An Unusual Presentation of Erythema Multiforme Following the Administration of Pfizer-BioNTech COVID-19 mRNA Vaccine in a Pediatric Patient

Coronavirus disease 2019 (COVID-19) caused a global calamity that forced emergency use authorization to Pfizer-BioNTech COVID-19 (BNT162b2) vaccine. It is efficacious in preventing symptomatic severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in seronegative recipients. The safety profile is still unclear; however, commonly reported symptoms post-vaccination are fatigue, headache, muscle pain, chills, and injection-site pain. COVID-19 disease elicits, to some extent, cutaneous side effects like urticaria, morbilliform rash, and chilblain-like eruption. Vaccination against COVID-19 was reported to induce similar dermatologic manifestations, such as urticarial rash, delayed large-local reaction, local injection-site reaction, and morbilliform eruption. Erythema multiforme (EM) is a rare manifestation post-vaccination, and only a few reports implicate it as a culprit in cutaneous eruptions following the BNT162b2 vaccine. This report delineates the presentation of a healthy 14-year-old girl to a dermatology clinic who developed EM post-vaccination with the first dose of BNT162b2. New-onset EM-eruption post-vaccination with BNT162b2 had been reported previously in 14 cases, and one case reported on the flare of preexisting-EM.


Case Presentation
A healthy 14-year-old female developed localized unilateral cutaneous eruption throughout the left upper extremity that manifested after the administration of the BNT162b2 vaccine.Approximately one-hour postvaccination, a localized fluid-filled bullous formed at the injection site.The next day, the bullous confluent into pruritic dusky-red two-zoned incomplete-ring targetoid scaly plaques (Figures 1-2).There was no face, ocular, mucosal, or systemic manifestation.New medications, previous history of similar lesions, signs of herpes-simplex-virus (HSV) infection, and prodromal symptoms were all denied.Referral for dermatological assessment was done 20 days post-eruption, and demonstrated ill-defined two-zoned scales with dusky-red incomplete-ring plaques over the left extremity, favoring the extensor surface (Figures 1-2).Histopathology showed a regenerative epidermis with scattered dyskeratotic keratinocytes (Figure 3).From a clinical and histopathological aspect, atypical EM secondary to the BNT162b2 vaccine was established.Usual management was offered with betamethasone-valerate 0.1% cream and fusidic-acid 2% cream to counteract any secondary bacterial infection.At the follow-up examination, EM-eruption had improved.Presentation of acute localized EM within the first four hours post-vaccination will hinder the patient from receiving the second dose of BNT162b2 and other mRNA vaccines.
One hypothesis that explains the abrupt onset of EM is pre-sensitization.Post-vaccination adverse events are generally attributed to the immune system's reaction to the vaccine's components like egg protein, gelatin, and polyethylene-glycol (PEG).Those ingredients are necessary to stabilize vaccines during transportation, prevent bacterial contamination, and improve the drug's water solubility; the latter is achieved by PEG [14].BNT162b2 vaccine does not contain any food or drug components; however, it is formulated with PEG to stabilize lipid nanoparticles containing active SARS-CoV-2 mRNA-protein [14].PEG is found in numerous medications and injectable steroids.Although safe, reports have shown that 70% of patients receiving PEG therapies will develop anti-PEG IgG [14,15].Thus, reaction to PEG-formulated products (i.e.vaccines) indicates previous sensitization.
Vaccine-induced EM is highly infrequent.Nonetheless, it has been implicated before in literature with diphtheria-pertussis-tetanus, measles-mumps-rubella, and human papillomavirus vaccines [2].Su et al. [16] have collected data from 1999 to 2017 and concluded the median time of EM onset post-vaccination is six days; while adverse events occurred within two weeks.The temporal association of the BNT162b2 vaccine and EM eruption in this report is unusual compared with the data from Su et al. [16] as it appeared within 24 hours.

TABLE 1: The table outlines the presentation and histological data of EM after the BNT162b2 vaccine
Almost all eruptions have manifested within two weeks, mostly in females, and after first-dose administration.Anatomical distribution has favored acral sites, but older patients had more of a generalized eruption.Most cases reported no mucosal involvement.There was no previous HSV infection except in one case that described a flare of preexisting EM.All reports described EM eruption in adults, there was no pediatric report.All cases were managed conservatively, except two cases that needed hospital admission due to the severity of the lesions [4,9].The only consistent factor that supported EM diagnosis among those reported cases is clinical and histopathological correlation.

Conclusions
EM pathogenesis, theoretically, involves a stimulus triggering a delayed hypersensitivity reaction.This stimulus could be PEG, and previous sensitization could explain the rapid manifestation in this report.EM secondary to the BNT162b2 vaccine is unusual.Nonetheless, the clinical picture along with histopathological correlation is suggestive of EM.
have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

FIGURE 1 :
FIGURE 1: (A) Acute localized cutaneous eruption after the BNT162b2 vaccination over the left upper extremity.The eruption materialized firstly on the injection site, deltoid area, and disseminated downward through the arm and hand favoring the extensor surface.(B) Scale formation on the ill-defined incomplete ring-shaped dusky-tanned twozoned targetoid plaque.(C) Two-zoned dusky purpuric center surrounded by a pale targetoid plaque over the extensor surface of the left arm.

FIGURE 2 :
FIGURE 2: (A) Poorly defined morphed targetoid plaques with signs of PIH over the left deltoid area.(B) Incomplete ring-formation of targetoid lichenoid plaques with signs of PIH, xerosis, and excoriation on the anterior aspect of the arm.(C) Targetoid plaques taking the shape of incomplete rings with signs of post-inflammatory hyperpigmentation on the dorsal aspect of the hand.PIH: post-inflammatory hyperpigmentation