Oral Findings in Patients with COVID-19 Infection: Report of Two Cases and Review of Literature

Few reports have been published highlighting oral findings in COVID-19 patients. Since the outbreak of the recent pandemic caused by SARS-CoV-2, it is important to illustrate in the very near future how recurrent these oral findings are in the symptomatic COVID-19 patients in contrast to those asymptomatic ones, as there are multiple findings reported. This case study reports a new combination of oral findings in two COVID-19 patients from India, one symptomatic, and other asymptomatic. Cases presenting oral findings in asymptomatic COVID-19 patients are the rarest. Moreover, till now, petechial or purpuric lesions, solely as theoral findings without any associated skin lesions and oral mucosal hyperpigmentation of our patients are the rare oral findings to be reported in COVID-19 patients. These cases provide evidence for a deeper understanding of the oral alterations seen in COVID-19 patients that need to be addressed at present. Case Report Rai et al.; JPRI, 33(47B): 265-273, 2021; Article no.JPRI.74977 266


INTRODUCTION
Coronavirus Disease 2019 , is an ongoing pandemic which has spread to the whole world. It is an illness caused by the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) which is the seventh type of coronavirus family to affect humans. According to WHO, the most probable diagnostic clinical features are-fever, cough, and an acute respiratory infection, which spreads from human to human via droplet transmission and direct contact with oral, nasal, and eye mucosal membranes [1].
The virus has been reported to dysregulate immune mechanisms. Till now, only a few reports have been published in the literature emphasizing on the oral findings in these patients like ulcerations, blisters, gingivitis, dysgeusia, fungal co-infections, halitosis, xerostomia associated with reduced saliva secretion, erythema, dry mouth etc.
We describe two cases of COVID -19 patients from India. The main objective of this article is to report a new combination of oral manifestations in two COVID-19 patients (one symptomatic and the other asymptomatic).
After two days of hospitalization, the patient complained of burning sensation all over the mouth during eating. After taking written consent from the patient, oral examination was done. White membranous plaques were found on the left buccal mucosa and posterior part of the hard palate .The provisional diagnosis for these white lesions was made to be oral candidiasis as clinically these lesions were scrappable and left erythematous areas behind after scrapping (Fig.  1C). Use of chlorhexidine mouthrinses (0.2%), twice daily was advised to the patient. With this, small reddish vesiculobullous lesions were also present on the buccal mucosa. (Fig. 1C) for which patient was advised Anabel Ir 0.2% (choline salicylate) and lidocaine gel for topical application 3-4 times a day. Also, small hemorrhagic lesions, suggestive of petechiae or purpuric spots were found on the upper and lower labial mucosa ( Fig. 1A & B). Patient was an upper denture wearer for the past 6 years. Patient's RT-PCR on the 10th day of hospitalization was negative. Follow-up after two weeks (Fig. 1D, E, F) and three weeks after negative RT-PCR ( Fig. 1-G, H, I) revealed that white plaques were resolved and hemorrhagic lesions were reduced in number.

Patient 2
A 64 year-old-female, tested COVID-19 positive on being tested by a nasopharyngeal and oral swab following RT-PCR for SARS CoV-2 RNA amplification. Commenting on the general health, the patient was healthy before this infection and was not on any long-term medications. She was in direct contact with the first patient but did not present any symptoms. This patient underwent all the investigations similar to patient 1, but the findings were within normal range. The patient was advised a similar course of treatment except for antiviralsramidesivir and favipiravir. She was hospitalized for observation and isolation. On day-3 of hospitalization, oral examination revealed presence of a pale ulcer, 2-3 mm in diameter on the lower labial mucosa (Fig. 2-B). The patient 2 reported complaint of burning sensation after having any kind of oral intake after getting admitted in the hospital . Clinically ,there were no signs of candidiasis . Also, in the oral cavity, there was pigmentation present on buccal mucosa and soft palate ( Fig. 2-A). Resolution of the ulcer without any scarring can be appreciated on labial mucosa, two weeks after repeating RT-PCR for (

DISCUSSION
The total number of reports on oral findings in COVID-19 patients suggests that the oral lesions associated with this disease are common manifestations (e.g. candidal lesions, ulcers etc) which may be seen as a secondary effect of therapeutic treatment given to the patients. Therefore, cases of associated oral findings are reported less in number. This could also be possible due to a lack of intraoral examinations because of the recommended protective measures for SARS-CoV-2 infections. Dysgeusia is the only well-known recorded oral manifestation of COVID-19 infection in the literature.
Studies reporting oral manifestations of COVID-19 infections are limited.

Petechial or Purpuric Lesions
In Patient 1, rare oral finding in COVID-19 patients was found on the upper and lower labial mucosa, i.e. small rounded reddish petechiae and purpuric lesions without any other mucocutaneous manifestations on the body, suggestive of having a recent viral infection like COVID-19 infection. Petechiae in febrile conditions ,and milder forms of thrombocytopenia are commonly found in viral infections, and have also been mentioned in 36% of COVID-19 patients [13,14,15].
The patient was on a prophylactic-dose of Clexane, a low molecular weight heparin (LMWH). So, this could also be a drug reaction and a cause for thrombocytopenia leading to oral petechiae and purpuric lesions. However, these lesions started to disappear much before the prescribed medicine (LMWH) was stopped giving to the patient. A study on the occurrence of enanthems in COVID -19 patients, suggests that these types of spots are associated more with viral etiology rather than an adverse drug reaction [9]. But that study reported the palatal enanthems along with other dermatological manifestations like skin rash on the bodies which were not observed in our patient.

Oral Candidiasis
Pseudo-membranous white plaques on left buccal mucosal lining in patient 1 suggest fungal infection-candidiasis, may be due to dysregulated immune system. Oropharyngeal candidiasis(OPC) was reported in hospitalized COVID -19 patients within 8 days of onset of this disease [11]. On the other hand, study by Abanoub Riad et al., it has been mentioned that most of the reported candidiasis cases in COVID-19 patients are the oral white pseudo membranous plaques that extend over the regions like oral mucosa, tongue etc. and these lesions can start occurring from day 1 since COVID-19 symptoms emergence [16]. Broadspectrum antibiotics, ICU admission, lymphocytopenia, mechanical ventilation and systemic corticosteroids are the potential risk factors for hospitalized COVID-19 patients to develop OPC.
Chronic denture use could be linked to candidal lesions. However, in patient 1, these lesions resolved in 14 days when the patient turned COVID-19 negative, suggesting that the candidal lesions may not have been due to denture wearing. The whitish plaques resolved after the patient turned negative for the infection, suggesting that the candidal lesions may not have been due to denture wearing. However, it must be noted that these lesions resolved after giving oral hygiene instructions to the patient about the usage of chlorhexidine mouthwash 0.2%,twice daily. The patient was also observed for signs of improvement. The resolution of these lesions could also be due to antioxidants like vit C and vit E, which are believed to be effective in reducing the production of cytokines storm in COVID-19 patients. Clinical studies and reports demonstrate that prompt administration of highdose i.v. Vit-C improves the outcome of COVID-19 infection. Moreover, it has been documented that vitamin C boosts immunity by keeping high levels of disease-fighting white blood cells in the body, so that the body can fight against infections, especially opportunistic ones such as candidiasis.

Burning Sensations, Dry Mouth and Dysgeusia
Both the patients reported burning sensations during eating along with dryness in mouth which supports the study conducted in COVID -19 patients assessing the first symptoms of olfactory and taste functions [10] as 51.4% of the patients experienced dry mouth which had a strong association with burning sensations in mouth, although the exact cause for these burning sensations is not known. However, there was no diffuse enanthem or depapillation of tongue and no lesion on palate in both of our patients.
The patients also experienced altered taste sensations (dysgeusia) possibly due to the suggested mechanism of SARS-CoV-2 i.e. the virus can bind angiotensin-converting enzyme -2 receptor expressing cells which may act as target cells for its entry, and is readily expressed in the epithelial cells of tongue surface more than the other parts of oral cavity, causing alteration in taste sensations [17].  [18]. The researcher group also excluded other potential causes for these oral findings in all the patients by doing serological testing. Psychosocial stress should also not be neglected while assessing these oral ulcers. Therefore, all patients positive for this virus should have a complete oral examination to better understand these oral alterations.

Mucosal Pigmentation
Oral mucosal hyperpigmentation was another finding in patient 2, which should be linked with post inflammatory pigmentation. SARS CoV-2 has the potential to damage cells of oral mucosa, further causing inflammatory reactions like cytokine surge in which the serum levels of inflammatory mediators such as IFN-γ, IP-10, TNF-α, IL-15 and IL-1β are increased [17]. This might be the chief reason for increased mucosal discoloration in these patients, especially if there is a presence of comorbidities. Drug reactions should also be considered as a cause for mucosal hyperpigmentation. However, pigmentation was markedly reduced than earlier in later follow-ups ( Fig. 2A). So, the incidence of this finding could be more likely to be postinflammatory pigmentation after SARS-CoV-2 infection.

CONCLUSION
Cases presenting oral findings associated with asymptomatic COVID-19 patients are the rarest in the literature. Oral ulcers or blisters have been reported in more than half of the cases. For suspected diagnosis, more than 43% of the reported cases suggest the viral etiologies like SARS-CoV-2 virus could be held responsible for the occurrence of these oral lesions. Pre-existing comorbidities can also be ruled out as causative factors of oral lesions as nearly half the reported cases presented with co-morbidities like diabetes and hypertension. Cells with ACE-2 receptor distribution can become host cells for the SARS-CoV-2 virus and further cause various reactions in the cells of the oral cavity [17].
Thus, we are reporting these oral findings in the COVID-19 patients and conclude with that (i) These cases provide the dental professionals with comprehensive information about the oral findings seen in COVID-19 patients and emphasize on the importance of intraoral examinations in these patients (ii) Co-infections, lack of oral hygiene, impairment in immunity, variety of drug reactions alone or aggravated in viral infection like COVID-19 and hyperinflammatory response after COVID-19 infection need to be considered while evaluating these type of findings in the COVID-19 patients. (iii) Also, the collection of these findings to update the community rapidly is important, as well as these findings are still new in the literature and their exact association with COVID-19 is currently unclear.

CONSENT
All authors declare that 'written informed consent was obtained from the patient (or other approved parties) for publication of this case report and accompanying images.

ETHICAL APPROVAL
All authors hereby declare that all experiments have been examined and approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.