Recurrent aphthous stomatitis (RAS) is a common intraoral condition presenting painful ulcers [1,2]. Although the etiology of RAS is still unclear, several predisposing factors including local, systemic, immunologic, genetic, allergic, nutritional, microbial factors and some immunosuppressive medications have been suggested [1,2].

Interestingly, recent case studies raised the possibility that cutaneous and oral mucosal manifestations may be associated with the coronavirus disease 2019 (COVID-19) vaccination [3-8]. Dentists as well as dermatologists could be perplexed if they encountered acute onset soft tissue lesions following COVID-19 vaccination due to the unknown prevalence and association between them.

Considering the current situation in which COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 infection, has become a serious global burden in political, economic and social as well as medical aspects, COVID-19 vaccinations are required and becoming increasingly essential [3].

However, administration of COVID-19 vaccines may present inherent inflammatory nature with high reactogenicity such as fever, headache, fatigue, and muscle pain [9]. At this time all possible side effects from major serious complications to minor events are of great concerns to people. Furthermore, unexpected and unwanted effects, major or minor, can make people anxious and negatively affect their willingness to get vaccinated [3].

In this report, we present the case of an acute onset of aphthous stomatitis in a healthy adult after Moderna COVID-19 vaccination and discuss clinical reasoning and implications of our observation.

The Institutional Reviewed Board (IRB) approval of this study was exempted by the IRB of Dankook University Dental Hospital and written informed consent was obtained from the patient.

A 43-year-old male presented to the orofacial pain clinic with acute onset of intraoral stomatitis. He had received second injection of the COVID-19 vaccine (mRNA-1273; Moderna Inc., Cambridge, MA, USA) 5 days ago. On the day of receiving the vaccine, he developed fever and headache without myalgia. The patient said that he also received Moderna for the first vaccine 5 weeks ago, and at that time, he only had temporary fever and headache. He took 5 Tylenol tablets (Janssen Korea, Seoul, Korea) a day for 3 days after the second vaccination. He reported that the fever and headache were relieved. Over the next 2 days, swollen sensation without pain of the right side of the lower jaw, including the posterior gingiva, gradually occurred. He presented to the local dental clinic and was referred to the Department of Orofacial Pain and Oral Medicine, Dankook University Dental Hospital. On examination, the patient had no fever and looked healthy. Facial asymmetry and extraoral swelling were not observed. However, intraoral examination revealed non-painful large ulcer on the alveolar mucosa and vestibule between the 1st premolar and the 2nd molar on the right side of the maxilla (Fig. 1). The ulcer was well-demarcated with widespread superficial white change on the buccal mucosa and the lower lip of the affected side. On rubbing, detachment of white superficial mucosa on the peripheral margin was seen without submucosal erosive changes. His medical history presented that he had a herpes zoster infection on his left chest two or three years ago. The lesion was resolved after dermatologic management and never recurred. Additionally, the patient reported a history of recurrent oral ulcerations once or twice a year when he was tired, but it was not as large as this time. The patient denied any events of intraoral thermal and mechanical trauma and social history of drinking and smoking.

Laboratory tests were performed for differential diagnosis including viral infection, bacterial infection, autoimmunity and systemic condition related oral disease (Table 1).

Polymerase chain reaction testing of the lesion were negative for herpes simplex virus (HSV) 1 and 2, cytomegalovirus (CMV) and varicella zoster virus (VZV). Serum IgG testing, not serum IgM testing, was positive for HSV, CMV and VZV, indicating prior infection with viral infection. Testing for human immunodeficiency virus, C-reactive protein, creatine phosphokinase, rapid plasmin reagin, antistreptolysin O titer and antinuclear antibody were also negative. Blood chemistry revealed elevated cholesterol, alanine aminotransferase and aspartate transaminase. Comple blood count was non-specific except elevated lymphocyte.

On the basis of temporal association between occurrence of oral lesion and vaccination, along with his clinical and laboratory findings, he was diagnosed with major aphthous stomatitis following Moderna COVID-19 (mRNA) vaccination. He was prescribed 0.05% dexamethasone solution for topical use. On his follow up, the ulcerated lesion was resolved two weeks later (Fig. 2). This case was reported to the public health center of Cheonan, Korea as a suspected case of an adverse reaction to the corona vaccination.

The well-known presenting orofacial symptoms of COVID-19 infection are loss of taste or smell and sore throat [4]. Despite the current survey indicating that there is no observed significant association between COVID-19 vaccination and orofacial manifestations [5], there are currently increasing case reports on the mucocutaneous manifestation following COVID-19 vaccination.

To our knowledge, this is the first case report to present a potential association between acute onset of aphthous stomatitis and COVID-19 vaccination in Korean.

Diseases which cause oral ulcers include wide spectrum of etiology from simple mechanical trauma to allergy, malnutrition, hematologic disorder, various bacterial and viral infection, gastrointestinal diseases, autoimmunity, various medications and psychologic factors. From history taking including the timing of the onset of oral ulcer with respect to the vaccination, physical examination, and further laboratory test, it was clinically reasoned that our patient can be categorized into a form of aphthous stomatitis triggered by the COVID-19 vaccine.

The RAS is the most common ulcerative conditions of the oral regions presenting recurrent occurrence, painful burning sensation, circumscribed margins, and yellow or gray floors surrounded by erythematous haloes. It occurs mainly on the non-keratinized mucosa such as buccal, labial and tongue rather than the heavily keratinized mucosa of the palate and gingiva [1,2].

It can be presented with minor, major and herpetic form depending on the number and size of ulcer. Among them, major RAS, which accounts for about 10% to 15% of patients, exhibits the most similar clinical presentation to this case when considering the solitary ulcer with the size exceeding 1 cm on the vestibular and labial mucosa [1,2].

However, our patient presented slightly different clinical features from the typical form of RAS. Ulcer-related pain and erythematous halos were not seen in this case. Also, widespread white changes of labial mucosa with peripheral detachment on rubbing, which are thought to be epithelial detachment rather than keratinization, was observed on the labial mucosa of this case.

Therefore, this case could be clinically diagnosed as an atypical variant of major aphthous ulcer. Although it is unclear whether the oral lesion was a flare of a pre-existing RAS or new-onset aphthous stomatitis, our clinical reasoning is that the immune responses induced by the vaccination could lead to a flare-up of RAS in a healthy patient considering his medical history of infrequent occurrence of RAS.

Although reports of cutaneous and oral mucosal manifestations after COVID-19 vaccination are currently scarce, there are some clinical reports on this occurrence.

A case of new-onset cutaneous lichen planus one week after COVID-19 vaccination was reported in a 56-year-old female without significant past medical history [10]. In addition, vulvar aphthous ulcer in an adolescent after Pfizer-BioNTech COVID-19 vaccination was presented [11]. Kulkarni and Sollecito [3] suggested that various oral lichen planus which is T-cell mediated chronic inflammatory condition of unknown etiology and further other immune-mediated oral conditions such as pemphigoid, pemphigus, and chronic ulcerative stomatitis may experience an exacerbation of oral conditions after COVID-19 vaccination.

Both of mRNA vaccines (Pfizer/BioNTech and Moderna) and viral vector vaccine (Johnson & Johnson), which are authorized by the United States Food and Drug Administration (FDA), are shown to have an immunostimulatory activity and particularly upregulate T-cell mediated immunity with a subsequent elevation of various inflammatory cytokines of IL-2, TNF-a, and IFN-r in clinical trials and animal studies [3,12,13]. Regardless of vaccine types, all three vaccines contain sequences that encode the viral spike protein and therefore use gene therapy. Viral vectors are known to induce inflammation through toll-like receptor (TLR) 2 and 9 and stimulate CD4+ Th1 and humoral immune responses in humans [9,14]. In case of mRNA vaccines, multiple pathways of RNA-induced inflammation through TLR 3, 7, 8 are known to be activated. Furthermore, lipid nanoparticles used as an enclosure for mRNA of Pfizer also have shown inherent immunostimulatory effect regardless of their mRNA [9].

These previously reported clinical findings and relevant clinical reasoning urge dental professionals to have awareness and vigilance for flares for oral mucosal diseases like oral lichen planus, pemphigus vulgaris, and recurrent aphthous ulcers which have a T-cell immune response in their pathogenesis. On the other hand, unpredictable and rare occurrence of oral mucosal manifestations following COVID-19 vaccination could be in part explained by the diverse phenotype and function of T-cell subsets of the oral mucosa which remain largely undetermined [15].

In summary, this acute onset of oral aphthous stomatitis shortly after the administration of COVID-19 vaccine, which may be a flare of existing condition of typical RAS or a newly onset of aphthous stomatitis, may or may not have been directly related to the COVID-19 vaccination. Despite the unclear etiology of this oral mucosal lesion, the stomatitis quickly relieved by topical steroid solution within 2 weeks.

Considering the close temporal association between the oral lesion and vaccination and atypical clinical manifestation of aphthous stomatitis, it is clinically reasonable to reckon that aphthous stomatitis, which is temporary and less serious, can be one of the possible, short-term oral manifestations of COVID-19 vaccination. Dental professionals should be aware of this possible association and properly manage our patients to reduce their worries and fear in regard to unexpected oral flare-up.

Further studies to shed light on prevalence and pathophysiologic association of this oral lesion and COVID-19 vaccination deserve attention.

No potential conflict of interest relevant to this article was reported.