Erythema Multiforme Major following SARS‐CoV‐2 vaccine

Abstract Erythema multiforme major, an immune‐mediated skin reaction to infections or medications with oral involvement, should be taken into account as a potential side effect of several vaccines, including SARS‐CoV‐2. Correct patient history collection allows prompt recognition and subsequent successful medical management with oral corticosteroids.

The patient presented to our emergency department on day 5 after the appearance of lesions, due to worsening of the clinical picture and the inability to hydrate and feed.
The otolaryngological evaluation confirmed an oral floor swelling accompanied by diffuse oral mucosal erosive lesions (Figure 1). The dermatologist identified two round erythematosus-brownish target-like lesions (on the right thigh and calf) on unscathed skin, roughly 1 cm wide, without bubbles or detachment ( Figure 2). There was no conjunctivitis or genital involvement. Laboratory tests identified only a moderate C-reactive protein increase (23.9 mg/L, normal range <10 mg/L) and the nasopharyngeal swab for SARS-CoV-2 proved negative. The infectious disease specialist requested serological testing for Chlamydia pneumoniae (IgG and IgM), Mycoplasma pneumoniae (IgG and IgM), T. pallidum, herpesviruses 1 and 2, hepatitis C, and hepatitis B. All serological testing was normal and safe for herpesvirus IgG (22.1 titration index, with positive values >1) and HBsAb resulting from mandatory vaccination (438 international units per liter, with positive values >10). Based on clinical appearance and medical history, a diagnosis of drug-related erythema multiforme was made, 1 and IV methylprednisolone 1 mg/kg and fluid supplementation were started. IV morphine was required for pain management during the first 48 hours. A progressive improvement of the clinical picture with C-reactive protein normalization (9.3 mg/L) allowed for oral fluid intake on day 4, while oral feeding and IV steroids tapering began on day 5. The following day, the patient was dismissed on oral prednisone tapering, with almost complete resolution of the clinical picture. No recurrence was noted at the 1-month evaluation.

| DISCUSSION
To our knowledge, the authors present the first mRNAvaccine-induced case of EMM. Although the relationship between EM and immunization procedures is already established, its link with recent mRNA vaccines is less clear. The pathophysiological mechanics might mimic the same immune response to SARS-CoV-2-mediated EM. 3 This report illustrates the diagnostic challenge posed by EMM, ie, its prevalently oral manifestation. In contrast with full-scale dermatological presentations (predominant both in mild EM cases, Stevens-Johnson syndrome, or toxic epidermal necrolysis-the latter two already described after SARS-CoV-2 immunization 4 ), oral lesions and symptoms might be also suggestive of fungal or viral infections. Mycoplasma pneumoniae-induced rash and mucositis might share the presentation with EMM, although often in younger patients, usually in their first or second decade. 5 In the presented case, serological information allowed to rule out M. pneumoniae infection. It has to be noted also that the differential diagnosis between Stevens-Johnson syndrome and EMM might represent a clinical issue. 6 Histological evaluation of skin lesions, which bear different features in EMM and Stevens-Johnson syndrome might represent an additional tool. In this specific case, the dermatologist considered the EMM diagnosis consistent with the clinical features and therefore decided not to perform any biopsy on the few skin lesions that appeared on the patient.
Dermatological manifestations can be mild or subtle and, unless the patient's drug and personal history hint at an immune-mediated reaction, the corticosteroid treatment might get delayed.
Although EMM is a known vaccine ADR, the exceptional pandemic circumstances turned the spotlight back on potential vaccine risks, which have been long known and adequately managed in a large number of patients. 7,8 ADRs to new mRNA vaccines have been therefore widely covered by the media and often speculatively manipulated into sensational claims, impacting negatively on vaccine public acceptance. 9,10 The prompt recognition of infrequent ADRs such as EMM represents the most suitable tool to improve patients' outcomes and trust toward healthcare providers.