, dyspnea, CT showing “ground-
(2021) tongue hemorrhagic glass” pattern in both lungs
crusting
27 Brandão 72 M Upper and Same as above NR þ Fever, dyspnea 5 þ
et al.10 lower lips
(2021)
28 Brandão 81 M Upper and Same as above 10 þ Cough, chest tightness, chills, 5 þ
et al.10 lower e15 mm fever, dyspnea, CT showing
(2021) labial “ground-glass” pattern in both
mucosa, lungs
tongue
29 Brandão 83 F Tongue An aphtha-like ulcer 15 mm þ Abdominal distension, mild 2 þ
et al.10 and palate with focal necrosis dyspnea
(2021)
30 Ciccarese 19 F Lips Ulcerations with NR  Fever, fatigue, hyposmia 7 þ
et al.6 crusting
(2021)
31 Ansari 56 F Palate Ulcerations with NR þ Fever, shortness of breath 5 þ
et al.14 irregular margins
(2021)
32 Ansari 75 M Tongue Several small ulcers NR þ Hypoxia 7 þ
et al.14 with irregular
(2021) margins
33 Kämmerer 46 M NR Multiple sharply NR þ Fatigue, dry cough, fever, 15 þ
et al.18 circumscribed respiratory distress, CT
(2021) ulcerations showing “ground-glass”
pattern in both lungs
34 Martı́n 56 M Palate Multiple ulcerations NR þ Fever, hyposmia, enlarged NR NR (pending
Carreras- with unilateral lymph nodes the result)
Presas affection
et al.15
(2021)
35 Martı́n 58 M Palate Multiple small NR þ NR NR NR
Carreras- ulcerations with
Presas unilateral affection
et al.15
(2021)
36 Martı́n 65 F Labial Blisters and NR þ High fever, diarrhea, skin rash, NR þ
Carreras- mucosa ulcerations bilateral pneumonia
Presas
et al.15
(2021)
37 Al-Khanati 24 M Lower Multiple aphtha-like 15 þ Headache, fatigue, fever, NR 
et al.11 labial ulcerations e17 mm dizziness, nausea, sore throat
(2020) mucosa
38 Corchuelo 40 F Tongue, Aphtha-like ulcers NR þ Asymptomatic NR þ
and Ulloa12 attached
(2020) gingiva of
tooth 34
(continued on next page)

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Table 1 (continued )
Case References Age Sex Lesion site Clinical features Lesion Pain General symptoms Onset Confirmation
No. (Year of size (day) of COVID-19
publication)
39 Malih 38 M Left tonsil Aphthous NR NR Fatigue, anosmia, fever, skin NR þ
et al.35 stomatitis-like rash, malaise
(2020) lesions
40 Dominguez- 19 M Lower Four clustered NR NR Anosmia, fever, headache, 0 þ
Santas labial aphthae malaise, and dyspnea
et al.13 mucosa
(2020)
41 Dominguez- 33 M Upper An aphtha-like NR NR Anosmia, fever, headache, 3 þ
Santas gingiva ulcers malaise, dyspnea, pneumonia
et al.13 of right lower pulmonary field,
(2020) mild lymphopenia
42 Dominguez- 37 M Tongue Seven aphtha-like NR NR Anosmia, fever, headache, 5 þ
Santas (right ulcers malaise, and dyspnea
et al.13 ventral
(2020) side)
43 Dominguez- 43 F Buccal An aphtha-like ulcer NR NR Anosmia, fever, headache, 4 þ
Santas mucosa malaise, dyspnea, bilateral
et al.13 (right) pneumonia, mild lymphopenia
(2020)
44 Eghbali 56 F Lower Preceding vesicles NR þ High fever, fatigue 2 þ
Zarch labial
et al.36 mucosa
(2020)
45 Soares 42 M Buccal A “punched-out” NR þ Fever, cough, shortness of NR þ
et al.17 mucosa ulcer breath, skin petechia-like and
(2020) small vesicobullous lesions
46 Putra 29 M NR Aphthous NR þ Fever, cough, anosmia, skin 7 þ
et al.3 stomatitis-like petechia- lesions, sore throat
(2020) lesions
47 Amorim Dos 67 M Tongue Multiple pinpoint NR NR Dyspnea, fever, diarrhea, CT 24 þ
Santos yellowish ulcers showing “ground-glass”
et al.19 pattern in both lungs
(2020)
48 Chérif 35 F Upper lip Ulcerations NR NR Fever, myalgia, dyspnea, NR þ
et al.37 cough, vomiting, diarrhea,
(2020) rash
49 Sinadinos 56 M Palate Recurrent herpes- NR þ Sore throat NR NR (pending
and like stomatitis the result)
Shelswell16
(2020)
50 Sinadinos 58 M Palate Unilateral palatal NR þ NR NR NR (pending
and ulcerations the result)
Shelswell16
(2020)
51 Sinadinos 65 F Tongue Erythema NR þ Bilateral pneumonia NR þ
and multiform-like
Shelswell16 ulcerations
(2020)
NR: not reported.
CT: chest computed tomography.

symptoms concurring or slightly preceding the oral lesions. 40 reported cases was 3.2 days (Table 1). The mean incu-
The latency period from the onset of systemic symptoms to bation period of COVID-19 in several studies was reported
oral lesions were under 10 days, except two cases (case 33 to be a maximum 8 days and their pooled mean incubation
and 47).9,10,13e15,18,19 The mean of the latency period in the period was 6.2 days.20 These findings suggest that the oral

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 Journal of Dental Sciences 16 (2021) 1066e1073

ulceration may be one of the early symptoms of COVID-19. Discussion

In addition, the oral ulcerations may sometimes appear in
the asymptomatic patients so that oral ulcerations may be The clinical presentations of the oral ulcerative lesions in
the hint to warn us about the underlying infection in those COVID-19 patients are various but distinct. Some may look
asymptomatic COVID-19 patients. like aphthous ulcerations (minor or herpetiform type),
while there is no evidence of RAS in these patients. These
Histological findings and immune profile of oral aphtha-like oral lesions occur predominantly in relatively
young patients with mild symptoms. Widespread oral ul-
ulcerative lesions in COVID-19 patients
cerations accompanied with necrosis are observed in the
more severe and immunosuppressed older individuals. This
Based on the current literatures, it seems that there are no difference may be related to the way by which SARS-CoV-2
pathognomonic findings in these oral ulcerative lesions infects cells. SARS-CoV-2 enters the cells by the synergy of
histologically. The biopsy results revealed non-specific ul- its own spike protein, angiotensin-converting enzyme 2
cerations with granulation tissue base and diffuse chronic (ACE2) on the surface of host cell, and transmembrane
inflammatory cell infiltration. Residual surface epithelium protease serine 2 (TMPRSS2). The viral spike protein can
showed edematous change and neutrophilic exocytosis.14 In recognize ACE2 on the host cell surface, and then TMPRSS2
addition to the above findings, focal areas of necrosis and is triggered to cleave the spike protein for priming cell
hemorrhage were observed in case 45. Besides, both su- membrane fusion.21,22 The levels of ACE2 and TMPRSS2 are
perficial and deep small blood vessels were obliterated by found to be positively correlated with age and the disease
thrombi, which was mainly composed of endothelial cells severity, which may explain why the elderly tend to possess
(positive for CD34) and fibrin. Adjacent minor salivary high risk for severe diseases and why the elderly usually
glands exhibited an intense lymphocytic infiltration. show more widespread and serious oral lesions.21
Immunohistochemically, CD3 and CD8 positivities were The development of the oral ulceration could be possibly
observed in most inflammatory cells in basal cell layer of associated with the pathogenesis of COVID-19 as well.
the epithelium, in the connective tissue, and in salivary Because oral epithelial cells have proved to express ACE2,
gland tissue. Some other inflammatory cells demonstrated the disruption of oral epithelial cells may occur when the
positivities for CD4, CD20, CD68, CD138, and CD163. This SARS-CoV-2 spread to these epithelial cells.10 Besides,
immunohistochemical pattern indicates that the compo- increased cytokines, such as interleukin 6 (IL-6) and inter-
nents of the inflammatory cells are mainly CD3-positive and leukin 10 (IL-10), in COVID-19 patients may lead to
CD8-positive T lymphocytes.17 However, biopsy was lack in chemotaxis of lymphocytes and neutrophils to the lesion
many cases, so further studies are needed to explore the site, and thus neutrophilic exocytosis and CD3-positive and
microscopic details of these oral ulcerative lesions. CD8-positive lymphocytes are observed in the reported
cases.23 Patients with RAS have been proved to have
Concomitant infections or symptoms in 51 increased levels of CD8-positive T lymphocytes and/or
COVID-19 patients with oral ulcerative lesions decreased CD4-positive T lymphocytes by Wardhana and
Datau.24 Pedersen et al. have also found that the propor-
tion of CD8-positive T lymphocytes is significantly increased
The concomitant infections or symptoms in 51 COVID-19
in the active RAS, though the total counts of CD4-positive
patients with oral ulcerative lesions are shown in Table 2.
and CD8-positive T lymphocytes are significantly lower in
For the concomitant infections in 51 COVID-19 patients with
the patients than in the control subjects.25 However, the
oral ulcerative lesions, 4 (7.8%) patients had HSV infection
immunopathological responses in COIVD-19 are compli-
and 2 (3.9%) patients had oral candidiasis. Regarding the
cated and have not been thoroughly studied, either sys-
concomitant symptoms in 51 COVID-19 patients with oral
temic or local, and lack of sufficient biopsy samples of the
ulcerative lesions, anosmia or hyposmia (17 patients,
oral ulcerative lesions even makes them full of unknowns.
33.3%) was the most common concomitant symptoms, fol-
In addition, necrosis and co-infection of HSV or candida
lowed by dysgeusia, ageusia or hypogeusia (9 patients,
are also noted in some severe cases. The expression of ACE2
17.6%), xerostomia (2 patients, 3.9%), and COVID tongue
on endothelial cells may be involved in the tissue necrosis
(geographic tongue-like lesion, 2 patients, 3.9%).
in these lesions. The expression of ACE2 on endothelial cells
makes the viral particles prone to aggregation in the
Table 2 Concomitant infections or symptoms in 51 COVID- endothelia at the lesion sites. Recruitment of immune cells,
19 patients with oral ulcerative lesions. either by direct viral infection of the endothelial cells or
immune-mediated, can lead to extensive endothelial
Concomitant infection or symptom Patient number
dysfunction and cause endotheliitis, giving rise to the ne-
(%)
crosis of infected tissue.26
Herpes simplex virus infection 4 (7.8) There are two types of HSV: type 1 (HSV-1) and type 2
Candidiasis 2 (3.9) (HSV-2). HSV-1 usually infects the oral, facial, and ocular
Anosmia or hyposmia 17 (33.3) areas as well as skin above the waist. The natural history of
Dysgeusia, ageusia, or hypogeusia 9 (17.6) HSV infection includes primary infection, latency, and
Xerostomia 2 (3.9) recurrent infection. Primary HSV-1 infection typically oc-
COVID tongue (geographic tongue-like 2 (3.9) curs at a young age and often is asymptomatic. After pri-
lesion) mary HSV-1 infection is established, the virus is taken up by

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 Y.-H. Wu, Y.-C. Wu, M.-J. Lang et al.

sensory nerves, and often transported to the associated (33.3% of 51 COVID-19 patients), but other symptoms such
sensory ganglia where the virus remains in a latent state. as dysgeusia (17.6%) and xerostomia (3.9%) were relatively
The most common site of latency for HSV-1 is the trigeminal uncommon (Table 2). The relatively-high frequency of the
ganglion. The virus uses the axons of the sensory neurons to olfactory alterations in our reported cases might also be
travel back and forth to the skin or mucosa and usually due to that anosmia or hyposmia was an annoying symptom
infects the epithelium supplied by the sensory ganglion for the patients and thus the patients usually reported it to
when reactivated. Recurrent (secondary) herpes infection the caring physicians. On the contrary, the 51 COVID-19
occurs with reactivation of the virus. Old age, physical or patients in our study might think that dysgeusia and xero-
emotional stress, fatigue, severe systemic disease, and stomia were less disturbing symptoms and thus they forgot
malignancy have been associated with reactivation.27,28 to report them to the caring physicians. Besides, COVID
Therefore, the COVID-19-induced immunocompromised tongue, a geographic tongue-like lesion, is not a well-
status is probably the etiological factor causing concomi- reported and universally-recognized lesion in COVID-19
tant HSV infection. Moreover, HSV reactivation is also patients (2 cases in our 51 COVID-19 patients); therefore,
common in non-immunocompromised patients with pro- the lower occurrence rate of COVID tongue in our 51 COVID-
longed mechanical ventilation in ICU.29 19 patients is understandable. The higher expression of
Oral candidiasis is a kind of opportunistic infection in ACE2 and TMPRSS2 on the tongue epithelial cells may result
immunocompromised patients. It often occurs in patients in easy destruction and depapillation of filiform and
with immune deficiency diseases, specific nutritional de- fungiform papillae from the dorsal surface of the tongue
ficiencies and malnutrition, endocrine disorders, malig- when the patients are infected with SARS-CoV-2, and this
nancies, xerostomia, and in patients taking corticosteroids may explain why there is geographic tongue-like lesion on
or broad-spectrum antibiotics.27 In COVID-19 patients, the dorsal surface of the tongue in COVID-19 patients and
immunocompromised status, xerostomia, administration of why some of the COVID-19 patients may have hypogeusia
corticosteroids in patients with severe COVID-19, and tak- because taste cells are contained in the shedding fungiform
ing antibiotics in patients with bacterial pneumonia co- papillae on the dorsal and lateral borders of the tongue.34
infection may play important roles in causing concomitant Taken together, the pathogenetic mechanism may play
oral candidiasis. Moreover, Le Balc’h et al. also found that an important role in the clinical presentations of COVID-19.
COVID-19 patients with acute respiratory distress syndrome The distribution and levels of ACE2 and TMPRSS2 in human
usually tend to have bacterial, fungal, or viral co- cells determine which tissue or organ is prone to be infec-
infections.29 ted and what clinical manifestations may be present. In this
Moreover, xerostomia or dry mouth, the common comprehensive review, the 51 COVID-19 patients with oral
symptom in COVID-19 patients, may also play a role in ulcerative lesions showed a mean age of 41.4 years and a
causing oral ulcerations in COVID-19 patients. Loss of the slight female predilection. Most oral ulcerative lesions are
protection and lubrication of saliva may easily lead to manifested as aphtha-like ulcerations measuring less than
mucosal trauma and local microbial infections.30 The 1 cm in greatest dimension or forming clusters, but there is
occurrence of xerostomia may be attributed to the no previous history or other etiological factors of RAS
expression of ACE2 and TMPRSS2 on the salivary gland involved in the formation of oral ulceration. Some oral le-
cells. The infection of salivary gland cells by SARS-CoV-2 sions are present as widespread ulcerations accompanied
finally results in destruction of salivary acinar cells and with necrosis, which are mainly observed in the more se-
the impaired saliva-production function.31 In addition to vere and immunosuppressed older patients. There are
the salivary gland cells, taste bud cells and olfactory sup- usually systemic symptoms concurring or slightly preceding
porting cells are another cells that can express ACE2 and the oral lesions and the latency from the onset of systemic
TMPRSS2.32,33 Thus, when these cells are infected by SARS- symptoms to oral lesions are under 10 days, with the mean
CoV-2, destruction of taste bud cells and olfactory sup- of 3.2 day. The incubation periods of COVID-19 are almost
porting cells may subsequently lead to dysgeusia (or under 16 days, so the findings suggest that oral ulceration is
ageusia and hypogeusia) and anosmia (or hyposmia), one of the early symptoms of COVID-19.20 Besides, the oral
respectively.31,32 The neurotropism of SARS-CoV-2 (i.e., ulcerations may sometimes appear in the asymptomatic
this may result in easy infection of sensory nerves by SARS- patients. Therefore, the presence of oral ulcerative lesions
CoV-2 and dysfunction of these infected sensory nerves) may be helpful for early diagnosis and detection of the
and the alterations of cytokines in COIVD-19 patients may underlying COVID-19 infection in those asymptomatic
also play pivotal roles in causing dysgeusia (or ageusia and patients.
hypogeusia) and anosmia (or hyposmia).32,33 Interestingly,
the close relation between xerostomia and dysgeusia as
well as the synergy of gustatory and olfactory systems
Declaration of competing interest
make the interaction between these oral involvements
sophisticated.33 The authors have no conflicts of interest relevant to this
Fantozzi et al. conducted a survey of 326 COIVD-19 pa- article.
tients with confirmed SARS-CoV-2 infection and reported
that dysgeusia was the most common symptom (59.5%), References
followed by xerostomia (45.9%) and olfactory alterations
(hyposmia/anosmia, 41.4%).4 The most frequently 1. Huang C, Wang Y, Li X, et al. Clinical features of patients
concomitant symptoms in our reported 51 COVID-19 pa- infected with 2019 novel coronavirus in Wuhan, China. Lancet
tients with oral ulcerative lesions is anosmia or hyposmia 2020;395:497e506.

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