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Vulvar Aphthous Ulcers in Perimenarchal Adolescents After COVID-19 Vaccination: A Multicenter Case Series

Published:January 24, 2023DOI:https://doi.org/10.1016/j.jpag.2023.01.003

      Abstract

      This case series from three academic hospital-based pediatric and adolescent gynecology services outlines the temporal association between vulvar ulcers in female adolescents and COVID-19 vaccination. We identified eight cases and describe each patient's presentation, differential diagnosis, diagnostic work up, complications, treatment modalities, and overall course of illness. All cases seek to illustrate the clinical experiences of patients and providers interfacing with vulvar aphthous ulcers and contribute to the emerging literature exploring the novel association between vulvar aphthous ulcers and COVID-19 vaccination. To date, this is the largest described case series of this association in the literature.

      Keywords

      Introduction

      Vulvar aphthous ulcers (also known as Lipschutz ulcers) have been described since the early 1900s. These non-sexually acquired genital ulcers typically appear in the perimenarchal population as one to three painful ulcers that spontaneously resolve within 21 days. Etiology is not completely understood but there is believed to be a large immunologic component given a high association with a recent viral or bacterial infection.
      • Sadoghi B
      • Stary G
      • Wolf P
      • Komericki P.
      Ulcus vulvae acutum Lipschütz: a systematic literature review and a diagnostic and therapeutic algorithm.
      • Huppert JS
      • Gerber MA
      • Deitch HR
      • Mortensen JE
      • Staat MA
      • Adams Hillard PJ.
      Vulvar ulcers in young females: a manifestation of aphthosis.
      • Huppert JS.
      Lipschutz ulcers: evaluation and management of acute genital ulcers in women.
      • Huppert J.
      Adolescents with Vulvar Ulcers: COVID-19 disease, COVID-19 Vaccines, and the Value of Case Reports.
      • Vismara SA
      • Lava SAG
      • Kottanattu L
      • Simonetti GD
      • Zgraggen L
      • Clericetti CM
      • et al.
      Lipschütz's acute vulvar ulcer: a systematic review.
      Most recently, several case reports and case series have been published describing the development of vulvar ulcers during infection with SARS-CoV-2 as well as after COVID-19 vaccination.
      • Christl J
      • Alaniz VI
      • Appiah L
      • Buyers E
      • Scott S
      • Huguelet PS.
      Vulvar Aphthous Ulcer in an Adolescent With COVID-19.
      • Drucker A
      • Corrao K
      • Gandy M.
      Vulvar Aphthous Ulcer Following Pfizer-BioNTech COVID-19 Vaccine - A Case Report.
      • Falkenhain-Lopez D
      • Agud-Dios M
      • Ortiz-Romero PL
      • Sanchez-Velazquez A.
      COVID-19-related acute genital ulcers.
      • Jacyntho CMA
      • Lacerda MI
      • Carvalho MSR
      • Ramos M
      • Vieira-Baptista P
      • Bandeira S.
      COVID-19 related acute genital ulcer: a case report.
      • Popatia S
      • Chiu YE.
      Vulvar aphthous ulcer after COVID-19 vaccination.
      • Rubin ES
      • Sansone SA
      • Hirshberg A
      • Clement EG
      • Srinivas SK.
      Detection of COVID-19 in a Vulvar Lesion.
      • Shinn K
      • Koontz J
      • Manning W.
      Covid-19 associated non-sexually acquired acute genital ulceration.
      • Wijaya M
      • Zhao C
      • Forward E
      • Nguyen Y
      • Kherlopian A
      • Jollow D
      • et al.
      Acute Vulvar Aphthous Ulceration After COVID-19 Vaccination: 3 Cases.
      • Wojcicki AV
      • O'Flynn O'Brien KL.
      Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.
      • Hsu T
      • Sink JR
      • Alaniz VI
      • Zheng L
      • Mancini AJ.
      Acute Genital Ulceration After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination and Infection.
      In this report, we describe a series of eight cases of perimenarchal adolescent females who developed vulvar aphthous ulcers subsequent to COVID-19 vaccination without evidence of prior SARS-CoV-2 infection. This case series contributes to the emerging literature describing vulvar ulceration after COVID-19 vaccination and further elucidates typical clinical features, optimal treatment modalities, and overall course of this novel association.

      Methods

      A pediatric and adolescent gynecology provider at each of the three centers searched their clinical practice records and collected their encounters for all cases of female adolescents presenting with vulvar aphthous ulcers after COVID-19 vaccine from April 2021 to September 2021. For each case identified, the provider reviewed the electronic medical record (EMR) to identify the age of the patient, menarchal status, date, brand and dose of vaccine received, date of clinical presentation, time to initial symptoms and resolution of symptoms, clinical description of average lesion(s), work up, treatment, follow up and recurrence. This de-identified data was sent to the lead author to collate and analyze in a personal health information-compliant data storage service. The patients’ treating physicians obtained patient and guardian verbal assent for publication of de-identified clinical information and photographs. Written consent was obtained for published photographs.

      Results

      Eight cases of adolescents with vulvar aphthous ulcers were identified who had received the Pfizer-BioNTech COVID-19 vaccine within one or two days of the appearance of the ulcers (Table 1 & Figure 1). The ages of the adolescents ranged from 12 to 17 years with a mean age of 14.6 and all except one were post-menarchal (Table 1). Seven of the eight adolescents developed the ulcers after the second dose of the vaccine. Only one adolescent, notably with a prior history of vulvar aphthous ulcers, presented with symptoms after the first vaccine dose. None of the patients had a known history of COVID-19 or a recent exposure to SARS-CoV-2. In addition, there were no reported recent symptomatic viral illnesses. Table 1 highlights clinical characteristics, management, and outcomes for each of the eight reported patients with ulcers following vaccination.
      Table 1Characteristics, management, and outcomes for each patient with ulcers following vaccination
      Case 1Case 2Case 3Case 4Case 5Case 6Case 7Case 8
      Age at diagnosis1714131214151616
      Dose2nd1st2nd2nd2nd2nd2nd2nd
      Time to onset of vulvar ulcer from vaccine (Days)22112222
      Prior history vulvar lesion0 episode1 episode1 episode
      Time to resolution (Days)2025142121211010
      TreatmentMethylprednisolone taper, Amoxicillin, 5% lidocaine ointment, tylenol/NSAIDs, sitz bathsLidocaine 2% jelly, tylenol/NSAIDsPrednisone taper, Cephalexin, 2% lidocaine jelly, tylenol/NSAIDs, sitz bathsoral steroidszinc oxide, NSAID, xylocaine 2% sprayzinc oxide, NSAID, xylocaine 2% spray
      Menarchal statusPost-menarchalPost-menarchalPost-menarchalPre-menarchalPost-menarchalPost-menarchalPost-menarchalPost-menarchal
      Serologies/Culture
      HSVnegativeneagtivenegativexxxxx
      EBVordered but not completedxxnegativeordered but not completednegative
      CMVordered but not completedxxnegativeordered but not completednegative
      Genital culture4+ Staphylococcus aureusx4+ Corynebacterium species, 1+ Bacteroides fragilisnegativenegative
      BiopsyxChronic Infammationxxxxxx
      Referals/ConsultsxRheumatologyRheumatologyxxxxx
      Fig 1
      Fig 1Vulvar Ulceration and Resolution following COVID-19 Vaccination
      Most patients reported systemic symptoms including fevers, headache, and myalgias after vaccination prior to vulvar symptoms. Average symptom onset of vulvar pain and dysuria was two days after the second dose of vaccination with peak symptoms ranging from day two to day five from vaccination. All physical exams were consistent with aphthous ulcers, demonstrating multiple violaceous ulcerations with yellow fibrinous exudate, surrounding erythema and necrotic islands (Fig 1).
      Symptom resolution varied from 10 to 24 days. One patient was hospitalized for urinary retention in the setting of labial edema and found to have genital cultures positive for Corynebacterium and Bacteroides fragilis. Different institutions and physicians employed their own diagnostic plans. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) testing was performed in two patients and all tests were negative. Three patients were tested for herpes simplex virus (HSV) and found to be negative. Half of the patients had microbiology performed with fungal and bacterial cultures, with two patients exhibiting positive cultures. The patient with the vulvar culture positive for Corynebacterium and Bacteroides Fragilis was treated with a course of cephalexin. Another patient with a vulvar culture positive for Staphylococcus aureus was managed as an outpatient with amoxicillin.
      Two patients had a prior episode of aphthous ulcers and underwent a rheumatologic workup given the recurrence. One of these patients was hospitalized for urinary retention and uncontrolled pain. The other underwent outpatient vulvar biopsy of the ulceration and the pathology demonstrated chronic inflammation. Work up revealed negative testing for antiphospholipid antibody, systemic lupus erythematosus, Behcet's disease, and ANCA associated vasculitis in both these patients referred to rheumatology.
      Five patients required only symptomatic support, three received a course of oral steroids, and two received a course of antibiotics for positive vulvar cultures.
      For the three patients who received oral steroids, full resolution without evidence of further lesions ranged from 14 to 21 days. For those who received symptomatic treatment only, documented full resolution of lesions ranged from 10 to 25 days. Symptomatic treatment included non-steroidal anti-inflammatory drugs, acetaminophen, zinc oxide barrier cream, sitz baths, and topical lidocaine.
      One patient in this case series was identified to have a recurrence of ulceration after her Omicron booster vaccination. She received her booster twelve months after her initial COVID-19 vaccination. Her symptoms began two days after the booster at which time she was started on an oral prednisone taper. Her physical exam and overall course were notably milder with complete resolution of ulceration seven days later.

      Discussion

      The differential diagnosis of vulvar ulcers in adolescents is extensive and includes infectious (bacterial, viral, and fungal) as well as autoimmune and inflammatory associated causes of genital or oro-genital ulcerations such as Behçet's disease, Crohn's disease, and complex aphthosis. Most vulvar aphthous ulcers, however, are idiopathic with a negative infectious work-up and are most likely secondary to an immunologic response to infection or other source of inflammation that is commonly preceded by prodromal symptoms including fever, chills, fatigue, and malaise.
      • Huppert JS.
      Lipschutz ulcers: evaluation and management of acute genital ulcers in women.
      ,
      • Drucker A
      • Corrao K
      • Gandy M.
      Vulvar Aphthous Ulcer Following Pfizer-BioNTech COVID-19 Vaccine - A Case Report.
      ,
      • Rosman IS
      • Berk DR
      • Bayliss SJ
      • White AJ
      • Merritt DF.
      Acute genital ulcers in nonsexually active young girls: case series, review of the literature, and evaluation and management recommendations.
      Previously reported infectious triggers include EBV, Mycoplasma pneumoniae, CMV, influenza A and B, mumps virus, Salmonella, parvovirus B19, adenovirus, Toxoplasma gondii, and; most recently, SARS-CoV-2 infection.
      • Huppert JS
      • Gerber MA
      • Deitch HR
      • Mortensen JE
      • Staat MA
      • Adams Hillard PJ.
      Vulvar ulcers in young females: a manifestation of aphthosis.
      ,
      • Huppert JS.
      Lipschutz ulcers: evaluation and management of acute genital ulcers in women.
      ,
      • Christl J
      • Alaniz VI
      • Appiah L
      • Buyers E
      • Scott S
      • Huguelet PS.
      Vulvar Aphthous Ulcer in an Adolescent With COVID-19.
      ,
      • Falkenhain-Lopez D
      • Agud-Dios M
      • Ortiz-Romero PL
      • Sanchez-Velazquez A.
      COVID-19-related acute genital ulcers.
      • Jacyntho CMA
      • Lacerda MI
      • Carvalho MSR
      • Ramos M
      • Vieira-Baptista P
      • Bandeira S.
      COVID-19 related acute genital ulcer: a case report.
      • Popatia S
      • Chiu YE.
      Vulvar aphthous ulcer after COVID-19 vaccination.
      ,
      • Shinn K
      • Koontz J
      • Manning W.
      Covid-19 associated non-sexually acquired acute genital ulceration.
      ,
      • Wojcicki AV
      • O'Flynn O'Brien KL.
      Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.
      These eight cases illustrate the temporal association of vulvar ulcers with the Pfizer-BioNTech Covid-19 Vaccine in adolescent females and support the increasing number of case reports with similar findings.
      • Drucker A
      • Corrao K
      • Gandy M.
      Vulvar Aphthous Ulcer Following Pfizer-BioNTech COVID-19 Vaccine - A Case Report.
      ,
      • Popatia S
      • Chiu YE.
      Vulvar aphthous ulcer after COVID-19 vaccination.
      ,
      • Wijaya M
      • Zhao C
      • Forward E
      • Nguyen Y
      • Kherlopian A
      • Jollow D
      • et al.
      Acute Vulvar Aphthous Ulceration After COVID-19 Vaccination: 3 Cases.
      ,
      • Wojcicki AV
      • O'Flynn O'Brien KL.
      Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.
      Thus, COVID-19 vaccination may be a novel etiology for vulvar aphthous ulcers.
      While pathogenesis of vulvar aphthous ulcers remains uncertain, it is posited that a cell-mediated immune response to the acute phase of an infection results in a type 3 hypersensitivity reaction characterized by intravascular deposition of immune mediated complexes with subsequent complement activation and formation of microthrombi in dermal vessels and tissue necrosis.
      • Huppert JS.
      Lipschutz ulcers: evaluation and management of acute genital ulcers in women.
      ,
      • Jacyntho CMA
      • Lacerda MI
      • Carvalho MSR
      • Ramos M
      • Vieira-Baptista P
      • Bandeira S.
      COVID-19 related acute genital ulcer: a case report.
      Given that COVID-19 vaccination elicits a strong immunogenic reaction, it is possible that this systemic non-specific inflammatory response also contributes to the development of vulvar aphthous ulcers after vaccine administration. Indeed, studies have demonstrated that the Pfizer-BioNTech vaccine incites a robust immune response via activation of CD4+ and CD8+ T cells and cytokine production, specifically interferon gamma.
      • Wojcicki AV
      • O'Flynn O'Brien KL.
      Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.
      ,
      • Sahin U
      • Muik A
      • Derhovanessian E
      • Vogler I
      • Kranz LM
      • Vormehr M
      • et al.
      COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses.
      Given these findings, the presented cases further support the long-held hypothesis that vulvar aphthous ulcers are an immunologic response rather than a sign of a genital infection themselves. Additionally, this case series supports the multifaceted immune response from the COVID-19 mRNA based vaccine.
      Effective treatment has been shown in this case series as well as in other case reports and systematic literature reviews to include steroids, targeted antibiotic treatment for superinfected ulcers, and analgesia.
      • Dixit S
      • Bradford J
      • Fischer G.
      Management of nonsexually acquired genital ulceration using oral and topical corticosteroids followed by doxycycline prophylaxis.
      While there does not seem to be documented evidence of decreased time to resolution with a course of steroids in our cases, our series is limited by its retrospective nature, reliance on EMR documentation, and inconsistent utilization of steroids as part of the treatment pathway. Additional limitations of our case series included lack of longitudinal follow up for all patients to determine if patients subsequently tested positive for SARS-CoV-2 after resolution of ulceration, experienced recurrent ulcerations, or had aphthous ulcers following booster vaccinations. Lastly, not all cases had available photos for publication to include in our case series.
      While steroids have been used to treat severe aphthous vulvar ulcerations and have become a mainstay of COVID-19 treatment pathways, there is the potential for steroids to mitigate the COVID-19 vaccine's intended activation of the immune system for antibody production against SARS-CoV-2 infection. Future investigation is needed to understand optimal treatment modalities for vaccine-associated ulcers that do not interfere with the necessary immune response and thus vaccine efficacy and protection against SARS-CoV-2 infection. With expected increased vaccine uptake in this age group and the subsequent possible increased incidence of acute vulvar ulceration following vaccination, our case series will allow providers to be better equipped in counseling and managing patients who present with similar symptoms thus reducing misdiagnoses and delay to treatment.

      Disclaimers/Conflicts of Interest/Affiliations

      None for all authors

      Location studies conducted

      Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Pediatric and Adolescent Gynecology, Yale University School of Medicine, Yale New Haven Hospital, New Haven, CT
      Department of Surgery, Division of Gynecologic Surgery, University of Missouri–Kansas City School of Medicine, Children's Mercy Hospital, Kansas City, MO
      Pediatric and Adolescent Gynecology Clinic, Tecnologico de Monterrey, School of Medicine and Health Sciences, Monterrey, Mexico

      Declaration of Competing Interest

      The authors have no financial disclosures or conflicts of interest.

      Source of funding

      The author(s) received no specific funding for this work.

      Acknowledgements

      Claudia Hernandez Escobar, MD

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