Treatment Following Erythema Multiforme in the Oral Mucosa

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Int. J. Odontostomat., 15(1):222-225, 2021.
Treatment Following Erythema Multiforme in the Oral Mucosa After qHPV Vaccine with Low-Level
Laser Therapy: Case Report
Tratamiento del Eritema Multiforme en la Mucosa Oral Después de la Vacuna Contra el qHPV con Terapia con Láser de Baja Potencia: Reporte de un Caso
Amanda de Paula Magalhães1; Juliana Allázia Balbino1; Stella Cristina Soares Araújo2; Fabiana de Freitas Bombarda-Nunes3 & Fernanda Mombrini Pigatti4
MAGALHÃES, A. P.; BALBINO, J. A.; ARAÚJO, S. C. S.; BOMBARDA-NUNES, F. F. & PIGATTI, F. M. Treatment following erythema multiforme in the oral mucosa after qHPV vaccine with low-level laser therapy: Case report. Int. J. Odontostomat., 15(1):222-225, 2021.
ABSTRACT: Erythema multiforme (EM) is a mucocutaneous condition of uncertain etiology, although the hypersensitivity reaction to a wide variety of agents may be related to the onset of the lesions. In about half of the affected patients it is possible to identify a previous infection. This article aims to report a case of EM in the oralmucosa after qHPV vaccine (Gardasil ), to highlight the diagnostic process and the proposed treatment. Female patient, 16 years old, after 10 days of receiving the first dose of the qHPV vaccine. On physical examination, she presented multiple ulcers and hemorrhagic crusts to the touch, based on the clinical picture and the history of the disease, a diagnostic hypothesis was EM. Low-level laser therapy (LLLT) was chosen as an alternative treatment, since the exercises applied were not successful. The patient was followed up, reported decreased pain and burn and, after one year of treatment, there was no recurrence of the lesions. Laser treatment showed an effective treatment alternative, in addition to the low cost and ease of application.
KEY WORDS: erythema multiforme, human papillomavirus recombinant vaccine quadrivalent, lasers.


Erythema multiforme (EM) is an acute selflimiting disease that is typically associated with hypersensitivity reactions to viruses as well as drugs (Samim et al., 2013; Lerch et al., 2018). Infrequently vaccination is linked as a triggering factor for EM (Katoulis et al., 2010; Chahal et al., 2018). Oral involvement is symptomatic and often shows characteristic crusting ulceration of the lips and ulcerations often involving buccal mucosa or other mucosal surfaces (Fitzpatrick et al., 2019).
Quadrivalent human papillomavirus (qHPV) vaccine is a non-infectious vaccine developed for the

prevention of cervical cancer and condyloma acuminatum. It was approved in September 2006 in the European Union for use in females 9–26 years of age, following its approval in the USA in June 2006 (Katoulis et al.). In 2008, the mass media reported suspected links between the qHPV vaccine and serious adverse events; however, several studies have found that the vaccine is safe, and the main adverse events are mild local reactions (Pérez-Carmona et al., 2010). Herein, we discuss a case of oral EM in a 16-year-old woman who received the qHPV vaccine. We also discuss the management of this patient with low-level laser therapy.

1 Cirujana Dentista, Práctica privada, Espírito Santo, Brazil. 2 Servicio de Cirugía Oral y Maxilofacial, Hospital João XXIII, Minas Gerais, Brazil. 3 Centro Universitario FAESA campus Vitória, Espírito Santo, Brazil. 4 Universidad Federal de Juiz de Fora campus Governador Valadares, Minas Gerais, Brazil.

Received: 2020-07-13

Accepted: 2020-09-15

MAGALHÃES, A. P.; BALBINO, J. A.; ARAÚJO, S. C. S.; BOMBARDA-NUNES, F. F. & PIGATTI, F. M. Treatment following erythema multiforme in the oral mucosa after qHPV vaccine with low-level laser therapy: Case report. Int. J. Odontostomat., 15(1):222-225, 2021.

CASE REPORT A 16-year-old female presented with several oral
lesions associated with dysphagia and dysphonia of a few days’ duration. The patient did not report any relevant
Fig. 1. Initial clinical aspect of the lesions, with multiple ulcers and bleeding crusts in the lip.

systemic alterations. However, the mother said that approximately ten days before the onset of oral lesions the patient had received an intramuscular injection of a second dose of the qHPV vaccine (Gardasil).
Extra-oral examination revealed multiple ulcers and bleeding crusts on touch. The lesions were located on the lip, mainly in the lower lip vermillion (Figs. 1, 2 and 3). The intraoral examination revealed lesions in the labial mucosa and bilateral buccal mucosa characterized by membrane-covered ulcerations.
A low-energy AsGaInP laser (Therapy XT, DMC São Carlos/SP, Brazil) 660 nm, 0.028 cm beam diameter, exposure 35J/cm2(100mW), with 1 J per point of application and 10 seconds irradiation time per point were respectively used. Laser irradiation was initiated immediately on the first appointment. This treatment was repeated four times at 48-hour intervals while signs and symptoms persisted. The method of application of the laser was point contact directly on the lesions over their entire extension. With the following applications, there was a gradual improvement in the clinical picture (Figs. 4, 5 and 6). The patient was followed up, and after one year of treatment, there was no recurrence of lesions.

Fig. 2. Appearance of the ulcers and bleeding crusts in lower lip mucosal.

Fig. 4. Clinical aspect 48 hours after laser therapy.

Fig. 3. Appearance of the ulcers and bleeding crusts in upper lip mucosal.

Fig. 5. Clinical aspect of lower lip mucosal 48 hours after laser therapy.

MAGALHÃES, A. P.; BALBINO, J. A.; ARAÚJO, S. C. S.; BOMBARDA-NUNES, F. F. & PIGATTI, F. M. Treatment following erythema multiforme in the oral mucosa after qHPV vaccine with low-level laser therapy: Case report. Int. J. Odontostomat., 15(1):222-225, 2021.

Fig. 6. Clinical aspect of upper lip mucosal 48 hours after laser therapy.
EM is considered a cell-mediated immune reaction, in which cytotoxic CD8+ T lymphocytes in the epidermis induce apoptosis of keratinocytes presenting viral antigens. Most authors agree that antigens in the vaccine act like keratinocyte-expressed antigens, thus similarly triggering EM (Katoulis et al.; Chahal et al.).
The prevalence of EM is less than 1 % and usually occurs in young people between 20 and 40 years old, being more common in women (Lerch et al.).
Clinically, erythema multiforme can be categorized into two variations. Acute EM refers to a single episode. Chronic EM can be a long-lasting evolution or recurrent which refers to repeated flares of EM over the years (Paulino et al., 2018; de RisiPugliese et al., 2019).
The EM is commonly found in the oral cavity, with prevalence ranging from 35 % to 65 %. Lesions in the oral mucosa ranging from diffuse erythema to multifocal ulcers. Initially it may be present in the form of vesicles or blisters, there may be oral pain that compromises food, food intake and speech (Samim et al.). Consequently, the patient evolves with dysphagia and dysphonia, as shown in the case reported.
Some vaccines have already been associated with EM (Katoulis et al.; Su et al., 2020). According to reports by the Vaccine Adverse Evente Reporting System (VAERS), between 1999 and 2017, 984 cases of EM emerged after vaccination, with smallpox being responsible for most cases (Samim et al.).

HPV vaccine probably was the causal agent in our patient in the absence of other known causes of EM and by the temporal relationship between the development of EM and the vaccination. However, as the age of immunization is also the age when EM is more frequent, the possibility of a coincidence cannot be ruled out (Kang et al., 2008).
The literature reports a time interval between administration of the vaccine and the development of EM between 1 to 3 weeks, which corroborates the time of manifestation of the reported case (Samim et al.). In a recent study, 26 % of the reported cases of EM, occurred 7 to 14 days after vaccination (Su et al.).
The treatment of EM is not systematized, and several drugs with very different mechanisms of action are used, including antiherpetic drugs, corticosteroids, antibiotics, and immunosuppressive treatments (de Risi-Pugliese et al.).
Herein, we report the use of low-level laser therapy to treat oral lesions with favorable results. The LLLT is a phototherapy that stimulate tissue regeneration, reduce inflammation, and control pain (Anschau et al., 2019). Previous reports described LLLT in the treatment of oral ulcers of a Stevens–Johnson syndrome patient exhibiting pain relief and improvement in oral functions (Simões et al., 2011; Rocha et al., 2019).
Treatment of EM is not codified, and the patient was exclusively managed with LLLT and oral care with a favorable outcome. Lasers offer several benefits due to its easy application, non-invasiveness, good response, and no adverse effects as an adjuvant to traditional treatment measures.
We report the first case of erythema multiforme following HPV vaccination treated by low-level laser therapy. The outcome in this case suggests that LLLT may be a new adjuvant modality for EM complications.
MAGALHÃES, A. P.; BALBINO, J. A.; ARAÚJO, S. C. S.; BOMBARDA-NUNES, F. F. & PIGATTI, F. M. Tratamiento del eritema multiforme en la mucosa oral después de la vacuna contra el qHPV con terapia con láser de bajapotencia: reporte de un caso. Int. J. Odontostomat., 15(1):222-225, 2021.

MAGALHÃES, A. P.; BALBINO, J. A.; ARAÚJO, S. C. S.; BOMBARDA-NUNES, F. F. & PIGATTI, F. M. Treatment following erythema multiforme in the oral mucosa after qHPV vaccine with low-level laser therapy: Case report. Int. J. Odontostomat., 15(1):222-225, 2021.

RESUMEN: El eritema multiforme (EM) es una afección mucocutánea de etiología incierta, aunque la reacción de hipersensibilidad a una amplia variedad de agentes puede estar relacionada con la aparición de las lesiones. En aproximadamente la mitad de los pacientes afectados es posible identificar una infección previa. Este artículo tiene como objetivo informar un caso de EM en la mucosa oral después de la vacuna qHPV (Gardasil®), para resaltar el proceso de diagnóstico y el tratamiento propuesto. Paciente de 16 años, después de 10 días de recibir la primera dosis de la vacuna qHPV. En el examen físico, presentó múltiples úlceras y costras hemorrágicas al tacto, según el cuadro clínico y la historia de la enfermedad, una hipótesis diagnóstica fue EM. La terapia con láser de baja potencia (TLBP) se eligió como un tratamiento alternativo, ya que los ejercicios aplicados no tuvieron éxito. La paciente fue seguida, informó disminución del dolor y las quemaduras y, después de un año de tratamiento, no hubo recurrencia de las lesiones. El tratamiento con láser mostró una alternativa de tratamiento efectivo, además del bajo costo y la facilidad de aplicación.
PALABRAS CLAVE: eritema multiforme, vacuna tetravalente recombinante contra el virus del papiloma humano, rayos láser.
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Chahal, D.; Aleshin, M.; Turegano, M.; Chiu, M. & Worswick, S. Vaccine-induced toxic epidermal necrolysis: A case and systematic review. Dermatol. Online J., 24(1):13030/qt7qn5268s, 2018.
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Fitzpatrick, S. G.; Cohen, D. M. & Clark, A. N. Ulcerated lesions of the oral mucosa: clinical and histologic review. Head Neck Pathol., 13(1):91-102, 2019.
Kang, L. W.; Crawford, N.; Tang, M. L. K.; Buttery, J.; Royle, J.; Gold, M.; Ziegler, C.; Quinn, P.; Elia, S. & Choo, S. Hypersensitivity reactions to human papillomavirus vaccine in Australian schoolgirls: retrospective cohort study. BMJ, 337:a2642, 2008.
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Lerch, M.; Mainetti, C.; Terziroli Beretta-Piccoli, B. & Harr, T. Current perspectives on erythema multiforme. Clin. Rev. Allergy Immunol., 54(1):177-84, 2018.
Paulino, L.; Hamblin, D. J.; Osondu, N. & Amini, R. Variants of erythema multiforme: a case report and literature review. Cureus, 10(10):e3459, 2018.
Pérez-Carmona, L.; Aguayo-Leiva, I.; González-García, C. & JaénOlasolo, P. The quadrivalent human papillomavirus vaccine: erythema multiforme and cutaneous side effects after administration. Dermatology, 221(3):197-200, 2010.

Rocha, A. L.; De Souza, A. F.; Nunes, L. F. M.; Cunha, N. D. S.; Lanza, C. R. M.; Travassos, D. V. & da Silva, T. A. Treatment of oral manifestations of toxic epidermal necrolysis with low-level laser therapy in a pediatric patient. Pediatr. Dermatol., 36(1):e27e30, 2019.
Samim, F.; Auluck, A.; Zed, C. & Williams, P. M. Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent. Clin. North Am., 57(4):583-96, 2013.
Simões, A.; de Freitas, P. M.; Bello-Silva, M. S.; Tunér, J. & de Paula Eduardo, C. Laser phototherapy for Stevens-Johnson syndrome: a case report. Photomed. Laser Surg., 29(1):67-9, 2011.
Su, J. R.; Haber, P.; Ng, C. S.; Marquez, P. L.; Dores, G. M.; PerezVilar, S. & Cano, M. V. Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis reported after vaccination, 1999-2017. Vaccine, 38(7):1746-52, 2020.
Corresponding author: Profa. Dra. Fernanda Mombrini Pigatti Universidade Federal de Juiz de Fora campus Governador Valadares Departamento de Odontologia Estomatologia e Patologia Maxilofacial Minas Gerais BRAZIL
Email: [email protected]

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Treatment Following Erythema Multiforme in the Oral Mucosa