957289

research-article2020
JDRXXX10.1177/0022034520957289Journal of Dental ResearchOral Manifestations in Patients with COVID-19

Clinical Review
Journal of Dental Research
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Oral Manifestations in Patients with © International & American Associations
for Dental Research 2020

COVID-19: A Living Systematic Review Article reuse guidelines:

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DOI: 10.1177/0022034520957289
https://doi.org/10.1177/0022034520957289
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J. Amorim dos Santos1, A.G.C. Normando1,2, R.L.Carvalho da Silva1,

A.C. Acevedo1, G. De Luca Canto3, N. Sugaya4, A.R. Santos-Silva2 ,
and E.N.S. Guerra1

Abstract
This living systematic review aims to summarize evidence on the prevalence of oral signs and symptoms in patients with COVID-19. The
review was reported per the PRISMA checklist, and the literature search was conducted in 6 databases and in gray literature. Studies
published in any language mentioning oral symptoms and signs in patients with COVID-19 were included. The risk of bias was assessed
by the Joanna Briggs Institute appraisal tools. The certainty of evidence was evaluated through GRADE assessment. After a 2-step
selection, 40 studies were included: 33 cross-sectional and 7 case reports. Overall, 10,228 patients (4,288 males, 5,770 females, and 170
unknown) from 19 countries were assessed. Gustatory impairment was the most common oral manifestation, with a prevalence of 45%
(95% CI, 34% to 55%; I2 = 99%). The pooled eligible data for different taste disorders were 38% for dysgeusia and 35% for hypogeusia,
while ageusia had a prevalence of 24%. Taste disorders were associated with COVID-19 (odds ratio [OR], 12.68; 95% CI, 6.41 to 25.10;
I2 = 63%; P < 0.00001), mild/moderate severity (OR, 2.09; 95% CI, 1.25 to 3.49; I2 = 66%; P = 0.005), and female patients (OR, 1.64;
95% CI, 1.23 to 2.17; I2 = 70%; P = 0.0007). Oral mucosal lesions presented multiple clinical aspects, including white and erythematous
plaques, irregular ulcers, small blisters, petechiae, and desquamative gingivitis. Tongue, palate, lips, gingiva, and buccal mucosa were
affected. In mild cases, oral mucosal lesions developed before or at the same time as the initial respiratory symptoms; however, in those
who required medication and hospitalization, the lesions developed approximately 7 to 24 d after onset symptoms. Therefore, taste
disorders may be common symptoms in patients with COVID-19 and should be considered in the scope of the disease’s onset and
progression. Oral mucosal lesions are more likely to present as coinfections and secondary manifestations with multiple clinical aspects
(PROSPERO CRD42020184468).

Keywords: gustatory dysfunction, coronavirus infections, meta-analysis, oral-systemic disease(s), systematic reviews, evidence-based
medicine

Introduction
Recently, a global pandemic burden has emerged by the
human-to-human transmission of a novel coronavirus disease
(COVID-19). Since the outbreak in December 2019, COVID-
19 has affected >11,301,800 people (World Health Organization
2020b; Zhou, Yang, et al. 2020). The most common symptoms
are fever and dry cough and in some cases shortness of breath,
dysosmia, and dysgeusia (Guan et al. 2020; Lechien et al. 2020
[see Appendix References 1]). Most human cases of COVID-
19 are mild (80%), while 20% of infected patients may develop
severe disease, and 5% may become critically ill and develop
pneumonia or acute respiratory distress syndrome, which
requires mechanical ventilation and intensive care unit hospi-
talization (Epidemiology Working Group and Chinese Center
2020).
Current research shows that coronavirus invades human
cells via the receptor angiotensin-converting enzyme 2 (ACE2)
through scRNA-seq data analyses. The study identified the
organs that are at risk and are vulnerable to severe acute respi-
ratory syndrome coronavirus 2 (SARS-CoV-2) infection (e.g.,
lung; Zou et al. 2020). Therefore, cells with ACE2 receptor
distribution may become host cells for the virus and cause
inflammatory response in related organs and tissues, such as
the tongue mucosa and salivary glands (Wang et al. 2020; Xu,
Li, et al. 2020; Xu, Zhong, et al. 2020). SARS-CoV-2 interac-
tion with ACE2 receptors may also impair taste bud sensitivity,
which could induce dysfunctional gustatory responses (Mariz
1
Laboratory of Oral Histopathology, Health Sciences Faculty, University
of Brasilia, Brasilia, Brazil
2
Oral Diagnosis, Piracicaba Dental School, University of Campinas, São
Paulo, Brazil
3
Brazilian Centre for Evidence-Based Research, Department of
Dentistry, Federal University of Santa Catarina, Florianópolis, Brazil
4
Stomatology Department, School of Dentistry, University of São Paulo,
São Paulo, Brazil
A supplemental appendix to this article is available online.
Corresponding Author:
E.N.S. Guerra, Health Sciences Faculty, University of Brasilia, Asa Norte,
Brasília, DF 70910-900, Brazil.
Email: elieteneves@unb.br
2 Journal of Dental Research 00(0)
et al. 2020). Available evidence has not yet established an effi-
cient and safe pharmacologic therapy against COVID-19, and
the potential ones are related to several adverse reactions
(Godinho et al. 2020; National Center for Biotechnology
Information 2020).
Therefore, COVID-19 acute infection, with associated ther-
apeutic measures, could contribute to adverse outcomes con-
cerning oral health. The oral signs and symptoms related to
COVID-19 are taste disorders, unspecific oral ulcerations, des-
quamative gingivitis, petechiae, and coinfections such as can-
didiasis (Amorim dos Santos et al. 2020; Cebeci Kahraman
and ÇaŞkurlu 2020; Martín Carreras-Presas et al. 2020).
However, it is still uncertain whether these manifestations
could be a typically clinical pattern resulting from the direct
SARS-CoV-2 infection or a systemic consequence, given the
possibility of coinfections, impaired immune system, and
adverse reactions of medical treatment (Cox et al. 2020;
Dziedzic and Wojtyczka 2020).
Since the prevalence of clinical manifestations is still
unknown, the range of COVID-19 manifestations on the oral
cavity has been considered of broad and current interest. The
emerging approach of a living systematic review (LSR) enables
continuous surveillance of recently published studies through
periodical searches to include new relevant information, espe-
cially in a topic that is constantly updated (Elliot et al. 2017),
as in COVID-19 context. Therefore, the objective of this LSR
was to provide a comprehensive up-to-date summary of oral
manifestations in patients with COVID-19 by reviewing all
relevant observational studies to answer the following ques-
tion: What is the prevalence of oral signs and symptoms in
patients with COVID-19?
Materials and Methods
Protocol and Registration
A systematic review protocol based on PRISMA-P (Moher
et al. 2015) was developed and registered at the International
Prospective Register of Systematic Reviews (PROSPERO)
database under registration CRD42020184468. The present
LSR was reported according to the PRISMA checklist
(Preferred Reporting Items for Systematic Reviews and Meta-
analyses; Moher et al. 2009).
Study Design and Eligibility Criteria
This is an LSR with meta-analysis to assess the prevalence of
oral manifestations related to COVID-19. The COVID-19
research has been evolving quickly; therefore, the “living”
design is adequate to ensure emerging evidence incorporation as
it becomes available (Elliot et al. 2017). The review’s data will
be updated every 6 mo over the next 2 y to maintain dynamic
results and conclusions. For this purpose, 5 mo after publication
and after every update, the search will be retaken, and we will
take at most 1 mo to apply the review process for study selection,
data collection, risk of bias, and synthesis of results.
The inclusion criteria were defined via the PECOS strategy
and consisted of observational studies that investigated the
prevalence of oral disorders in patients with COVID-19. For
taste disorders, only cross-sectional studies were considered.
However, for oral mucosal lesions, case reports were included,
given the lack of available data until this time. There were no
language or publication time restrictions. Dysgeusia, hypogeu-
sia, and ageusia represented the taste disorder subtypes.
Infectious opportunistic lesions (fungal, viral, and bacterial)
and autoimmune and inflammatory lesions (stomatitis, gingi-
vitis) were considered disorders of the oral cavity, as were sali-
vary gland disorders and other oral signs and symptoms in
mucosal tissue.
Information Sources and Search Strategy
Electronic search strategies for the following bibliographic
databases were developed (Appendix Table 1): Embase,
LILACS, Livivo, PubMed, Scopus, and Web of Science. An
additional search in the gray literature was performed, includ-
ing Google Scholar and OpenGrey, as well as a manual search
across reference lists of included studies. The search included
all articles published until June 6, 2020, across all databases. A
software reference manager (EndNote X7; Thomson Reuters)
was used to collect references and remove duplicate articles.
The same search strategies will be run on every update.
Study Selection
The selection was completed in 2 phases. In phase 1, two
authors (J.A.S. and A.G.C.N.) independently reviewed the titles
and abstracts of all the references through Rayyan software
(Ouzzani et al. 2016) and selected those appearing to meet the
inclusion criteria, and the remaining were discarded. The third
author (E.N.S.G.) was involved when required to make a final
decision. In phase 2, the same selection criteria were applied to
the full-text articles to confirm those studies that reported the
prevalence of oral conditions in patients with COVID-19. The
same 2 authors independently participated in phase 2. Reference
lists for all included articles were critically assessed by 3
authors and the new articles selected for selection analysis. Any
disagreement in either phase was resolved by discussion and
mutual agreement among the 3 authors. The final selection was
always based on the full text of the publication.
Data Collection
Initially, the first (J.A.S.) and second (A.G.C.N.) authors col-
lected the required information from the selected articles.
Then, the third author (E.N.S.G.) cross-checked the collected
data and confirmed its accuracy. Again, any disagreement was
resolved by discussion and mutual agreement among the 3
authors. The experts were involved as required for a final deci-
sion. When the necessary data could not be completed, attempts
were made to contact the authors to retrieve the missing
information.
Oral Manifestations in Patients with COVID-19 3
Risk of Bias within Studies
The risk-of-bias assessment was independently evaluated by 2
authors (J.A.S. and A.G.C.N.) using the Joanna Briggs
Institute’s Critical Appraisal Checklist for Studies Reporting
Prevalence Data (Munn et al. 2015) and Critical Appraisal
Checklist for Case Reports (Moola et al. 2017). The third author
(E.N.S.G.) was consulted in case of disagreements. Decisions
about scoring were discussed by all reviewers before critical
appraisal assessments, and a study was characterized as having
a high risk of bias when it reached a “yes” score of up to 49%,
moderate when 50% to 69%, and low when >70%.
Summary Measures
The main outcome was the prevalence of oral manifestations.
The outcomes were divided into 2 groups: taste disorders and
oral mucosal lesions. For taste disorders, secondary outcomes
were the prevalence of different disorders (dysgeusia, hypo-
geusia, and ageusia), as well as associations between taste dis-
orders and COVID-19 positivity, severity, and patients’ sex.
For oral mucosal assessment, secondary outcomes included the
clinical presentation of the lesion and its diagnosis hypothesis,
based on whether it was a coinfection, an autoimmune and
inflammatory manifestation, or a primary sign of SARS-CoV-2
infection.
Synthesis of Results and Statistical Analysis
Qualitative synthesis was conducted by grouping and compar-
ing data reported in the included studies regarding primary and
secondary outcomes. The meta-analyses of taste disorder pro-
portions were performed via cross-sectional studies through
the MetaXL 5.3 add-in Microsoft Excel software. The overall
prevalence of gustatory disorders and the individualized analy-
sis for disorder subtypes (dysgeusia, hypogeusia, and ageusia)
in patients with COVID-19 were expressed through relative or
absolute frequencies and 95% CI. The association analyses of
taste disorders and COVID-19 positivity, severity, and patient
sex were generated with RevMan 5.4 (Nordic Cochrane
Centre). The outcomes were measured using the dichotomous
analysis of odds ratio (OR), considering 95% CIs. The I2 test
was used to calculate statistical heterogeneity, which defined
whether a fixed (I2 < 50%) or random (I2 ≥ 50%) effect model
should be applied. In addition, a sensitivity analysis was per-
formed to ascertain if the studies with a high risk of bias inter-
fered with the final result of the meta-analysis.
Certainty of Evidence
The GRADE instrument (Grading of Recommendation,
Assessment, Development, and Evaluation; Guyatt et al. 2008;
Murad et al. 2017) assessed evidence quality and grading of
recommendation strength in all studies included in the quanti-
tative and qualitative synthesis. The certainty of evidence was
rated for taste disorder prevalence and associations and for oral
mucosal lesions. This assessment was based on study design,
risk of bias, inconsistency, indirectness, imprecision, and other
considerations. Evidence quality was characterized as high,
moderate, low, or very low (Atkins et al. 2004; Murad et al.
2017). GRADE was assessed per http://gradepro.org.
Results
Study Selection and Characteristics
In the first phase, 1,688 records were identified from databases,
and after removal of duplicates, 1,211 references remained for
title and abstract screening. After all records were evaluated, 75
articles were selected to the second phase. A full-text reading
was conducted, and 35 studies were excluded according to pre-
defined eligibility criteria (Appendix Table 2). Thereafter, 40
studies were selected for synthesis (see Appendix References
1), of which 33 were cross-sectional appraising taste disorders
and 7 were case reports assessing oral mucosal lesions. A flow-
chart detailing the process is presented in Figure 1.
The included studies were distributed worldwide, wherein
57.5% were performed in Europe, 25% in Asia, 12.5% in North
America, and 5% in South America (Table 1, Appendix Fig.
1A). All studies were published between March and June 2020.
English was the only publishing language.
Risk of Bias within Studies
Risk-of-bias assessment in individual studies is summarized
in Table 1 and detailed in Appendix Table 3. Case reports and
cross-sectional studies were evaluated with the appropriate
checklist for each study design (Munn et al. 2015; Moola
et al. 2017).
Synthesis of Studies
A total of 10,228 patients with COVID-19 were included in this
LSR. Reverse transcriptase polymerase chain reaction for detec-
tion of viral RNA and serologic assays for detection of IgG/IgM
antibodies were the most employed methods for COVID-19
confirmation (Appendix Table 4). Taste disorders were relevant
symptoms as compared with data on overall signs and symp-
toms in patients with COVID-19. Smell dysfunction was exten-
sively reported in the included studies assessing taste disorders,
and its prevalence varied from 4.9% (Romero-Sánchez et al.
2020) to 69.8% (Vaira, Hopkins, Salzano, et al. 2020) in patients
with COVID-19. At least 14 studies included in this LSR
reported a higher prevalence of taste disorders in comparison
with smell dysfunction. Descriptive characteristics of patients
with COVID-19 and associated details are provided in Table 1
(for details of diagnosis test for COVID-19 and treatments
applied, see Appendix Table 4).
All cross-sectional studies appraised gustatory outcomes
(Table 2), from which 10,220 patients were identified (4,283
males, 5,767 females, 170 unreported). Almost all studies diag-
nosed taste disorders through in-person, online, or phone call
4 Journal of Dental Research 00(0)

Figure 1.  Flow diagram of literature search and selection criteria adapted from PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-
analyses).

questionnaires, except that by Vaira, Hopkins, Salzano, et al.
(2020), who conducted a standardized and validated test using
prepared solutions (data provided in Table 2). Questionnaire
methods are subjective, and taste disorder subtypes (dysgeusia,
hypogeusia, and ageusia) were diagnosed according to the pro-
fessional’s concept in each study, which may impair the quality
of data collection. Also, it is important to highlight that many
patients with smell disorders may complain of a loss of taste;
however, <5% of them present a measurable taste impairment
(Hummel et al. 2011).
In addition, oral mucosal lesions were presented only in
case reports, and their characteristics are summarized in
Table 3. Just 7 studies assessed 8 confirmed COVID-19 case
reports (5 male and 3 female).
Prevalence of Taste Disorders.  Taste disorders were assessed in
all cross-sectional studies. The study sample sizes ranged from
10 to 3,191 patients with COVID-19, of which 10,220 were
considered in gustatory disorders assessments. The sample age
ranged from 11 to 88 y. Considering that COVID-19 severity
definition was variable among included studies, we grouped
nonhospitalized patients with mild/moderate cases and hospi-
talized patients with severe cases, according to categorization
terms reported by authors (Table 1).
Oral Manifestations in Patients with COVID-19 5

Table 1.  Descriptive Characteristics of Included Studies (n = 40).

Age, y, Mean ± SD Risk of

Studya Design Sample, n (Range) COVID-19 Severity, % COVID-19 Signs and Symptoms Reported, % Biasb

Aggarwal (2020), CS 16, M:12, F:4 65.5 50 hospitalized, 50 Anosmia (19), arthralgia (25), chest pain (6), diarrhea (6), dry Moderate
United States ICU cough (88), dysgeusia (19), dyspnea (81), fatigue (50), fever
(94), headache (25), lightheadedness (19), nausea/vomiting
(13), sore throat (12.5)
Amorim dos Santos CR Case 1, M 67 ICU Bilateral diffuse hyperdense infiltrations in both lungs, Low
(2020), Brazil diarrhea, dyspnea, erythema in palatine tonsil region, fever,
geographic tongue, multiple pinpoint yellowish ulcers and
white plaque on the tongue dorsum, respiratory symptoms
Ansari (2020), Iran CR Case 1, F; case 56; 75 Hospitalized Fever, shortness of breath, and oral ulcers; dysphasia, Low
2, M hypoxia, and oral ulcers
Beltran-Corbellini CS 79, M:48, F:31 61.6 ± 17.4 Hospitalized Smell and/or taste disorders (39.2) Low
(2020), Spain
Bénézit (2020), France CS 68, NR NR Nonhospitalized Hypogeusia (62) and hyposmia (45) High
Carignan (2020), CS 134, M:64, F:70 57.1 (41.2 to 2.2 hospitalized Anosmia (51.5), anosmia and/or dysgeusia (64.9), arthralgia Low
Canada 64.5) (27.6), asthenia (77.6), blurred vision (4.5), chest pain
(26.1), chills (53.0), cough (72.4), diarrhea (44.8), dysgeusia
(63.4), dyspnea (41.8), fever (objective) (37.3), fever
(subjective) (34.3), headache (64.9), loss of appetite (56.0),
myalgia (56.7), nasal congestion (43.3), nasal drip (44.8),
nausea (29.8), rash (6.0), red eyes (0.7), sneezing (39.6),
sore throat (44.8), sputum production (29.8), vertigo or
dizziness (20.1), vomiting (6.7)
Cebeci Kahraman CR Case 1, M 51 Nonhospitalized Fatigue, fever, severe dry cough, smell and taste disorders, Low
(2020), Turkey sore throat, erythematous surface in the oropharynx and
on the hard palate, oral petechiae, and pustular enanthema
Chaux-Bodard (2020), CR Case 1, F 45 Nonhospitalized Mild asthenia, single ulcer on tongue surface, and an Moderate
France erythematous plane lesion on the big toe
Chary (2020), France CS 115, M:34, F:81 47 (20 to 83) 24 hospitalized, Cough (43), diarrhea (17), fever (61), headache (54), Low
4 ICU myalgia (50), odynophagia (18), rhinitis (22), smell or taste
disorders (70)
de Maria (2020), Italy CS 95, NR NR Nonhospitalized Diarrhea, dysgeusia, fatigue, influenza-like-illness with fever Low
(37.5 to 38 °C), myalgias, nausea
Dell’Era (2020), Italy CS 355, M:192, F:163 50 (40 to 59.5) Nonhospitalized Cough (47.9), diarrhea (19.7), dyspnea (21.7), fatigue (40.3), Low
fever (72.1), smell disorders (66.7), taste disorders (65.4)
Gelardi (2020), Italy CS 72, M:39, F:33 49.7 (19 to 70) NR Anosmia (11), breathlessness (47), cough (80), diarrhea (11), Low
dysgeusia (25), fever (86), headache (22), myalgia (18), nasal
congestion (7), nausea/vomiting (15), weakness (40)
Giacomelli (2020), CS 59, M:40, F:19 60 (50 to 79) Hospitalized Abdominal symptoms (8.5), ageusia (13.6), anosmia (11.9), Low
Italy arthralgia (5.1), asthenia (1.7), coryza (1.7), cough (37.3),
dysgeusia (15.3), dyspnea (25.4), fever (72.8), headache
(3.4), hyposmia (11.9), sore
throat (1.7)
Kim (2020), South CS 172, M:66, F:106 26 (22 to 47) Nonhospitalized Abdominal pain (2.9), anorexia (13.4), chills (18.0), cough Low
Korea (40.1), diarrhea (15.7), dizziness (18.6), dyspnea (4.1),
fatigue (26.7), fever (11.6), headache (31.4), hemoptysis
(0.6), hypogeusia (33.7), hyposmia (39.5), myalgia (31.4),
nasal congestion (34.3), nausea (4.1), pleuritic chest pain
(1.7), rhinorrhea (26.2), sore throat (18.0), sputum (39.5),
vomiting (1.2)
Klopfenstein (2020), CS 54, M:18, F:36 47 ± 16 37 hospitalized, Abdominal pain (28), anosmia (100), arthralgia (72), blurred Low
France 9 ICU vision (7), conjunctival hyperemia (4), cough (87), diarrhea
(52), dry eyes (4), dysgeusia (85), dyspnea (39), epistaxis
(11), fatigue (93), feeling of fever (22), fever (74), headache
(82), hearing loss (7), hemoptysis (6), myalgia (74), nasal
obstruction (30), nausea (35), rhinorrhea (57), sneezing
(33), sore throat (43), sputum production (22), tearing (7),
tinnitus (11), vomiting (6)
Kluytmans-van den CS 86, M:15, F:71 49 (22 to 66) 2 hospitalized Abdominal pain (6), chest pain (29), cough (77), diarrhea Low
Bergh (2020), or loose stools (19), general malaise (76), headache (57),
Netherlands loss of appetite or nausea (17), objective fever (53), runny
nose (53), severe myalgia (63), shortness of breath (38),
sore throat (40), subjective fever (12), taste disorders (7),
other (20)
Lapostolle (2020), CS 197, M:81, F:109, 44 (31 to 54) 8 hospitalized Ache/myalgia (44), ageusia (28), anorexia (22), anosmia (31), Low
France NR: 7 asthenia (52), chest pain (22), diarrhea (25), dry cough
(55), eye disease (5); fever (42), headache (50), hemoptysis
(2), nausea (18), pharyngalgia (22), rhinopharyngitis (13),
shortness of breath (40), vomiting (17)

(continued)
6 Journal of Dental Research 00(0)

Table 1. (continued)

Age, y, Mean ± SD Risk of

Studya Design Sample, n (Range) COVID-19 Severity, % COVID-19 Signs and Symptoms Reported, % Biasb

Lechien (2020), CS 417, M:154, F:263 36.9 ± 11.4 (19 Nonhospitalized Abdominal pain, anosmia, arthralgia, asthenia, cough, diarrhea, Low
Belgium, Canada, to 77) dysgeusia, dysphagia, dyspnea, ear pain, face pain/heaviness,
France, Italy, Spain, fever, headache, hyposmia, loss of appetite, myalgia,
Switzerland nasal obstruction, nausea and vomiting, postnasal drip,
rhinorrhea, sore throat, sticky mucus
Lee, Lockwood, CS 56, M:23, F:33 38 (31.8 to 47.2) 7.3 hospitalized Abdominal pain (12.5), anosmia (42.9), cough (66.1), diarrhea Low
(2020), Canada (35.7), dysgeusia/ageusia (57.1), fatigue (7.1), fever (46.4),
headache (17.9), hyposmia (12.5), nasal congestion (41.1),
rhinorrhea (26.8), shortness of breath (37.5), sore throat
(37.5), other (44.6)
Lee, Min, (2020), CS 3,191, M:1,161, 44 (25 to 58) NR Anosmia (12.19) and dysgeusia (11.06) Low
South Korea F:2,030
Levinson (2020), Israel CS 42, M:23, F:19 34 (15 to 82) Hospitalized with mild Abdominal pain (17), anosmia (33), chest pain (5), chills Moderate
symptoms (5), conjunctivitis (2), coryza (40), cough (69), diarrhea
(21), dizziness (21), dysgeusia (36), dyspnea (43), fatigue
(69), fever (88), headache (48), hemoptysis (2), myalgia or
arthralgia (57), nausea or vomiting (12), palpitation (12),
sore throat (31)
Liguori (2020), Italy CS 103, M:59, F:44 55 ± 14.6 Hospitalized Anxiety (33.01), auditory disorder (1.94), confusion (22.33), Low
nonsevere cases daytime sleepiness (33.01), depression (37.86), dizziness
(26.21), dysgeusia (46.60), fatigue (32.04), headache
(38.83), hyposmia (38.83), muscle ache (24.27), numbness/
paresthesia (5.8), sleep impairment (49.51)
Mao (2020), China CS 214, M:87, F:127 52.7 ± 15.5 Hospitalized 41.1 Abdominal pain (4.7), acute cerebrovascular disease (2.8), Low
severe and 58.9 anorexia (31.8), ataxia (0.5), seizure (0.5), cough (50.0),
nonsevere cases diarrhea (19.2), dizziness (16.8), fever (61.7), headache
(13.1), impaired consciousness (7.5), nerve pain (2.3),
skeletal muscle injury (10.7), smell impairment (5.1), taste
disorders (5.6), throat pain (14.5), vision impairment (1.4)
Martín Carreras- CR Case 3, F 65 Nonhospitalized Diarrhea, high fever, rashes on oral mucosa, rashes under Low
Presas (2020), Spain the breasts and other parts of the skin, including back and
genital area
Meini (2020), Italy CS 100, M:60, F:40 65 ± 15 NR Smell disorder (29) and taste disorder (41) Low
Mercante (2020), Italy CS 204, M:110, F:94 52.6 ± 14.4 NR Diarrhea (8.3), dizziness (21.1), dry cough (44.6), dyspnea Low
(5.9), ear fullness (10.8), ear pain (6.4), facial pain and/or
pressure (12.7), fatigue (22.6), fever (65.7), headache (15.7),
myalgia or arthralgia (9.9), nasal obstruction (34.3), nausea
or vomiting (5.9), postnasal drip (23.0), runny nose (35.8),
smell disorders (41.7), sneezing (32.3), taste disorders
(55.4), thick nasal discharge (14.2)
Merza (2020), Iraq CS 15, M:9, F:6 28.06 ± 16.42 86.7 mild, 6.7 mild/ Asymptomatic (40), chill (6.7), cough (46.7), fatigue (20), Low
moderate, 6.7 fever (53.3), rhinorrhea (13.3), shortness of breath (20),
moderate/severe smell disorder (13), sore throat (6.7), taste disorders (26.7)
Noh (2020), South CS 199, M:69, F:130 38.0 ± 13.1 Residential treatment Ageusia (22.6), anorexia (0.5), anosmia (26.1), asymptomatic Low
Korea care with mild (26.6), chest pain (3.5), cough (41.2), diarrhea (4.5),
symptoms fatigue (4.0), fever (19.1), headache (3.5), myalgia (17.1),
pneumonia (2.5), rhinorrhea/nasal stuffiness (30.2), sore
throat (7.5), sputum (20.6)
Paderno (2020), Italy CS 508, M:285, F:223 55 ± 15 (18 to 91) 58 hospitalized, 42 Arthromyalgia (50.4), asthenia (69.2), diarrhea (33.6), dry Low
and Sweden nonhospitalized cough (64.5), dyspnea (50), fever (89.5), headache (38.9),
nasal congestion (22.4), nausea (22.4), ocular discomfort
(16.7), pharyngodynia (21.2), smell disorder (55.7), syncope
(8.2), taste disorder (63.2)
Patel (2020), United CS 141, M:83, F:58 45.6 (20 to 93) 34.8 hospitalized, 65.2 Ageusia (63.1), anosmia (56.7), cough (72.3), diarrhea (31.9), Low
Kingdom nonhospitalized fever (75.7), myalgia (66), nasal congestion (42.6), shortness
of breath (61), vomiting (13.5)
Putra (2020), CR Case 1, M 29 NR Anosmia, back pain, dry cough, fever, myalgia, rhinorrhea, Low
Indonesia sore throat, pin and needles sensation, viral exanthema, and
stomatitis aphthous
Romero-Sánchez CS 841, M:473, F:368 66.42 ± 14.96 Hospitalized Anosmia (4.9), anxiety (8.1), asthenia (51), cough (76.7), Low
(2020), Spain 9.16 ICU depression (5.2), dizziness (6.1), dysgeusia (6.2), dyspnea
(75.7), fever (87.9), gastrointestinal symptoms (54.1),
headache (14.1), myalgia (17.2), syncope (0.6)

(continued)
Oral Manifestations in Patients with COVID-19 7

Table 1. (continued)

Age, y, Mean ± SD Risk of

Studya Design Sample, n (Range) COVID-19 Severity, % COVID-19 Signs and Symptoms Reported, % Biasb

Sayin (2020), Turkey CS 64, M:25, F:39 37.78 ± 11.34 NR Chills (29.7), cough (43.8), fever (28.1), gastrointestinal Low
distress (17.2), headache (31.3), malaise (64.1), nasal
congestion (28.1), pneumonia (23.4), rhinorrhea (17.2),
smell disorders (67.1), taste disorders (71.8), other (18.8)
Sierpinski (2020), CS 1,942, M:773, 50 Nonhospitalized Diarrhea (24.2), lack of appetite (47), smell disorder (49.2), Low
Poland F:1,169 taste disorders (47.5)
Soares (2020), Brazil CR Case 1, M 42 Hospitalized Cough, fever, shortness of breath, petechia-like and small Low
vesicobullous lesions in the skin, and oral ulcerated lesion
and multiple reddish macules
Speth (2020), CS 103, M:50, F:53 46.8 ± 15.9 3.8 hospitalized, 18 Cough (68), fever (74.8), mucus production (35), nasal Low
Switzerland and already released of obstruction (49.5), shortness of breath (46.6), smell
United States hospitalization, 78 disorder (61.2), taste disorder (65)
nonhospitalized
Sultan (2020), United CS 10, M:7, F:3 NR (31 to 62) Hospitalized Confusion (10), cough (80), dyspnea (70), fatigue (30), fever High
States (90), gastrointestinal symptoms (30), myalgia (10), pleuritic
chest pain (10), taste disorders (10)
Vaira, Hopkins, CS 345, M:146, F:199 48.5 ± 12.8 (23 53.3 hospitalized Smell disorder (69.8), taste disorder (44.8) Low
Salzano (2020), Italy to 88)
Yan (2020), United CS 128, M:61, F:67 53.5 (40 to 65), 20.3 hospitalized Anosmia (58.5), cough (87.5), diarrhea (37.5), dysgeusia Low
States 43 (34 to 54)c (54.6), dyspnea (50), fatigue (70.3), fever (70.3), headache
(48.4), nasal obstruction (27.3), rhinorrhea (13.2), sore
throat (42.9), sputum production (15.6)
Zayet (2020), France CS 95, M:16, F:79 39.8 ± 12.2 (18 Nonhospitalized Anosmia (63.2), cough (78.9), dysgeusia (65.3), dyspnea Low
to 73) (42.1), gastrointestinal symptoms (56.8), headache (77.7),
myalgia and/or arthralgia (74.7), rhinorrhea (62.1)

CR, case report; CS, cross-sectional; F, female; ICU, intensive care unit; M, male; NR, not reported.
a
See Appendix References 1 for included studies.
b
Assessed by the Joanna Briggs Institute critical appraisal tools for case reports and prevalence studies.
c
Median: hospitalized and nonhospitalized.

After a sensitivity analysis, the 2 studies classified as high
risk of bias were removed from the meta-analysis (Bénézit
et al. 2020; Sultan et al. 2020). The overall prevalence of gus-
tatory disorders was 45% (95% CI, 34% to 55%; I2 = 99%;
Fig. 2A). When each disorder was assessed separately, the
prevalence of dysgeusia was 38% (95% CI, 22% to 56%; I2 =
98%), 35% for hypogeusia (95% CI, 21% to 51%; I2 = 97%),
and 24% for ageusia (95% CI, 15% to 35%; I2 = 97%; Fig. 2B,
Appendix Table 5). The mean duration of these conditions
was 15 d, and patients seemed to fully recover. Taste disorders
were presented in 53% of North American patients with
COVID-19, in 50% of Europeans, and in 27% of Asians
(Appendix Fig. 1B).
Association between Taste Disorders and COVID-19 Character-
istics.  The OR analysis showed a positive association between
taste disorder symptoms and COVID-19, with an OR of 12.68
(95% CI, 6.41 to 25.10; I2 = 63%; P < 0.00001; Fig. 3A).
Regarding COVID-19 severity, an association was observed
between taste disorders and mild/moderate COVID-19 cases as
compared with severe ones, presenting an OR of 2.09 (95% CI,
1.25 to 3.49; I2 = 66%; P = 0.005; Fig. 3B). Furthermore, taste
disorders were significantly associated with female patients
(OR, 1.64; 95% CI, 1.23 to 2.17; I2 = 70%; P = 0.0007; Fig.
3C). Detailed data in the OR analysis are reported in Appendix
Tables 6 to 8.
Description of Oral Mucosal Lesions in Patients with COVID-19
from 7 Studies. Oral mucosal lesions showed miscellaneous
clinical aspects, varying in localization, size, color appearance,
and quantity. Patients presented blisters, ulcers, erosion, mac-
ule, and plaques. Four patients presented oral mucosal lesions
in a localized area, while the lesions were diffuse in 3 patients,
and data were not reported for 1 patient. Tongue mucosa was
affected in 5 cases, while injuries on the lips and palate were
reported in 3 cases each, and buccal mucosa and gingiva were
described once in different patients (Table 3). Appendix Figure
2 summarizes the clinical aspects of lesions.
In 2 cases, first oral manifestations developed in association
with the initial systemic symptoms (Chaux-Bodard et al. 2020;
Martín Carreras-Presas et al. 2020). In addition, patients with
severe COVID-19 infection (i.e., with medication use or hospi-
talization need) developed late lesions between the 7th and
24th day after symptom onset (Amorim dos Santos et al. 2020;
Ansari et al. 2020; Cebeci Kahraman and ÇaŞkurlu 2020;
Martín Carreras-Presas et al. 2020; Putra et al. 2020). In all
patients, the lesions healed within 3 to 21 d through topical
treatments, by oral hygiene, or spontaneously.
Two patients presented negative serological test results for
herpes simplex virus type 1 and 2 antibodies (Ansari et al.
2020), and 1 showed negative immunohistochemical reactions
against herpes simplex virus types 1 and 2, cytomegalovirus,
Treponema pallidum, and Epstein-Barr virus (Soares et al.
2020). However, other infectious, inflammatory, and autoim-
mune disorders could not be excluded for diagnosis. Therefore,
oral mucosal lesions seemed to develop as secondary manifes-
tations and coinfections related to a weakened systemic condi-
tion of the patients.
8 Journal of Dental Research 00(0)
Table 2.  Taste Disorders Characterization in Patients with COVID-19 (n = 33 Cross-sectional Studies).
Studya
Aggarwal (2020), United
States
Beltran-Corbellini (2020),
Spain
Bénézit (2020), France
Carignan (2020), Canada
Chary (2020), France
de Maria (2020), Italy
Dell’Era (2020), Italy
Gelardi (2020), Italy
Giacomelli (2020), Italy
Kim (2020), South Korea
Klopfenstein (2020), France
Kluytmans-van den Bergh
(2020), Netherlands
Lapostolle (2020), France
Lechien (2020), Belgium,
Canada, France, Italy,
Spain, Switzerland
Lee, Lockwood, (2020),
Canada
Lee, Min, (2020), South
Korea
Levinson (2020), Israel
Liguori (2020), Italy
Mao (2020), China
Meini (2020), Italy
Mercante (2020), Italy
Merza (2020), Iraq
Noh (2020), South Korea
Paderno (2020), Italy and
Sweden
Patel (2020), United
Kingdom
Romero-Sánchez (2020),
Spain
Sayin (2020), Turkey
Sierpinski (2020), Poland
Speth (2020), Switzerland
and United States
Sultan (2020), United States
Vaira, Hopkins, Salzano
(2020), Italy
Yan (2020), United States
Zayet (2020), France
Blank cells indicate not reported.
TD, taste disorders.
a
See Appendix References 1 for included studies.
b
Taste disorders in general.
c
Based on Vaira, Salzano, Petrocelli, et al. (2020).
Taste Disorders, %  
Duration, d,
Dysgeusia Hypogeusia Ageusia Period of Appearance Mean ± SD (Range) TD Diagnosis Method
19  
10.1 8.8 17.7 First symptoms in 11 (35.5%) 7.1 ± 3.1 Questionnaire applied by phone
62 Questionnaire applied online
63.4 50.7 Questionnaire applied by phone
31.3 31.3 15 (4 to 27) Questionnaire applied by phone
50.5b Occurred early (within 5 d Questionnaire applied in personal
from onset of fever)
66.4b First symptoms in 31 (13.3%) 10 (2 to 25) Questionnaire applied in person or
by phone
72.2 Mean 2.8 d (range, 1 to 4) 16.1 (7 to 22)  
before the respiratory
symptoms
15.2 13.55 Before hospitalization in 91% Questionnaire applied in person
of patients
33.7 First symptom in 44 (28.6%) Questionnaire applied in person
85.1 Recorded medical files
7b Questionnaire applied in person
28 Questionnaire applied by phone
21.1 78.9 Questionnaire applied in person or
by phone
57.1b First symptoms in 26 patients Questionnaire applied online
(46.4%)
13.05 6.0 (3.0 to 10.0) Questionnaire applied by phone
33.3 Mean 3.3 d after illness onset 7.1 (0 to 7) Questionnaire applied online or
(range, 0 to 7 d) by phone
46.6 More frequent on patients Questionnaire applied in person
interviewed after the 7th day
of hospitalization
5.6b Median onset until hospital Recorded medical files
admission: 2 d (range, 1 to 5)
41b 32 Questionnaire applied by phone
55.4b Questionnaire applied by phone
26.7b  
22.6 7.5 ± 5.6 Questionnaire applied in person
63.1b First symptom in 57 (11.22%), Complete resolution: Questionnaire applied in person
delayed symptom in 451 9.2 ± 5.4; ongoing
(88.7%) disorder, 12.4 ± 6.8
63.1 Questionnaire applied by phone
6.2 Fist symptom in 31 (60%) Recorded medical files
25 56.3 12.5 First symptom in 14 (30.4%) Questionnaire applied in person
47.5b Questionnaire applied by phone
25.2 39.8 Questionnaire applied by phone
10b  
34.5 10.4 Taste disorders were more 191 of 256 (74.6%) Standardized and validated test
frequent on days 0 to 4 of followed up presented using prepared solutionsc
the disease ≤7 d of chemosensitive
symptoms duration
54.6 Recorded medical files
65.3 38% with dysgeusia and Questionnaire applied in person
anosmia were tested >5 d
after the onset of symptoms
Oral Manifestations in Patients with COVID-19 9

Table 3.  Oral Lesion Characterization in Patients with COVID-19 (n = 7 Studies).

Oral Signs and Location on Oral History of Duration and Treatments for Oral
Studya Symptoms Mucosa Appearance Recovery Conditions Reported Diagnosis

Amorim dos 1) White plaque. 2) 1) Tongue On the 24th day of 14 d after the first Fluconazole, oral 1) Fungus infection. 2) Herpetic
Santos Multiple pinpoint dorsum. hospitalization, oral examination, nystatin, and recurrent oral lesion. 3)
(2020), yellowish ulcers. 2) Tongue the white plaque the lesions on the chlorhexidine Fibroma. 4) Geographic
Brazil 3) Nodule. dorsum. 3) was persistent and tongue dorsum digluconate tongue. Authors suggested
4) Severe Lower lip associated with resolved almost (0.12%) alcohol- that oral lesions, coinfections,
geographic yellowish ulcers. completely. Severe free mouth and secondary manifestations
tongue + Two weeks later, geographic tongue rinses, hydrogen may be due to systemic
fissured tongue. severe geographic improved to peroxide, and condition of the patient
5) Extremely tongue was moderate within oral health care
viscous saliva observed approximately 17 d
after its appearance
Ansari Several painful Case 1: Hard Case 1: 5 d after Approximately 7 d Diphenhydramine, Diffuse edema with
(2020), ulcers, with palate. Case the onset of of duration until dexamethasone, desquamation, granulation,
Iran irregular margins 2: Anterior symptoms. Case complete recovery tetracycline, and and ulceration under the
and varying region of the 2: 1 wk after lidocaine mucosa, with invasion of
sizes in red and tongue hospitalization mononuclear and neutrophilic
nonhemorrhagic cells, indicating a secondary
background bacterial infection. Negative
serologic tests for herpes
simplex virus type 1 and 2.
Authors suggested that oral
lesions are due to COVID-19
Cebeci 1) Largely 1) Oropharynx 10 d after the onset After a few days of Antibiotic therapy Diffuse oropharyngeal
Kahraman erythematous and hard symptoms therapy erythema, petechia, and
(2020), surface. 2) Few palate. 2) pustule formation. Authors
Turkey petechiae. 3) Palate midline. suggested that oral mucosal
Numerous 3) Near may be involved in COVID-19
pustular soft palate symptoms
enanthema border, more
(1 to 3 mm in prominent on
diameter) the left side
Chaux- Irregular ulcer Dorsal side of First symptom: 10 d of duration until Not reported COVID-19 is associated with
Bodard the tongue a painful complete recovery inflammatory reactions, such
(2020), inflammation as vascular inflammation.
France of a tongue The ulcer observed after
papilla. 24 h later: a macular erythematous
erythematous lesion could be explained by
macula. After, the vasculitis. Authors suggested
lesion turned to that these oral ulcers could
an irregular and be an inaugural symptom of
asymptomatic ulcer COVID-19
Martín 1) Pain. 2) Small 1) Tongue. 2) 1) With first 3 d of duration and 1) Hyaluronic acid Suggestive of erythema
Carreras- blisters. 3) Internal lip symptoms. 2 and treatment until and chlorhexidine multiforme. Authors
Presas Desquamative mucosa. 3) 3) 1 mo after first recovery mouthwash. 2) suggested that SARS-CoV-2
(2020), gingivitis Gingiva symptoms Prednisolone may provoke exanthematic
Spain 30 mg/d lesions
Putra (2020), Stomatitis Not reported 7 d after the first 3 d of duration until Usual hygiene oral Stomatitis aphthous. Authors
Indonesia aphthous symptom (fever) recovery care suggested a diagnosis of hand,
foot, and mouth disease
Soares 1) Painful 1) Buccal Not reported 21 d of duration until Not reported Diffuse chronic inflammatory
(2020), ulceration. 2) mucosa. 2) complete recovery infiltrate with focal areas of
Brazil Multiple reddish Scattered necrosis and hemorrhage in
macules of along the hard the lamina propria. Intense
different sizes palate, tongue, lymphocytic infiltration in
and lips adjacent minor salivary glands.
Negative IHC reactions
against HHV-1, HHV-2, CMV,
treponema pallidum, and EBV.
Authors suggested that oral
mucosal may be involved in
COVID-19 symptoms

CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV, human herpesvirus; IHC, immunohistochemical.
a
See Appendix References 1 for included studies.
10 Journal of Dental Research 00(0)

findings of 10,228 patients with

COVID-19 provide the best available
evidence in terms of oral manifesta-
tions related to coronavirus disease
2019. Taste disorders were the most
common oral symptoms in patients
with COVID-19, presenting a higher
prevalence in Europe and North
America than in Asia and a signifi-
cant association with COVID-19–
positive diagnosis, mild/moderate
COVID-19 severity, and female
patients.
Chemosensory disorders are
defined as diseases or problems asso-
ciated with the sense of smell and/or
taste. Taste disorders are classified as
quantitative or qualitative disorders,
of which hypogeusia is a decreased
sense of taste, ageusia is the absence
of a sense of taste, and dysgeusia is a
qualitative distortion of taste percep-
tion (Maheswaran et al. 2014).
Although chemosensory disorders
are commonly mentioned in flu-like
diseases, these conditions were not
reported during previous SARS and
MERS outbreaks (Pellegrino et al.
2020). Interestingly, in the present
pandemic by SARS-CoV-2, olfactory
and gustatory disorders have become
extensively noticed as common
symptoms of COVID-19. In this
LSR, patients with COVID-19 pre-
sented a prevalence of 45% for over-
all taste disorders, 38% for dysgeusia,
35% for hypogeusia, and 24% for
ageusia. In addition, a significant
association was found between taste
Figure 2.  Prevalence of taste disorders. (A) Forest plot shows the pooled prevalence of taste
disorders and COVID-19 positivity
disorders in patients with COVID-19. (B) The prevalence of individual taste disorders: dysgeusia,
hypogeusia, and ageusia. I2, inconsistency index. when compared with patients with-
out COVID-19 who presented simi-
lar symptoms. These results confirm that taste disorders may
Certainty of Evidence be a significant and specific symptom of mild/moderate
The certainty of evidence from outcomes assessed by the COVID-19 cases. Although not specific, chemosensitive disor-
GRADE system was high for the prevalence of taste disorders ders have been suggested as important markers of early infec-
in patients with COVID-19. Also, the system showed a moder- tion; however, several clinical conditions decrease the oral
ate certainty of evidence for the association of taste disorders intake and may impair the identification of taste disorders in
and COVID-19 positivity, severity, and patient sex. In contrast, those cases (Paderno et al. 2020; Romero et al. 2020; Vaira,
a low certainty of evidence was observed regarding the descrip- Hopkins, Salzano, et al. 2020; Yan et al. 2020). Taste disorders,
tion of oral mucosal lesions in patients with COVID-19 as easily and early detectable symptoms, would allow mild/
(Appendix Table 9). moderate case identification and self-isolation orientation,
directly contributing to contain the quick spreading of the dis-
Discussion ease, especially in countries with reduced testing capability
(Kucharski et al. 2020; Prather et al. 2020; World Health
The present LSR approach was chosen since the quick emer- Organization 2020a).
gence of COVID-19 evidence demands incorporation of data Although taste disorder pathogenesis in patients with
as they become available (Elliot et al. 2017). At this time, the COVID-19 is not completely understood, several hypotheses
Oral Manifestations in Patients with COVID-19 11

Figure 3.  Forest plots show the association of taste disorders and (A) patients with and without COVID-19, (B) mild/moderate and severe cases of
COVID-19, and (C) male and female patients. I2, inconsistency index; M-H, Mantel-Haenszel test; OR, odds ratio; Q, Cochran’s Q test; Z, Z test; χ2,
chi-square test.

have been raised (Finsterer and Stollberger 2020; Mariz et al.
2020; Vaira, Salzano, Fois, et al. 2020). Finsterer and Stollberger
(2020) highlighted the possibility of a local inflammatory
response resulting from rhinitis triggers, which could hamper
the normal function of taste buds. However, the occurrence of
signs and symptoms due to nasal mucosal inflammation is not
mandatory for taste impairment in patients with COVID-19.
Taste disorders may precede these manifestations, and many
studies demonstrated a higher prevalence of taste disorders than
rhinorrhea or no association between symptoms (Beltran-
Corbellini et al. 2020; Chary et al. 2020; Finsterer and
Stollberger 2020; Kim et al. 2020). Correspondingly, Vaira,
Salzano, Fois, et al. (2020) mentioned that taste sensation may
pose as an adverse event by concomitant olfactory disorder in
12 Journal of Dental Research 00(0)
patients with COVID-19. Nonetheless, patients with COVID-
19 present taste disorders even without smell dysfunction, since
the prevalence of taste disorders is frequently higher (Table 1).
Taste disorder, as a side effect of certain drugs for COVID-19
treatment, is another questionable hypothesis. The association
found between taste disorders and mild/moderate cases corrob-
orates the conclusion of Finsterer and Stollberger (2020) that
these symptoms also occur in patients with COVID-19 who are
drug-free.
The interaction of SARS-CoV-2 with gustatory components
and ACE2 receptors supports a direct effect in COVID-19–
related taste disorders. First, the peripheral nervous system is
affected by the new coronavirus, and as gustatory buds are
innervated by cranial nerves, related functions may be impaired,
resulting in taste disorders (Kinnamon and Cummings 1992;
Finsterer and Stollberger 2020). Second, SARS-CoV-2 may
bind essential salivary mucin components, such as sialic acid,
consequently accelerating taste particle degradation and dis-
turbing gustatory sensation (Milanetti et al. 2020; Pushpass
et al. 2020; Vaira, Salzano, Fois, et al. 2020). Moreover, the
tongue presents a high expression of ACE2 (Hamming et al.
2004; Xu, Zhong, et al. 2020), and its interaction with SARS-
CoV-2 may affect normal gustatory functions through dopamine
and serotonin synthesis pathway coregulation (Finsterer and
Stollberger 2020; Mao et al. 2020; Nataf 2020). In addition,
ACE inhibitors and ACE2 blockers are frequently associated
with impairment of taste sensation (Tsuruoka et al. 2004;
Unnikrishna et al. 2004). These drugs play a role in taste disor-
ders by G protein–coupled and sodium channel inactivation
(Vaira, Salzano, Fois, et al. 2020). Similar to what patients with
COVID-19 experience after infection recovery, the effect on
gustatory sense by ACE inhibitors regresses a few weeks after
discontinuation. Furthermore, ACE2 high expression was dem-
onstrated in the taste buds of rats and was associated with angio-
tensin II production in mice taste buds. These findings might
also suggest the inability of ACE2 to degrade this protein during
COVID-19 infection, resulting in disorderly taste responses
(Shigemura et al. 2019; Mariz et al. 2020; Sato et al. 2020).
Our results suggest different susceptibility or response to
SARS-CoV-2 symptoms from different populations, given that
the North American population presented a taste disorder prev-
alence of 53%, European 50%, and Asians 27%. The Asian
population also presented a lower prevalence than the world-
wide pooled prevalence (45%). Western patients (North
America and Europe) seem to be more susceptible to taste dis-
orders than the Asian population (Dell’Era et al. 2020; Lechien
et al. 2020). These differences were observed since initial stud-
ies on this subject were conducted in different regions (Lee,
Min et al. 2020; Mao et al. 2020; Yan et al. 2020; Zayet et al.
2020). Zhao et al. (2020) suggested in a single-cell RNA-seq
that Asians presented a distinct expression of ACE2 receptor as
compared with Americans. In accordance, Cao et al. (2020)
evidenced a higher polymorphism of functional RNA coding
associated with ACE2 expression in Asian population tissues.
Controversially, Cai (2020) reported no ethnicity differences in
ACE2 expression in lung tissues. Also, this LSR found a sig-
nificant association between female patients with COVID-19
and taste disorders. In a sex-based analysis, Cao et al. (2020)
reported no significant disparities regarding ACE2 gene
expression in the lungs. However, hormonal modulation and
innate immune response to viral infections seemed to be exac-
erbated in women, which may contribute to higher dysfunction
on the gustatory system (Liguori et al. 2020; Sierpiński et al.
2020). Further investigation on ACE2 expression symptoms
related to tissue and organs other than the lungs is required to
confirm ethnic and sex-based differences.
Different from taste disorders, oral mucosal lesions were
described in only a few case reports, presenting controversial
conclusions on whether this type of condition is directly
caused by SARS-CoV-2 or represents secondary manifesta-
tions. Nonetheless, the manifestations showed miscellaneous
clinical aspects, such as ulcers, blisters, macules, and plaques,
varying in quantity, color appearance, and localization. A
divergent mucosal lesion pattern related to a single virus is
uncommon (Galván Casas et al. 2020). Cox et al. (2020), thus
accentuating the importance of coinfection investigation in
severe respiratory diseases. Studies recorded bacterial and
fungal coinfections in many fatal COVID-19 cases (Chen
et al. 2020; Zhou, Yu, et al. 2020). Admitted patients fre-
quently receive antibiotics; however, no specification on bac-
terial sensitivity is provided (Cox et al. 2020). Also, most
patients presented oral mucosal injury during the hospitaliza-
tion period, supporting the hypothesis of coinfections, immu-
nity impairment, or adverse reactions from medications to
COVID-19 treatment. In these senses, the oral examination in
patients with COVID-19 should not be neglected but rather
encourage a multidisciplinary approach that includes dentist
professionals. Thus, the importance of the clinical oral exami-
nation of patients with infectious diseases in the intensive care
unit should be emphasized, given the need for support, pain
control, and quality of life.
Limitations
There are some limitations that should be highlighted. First,
most authors have not clarified the definition of each level of
severity for COVID-19; therefore, patients were grouped
according to reported categorization terms: “mild/moderate”
with “nonhospitalized” and “severe” with “hospitalized.”
Second, the prevalence of oral mucosal lesions is underrepre-
sented (just 7 studies) and could not be calculated since only
case reports were published at this time. Third, many included
studies were published as letters to the editor, leading to unde-
tailed reported outcomes. Also, most oral manifestations may
go unnoticed, and there is a difficulty in registering the oral
findings, due to exposure and contamination risk during photo-
graphic image conduction. Moreover, in terms of gustatory
disorders, almost all tests performed are subjective methods
based on questionnaires, which may not accurately diagnose
these conditions. Therefore, authors should have considered
standardized and validated tests to improve data collection
quality, as Vaira, Hopkins, Salzano, et al. (2020) did. In addi-
tion, disorder classification (dysgeusia, hypogeusia, and ageu-
sia) is not always considered correctly. Finally, many patients
Oral Manifestations in Patients with COVID-19 13
are sedated or weaning from sedation at the time of investiga-
tion, which may have impaired the identification of taste disor-
der intensity or even its diagnosis.
Conclusion
Oral symptoms are not frequently described in COVID-19
clinical studies. Given a small number of reported studies, taste
alterations are the most prevalent reported oral manifestation.
The global prevalence of taste disorders in patients with
COVID-19 is 45%. We also found with a moderate certainty of
evidence that taste disorders are associated with COVID-19
positivity, mild/moderate severity, and female sex. There is a
low certainty of evidence regarding oral mucosal lesions in
patients with COVID-19 and their etiopathogenesis. The mul-
tiple clinical aspects suggest coinfections, immunity impair-
ment, and adverse reactions rather than a genuine oral mucosa
infection primarily caused by SARS-CoV-2.
Author Contributions
J. Amorim dos Santos, A.G.C. Normando, E.N.S. Guerra, contrib-
uted to conception, design, data acquisition, analysis, and interpre-
tation, drafted and critically revised the manuscript; R.L. Carvalho
da Silva, A.C. Acevedo, G. De Luca Canto, N. Sugaya, A.R.
Santos-Silva, contributed to conception, data analysis, and inter-
pretation, critically revised the manuscript. All authors gave final
approval and agree to be accountable for all aspects of the work.
Acknowledgments
J. Amorim dos Santos, G. De Luca Canto, A.R. Santos-Silva, and
E.N.S. Guerra are supported by the National Council for Scientific
and Technological Development, Ministry of Education, Brazil.
The authors thank the Department of Research and Innovation,
University of Brasilia, Brazil. The funding agencies have no role
in the submitted work. The authors declare no potential conflicts
of interest with respect to the authorship and/or publication of this
article.
ORCID iDs
A.R. Santos-Silva https://orcid.org/0000-0003-2040-6617
E.N.S. Guerra https://orcid.org/0000-0002-7622-1550
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