10.14639/0392-100X-N1584
COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently discovered coronavirus, which in 2020 led to a global pandemic. Clinical manifestations of COVID-19 are very diverse and symptoms range from mild to severe. Correlated symptoms might also manifest in the oral cavity, which is a potential pathway for viral infection, and therefore might be a potential pathway for SARSCoV- 2. In recent research among patients with SARS-CoV-2 infection, taste and olfactory disorders, dry mouth, drones and inflammation of mouth, bitter taste in mouth, difficulty in swallowing and burning sensations have been reported. There have been cases of oral mucosal lesions in patients diagnosed with COVID-19 disease. Some correlations between periodontitis and severity of COVID-19 disease have also been observed. Oral mucosa, due to occurrence of ACE2 receptors, is highly susceptible to SARS-CoV-2 infection. The occurrence of changes on oral mucosa should increase the alertness of dental practitioners. However, knowledge in this area is still limited and in the field of oral manifestations of COVID-19 more research and patient observations are required.
text/xml
1827-675X
1584
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Daniela Alterio
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
oral mucosa
COVID-19 manifestation in the oral cavity – a narrative literature review
Text.Serial.Journal
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2021-11-05
2021-03-24
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2021-11-02
395-400
1
Daniela Alterio
2021/11/05
10.14639/0392-100X-N1584
395
Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, Milan, Italy
1827-675X
oral mucosa
400
COVID-19 manifestation in the oral cavity – a narrative literature review
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:395-400; doi: 10.14639/0392-100X-N1584




Review


COVID-19 manifestation in the oral cavity – a narrative
literature review
Manifestazioni nella cavità orale dell’infezione da COVID-19 – revisione della letteratura
Aida Kusiak1, Dominika Cichońska1, Monika Tubaja1, Andrzej Skorek2, Barbara Alicja Jereczek-Fossa3,4,
Giulia Corrao3,4, Giulia Marvaso3,4, Daniela Alterio4
1
 Department of Periodontology and Oral Mucosa Diseases, Medical University of Gdansk, 80-210 Gdansk, Poland; 2 Department
of Otolaryngology, Medical University of Gdansk, 80-210 Gdansk, Poland; 3 Department of Oncology and Hemato-Oncology,
University of Milan, Milan, Italy; 4 Division of Radiotherapy, IEO European Institute of Oncology, IRCCS, Milan, Italy


SUMMARY
COVID-19 is an infectious disease caused by severe acute respiratory syndrome corona-
virus 2 (SARS-CoV-2), a recently discovered coronavirus, which in 2020 led to a global
pandemic. Clinical manifestations of COVID-19 are very diverse and symptoms range from
mild to severe. Correlated symptoms might also manifest in the oral cavity, which is a
potential pathway for viral infection, and therefore might be a potential pathway for SARS-
CoV-2. In recent research among patients with SARS-CoV-2 infection, taste and olfactory
disorders, dry mouth, drones and inflammation of mouth, bitter taste in mouth, difficulty
in swallowing and burning sensations have been reported. There have been cases of oral
mucosal lesions in patients diagnosed with COVID-19 disease. Some correlations between
periodontitis and severity of COVID-19 disease have also been observed. Oral mucosa,
due to occurrence of ACE2 receptors, is highly susceptible to SARS-CoV-2 infection. The
occurrence of changes on oral mucosa should increase the alertness of dental practitioners.    Received: March 24, 2021
However, knowledge in this area is still limited and in the field of oral manifestations of    Accepted: June 11, 2021
COVID-19 more research and patient observations are required.
                                                                                               Correspondence
KEY WORDS: COVID-19, SARS-CoV-2, oral cavity, oral mucosa                                      Dominika Cichońska
                                                                                               Department of Periodontology and Oral Mucosa
RIASSUNTO                                                                                      Diseases,Medical University of Gdansk, Orzeszko-
I sintomi correlati all’infezione da SARS-CoV-2 si possono manifestare anche nella cavità      wej 18 St., 80-208 Gdansk, Poland
                                                                                               E-mail: dominika.cichonska@gumed.edu.pl
orale, e potrebbe rivestire un ruolo cruciale nella diagnosi precoce della malattia. Abbiamo
condotto una revisione della letteratura, riguardante le manifestazioni nella cavità orale
                                                                                               Funding
dell’infezione da SARS-CoV-2. La cavità orale rappresenta uno dei punti di ingresso dei        None.
patogeni nel corpo umano e pertanto costituisce una potenziale sede di annidamento anche
del SARS-CoV-2. ACE2 è il recettore principale che interagisce con la proteina spike del       Conflict of interest
virus, ritrovata nei tessuti della mucosa orale. Sono stati osservati casi di lesioni della    The Authors declare no conflict of interest.
mucosa orale in pazienti con diagnosi di infezione da COVID-19. Sono state anche ripor-
tate alcune associazioni tra parodontite e gravità della malattia COVID-19. La mucosa
orale, a causa della presenza dei recettori ACE2, è altamente suscettibile all’infezione da      How to cite this article: Kusiak A, Cichońska D,
                                                                                                 Tubaja M, et al. COVID-19 manifestation in the
SARS-CoV-2. Tuttavia, le evidenze in questo settore sono ancora limitate e sono necessarie
                                                                                                 oral cavity – a narrative literature review. Acta
ulteriori ricerche e osservazione dei pazienti.                                                  Otorhinolaryngol Ital 2021;41:395-400. https://
PAROLE CHIAVE: COVID-19, SARS-CoV-2, cavità orale, mucosa orale                                  doi.org/10.14639/0392-100X-N1584

                                                                                               © Società Italiana di Otorinolaringoiatria
                                                                                               e Chirurgia Cervico-Facciale

Introduction                                                                                                  OPEN ACCESS
COVID-19 is an infectious disease caused by severe acute respiratory syn-                      This is an open access article distributed in accordance with
                                                                                               the CC-BY-NC-ND (Creative Commons Attribution-Non-
drome coronavirus 2 (SARS-CoV-2), a recently discovered coronavirus.                           Commercial-NoDerivatives 4.0 International) license. The
COVID-19 emerged in China and spread rapidly around the world, posing                          article can be used by giving appropriate credit and mentio-
                                                                                               ning the license, but only for non-commercial purposes and
a huge threat to the human population, which led to a global pandemic de-                      only in the original version. For further information: https://
clared in March 2020 by the World Health Organization (WHO) 1. In Febru-                       creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                       395
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ary 2021, COVID-19 was diagnosed in almost 104 million            plicated dyspnoea and pneumonia. Other less frequently
people and contributed to the death of more than 2 million        reported symptoms include headache, haemoptysis, diar-
patients, becoming the worst health challenge that our gen-       rhoea, runny nose and phlegm-producing cough 12. In the
eration has had to face.                                          most severe cases, symptoms rapidly progress to acute
Coronaviruses are a diversified class of RNA-viruses with         respiratory distress syndrome, respiratory failure and
zoonotic origin, characterised by high transmission in hu-        multiple organ failure, becoming the cause of death 7. Pa-
mans and respiratory infections. In 2002 and 2012, two            tients with general comorbidities such as diabetes, cancer,
highly pathogenic coronaviruses appeared in population,           cardiovascular diseases are more susceptible to develop
a severe acute respiratory syndrome coronavirus (SARS-            complications of COVID-19 7,8,13. Middle-aged and elder-
CoV) and Middle East respiratory syndrome coronavirus             ly patients with chronic diseases are also more suscepti-
(MERS-CoV), becoming the cause of deadly respira-                 ble to respiratory failure and have poorer prognoses 11. In
tory illness 2. SARS-CoV-2 is significantly different from        addition, patients with moderate and severe periodontitis
SARS-CoV and MERS-CoV in both its genome structure                are more susceptible to general health complications of
and spike protein structures. SARS-CoV-2 has higher affin-        COVID-19 14. Although periodontitis is commonly corre-
ity to the cellular receptor angiotensin-converting enzyme        lated with other chronic inflammatory diseases as diabetes
2 (ACE2), which results in easier entrance to human cells         and hypertension, which are known risk factors of severe
than SARS-CoV and MERS-CoV, faster spread in humans               COVID-19 15,16, periodontitis has a significant impact on
and higher mortality rate 3,4. The infectivity of SARS-CoV-2      the severity of COVID-19 14.
is strictly correlated with the ability of virus to enter human   The influence of SARS-CoV-2 on the human body remains
body cells with ACE2 as the primary receptor interacting          unknown, although there are also symptoms in the oral cav-
with virus spike protein when entering the cell 5.                ity, which may play a crucial role in the early diagnosis of
SARS-CoV-2 is characterised by high level of transmissi-          COVID-19 17.
bility and ability to spread from human to human by aero-
sol and contact 6. This virus is viable in air for 3 hours and    Materials and methods
on plastic and stainless-steel surfaces for 72 hours 7. The
incubation period for the virus varies from 1 to 14 days.         A literature search for relevant papers in the literature from
After symptoms are observed, a diagnosis can be achieved          January 2020 to February 2021 was conducted using Pub-
by real-time PCR (RT-PCR). SARS-CoV-2 can be detected             Med and Scopus databases. We included only studies on
in fluids from throat swabs, secretions of the lower respira-     the oral manifestations of SARS-CoV-2 infection. Key
tory tract and blood 7,8.                                         words included: SARS-CoV-2 infection, SARS-CoV-2
The aim of this review is to summarise current knowledge          symptoms, SARS-CoV-2 in oral cavity, COVID-19 symp-
about the oral manifestations of SARS-CoV-2, which could          toms, COVID-19 disease, SARS-CoV-2 in saliva, oral cav-
improve diagnosis of COVID-19.                                    ity, taste impairment, dry mouth, oral mucosa lesions.


Clinical manifestations of COVID-19                               ACE2 receptors in oral mucosal tissues
COVID-19 is mainly associated with pneumonia, which in
                                                                  and saliva
more severe cases can develop into acute respiratory dis-         The infectivity of SARS-CoV-2 is dependent on the ability
tress syndrome (ARDS). The severity of infection can be           of the virus to enter human cells and it has been shown that
assessed based on the results of a biochemical blood test         ACE2 is the primary receptor interacting with virus spike
including level of albumin, lactate dehydrogenase, C-reac-        protein, which enables cell entry 5. The oral cavity is one
tive protein, lymphocytes and neutrophils 9. Patients with        of the entry points to the body and a potential pathway for
COVID-19 disease present symptoms such as leukocyto-              viral infection, and therefore might be a potential pathway
sis, leukopenia and lymphopenia, hypoalbuminaemia, an             for SARS-CoV-2 18. There is also a possibility that oral mu-
increase of lactate dehydrogenase, aspartate transaminase,        cosa might be a potential route of entry for SARS-CoV-2
alanine aminotransferase, bilirubin and D-dimer 10. To im-        into human cells 19. The SARS-CoV-2 cellular entry recep-
prove prognosis of COVID-19, patients should be provided          tor ACE2 is found in oral mucosal tissues including the
with respiratory support at early stages of the disease 11.       tongue and floor of the mouth 20. However, ACE2-positive
Clinical manifestations of COVID-19 are very different            cells are also observed in other oral mucosa tissues such
and observed symptoms range from mild to severe. The              as buccal and gingival epithelial cells 21. The presence of
most common symptoms are fever, cough, fatigue, com-              ACE2 receptors in oral tissues suggests that the oral cavity



396
                                                                                 COVID-19 manifestation in oral cavity - a narrative literature review




can be perceived an initial site of entry for SARS-CoV-2 21.             females. Oral manifestations of COVID-19 included loss
Another potential reservoir for SARS-CoV-2 in the oral                   of taste, dry mouth, dryness and inflammation of mouth.
cavity might be gingival sulcus, which is a well-established             Loss of taste was reported in 47.2% cases (36.5% in males,
ecosystem promoting colonisation of microorganisms 22,23.                57.1% in females), dry mouth among 46.3% cases (46.2%
In both clinically healthy and pathological pockets, other               in males, 46.4% in females) and dryness and inflammation
viruses, such as herpes simplex virus and human papilloma                of mouth among 11.1% of patients (13.5% in males, 8.9%
virus have been discovered 24,25. SARS-CoV-2 RNA has                     in females). This study demonstrated that patients infected
also been identified in the ulcerated squamous cell carci-               by SARS-CoV-2 generally present symptoms related to the
noma of the tongue. This finding could be of some interest               oral cavity like loss of taste and dry mouth, which might be
as it emphasises the potential risk for pathologists handling            included in diagnostic criteria of COVID-19 27.
samples from asymptomatic patients with unknown SARS-                    In a multicentre case series by Qiu et al., olfactory and/
CoV-2 status 26. Therefore, according to the study by Chen               or taste dysfunction were reported among patients with
et al. SARS-CoV-2 can be detected in saliva. This might                  COVID-19. This study included 349 patients and in 41%
be correlated to the presence of ACE2 receptors and their                of cases such symptoms were present. 10% of patients pre-
tissue distribution 27. In research by Liu et al., it was shown          sented only olfactory or gustatory symptoms and 19% of
that salivary gland epithelial cells are characterised by high           patients presented olfactory and/or gustatory symptoms
expression of ACE2 receptors 28. It should be mentioned                  prior to any other COVID-19 symptoms. This study also
that ACE2 expression is higher in minor salivary glands                  suggested that loss of smell and taste among patients might
than in lungs, which might lead to the possibility that sali-            be a screening criteria that is useful in early identifications
vary glands might be an important site for SARS-CoV-2. It                of COVID-19 29.
has also been observed that the possibility of SARS-CoV-2                In a cross-sectional study on 59 patients hospitalised for
nucleic acids in saliva is higher among patients with more               COVID-19, cases of olfactory and taste disorders were
progressed infection 27. Furthermore, dysfunction of sali-               observed, 33.9% of patients reported at least one taste or
vary glands in late stage of COVID-19 infection was ob-                  olfactory disorder and 18.6% reported both taste and ol-
served 27. According to Xu et al., contaminated saliva se-               factory disorder, 20.3% of patients observed those symp-
creted by infected salivary glands are probably a potential              toms before hospitalisation and in 13.5% the symptoms
reservoir for SARS-CoV-2 and might be the main reason                    appeared during hospitalisation. Smell and taste disorders
for the spread of COVID-19 through asymptomatic infec-                   were reported more often by females (52.6%) than males
tion 18.                                                                 (25%) 30.
                                                                         In an observational study by Sinjari et al. on a group of
                                                                         20 SARS-CoV-2 positive hospitalised patients, oral mani-
COVID-19 disease oral manifestations                                     festations such as dry mouth, taste disorders, burning sen-
The most frequently observed oral manifestations among                   sations and difficulty in swallowing were observed. 30%
patients with SARS-CoV-2 infection are taste and olfactory               of patients in this study developed xerostomia during hos-
disorders, dry mouth, drones and inflammation of mouth,                  pitalisation, 25% of patients reported impaired taste, 15%
bitter taste in mouth, difficulty in swallowing and burning              burning sensation of the mouth and 20% difficulty in swal-
sensations in mouth (Tab. I).                                            lowing. It should be stressed that burning sensations were
In research by Chen et al., there was a questionnaire on                 reported only by female patients. Considering sex and age
the oral health status of patients with infection by SARS-               of patients, no significant results were observed 31.
CoV-2. The study included 108 patients, 52 males and 56                  Although taste disorder in the most common oral mani-


Table I. Mostly commonly reported COVID-19 oral manifestations.
 Author                               Number of patients              Type of study                        COVID-19 oral manifestations
Chen et al. (2020) 27                          108                    Clinical study                   Loss of taste, dry mouth, dryness and
                                                                                                               inflammation of mouth
Qiu et al. (2020) 29                           394                Multicentre case series                  Olfactory and taste disorders
Giacomelli et al. (2020) 30                    59                 Cross-sectional study                    Olfactory and taste disorders
Sinjari et al. (2020) 31                       20                  Observational study             Dry mouth, taste disorders, burning sensations,
                                                                                                               difficulty in swallowing
Luo et al. (2020) 32                           60                 Cross-sectional study                  Dry mouth, bitter taste in mouth




                                                                                                                                                397
A. Kusiak et al.




festation, other SARS-CoV-2 conditions related to oral               manifestations in a 42-year-old male diagnosed with COV-
cavity have also been observed. In research by Luo et al.,           ID-19 35. Intramural examination revealed the ulcerated le-
symptoms in 60 hospitalised patients with COVID-19 were              sion and multiple reddish macules of different sizes scat-
analysed. A large variety of conditions were included, in-           tered along the hard palate, tongue and lips. Petechia-like
cluding SARS-CoV-2 oral manifestations. 29% of patients              and small vesicobullous lesions on skin were also observed.
reported dry mouth and 13% experienced bitter taste in the           After 3 weeks observation, lesions on both the oral mucosa
mouth 32.                                                            and skin subsided 35.
Taste disorder observed as an early symptom of COVID-19              Oral mucosa lesions have also been diagnosed in a 19-year-
before other symptoms may support the hypothesis that                old SARS-CoV-2 positive patient 36. Intraoral examination
oral cavity mucosa might be an initial site of infection by          revealed erosions, ulcerations and blood crusts on the inner
SARS-CoV-2, especially taking into consideration the fact            surface of the lips and palatal and gingival petechiae. Skin
that taste receptors are widely distributed in tongue, where         lesions were also observed. Both mucosal and skin lesions
96% of the oral ACE2-positive cells are observed 20,21.              disappeared after 10 days 36.
It has been shown that ACE2-positive salivary gland epi-             In a case report by Amorim Dos Santos et al., oral mucosa
thelial cells are early targets of other coronaviruses, and          changes in a patient with COVID-19 were observed. Oral
that salivary gland functions may be affected at an early            manifestation included a persistent white plaque on the
stage of the infection 28. This might be a possible expla-           tongue dorsum refractory to antifungal therapy and mul-
nation for a dry mouth symptom reported by patients un-              tiple ulcers in the tongue dorsum resembling herpetic oral
dergoing SARS-CoV-2, although this hypothesis requires               lesions 37.
further research 21.                                                 In a report by Patel et al., necrotising periodontal disease
The presence of oral mucosa cells with high ACE2 receptor            was observed in a 35-year-old female suspicious for COV-
distribution might lead to inflammatory reactions in such            ID-19. The patient presented with fever, submandibular
organs and tissues as tongue and salivary glands 21. Accord-         lymphadenopathy and halitosis. Oral manifestations of the
ing to Dziedzic et al., SARS-CoV-2 infection is the reason           disease like painful, diffuse erythematous and edematous
for diversified oral cavity disorders caused by both suscep-         gingiva with necrosis of papillary areas were also observed.
tible oral tissues and impairment of the immune system.              The oral lesions recovered after 5 days were diagnosed as
Oral ulcerations, gingivitis, recurrent oral herpes simplex          necrotising periodontal disease due to bacterial coinfec-
virus infections, opportunistic fungal infections and xeros-         tions along with COVID-19 38.
tomia caused by a decreased salivary flow have been ob-              The diverse impact of COVID-19 on oral health, includ-
served among patients with COVID-19 33. Rarely reported              ing both subjective symptoms reported by patients and oral
oral manifestations are presented in Table II.                       mucosa lesions undoubtedly require a proper dental care.
According to Carreras-Presaset et al., oral vesiculobullous          Patients recovering from COVID-19, especially if hospital-
lesions among patients with COVID-19 have also been re-              ised, should be provided with special oral health monitor-
ported. There were symptoms such as pain of palate, pain             ing to ensure their full recovery 33.
of tongue and many small ulcers on the palate with unilat-           The changes observed on the oral mucosa related to
eral affection. Blisters on the internal lip mucosa and des-         COVID-19 are not pathognomonic, and their treatment is
quamative gingivitis has been observed. Patients presented           symptomatic and does not differ from the treatment of oral
ulcers or blisters, which commonly appear in other viral             mucosa lesions resulting from other diseases or disorders.
infections, such as hand, foot, and mouth disease and her-           Treatment includes the use of drugs that accelerate healing
petic gingivostomatitis 34.                                          and painkillers, a gentle diet, maintain proper oral hygiene
Soares et al. have also reported the occurrence of oral              and saliva substitutes in case of dry mouth symptoms 34-39.


Table II. Rarely reported COVID-19 oral manifestations.
 Author                                              Type of study                         COVID-19 oral manifestations
 Carreras-Presaset et al. (2021)   34
                                                     Case report          Pain of palate, pain of tongue, small ulcers on the palate, blisters,
                                                                                                desquamative gingivitis
 Soares et al. (2020) 35                             Case report      Ulcerated lesion and reddish macules on the hard palate, tongue and lips
 Ciccarese et al. (2020) 36                          Case report     Erosions, ulcerations and blood crusts on lips; palatal and gingival petechiae
 Amorim Dos Santos et al. (2020) 37                  Case report          Persistent white plaque and multiple ulcers on the tongue dorsum
 Patel et al. (2020) 38                              Case report                            Necrotising periodontal disease




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COVID-19 has become the subject of research by many                            10
                                                                                    Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et
                                                                                    al. Clinical, laboratory and imaging features of COVID-19: a system-
specialists from various fields of medicine, who, depend-                           atic review and meta-analysis. Travel Med Infect Dis 2020;34:101623.
ing on the clinical situation, attempt to develop appropri-                         https://doi.org/10.1016/j.tmaid.2020.101623
ate standards of management. This applies to treating the                      11
                                                                                    Liu K, Fang YY, Deng Y, et al. Clinical characteristics of novel
symptoms of SARS-CoV-2 infection as well as encourag-                               coronavirus cases in tertiary hospitals in Hubei Province. Chin
                                                                                    Med J (Engl) 2020;133:1025-1031. https://doi.org/10.1097/
ing proper treatment of patients with chronic diseases in a                         CM9.0000000000000744
new pandemic reality 40-42.                                                    12
                                                                                    Wang Y, Li X, Ren L, et al. Clinical features of patients infected with
                                                                                    2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
                                                                                    https://doi.org/10.1016/S0140-6736(20)30183-5
Conclusions                                                                    13
                                                                                    Wang D, Hu BO, Hu C, et al. Clinical characteristics of 138 hospi-
Oral mucosa, due to the presence of ACE2 receptors, is                              talized patients with 2019 novel coronavirus-infected pneumonia in
                                                                                    Wuhan, China. JAMA 2020;323:1061-1069. https://doi.org/10.1001/
highly susceptible to COVID-19 infection. Symptoms of                               jama.2020.1585
COVID-19 related to the oral cavity such as taste impair-                      14
                                                                                    Marouf N, Cai W, Said KN, et al. Association between periodontitis
ment, dry mouth and burning mouth syndrome may appear                               and severity of COVID-19 infection: a case-control study. J Clin Peri-
in patients with SARS-CoV-2 infection, becoming crucial                             odontol 2021;48:483-491. https://doi.org/10.1111/jcpe.13435
for identification of the disease. The occurrence of oral                      15
                                                                                    Ruan Q, Yang K, Wang W, et al. Clinical predictors of mortality due to
                                                                                    COVID-19 based on an analysis of data of 150 patients from Wuhan,
mucosa lesions related to SARS-CoV-2 infection should                               China. Intensive Care Med 2020;46:846-848. https://doi.org/10.1007/
increase alertness among dental practitioners. However,                             s00134-020-05991-x
knowledge in this area is still limited. More research and                     16
                                                                                    Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality
patient observations are required in the field of oral mani-                        of adult inpatients with COVID-19 in Wuhan, China: a retrospective
                                                                                    cohort study. Lancet 2020;395:1054-1062. https://doi.org/10.1016/
festations of COVID-19.                                                             s0140-6736(20)30566-3
                                                                               17
                                                                                    Herrera D, Serrano J, Roldán S, et al. Is the oral cavity relevant in
References                                                                          SARS-CoV-2 pandemic? Clin Oral Investig 2020;24:2925-2930. htt-
                                                                                    ps://doi.org/10.1007/s00784-020-03413-2
1
    Biadsee A, Biadsee A, Kassem F, et al. Olfactory and oral manifesta-       18
                                                                                    Xu J, Li Y, Gan F, et al. Salivary glands: potential reservoirs for cov-
    tions of covid-19: sex-related symptoms - a potential pathway to early          id-19 asymptomatic infection. J Dent Res 2020;99:989. https://doi.
    diagnosis. Otolaryngol Head Neck Surg 2020;163:722-728. https://                org/10.1177/0022034520918518.
    doi.org/10.1177/0194599820934380                                           19
                                                                                    Peng X, Xu X, Li Y, et al. Transmission routes of 2019-nCoV and
2
    Rodriguez-Morales AJ, Bonilla-Aldana D, Balbin-Ramon GJ, et al.                 controls in dental practice. Int J Oral Sci 2020;12:9. https://doi.
    History is repeating itself: probable zoonotic spillover as the cause of        org/10.1038/s41368-020-0075-9.
    the 2019 novel Coronavirus epidemic. Infez Med 2020;28:3-5.                20
                                                                                    Xu H, Zhong L, Deng J, et al. High expression of ACE2 receptor
3
    Kandeel M, Ibrahim A, Fayez M, et al. From SARS and MERS CoVs                   of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci
    to SARS- CoV-2: moving toward more biased codon usage in viral                  2020;12:8. https://doi.org/10.1038/s41368-020-0074-x
    structural and nonstructural genes. J Med Virol 2020;92:660-666.           21
                                                                                    Ren YF, Rasubala L, Malmstrom H, et al. Dental care and oral health
    https://doi.org/10.1002/jmv.25754                                               under the clouds of COVID-19. JDR Clin Trans Res 2020;5:202-210.
4
    Ren LL, Wang YM, Wu ZQ, et al. Identification of a novel coro-                  https://doi.org/10.1177/2380084420924385
    navirus causing severe pneumonia in human: a descriptive study.            22
                                                                                    Gomes-Filho IS, Cruz SSD, Trindade SC, et al. Periodontitis and res-
    Chin Med J (Engl) 2020;133:1015-1024. https://doi.org/10.1097/                  piratory diseases: a systematic review with meta-analysis. Oral Dis
    CM9.0000000000000722                                                            2020;26:439-446. https://doi.org/10.1111/odi.13228
5
    Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of       23
                                                                                    Badran Z, Gaudin A, Struillou X, et al. Periodontal pockets: a poten-
    SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-                    tial reservoir for SARS-CoV-2? Med Hypotheses 2020;143:109907.
    1448. https://doi.org/10.1126/science.abb2762                                   https://doi.org/10.1016/j.mehy.2020.109907
6
    Tang S, Mao Y, Jones RM, et al. Aerosol transmission of SARS-CoV-2?        24
                                                                                    Pallos D, Ruivo GF, Ferrari-Junior SH, et al. Periodontal disease and
    Evidence, prevention and control. Environ Int 2020;144:106039. htt-             detection of human herpesviruses in saliva and gingival crevicular
    ps://doi.org/10.1016/j.envint.2020.106039                                       fluid of chronic kidney disease patients. J Periodontol 2020;91:1139-
7
    Pereira LJ, Pereira CV, Murata RM, et al. Biological and social aspects         1147. https://doi.org/10.1002/JPER.19-0583
    of Coronavirus Disease 2019 (COVID-19) related to oral health. J Dent      25
                                                                                    Cappuyns I, Gugerli P, Mombelli A. Viruses in periodon-
    Res 2020;99:481-487. https://doi.org/10.1177/0022034520914246                   tal disease – a review. Oral Dis 2005;11:219-229. https://doi.
8
    Adhikari SP, Meng S, Wu YJ, et al. Epidemiology, causes, clinical               org/10.1111/j.1601-0825.2005.01123.x
    manifestation and diagnosis, prevention and control of coronavirus dis-    26
                                                                                    Guerini-Rocco E, Taormina SV, Vacirca D, et al. SARS-CoV-2 de-
    ease (COVID-19) during the early outbreak period: a scoping review.             tection in formalin-fixed paraffin-embedded tissue specimens from
    Dis Poverty 2020;9:29. https://doi.org/10.1186/s40249-020-00646-x               surgical resection of tongue squamous cell carcinoma. J Clin Pathol
9
    Liu Y, Yang Y, Zhang C, et al. Clinical and biochemical indexes                 2020;73:754-757. https://doi.org/10.1136/jclinpath-2020-206635
    from 2019-nCoV infected patients linked to viral loads and lung in-        27
                                                                                    Chen L, Zhao J, Peng J, et al. Detection of SARS-CoV-2 in saliva and
    jury. Sci China Life Sci 2020;63:364-374. https://doi.org/10.1007/              characterization of oral symptoms in COVID-19 patients. Cell Prolif
    s11427-020-1643-8                                                               2020;53:e12923. https://doi.org/10.1111/cpr.12923




                                                                                                                                                       399
A. Kusiak et al.




28
     Liu L, Wei Q, Alvarez X, et al. Epithelial cells lining salivary gland    35
                                                                                    Soares CD, Carvalho RA, Carvalho KA, et al. Letter to Editor: Oral
     ducts are early target cells of severe acute respiratory syndrome coro-        lesions in a patient with Covid-19. Med Oral Patol Oral Cir Bucal
     navirus infection in the upper respiratory tracts of rhesus macaques. J        2020;1;25:563-564. https://doi.org/10.4317/medoral.24044
     Virol 2011;85:4025-4030. https://doi.org/10.1128/JVI.02292-10             36
                                                                                    Ciccarese G, Drago F, Boatti M, et al. Oral erosions and petechiae
29
     Qiu C, Cui C, Hautefort C, et al. Olfactory and gustato-                       during SARS-CoV-2 infection. J Med Virol 2020;93:129-132. https://
     ry dysfuncion as an early identifier of COVID-19 in adults                     doi.org/10.1002/jmv.26221
     and children: an international multicenter study. Otolaryn-               37
                                                                                    Amorim Dos Santos J, Normando AGC, Carvalho da Silva RL, et
     gol Head Neck Surg 2020;16:194599820934376. https://doi.                       al. Oral mucosal lesions in a COVID-19 patient: new signs or sec-
     org/10.1101/2020.05.13.20100198                                                ondary manifestations? Int J Infect Dis 2020;97:326-328. https://doi.
                                                                                    org/10.1016/j.ijid.2020.06.012
30
     Giacomelli A, Pezzati L, Conti F, et al. Self-reported olfactory and
     taste disorders in patients with severe acute respiratory coronavirus
                                                                               38
                                                                                    Patel J, Woolley J. Necrotizing periodontal disease: oral manifestation
     2 infection: a cross-sectional study. Clin Infect Dis 2020;28;71:889-          of COVID-19. Oral Dis 2020;27:768-769. https://doi.org/10.1111/
     890. https://doi.org/10.1093/cid/ciaa330                                       odi.13462
31
     Sinjari B, D’Ardes D, Santilli M, et al. SARS-CoV-2 and oral mani-
                                                                               39
                                                                                    Górska R. Diagnosis and treatment of diseases of the oral mucosa.
                                                                                    Otwock: Med Tour Press International; 2011. pp. 238-243.
     festation: an observational, human study. J Clin Med 2020;7;9:3218.
     https://doi.org/10.3390/jcm9103218
                                                                               40
                                                                                    Corrao G, Bergamaschi L, Zaffaroni M, et al. COVID-19 impact in
                                                                                    radiotherapy practice in an oncology hub: a screenshot from Lom-
32
     Luo Y, Wu J, Lu J, et al. Investigation of COVID-19-related symptoms           bardy, Italy. Tumori 2020 Dec 16;300891620980065. https://doi.
     based on factor analysis. Ann Palliat Med 2020;9:1851-1858. https://           org/10.1177/0300891620980065 (Online ahead of print).
     doi.org/10.21037/apm-20-1113                                              41
                                                                                    Alterio D, Volpe S, Bacigalupo A, et al. Head and neck radiotherapy
33
     Dziedzic A, Wojtyczka R. The impact of coronavirus infectious dis-             amid the COVID-19 pandemic: practice recommendations of the Ital-
     ease 19 (COVID-19) on oral health. Oral Dis 2021;27;3:703-706.                 ian Association of Radiotherapy and Clinical Oncology (AIRO). Med
     https://doi.org/10.1111/odi.13359                                              Oncol 2020;37:85. https://doi.org/10.1007/s12032-020-01409-2
34
     Carreras-Presas CM, Amaro Sanchez J, Lopez-Sanchez AF, et al. Oral        42
                                                                                    Alterio D, Volpe S, Marvaso G, et al. Head and neck cancer radio-
     vesiculobullous lesions associated with SARS-CoV-2 infection. Oral             therapy amid COVID-19 pandemic: report from Milan, Italy. Head
     Dis 2021;27;3:710-712. https://doi.org/10.1111/odi.13382                       Neck 2020;42;1482-1490. https://doi.org/10.1002/hed.26319




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