Oral manifestations of COVID‐19 disease: A review article

Authors: Behzad Iranmanesh,Maryam Khalili, et. al. Dermatol Ther. 2021 Jan-Feb; 34(1): e14578. Published online 2020 Dec 13. doi: 10.1111/dth.14578PMCID: PMC7744903PMID: 33236823

Abstract

Dysgeusia is the first recognized oral symptom of novel coronavirus disease (COVID‐19). In this review article, we described oral lesions of COVID‐19 patients. We searched PubMed library and Google Scholar for published literature since December 2019 until September 2020. Finally, we selected 35 articles including case reports, case series and letters to editor. Oral manifestations included ulcer, erosion, bulla, vesicle, pustule, fissured or depapillated tongue, macule, papule, plaque, pigmentation, halitosis, whitish areas, hemorrhagic crust, necrosis, petechiae, swelling, erythema, and spontaneous bleeding. The most common sites of involvement in descending order were tongue (38%), labial mucosa (26%), and palate (22%). Suggested diagnoses of the lesions were aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, Kawasaki‐like, EM‐like, mucositis, drug eruption, necrotizing periodontal disease, angina bullosa‐like, angular cheilitis, atypical Sweet syndrome, and Melkerson‐Rosenthal syndrome. Oral lesions were symptomatic in 68% of the cases. Oral lesions were nearly equal in both genders (49% female and 51% male). Patients with older age and higher severity of COVID‐19 disease had more widespread and sever oral lesions. Lack of oral hygiene, opportunistic infections, stress, immunosuppression, vasculitis, and hyper‐inflammatory response secondary to COVID‐19 are the most important predisposing factors for onset of oral lesions in COVID‐19 patients.

1. INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a single‐chain RNA virus that is the cause of novel coronavirus disease known as COVID‐19. The most common clinical symptoms are fever, headache, sore throat, dyspnea, dry cough, abdominal pain, vomiting, and diarrhea. Angiotensin converting enzyme 2 (ACE 2) receptor is a known receptor for SARS‐CoV‐2 that is found in the lung, liver, kidney, gastrointestinal (GI) and even on the epithelial surfaces of sweet glands and on the endothelia of dermal papillary vessels. Todate, various cutaneous manifestations of COVID‐19 disease have been described including varicelliform lesions, pseudochilblain, erythema multiforme (EM)‐liker lesions, urticaria form, maculopapular, petechiae and purpura, mottling, and livedo reticularis‐like lesions. 1 , 2

At the beginning of COVID‐19 pandemic, it was assumed that lack of oral involvement is a differentiating feature of COVID‐19 exanthema relative to other viral exanthemas. Recently, SARS‐CoV‐2 has been detected from saliva of the patients and it has been demonstrated that reverse transcriptase‐polymerase chain reaction (RT‐PCR) from saliva can even be a more sensitive test in comparison with nasopharyngeal test. Furthermore, ACE2 has been found in oral mucosa, especially with more density on dorsum of tongue and salivary glands relative to buccal mucosa or palates. To date, there is only one systematic review that described oral manifestations of COVID‐19 disease; however, it mostly focused on impairment of taste. Dysgeusia is the first recognized oral symptom of COVID‐19 reported in 38% of patients, mostly in North Americans and Europeans, females, and patients with mild‐moderate disease severity. 1 In this review article, we described oral lesions of COVID‐19 patients.

2. METHODS

We searched PubMed library and Google Scholar for published literature using keywords “COVID‐19” or “SARS‐CoV‐2” or “coronavirus disease 2019” AND “oral” OR “buccal mucosa” in the abstract or title since December 2019 until September 2020. We also searched related articles in the reference lists of the found articles. Finally, we selected 35 articles after deletion of non‐English literature and opinion articles.

3. RESULTS

Oral manifestations included ulcer, erosion, bulla, vesicle, pustule, fissured or depapillated tongue, macule, papule, plaque, pigmentation, halitosis, whitish areas, hemorrhagic crust, necrosis, petechiae, swelling, erythema, and spontaneous bleeding. The most common sites of involvement in descending order were tongue (38%), labial mucosa (26%), palate (22%), gingiva (8%), buccal mucosa (5%), oropharynx (4%), and tonsil (1%). Suggested diagnoses of the lesions were aphthous stomatitis, herpetiform lesions, candidiasis, vasculitis, Kawasaki‐like, EM‐like, mucositis, drug eruption, necrotizing periodontal disease, angina bullosa‐like, angular cheilitis, atypical Sweet syndrome, and Melkerson‐Rosenthal syndrome. Oral lesions were symptomatic (painful, burning sensation, or pruritus) in 68% of the cases. Oral lesions were nearly equal in both genders (49% female, 51% male). Latency time between appearance of systemic symptoms and oral lesions was between 4 days before up to 12 weeks after onset of systemic symptoms. In three cases, oral lesions preceded systemic symptoms and in four cases oral and systemic symptoms appeared simultaneously. The longest latency period belonged to Kawasaki‐like lesions. Oral lesions healed between 3 and 28 days after appearance. Different types of therapies including chlorhexine mouthwash, nystatin, oral fluconazole, topical or systemic corticosteroids, systemic antibiotics, systemic acyclovir, artificial saliva, and photobiomodulation therapy (PBMT) were prescribed for oral lesions depends on the etiology 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 . The results of literature are summarized in Table Table11.

TABLE 1

Clinical and laboratory characteristics of patients with oral manifestations

First name author	Age	Sex	Underlying disease	Cutaneous	Oral	Oral Symptom	Site	Duration (days)	Systemic manifestations	Latency (days)	COVID‐19	Suggested etiology	Treatment	Lab tests
Verdoni 28	7/5(2/9‐16)Y	M = 7F = 3	–	MPAcral swelling	NA	–	LipOral cavity(80%)	–	FeverDiarrheaConjunctivitisMeningeal signlymphadenopathy		20%+(PCR)80%(IgG)30%(IgM)	Kawasaki‐like	–	–
Jones 29	6 M	F	–	MPAcral swelling	Cracked lipProminent papilla in tongue	–	LipTongue	–	FeverConjunctivitisTachypnea	2	+(PCR)	Kawasaki‐like	IVIGASA	Increased levels of CRP, ESRHypoalbuminemia
Pouletty 30	10(4/7‐12/5)Y	M = 8F = 8	Over weightAsthma	Rash	Cracked lip (87%)	–	Lip	–	FeverRespiratory &GI symptomAnosmia	–	69%+(PCR)	Kawasaki‐like	IVIGCSANTI IL1, IL6HCH	Increased levels of cardiac markersIncreased levels of CRP, ESRLymphocytopenia
Singh 19	44Y	M	DMHTN	Non blanch able erythema Necrosis	Extensive mucosal damage	–	LipTongue	–	MalaiseDyspnea	4		Vascular inflammation Ischemic reperfusion injury
Chiotos 31	5Y	F	–		Fissured lip	–	Lip	–	FeverDiarrheaConjunctivitis	–		Kawasaki‐like	IVIG	ThrombocytopeniaIncreased levels of cardiac marker
Chiotos 31	9Y	F	–	–	Fissured lipStraw berry tongue	–	LipTongue	–	FeverDiarrheaConjunctivitis	–	+(PCR)	Kawasaki‐like	IVIGASACS	Increased levels of CRP, ESR
Chiotos 31	12Y	M	–	–	Fissured lip	–	Lip	–	FeverAbdominal painDiarrhea	–	(−)(PCR)	Kawasaki like	IVIGMilrinone	Increased levels of Cardiac markerIncreased levels of CRP, ESR
Chiu 32	10Y	M	–	–	Cracked lipErythema	–	LipOropharynx	–	FeverCoughDiarrheaConjunctivitis	–	+(PCR)	Kawasaki‐like	Dopamine	LeukocytosisLymphocytopeniaIncreased levels of CRP, ESR, D‐dimer, ProcalcitoninIncreased levels of Cardiac markers
Mazzotta 26	9Y	M	–	UrticariaAngioedemaAcral edema	GlossitisCheilitis	Painful	–	–	FeverCoughDiarrheaConjunctivitis	28‐84	+(Ig G)	Kawasaki‐like	CS	–
Indu 13	NS	M	–	–	Ulcer	BurningItchingPainful	LipTongue	10	Fever	−4	+(PCR)	Zosteriform	–	–
Taşkın 25	61Y	F	–	Nodules	Minor aphthous ulcer	–	Hard palateBuccal	–	FeverFatigueMyalgiaArthralgia	–	+(PCR)	Atypical Sweet syndrome	AZTHCHOseltamivirTocilizomabFavipiravir	Increased levels of CRP, ESR, D‐dimerLeukocytosis
Taşlıdere 24	51Y	F	–	–	Swollen lipFissured tongue	–	LipTongue	–	MalaiseUnilateral Facial paralysisFacial edema	Coincident	–	MRS	HCHAZTCS	Increased levels of CRPNegative Serology for HSV, CMV,EBV, coxsackieGround glass opacity in CT scan
Brandão 7	28Y	M	–	–	Aphthous‐likeAgeusia	–	LipTongue	6	FeverCoughHeadacheMyalgiaChillsAnosmia	8	+(PCR)	–	Mouthwash	–
Brandão 7	29Y	M	–	–	Aphthous‐likeAgeusia	Painful	Tongue	5	CoughDyspneaFeverMalaiseHeadacheAnosmia	8	+(PCR)	–	Ipratropium bromideFenoterol hydrochloride	–
Brandão 7	35Y	M	–	–	Aphthous‐like	–	Tonsil	8	FeverMalaiseSore throatCoughHyposmiaAgeusiaOdynophagia	6	+(PCR)	–	–	–
Brandão 7	32Y	F	–	–	Aphthous ‐like	–	Tongue	5	DysgeusiaFeverCoughHeadacheAnosmia	10	+(PCR)	–	Dipyrone	–
Brandão 7	72Y	M	HTNDM	–	Aphthous‐likeNecrosisHemorrhagic ulcer	painful	Lip	7	FeverDyspnea	5	+(PCR)	–	P/TAZTCeftriaxoneAcyclovirPBM	Increased levels of CRPLymphocytopeniaPositive PCR for HSV
Brandão 7	83Y	F	HTNCOPDObesityParkinsonPancreatitis	–	Aphthous‐likePetechiaeNecrosis	painful	TongueHard palate	5	–	2	+(PCR)	–	CeftriaxonePBMTP/T	Negative PCR for HSVLymphocytopenia
Brandão 7	71Y	F	HTNDMCRFObesity	–	Aphthous‐likeHemorrhagic necrosisUlcer	painful	TongueLip	15	FeverCoughDyspnea	4	+(PCR	–	AZTCeftriaxoneAcyclovirPBMT	Positive PCR for HSV
Brandão 7	81Y	M	HTNCOPD	–	Aphthous‐likeNecrosisHemorrhagic ulcer	painful	LipTongue	11	Dry CoughDyspneaFeverChillsDysgeusia	5	+(PCR)	–	AZTCeftriaxoneAcyclovirPBMT	Increased levels of CRPGround glass opacity in CT scanPositive PCR for HSV
Malih 8	38Y	M	–	MP	Erythema Aphthous‐like	Painful	tonsil	–	FeverFatigueMyalgiaLoss of taste and smell	3	+(PCR)	–	Acetaminophen	–
Labé 22	3Y	M	–	ExanthemaPalmar edema	CheilitisGlossitisStomatitis	–	LipTongueOral cavity	–	FeverAstheniaCervical LAP	–	–	Kawasaki‐like	IVIG	Increased levels of CRPLeukocytosisGround glass opacity in CT scan
Labé 22	6Y	M	–	Target lesions	Erosion CheilitisHemorrhagic crust	painful	LipGingiva	21	Loss of appetite	7	+(PCR)	EM like	–	Negative serology for mycoplasma Negative PCR for HSV
Aghazadeh 9	9Y	F	–	Papule Plaque	VesiclesErosions	–	LipTongueBuccal	7	FeverWeaknessLoss of appetiteAbdominal painDiarrhea	Coincident	+(PCR)	Herpetiform	Acetaminophen	Bilateral ground glass opacity
Kämmerer 10	46Y	M	HLPCAD	–	Multiple ulceration covered by yellow gray membrane	Painful	Oral cavityGingiva	–	FeverFatigueDry coughRespiratory distressLAP submandibular	5 days after intubation	+(PCR)	Secondary herpetic Gingivostomatitis	AZTMeropenemAcyclovir	Increased levels of CRP, IL6,EosinopeniaPositive PCR for HSVPositive serology for HSV(IgM)Bilateral ground glass opacity in CT scan
Cruz Tapia 23	42Y	M	_	_	Macules	Burning	Hard palate	7	FeverMalaiseDysgeusiaHeadache	14	+(PCR)	Mucositis due to vasculitis and thrombosis	AcetaminophenMouthwashCS	_
Cruz Tapia 23	55Y	F	–	–	Tongue enlargementPurple blister	–	Tongue	5	FeverHeadacheNasal congestion	2	+(PCR)	Angina bullosa‐like	Acetaminophen	–
Cruz Tapia 23	51Y	F	HTN	_	Vascular‐like purple macule nonbleeding Purple plaque	–	Palate	–	FeverMalaiseDysgeusiaArthralgia	–	+(PCR)	Vascular disorder	CSAZTNSAID	–
Cruz Tapia 23	41Y	F	_	_	Erythematous blister	–	Hard palate	–	FeverMalaiseDysgeusiaHyposmia	–	+(PCR)	Angina‐bullosa‐like	AcetaminophenFexofenadine	–
Díaz Rodríguez 6	78Y	F	–	–	Dry mouthAtrophy of surface of tongueWhite & red patchesFissured tongue		Tongue Hard PalateSoft palateLip	15	–	–	+(PCR)	Pseudomembranous candidiasis Angular cheilitis due to StressImmunosuppression	Artificial salivaNystatinNeomycinCS	–
Díaz Rodríguez 6	53Y	M	–	–	Angular cheilitis	Burning	Lip	10	DysgeusiaAnosmia	Few days after discharge	+(PCR)	Cheilitis due to stress and immunosuppression	NystatinCSNeomycin,Mouthwash	–
Díaz Rodríguez 6	43Y	F	–	–	Multiple ulcer covered by yellow‐gray membraneLingual depapillation	Burning	Tongue	10	FeverMalaiseDysgeusiaAnosmiaDiarrheaPneumonia	14	+(PCR)	Aphthous‐like due to stress and immunosuppression	MouthwashCS	–
Chérif 27	35Y	F	–	Macule	Chapped lipsUlcerHypogeusia	–	TongueLip	10	FeverMyalgiaDyspneaDry coughVomitingDiarrhea	–	+(PCR)	Kawasaki‐like	HCHAZTCefuroxime	Thrombocytopenia AnemiaNeutrophiliaLymphopeniaIncreased levels of liver and cardiac markersIncreased levels of CRP,LDH,ferritin
Ansari 18	75Y	M	HTN	–	Irregular ulcer in erythematous background	Painful	Tongue(anterior)	7	Hypoxia	7	+(PCR)	Mucosal ulcer due to COVID‐19	AZT,Mouthwash	Negative Serology for HSV 1‐2
Ansari 18	56Y	F	DM	–	Irregular ulcer in erythematous background	Painful	Hard palate	7	FeverDyspnea	4	+(PCR)	Mucosal ulcer due to COVID‐19	RemidisivirAZT	Negative Serology for HSV 1–2
Biadsee 3	36.25Y	NS	HTNDMHypothyroidismAsthma	–	Plaque bleedingSwelling Xerostomia Dysgeusia	–	TonguePalateGingiva		FeverCoughMyalgiaSore throatAnosmiaGI symptoms	–	+(PCR)	–	–	–
Olisova 11	12Y	F	–	PurpuraMacule	Swollen,IrritatedPronounced lingual papilla	–	Tongue	3	FeverFatigueHeadache	3	+(PCR)	–	Paracetamol	Increased levels of ESR CRP
Tomo 36	37Y	F	–	–	Erythema Depapillation of tongue	Painful	Tongue(border)	14	FeverAstheniaDysgeusiaAnosmia	9	+(PCR)	Mucositis due to hypersensitivity to SARS‐CoV‐2	CSDipyroneMouthwash	–
Ciccarese 17	19Y	F	–	MaculesPapulesPetechiae	ErosionUlcerHemorrhagic crustPetechial	–	LipPalatalGingivalOropharynx	5	FeverFatigueHyposmiaSore throat	7	+(PCR)	Thrombocytopenia due to COVIDS‐19 and cefixime	IVIGCS	ThrombocytopeniaLeukocytosisIncreased levels of liver markers and LDH
Sakaida 16	52Y	F	–	MPPetechiae	Erosion	–	LipBuccal	–	FeverDyspneaDry cough	−3	+(PCR)	Drug eruption	NSAIDClarithromycinSAMLevofloxacinCs	LeukocytosisLymphopeniaNeutrophiliaIncreased level of CRP
Dominguez‐Santas 37	19Y	M	–	–	Minor aphthous	–	Lip	–	FeverHeadachAnosmiaMalaisedyspnea	0	+(PCR)	Cytokine storm due to COVID‐19	–	LymphocytopeniaNegative PCR for HSVNegative serology for syphilis,HIV, EBV,CMV, HBV,HCV
Dominguez‐Santas 37	37Y	M	–	–	Minor aphthous	–	Tongue	–	–	5	+(PCR)	Cytokine storm due to COVID‐19	–	LymphocytopeniaNegative PCR for HSVNegative serology for syphilis,HIV, EBV,CMV, HBV,HCV
Dominguez‐Santas 37	33Y	M	–	–	Minor aphthous	–	Mucogingivljunction	–	PneumoniaFeverMalaise	3	+(PCR)	Cytokine storm due to COVID‐19	–	LymphocytopeniaNegative PCR for HSVNegative serology for syphilis,HIV, EBV,CMV, HBV,HCV
Dominguez‐Santas 37	43Y	F	–	–	Minor aphthous	–	Buccal	–	Bilateral pneumonia FeverMalaise	4	+(PCR)	Cytokine storm due to COVID‐19	–	LymphocytopeniaNegative PCR for HSVNegative serology for syphilis,HIV, EBV,CMV, HBV,HCV
Putra 5	29Y	M	_	Papule	Aphthous Stomatitis	–	–	–	FeverMyalgiasore throatDry cough	6	+(PCR)	Enanthema due to COVID‐19	ParacetamolAZTHCHOseltamivirVitamin CVitamin D	Increase level of CRP
Martín Carreras‐Presas 12	65Y	F	HTNObesity	Rash	Desquamative gingivitis	Painful	TongueGingiva	28	FeverDiarrhea	25	+(serology)	EM‐like	AntibioticCSHCHHAL/R	–
Martín Carreras‐Presas 12	58Y	M	DMHTN	–	Unilateral multiple small ulcers	Painful	Palate	7	–	–	–	Herpetiform	Mouthwash	–
Martín Carreras‐Presas 12	56Y	M	–	–	Dysgeusia, Herpetiform Stomatitis	Painful	Hard Palate	10	Fever AstheniaLAP	2	NP	Herpetiform	Val acyclovirMouthwashHA	–
Jimenez‐Cauhe 21	60Y	M = 2F = 4	–	EM‐like	Macule Petechiae	–	Palate	–	–	19		Enanthema due to COVID‐19	AZTHCHL/R
Jimenez‐Cauhe 21	40Y			PurpuraEM‐like	PetechiaeMacule Petechiae	–	PalatePalate	–	–	224	–	Enanthema due to COVID‐19Enanthema due to COVID‐19	L/RHCHAZTTCSL/RHCHAZTTocilizomabCS	ThrombocytopeniaHighD‐dimerHigh D‐dimer
Jimenez‐Cauhe 21	50Y
Jimenez‐Cauhe 21	60Y		–	EM‐like	Macule Petechiae	–	Palate	–	–	19	+(PCR)	Enanthema due to COVID‐19	L/RHCHAZT	High D‐dimer
Jimenez‐Cauhe 21	60Y		–	PapuleVesicle	Petechiae	–	Palate	–	–	−2	+(PCR)	Enanthema due to COVID‐19	L/RHCHAZT	High D‐dimer
Jimenez‐Cauhe 21	40Y		–	purpura	Macule	–	Palate	–	–	12	+(PCR)	Enanthema due to COVID‐19	L/RHCH	ThrombocytopeniaHighD‐dimer
Patel 33	35Y	F	_	_	BleedingHalitosisGeneralized edematous erythematous gingivaNecrosis	Painful	Gingiva	5	FeverLAP submandibular	3	NP	Bacterial co‐infection	MetronidazoleMouthwash	_
Chaux‐Bodard 14	45 Y	F	‐	Patch	Ulcer	Painful	Tongue(dorsal)	10	Asthenia	–	+(PCR)	Vasculitis	–	–
Soares 15	42Y	M	DMHTN	PetechiaeVesicleBlister	UlcerMacules	Painful	BuccalTongueLipHard Palate	21	FeverCoughDyspnea	–	+(PCR)	Thrombotic vasculopathy due to SARS –CoV‐2	CSDipyrone	IHC: negative for other viral and trepnema palladium
dos Santos 4	67Y	M	CADHTNPCKRT	–	White plaque Multiple yellowish ulcer Geographic tongueErythema Hypogeusia	–	TonguePalateTonsil	14	FeverDiarrheaDyspnea	24	+(PCR)	Herpetiform lesions secondary to determination of systemic health and treatment	MouthwashFluconazoleNystatinAZTCeftriaxoneHCHMeropenemT/S	Positive Culture for +Saccharomyces cerevisiae
Corchuelo 20	40Y	F	–	–	PetechiaeWhitish areaBrown pigmentation	Painful	TongueLipGingiva	20	LAP of neck	–	+(IgG)	CandidiasisThrombocytopenia due to ibuprofenPIH	IbuprofenVitamin DAZTMouthwashNystatin	–
Jimenez‐Cauhe 35	66.7(58‐77)Y	F = 3	_	EM‐like	PetechiaeMacule	–	Palate	14‐21	_	19.5(16‐24)	_	EM‐Like	AZTCeftriaxoneCsHCHL/R	Increase levels of CRPHighD‐dimerLymphocytopeniaNegative serology for syphilis, M. Pneumonia and other viral
Cebeci Kahraman 34	51Y	M	_	_	Large erythematousPetechiaePustules	Painful	Hard palateOropharynxSoft palateAgeusia	A few days	FeverFatigueDry coughSore throatAnosmia	10	+(IgM)	Enanthema due to COVID‐19	Clarithromycin	–

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Abbreviations: AZT, azithromycin; CAD, chronic arterial disease; COPD, chronic obstructive pulmonary disease; CRF, chronic renal failure; DM, diabetes mellitus; HCH, hydroxychloroquine; HLP, hyperlipidemia; HTN, hypertension; L/EX, lower extremity; M, month; MP, maculopapular; MRS, Melkersson‐Rosenthal syndrome; P/T, piperacillin/tazobactam; PCK, poly cystic kidney; PIH, postinflammatory hyperpigmentation; RT, renal transplantation; SAM, ampicillin sulbactam; T/S, trimethoprim/sulfamethoxazole; Y, year.

4. DISCUSSION

Enanthema can develop in various types of viral diseases including dengue fever disease, Ebola virus disease, herpangina, human herpes virus (HHV) infections, measles, and roseola infantum. Infectious diseases, especially of viral etiology, constitute approximately 88% of causes of enanthema. Different types of enanthema such as aphthous‐like ulcers, Koplik’s spots, Nagayama’s spot, petechiae, papulovesicular, or maculopapular lesions, white or red patches, gingival and lip swelling have been reported with various viral infections. Both keratinized (hard palate, gingiva, and dorsum of tongue) and nonkeratinized (labial and buccal) mucosae can be involved. 38 Biadsee and colleagues demonstrated that 7% of the patients with RT‐PCR positive test had plaque‐like changes on the dorsum of tongue. Also, swelling of oral cavity (including palatal, lingual, and gum) was reported by 8% of the patients. Furthermore, appearance of oral lesions was simultaneously found with loss of taste and smell in the patients and more severe and disseminated oral lesions were reported in older patients and in severe COVID‐19. 3 In another study, enanthema was reported in 29% of cases with confirmed COVID‐19 and cutaneous exanthema. 35

4.1. Aphthous‐like lesions

Aphthous‐like lesions appeared as multiple shallow ulcers with erythematous halos and yellow‐white pseudomemberanes on the both keratinized and nonkeratinized mucosae. In one patient, oral lesions appeared simultaneously with systemic symptoms and in other patients, latency time was between 2 and 10 days. One patient had positive history of recurrent aphthous stomatitis (RAS) and two patients had positive PCR for herpes simplex virus (HSV). 4 , 5 , 6 , 7 , 8 , 37 Aphthous‐like lesions without necrosis were observed in younger patients with mild infection, whilst aphthous‐like lesions with necrosis and hemorrhagic crusts were observed more frequently in older patients with immunosuppression and severe infection. Lesions healed after 5 to 15 days. 7 Regression of oral lesions was in parallel association with improvement of systemic disease. Increased level of tumor necrosis factor (TNF)‐α in COVID‐19 patients can lead to chemotaxis of neutrophils to oral mucosa and development of aphthous‐like lesions. Stress and immunosuppression secondary to COVID‐19 infection could be other possible reasons for appearance of such lesions in COVID‐19 patients. 4

4.2. Herpetiform/zosteriform lesions

Herpetiform lesions presented as multiple painful, unilateral, round yellowish‐gray ulcers with an erythematous rim on the both keratinized and nonkeratinized mucosae. Manifestations of these lesions preceded, coincided with, or followed systemic symptoms. In one case, geographic tongue appeared after recovery of herpetiform lesions. Stress and immunosuppression associated with COVID‐19 was the suggested cause for appearance of secondary herpetic gingivostomatitis. 4 , 9 , 10 , 12 , 13

4.3. Ulcer and erosion

Ulcerative or erosive lesions appeared as painful lesions with irregular borders on the tongue, hard palate, and labial mucosa. Lesions appeared after a latency time of 4 to 7 days and in one case, lesions appeared 3 days before the onset of systemic symptoms and recovered after 5 to 21 days. In two cases, PCR for HSV‐1 and HSV‐2 was performed and was negative. Different factors including drug eruption (to NSAID in one case), vasculitis, or thrombotic vasculopathy secondary to COVID‐19 were suggested as causes for development of ulcerative and erosive lesions. 14 , 15 , 16 , 17 , 18 , 19

4.4. White/red plaques

White and red patches or plaques were reported on dorsum of tongue, gingiva, and palate of patients with confirmed or suspected COVID‐19. Candidiasis due to long‐term antibiotic therapy, deterioration of general status, and decline in oral hygiene can be the cause of white or red patches or plaques. 4 , 6 , 20

4.5. EM‐like lesions

EM‐like lesions appeared as blisters, desquamative gingivitis, erythematous macules, erosions, and painful cheilitis with hemorrhagic crust in patients with cutaneous target lesions in the extremities. Lesions appeared between 7 and 24 days after the onset of systemic symptoms and recovered after 2 to 4 weeks. 12 , 21 , 22

4.6. Angina bullosa‐like lesions

Angina bullosa‐like lesions presented as asymptomatic erythematous‐purple blisters without spontaneous bleeding on the tongue and hard palate in two confirmed cases of COVID‐19. 23

4.7. Melkerson‐Rosenthal syndrome

There was a report of a 51‐year‐old woman presenting with complaint of malaise and unilateral lip swelling, fissured tongue and right facial paralysis. She had past history of Melkersson‐Rosenthal syndrome since 4 years ago that was spontaneously cured with no relapse. Laboratory data demonstrated an increased level of CRP and computed tomography (CT) scan showed ground‐glass opacities in both lungs. The patient cured completely after treatment of COVID‐19 disease. 24

4.8. Atypical sweet syndrome

There was a report of 61‐year‐old female who presented complaining of fever, fatigue, arthralgia, myalgia, several erythematous nodules on the scalp, trunk and extremities, and minor aphthous ulcers on the hard palate and buccal mucosa. RT‐PCR for COVID‐19 was positive. Skin biopsy showed diffuse neutrophilic infiltration in the upper dermis with granulomatous infiltration in the lower dermis and subcutaneous area that was compatible with erythema nodosum‐like Sweet syndrome. 25

4.9. Kawasaki‐like disease

Oral lesions including cheilitis, glossitis, and erythematous and swollen tongue (red strawberry tongue) appeared in COVID‐19 patients with Kawasaki‐like disease (Kawa‐COVID). The long duration of latency between appearance of systemic symptoms (respiratory or gastrointestinal) and onset of oral or cutaneous symptoms could be due to a delayed hyperactivation response of the immune system and secondary release of acute inflammatory cytokines rather than direct effects of virus on the skin and oral mucosa. 22 , 26 , 27 , 28 , 29 , 30 , 31 , 32

4.10. Necrotizing periodontal disease

There was a report of a 35‐year‐old female suspicious for COVID‐19 who presented with fever, submandibular lymphadenopathy, halitosis, and oral lesions. Oral lesions included a painful, diffuse erythematous and edematous gingiva with necrosis of inter‐papillary areas. The suggested diagnosis was necrotizing periodontal disease due to bacterial coinfections (especially prevotella intermedia) along with COVID‐19. The lesions recovered after 5 days. 33

4.11. Vesicles and pustules

We found a report of a 9‐year‐old female presenting with fever, weakness, abdominal pain, and diarrhea that coincided with oral and acral erythematous papular exanthema. Oral lesions included vesicular eruptions and erosions on the tongue and buccal mucosa. PCR test for COVID‐19 was positive. Lesions cured after 1 week. 9

There was also another report on a 51‐year‐old male presented with fever, fatigue, dry cough, dysgeusia, anosmia, and a positive serology for COVID‐19. After 10 days, widespread erythema appeared on hard palate and oropharynx with petechiae and pustules on soft palate border. The suggested diagnosis was enanthema due to COVID‐19 and the lesions cured after a few days. 34

4.12. Petechiae

In a few studies, Petechiae were reported on the lower lip, palate, and oropharynx mucosa. Latency time for patients with petechiae was shorter compared to the patients with both petechiae and macular lesions. Thrombocytopenia due to COVID‐19 infection or the prescribed drug were suggested as possible causes of petechiae. 20 , 21 , 34 , 35

4.13. Nonspecific lesions (mucositis)

Erythematous‐violaceous macules, patches, papules and plaques on the tongue, lip mucosa, hard palate, and oropharynx were reported in several studies. Thrombotic vasculopathy, vasculitis, hypersensitivity associated to COVID‐19 could be the causes of mucositis in patients with COVID‐19. Mucosal hypersensitivity secondary to COVID‐19, thrombotic vasculopathy, and vasculitis might be the possible causes of mucositis in COVID‐19. 8 , 15 , 21 , 23 , 34 , 35 , 36

4.14. Postinflammatory pigmentation

There was one report of pigmentation in the attached and interpapillary gingiva in a 40‐year‐old female. Increased levels of inflammatory cytokines (including interleukin‐1 [IL‐1], tumor necrosis factor [TNF]‐α) and arachidonic acid metabolites (prostaglandins) secondary to production of stem cell factor (SCF) and basic‐fibroblast growth factor (bFGF) from keratinocytes of basal layer lead to postinflammatory pigmentations. 20

5. CONCLUSION

Aphthous‐like lesions, herpetiform lesions, candidiasis, and oral lesions of Kawasaki‐like disease are the most common oral manifestations of COVID‐19 disease. An older age and severity of COVID‐19 disease seem to be the most common factors that predict severity of oral lesions in these patients. Lack of oral hygiene, opportunistic infections, stress, underling diseases (diabetes mellitus, immunosuppression), trauma (secondary to intubation), vascular compromise, and hyper‐inflammatory response secondary to COVID‐19 might be are the most important predisposing factors for the development of oral lesions in COVID‐19 patients.

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