Aphthous stomatitis in COVID ‐19 patients: Case‐series and literature review

Abstract

Dear Editor We have read with great interest the review of Iranmanesh et al. (2020) on oral manifestations of coronavirus diseases (COVID‐19) which demonstrated the emergence of aphthous‐like lesions in 16 cases thus suggesting that neutrophil chemotaxis, stress, and immunosuppression could be causal pathways for this condition to appear in COVID‐19 patients. 1 As a result of this, we aim to report according to the CARE guidelines, the characteristics of 21 laboratory‐confirmed COVID‐19 patients with aphthous stomatitis. 2 We have also performed an updated literature search in Ovid MEDLINE, EMBASE, Cochrane Library, Epistemonikos from inception until November 26th, 2020 with a combination of keywords (COVID‐19 or SARS‐CoV‐2) and aphthous. A retrospective analysis of our hospital records for COVID‐19 patients during the period of April‐September 2020 revealed that out of 1237 patients tested positive by our screening clinic, 21 patients (1.7%) complained of intra‐oral pain related to aphthous stomatitis. The patients had undertaken polymerase chain reaction (PCR) testing of SARS‐COV‐2 due to various purposes including pre‐travel (14.3%) and post‐travel (9.5%) screening, direct (9.5%) and indirect (4.8%) contact with an infected case, presenting with mild (42.9%), and moderate (19%) respiratory symptoms (Table 1). TABLE 1 Demographic, clinical and laboratory characteristics of COVID‐19 patients with aphthous stomatitis, April‐September 2020 ID Gender Age Smoking Testing reason Ct a Severity b Cough Fever Anosmia Ageusia Location Pain Size Duration Onset TTT c 1 Male 19 Non‐smoker Before travel 31 Mild No No No No Buccal mucosa 4 1 2 0 CHX 2 Female 38 Non‐smoker Direct contact 15 Mild No No No No Tongue 5 1 3 0 CHX 3 Female 42 Non‐smoker Indirect contact 28 Mild No No No No Lower lip 4 3 2 0 CHX 4 Male 31 Non‐smoker After travel 18 Mild No No No No Lower lip 3 2 2 0 CHX 5 Female 56 Non‐smoker Mild symptoms 26 Mild Yes No No No Buccal mucosa 4 2 3 0 CHX 6 Female 27 Non‐smoker Moderate symptoms 20 Mild Yes No No No Upper lip 5 2 3 0 CHX 7 Female 46 Non‐smoker Mild symptoms 27 Moderate No Yes No No Upper gingiva 7 2 3 1 CHX 8 Female 20 Non‐smoker Mild symptoms 29 Mild No No Yes No Buccal mucosa 7 2 3 0 CHX 9 Female 31 Non‐smoker Mild symptoms 31 Mild No No No No Tongue 4 2 3 0 CHX 10 Male 20 Non‐smoker Mild symptoms 32 Mild No No Yes No Palate 6 2 3 0 CHX 11 Female 36 Smoker Moderate symptoms 12 Moderate Yes Yes Yes Yes Palate and upper and lower gingiva 8 4 4 0 PCM 12 Female 27 Non‐smoker Moderate symptoms 18 Mild No No No No Palate 8 2 4 0 PCM 13 Female 17 Non‐smoker After travel 31 Mild No No No No Buccal mucosa 4 1 2 0 CHX 14 Female 24 Non‐smoker Before travel 32 Mild No No No No Tongue 4 1 2 0 CHX 15 Female 38 Non‐smoker Mild symptoms 27 Moderate No Yes No No Buccal mucosa 5 1 2 0 CHX 16 Female 25 Non‐smoker Mild symptoms 24 Mild No No Yes No Upper gingiva 6 2 Missed 0 CHX 17 Female 16 Non‐smoker Moderate symptoms 19 Mild Yes No No No Upper lip 6 1 Missed 0 CHX 18 Female 26 Non‐smoker Direct contact 30 Mild No No No No Buccal mucosa 7 2 3 0 CHX 19 Male 37 Smoker Mild symptoms 32 Mild No No Yes Yes Buccal mucosa 7 2 3 1 PCM 20 Female 39 Non‐smoker Mild symptoms 29 Mild Yes No No No Upper lip 5 4 2 0 CHX 21 Female 48 Non‐smoker Before travel 30 Mild No No No No Lower lip 4 2 2 0 CHX a Ct: cycle threshold value. b Severity: COVID‐19 clinical course severity according to NHMRC, Australia. c TTT: treatment used was either chlorhexidine gluconate 0.12% mouthwash (CHX) or paracetamol (PCM). Their mean age was 31.57 ± 11.01 (16‐56) years old, and 17 patients (81%) were females. While the vast majority were non‐smokers, only two patients (9.5%) were smokers. The PCR test confirmed their infection with a mean cycle threshold (Ct) value of 25.76 ± 6.21 (12‐32). Regarding their characteristic symptoms of COVID‐19, three patients (14.3%) had persistent fever, five patients (23.8%) had a dry cough, five patients (23.8%) had anosmia, and two patients (9.5%) had ageusia. According to the Australian classification for COVID‐19, 18 patients (85.7%) experienced a mild course of the disease, whereas 3 patients (14.3%) had a moderate course. 3 On intraoral examination, solitary ulcerative white halos with well‐defined erythematous margins were observed in the buccal mucosa (33.3%), upper lip (14.3%), lower lip (14.3%), tongue (14.3%), palate (9.5%), gingiva (9.5%) and both of palate and gingiva (4.8%). The mean size of the ulcers was 2 ± 0.86 (1–4) mm, and they caused pain with a mean intensity of 5.38 ± 1.5 (3–8) which was measured by means of an 11‐item numerical rating scale (NRS) when with “0” denoting “no pain” and “10” denoting “pain as bad as you can imagine”. 4 The patients were asked whether they had experienced similar ulcerative lesions previously and based on their negative answer, the recurrent aphthous stomatitis (RAS) was ruled out. To manage their pain, 18 patients (85.7%) were prescribed chlorhexidine gluconate 0.12% (CHX) mouthwash, and 3 patients (14.3%) were prescribed paracetamol (PCM). The pain duration was reported by 19 patients with a mean of 2.68 ± 0.67 (2–4) days; however, 2 patients were missed from the follow up. It is worthy to note that prevalence of aphthous stomatitis among COVID‐19 patients could have been underestimated because we had not performed an intra‐oral examination for all positive COVID‐19 cases in order to confirm whether they had aphthous or not; nevertheless, our records are based on subjective reporting by the patients. Inferential statistics revealed that pain duration was significantly lower in patients treated with CHX (2.50 ± 0.52 days) than patients treated with PCM (3.67 ± 0.58 days); t(17) = −3.54, P = .003. This difference could be attributed to the severity of the aphthous condition, not to the drugs themselves. In case of CHX, patients had higher mean pain intensity (5 ± 1.24 vs 7.67 ± 0.58) and ulcer size (1.83 ± 0.79 vs 2.67 ± 1.15) than in case of PCM; t(19, 19) = −3.61, −1.61; P = .002, .125, respectively. Gender and age were not associated with any of the aphthous characteristics; however, tobacco smoking was the only risk factor significantly associated with pain intensity, the onset of aphthous stomatitis, anosmia, and ageusia P = .032, 0.042, .006, and ≤.001, respectively. On reviewing the currently growing evidence on aphthous stomatitis of COVID‐19 patients, we have found 22 cases reported in 8 publications (7 case reports, 1 prevalence study). 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 Fourteen cases (63.6%) were from Americas, five (22.7%) from Europe, two (9%) from the Middle East, and one (4.5%) from Asia‐Pacific (Table 2). The aphthous lesions were equally distributed across gender; however, female predominance was noticed in the prevalence study of Florida, which is similar to our series. 11 Seventeen patients (77.3%) were below 40 years old; similarly, the majority of our series (80.1%) was below 40 years old. The onset of aphthous lesions was reported in 10 patients only; it was estimated using the latency period since COVID‐19 symptoms emergence which ranged between 0 and 10 days with two patients experienced aphthous stomatitis concurrently with COVID‐19 symptoms onset. The most common sites were tongue, lower and upper lip; this pattern was in agreement with what we had found in our patients except for buccal mucosa which was affected only in one patient although it was the first site in our series. TABLE 2 COVID‐19 patients with aphthous lesions Study, location Number Gender Age Confirmation a Type Location b Onset b Description Dominguez‐Santas et al 5 , Madrid (Spain) 4 1 Female; 3 Males 43; 33; 37; 19 Confirmed Minor aphthous ulcers Buccal mucosa; opper gingiva; tongue; lower lip Latency from COVID‐19 symptoms: 4, 3, 5, 0 days, respectively. All lesions measured less than 1 cm. They mainly affected the nonkeratinized mucosa. The majority of them had a creamy‐colored fibrin surface with an erythematous peripheral ring. Malih et al 6 , Tehran (Iran) 1 Male 38 Confirmed Aphthous lesion Tonsil N/A Erythema and aphthous ulcer developed on left tonsil, which was found on laryngeal exam. Corchuelo et al 7 , Cali (Colombia) 1 Female 40 Confirmed Aphthous lesion Lower gingiva N/A Painful aphthous ulcerative lesion developed on the attached gingiva of the first lower premolar. Brandão et al 8 , Sao Paulo (Brazil) 7 2 Females; 5 Males 81; 83; 72; 32; 35; 29; 28 Confirmed Aphthous‐like stomatitis Upper, lower lip and tongue; tongue; upper and lower lip; tongue; tonsil; tongue; upper and lower lip Latency from COVID‐19 symptoms: N/A, N/A, N/A, 10, 6, 2, 8 days, respectively. Multiple shallow aphthous‐like painful lesions of varying sizes. Díaz Rodríguez et al 9 , Madrid (Spain) 1 Female 43 Confirmed Aphthous‐like stomatitis Tongue N/A In addition to the aphthous‐like ulceration, the patient reported burning tongue sensation and tongue depapillation. Al‐Khanati et al 10 , Damascus (Syria) 1 Male 24 Suspected Aphthous‐like stomatitis Lower lip The same day of COVID‐19 symptoms (fever, headache) Two aphthous‐like ulcers on the mucosa of the lower lip, which enlarged and became painful in 3 days. The patient suffered from burning sensation related to the tongue associated with halitosis. Katz et al 11 , Florida (USA) 6 6 Female 2 patients (10‐17 y); 4 patients (18‐34 y) Confirmed Recurrent oral aphthae N/A N/A The diagnosis of recurrent aphthous stomatitis (RAS) was made by physicians who might not be familiar with oral diagnosis. Putra et al 12 , Jakarta (Indonesia) 1 Male 29 Confirmed Aphthous lesion N/A Latency from COVID‐19 symptoms: 7 days. Aphthous stomatitis was noticed after 7 days of symptoms emergence and treated by typical oral hygiene. a Laboratory confirmation of the SARS‐COV‐2 infection by means of polymerase chain reaction (PCR) testing. b N/A: not reported by the investigators. To conclude, the current epidemiologic evidence does not seem to be different from the typical characteristics of aphthous stomatitis in terms of female predominance and young age affinity. 13 This series supports the demand for larger studies to shed light on pathophysiology and prevalence of this lesion positively associated with immuno‐compromised population. CONFLICT OF INTEREST The authors declare no potential conflict of interest. AUTHOR CONTRIBUTIONS Abanoub Riad: Writing‐original draft. Islam Kassem: Data curation; Investigation. Jan Stanek: Writing‐original draft; Investigation. Mai Badrah: Formal analysis. Jitka Klugarova: Writing‐review & editing. Miloslav Klugar: Supervision; Writing‐review & editing.