Abstract
Study Objective
To review and characterise reports of vulval aphthous ulcers (VAU) following COVID-19 vaccination in VigiBase, the World Health Organization global database of reported potential side effects of medicinal products, to demonstrate the importance and power of case reports for rare suspected adverse reactions and to investigate whether they suggest a potential for COVID-19 vaccination to be a trigger.
Methods
Cases reporting the Medical Dictionary for Regulatory Activities’ (MedDRA) Preferred Term (PT) “Vulvovaginal ulceration” and related PTs in adolescent patients aged 12 to 17 years in association with any COVID-19 vaccine were extracted from VigiBase. The cases were clinically reviewed, and causality was assessed by applying the Bradford Hill criteria to the obtained case series.
Results
As of June 30th, 2022, there were 444 reports for the selected MedDRA PTs following COVID-19 vaccination in VigiBase. Ninety-four de-duplicated reports concerned adolescent female patients. Thirty-seven cases were clinically consistent with the diagnosis of VAU. Upon causality assessment, the analysed case series fulfilled six of the nine Austen Bradford Hill criteria supporting a potential causal relationship.
Conclusion
VAU can be perceived as a traumatic experience, especially in adolescent patients. There is, furthermore, a risk that the ulcers will be misdiagnosed resulting in avoidable investigation and treatment burdens for patients. We communicate our findings to support the small number of published case reports and raise awareness of VAU occurring in a temporal association with COVID-19 vaccination. Furthermore, our analysis supports observations about the value of case reports for the recognition and assessment of rare adverse events.
Keywords
Introduction
A small number of case reports describing the occurrence of vulval aphthous ulcers (VAU) following COVID – 19 vaccination have been published
1
, 2
, 3
, 4
, 5
, 6
, 7
, 8
, 9
.Case reports following COVID-19 vaccination became the subject of an editorial by Dr JS Huppert on VAU and the value of well-documented case reports for early warnings of unintended adverse effects of interventions
10
. National and international pharmacovigilance databases are repositories of case reports of suspected adverse drug reactions (sADRs) that have the potential to lend support to published case reports and case series. Reports of vulvovaginal and genital ulceration following COVID-19 vaccination have been submitted to the WHO global database of reported potential side effects of medicinal products (VigiBase) managed by the Uppsala Monitoring Centre11
.VigiBase, the WHO global database of reported potential side effects of medicinal products [Internet]. Uppsala Monitoring Centre; Available from: https://who-umc.org/vigibase/vigibase-services/
VigiBase is a repository of over 30 million case reports submitted by more than 170 national pharmacovigilance centres worldwide, for example, the US Food and Drug Administration's Adverse Events Reporting System (FAERS) and the US Centre for Disease Control's Vaccine Adverse Events Reporting System (VAERS) or Health Canada's MedEffect program
12
, US Food and Drug Administration C for DE and. US Food and Drug Administration. Adverse Event Reporting System (FAERS) - Public Dashboard. FDA [Internet]. 2021 Oct 22 [cited 2022 Sep 14]; Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard
13
, US Centres for Disease Control and Prevention. US Centres for Disease Control and Prevention. Vaccine Adverse Event Reporting System (VAERS). [Internet]. [cited 2022 Sep 14]. Available from: https://vaers.hhs.gov/
14
. Reports in VigiBase are observations of sADRs predominantly from health care practitioners and patients either directly to national centres or indirectly through pharmaceutical companies. While reports vary in their level of documentation, case series of particular drug/adverse reaction combinations derived from the database can be assessed to ascertain if they provide evidence for a previously unknown or incompletely documented adverse reaction requiring further investigation.Health Canada. MedEffect Canada [Internet]. 2011 [cited 2022 Sep 14]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada.html
During a signal detection workshop performed in VigiBase in December 2021, focused on the use of the COVID-19 vaccines in adolescents, a preliminary safety signal of vulvovaginal ulceration following COVID-19 vaccination in adolescent girls (aged 12 to 17 years) was detected. The published case reports for VAU following COVID-19 vaccination
1
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, 3
, 4
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, 6
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and the lack of mention of the condition in the regulatory product information or elsewhere in the literature as a suspected adverse event following COVID-19 vaccination induced an in-depth assessment of the case series to investigate evidence and to characterise VAU cases. Table 1 gives an overview of differential diagnoses of selected forms of vulval ulcers.Table 1Differential diagnosis of selected forms of vulval ulcers
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,16
| Clinical characteristics | Diagnosis | |
|---|---|---|
| Infectious conditions | ||
| Herpes simplex virus | Clustered vesicles and painful ulcerations | Viral culture or PCR assay |
| Sexually transmitted conditions | ||
| Primary syphilis | Painless chancre characterized by an isolated ulcer with raised borders | Dark field microscopy of the chancre fluid |
| Systemic autoimmune conditions | ||
| Bechet's syndrome | Recurrent ulcerative oral and vulval lesions | Diagnosis of exclusion (no diagnostic laboratory tests) |
| Genital Crohn's disease | “Knife cut” genital ulcers along the inguinal or labial folds | Gastroscopy and ileocolonoscopy |
| Drug-related conditions | ||
| Stevens-Johnson syndrome/Toxic epidermal necrolysis | Generalized skin lesions | Skin surface area detachment at maximum extent |
| Others | ||
| Vulval aphthous ulcers | Large, often bilateral “kissing ulcers” with a nephrotic appearing base and grey exudate most often on the labia minora | Diagnosis of exclusion (bacterial and viral serology) |
VAU, also known as Lipschütz ulcers (LU) is a form of acute genital ulceration typically affecting sexually inactive adolescent girls or young women
7
. It is a relatively uncommon condition characterized by the rapid onset of painful, necrotic ulcers of the vulva or lower vagina (mainly the labia minora and the labia majora)17
. Its incidence is unknown and impossible to estimate due to its poorly understood pathophysiology and, presumably, considerable underdiagnosis18
. The ulcers are usually self-limiting and spontaneous healing takes between two and six weeks19
. Experiencing such ulcers, especially in young patients, can be traumatising and can create unnecessary distress for the patients and their parents or guardians who may have concerns regarding, for example, sexual abuse1
,3
,18
. Furthermore, VAU can easily be misdiagnosed as infectious potentially resulting in avoidable treatment burden for the patients. Treatment of VAU consists of pain control and wound care. In cases of severe pain causing urinary retention, hospitalisation and bladder catheterisation may be required19
. Differentiating VAU from other causes of acute genital ulceration should include tests for organisms that may have directly caused ulceration, ie, bacterial and fungal infections, and herpes simplex. If there has been sexual activity, infections such as gonorrhoea and chlamydia should be excluded19
,20
. Any manifestations of non-infectious causes such as autoimmune disorders and inflammatory disease should also be considered in the differential diagnosis, especially Behcet's Disease. The latter is a vasculitic disease characterised chiefly by recurring oral and often genital ulcers.Sidbury R. Acute genital ulceration (Lipschütz ulcer). [Internet]. Moise LL, Corona R, editors. UpToDate; 2020 [cited 2022 Jan 18]. Available from: https://www.uptodate.com/contents/acute-genital-ulceration-lipschutz-ulcer
21
. Slow resolution of vulval ulcers, the presence of oral ulcers and recurrence without vaccine exposure should suggest the diagnosis21
. Exacerbations of Behcet's Disease after COVID-19 vaccination have been observed in a case series22
.The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus Type 2 (SARS-CoV-2) has led to the unprecedented rapid development of vaccines using various platforms (eg, mRNA, viral vectors, and others). The two mRNA-based vaccines developed by Pfizer/BioNTech and Moderna accounted for the biggest share of doses administered at the time of writing (May 2022)
23
. Furthermore, at the time of writing the Pfizer/BioNTech COVID-19 vaccine was the only one authorised for immunization of adolescents from 12 to 17 years of ageCraven J. Regulatory Affairs Professionals Society. COVID-19 vaccine tracker. [Internet]. 2022 [cited 2022 Aug 9]. Available from: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker
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,Ritchie H, Mathieu E, Rodés-Guirao L, Apple C, Giattino C, Ortiz-Ospina E, et al. COVID-19 vaccinations [Internet]. Our World In Data; 2022 [cited 2022 Jan 27]. Available from: https://ourworldindata.org/covid-vaccinations?country=∼OWID_WRL
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.We present here an assessment of the VigiBase case series of vulvovaginal ulceration in adolescent females.
Following a finding of statistical disproportionality for the combination of vulvovaginal ulceration and COVID-19 vaccination compared with the overall reporting for vaccines in VigiBase, the objectives were to assess if the report descriptions
- a)fit the criteria for VAU26or indicated other pathologies (note VAU and LU are not in the MedDRA terminology used for entering suspected adverse reactions into the database and therefore could not be sought for specifically)
- b)showed evidence of a potentially causal link with COVID-19 vaccination that should be investigated further
Method
Cases reporting the MedDRA preferred terms (PTs) vulvovaginal ulceration, vaginal ulceration, vulval ulceration and genital ulceration occurring in adolescent females (12 to 17 years of age) after COVID-19 vaccination were extracted and examined manually for descriptions of the ulcers, whether they were reported as VAU/LU, investigation results, time to onset from vaccination, time to recovery, as well as patients’ medical histories and concomitant medicines as evidence of competing or contributory causes for the ulceration. Table 2 shows the criteria that were used to assess which reports were likely to represent VAU when the diagnostic terms VAU or LU were not specifically mentioned.
Table 2Diagnostic criteria for VAU
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.| Major criteria | Minor criteria (minimum 2) |
|---|---|
| Acute onset of one or more painful vulval ulcers | Ulcers of the vestibule or labium minorum |
| AND | OR |
| Exclusion of infectious or non-infectious causes | No history of sexual intercourse in the last three months, or ever |
| OR | |
| Flu-like symptoms (fever, chills, fatigue, malaise) | |
| OR | |
| Systemic illness in the preceding two to four weeks |
The case reports identified as VAU were assessed as a case series using the Bradford Hill Criteria for Causation
27
. The nine Bradford Hill Criteria are (i) strength of association, (ii) consistency, (iii) specificity, (iv) temporality, (v) biological gradient (ie, dose-response relationship), (vi) plausibility, (vii) coherence, (viii) analogy, and (ix) experimental evidence. These criteria were first developed for epidemiological studies but have more recently been applied to pharmacovigilance data27
. Each criterion lends some support to a causal association between an intervention and event. Aggregation of cases and application of the criteria allows the information they contain to be complementary and to some extent compensates for missing data in some reports.The published case reports of VAU/LU occurring in females aged 12 to 17 years were also examined and compared with the VigiBase reports identified as likely VAU/LU.
Results
As of June 30th, 2022, there were 444 reports for the MedDRA PTs “Genital ulceration”, “Vulval ulceration”, “Vaginal ulceration”, and “Vulvovaginal ulceration”, following COVID-19 vaccination in all age groups. Reporting was found to be statistically disproportionate for all terms except the PT “Genital ulceration”, meaning that the observed number of reports exceeded the number of expected reports for the combination COVID-19 vaccine and the above listed PTs compared with the background of all vaccine reports in VigiBase. While commencement of vaccination for the 12- to 17-year age group had started only by the fourth quarter of 2021 this age group already represented a substantial proportion (23%) of the 444 reports. The following analysis will focus on this age group.
After removal of duplicates and one misdiagnosis, 94 reports remained for analysis. Thirty-three cases included the diagnosis “Lipschütz ulcer” (LU). After application of the above-mentioned criteria (Table 2), an additional four cases were identified as clinically consistent with LU. These 37 reports were sent from four countries, with the USA contributing most (n=31; 84%). Most were not marked as serious (n=34; 92%). Information on the administered dose number was available in 19 cases, with most cases occurring after administration of the second dose (n=16; 84%). Information about the time to onset was available in 34 cases. The median time to onset was two days, with an interquartile range between two and three days.
Supporting evidence for the LU diagnosis was not always provided, but in three cases the diagnosis was reported to have been made by specialists: the first by a gynaecologist, the second by a gynaecologist and a paediatrician, and the third by a gynaecologist and a dermatologist. Whether the second major criterion (exclusion of infectious and non-infectious causes) was completely fulfilled, was difficult to interpret as it was not always clear if all appropriate exclusion tests had been conducted. Fever is somewhat difficult to interpret as a minor criterion since it is a common reaction to vaccines, usually occurring with a close temporal relationship to administration. However, few potential causes of acute genital ulceration alternative to VAU/LU were listed amongst the 94 reports. These included two patients taking ibuprofen, a rare cause for mucosal ulceration, and one with concomitant bacterial vaginosis, which could be a complication of ulceration rather than its cause. In addition, two patients had had recent viral infections (EBV and COVID-19) which may have been the triggers for the VAU. In two cases (Table 4, cases 6 and 24) patients experienced a positive rechallenge (ie, the reoccurrence of symptoms following a subsequent vaccine dose).
Table 3 shows the patient's characteristics for the 37 identified LU reports.
Table 3Case characteristics of cases clinically consistent with VAU diagnosis
| PATIENT | |
|---|---|
| Age [years] | |
| Median | 13 |
| Interquartile range | 1 (13-14) |
| REACTION | |
| Serious (n;%) | 3 (8.1) |
| Time-to-onset [days] | |
| Median | 2 |
| Interquartile range | 0.75 (2-2.75) |
| Outcome (n;%) | |
| Recovered/recovering | 6 (86) |
| Not recovered | 1 (14) |
| Unknown | 30 |
| VACCINE | |
| Brand (n;%) | |
| Pfizer/BioNTech | 35 (95) |
| Moderna | 1 (2.5) |
| Janssen | 1 (2.5) |
| Dose number (n;%) | |
| 1st dose | 1 (5.3) |
| 2nd dose | 16 (84) |
| 3rd dose | 3 (16) |
| Unknown | 18 |
a Percentages calculated after excluding unknown values
Table 4Overview of VAU/LU cases reported as LU and four additional cases with criteria for VAU
| Case number | Patient age [years] | Vaccine | Dose number | Relevant reactions (MedDRA PT) | Time-to-onset [days] | Investigations | LU diagnosis on report | Additional information |
|---|---|---|---|---|---|---|---|---|
| 1 | 13 | Pfizer/BioNTech | 2 | Genital ulceration | 4 | Blood test Culture SARS-CoV-2 test negative | Yes | Not sexually active Exclusion of STD |
| 2 | 12 | Pfizer/BioNTech | - | Erythema, Pyrexia, Vulval disorder, Vulval ulceration, Vulvovaginal pain, Vulvovaginal swelling | 3 | SARS-CoV-2 test negative | Yes | |
| 3 | 16 | Pfizer/BioNTech | 3 | Pain, Pyrexia, Vaginal ulceration | 2 | Yes | ||
| 4 | 13 | Pfizer/BioNTech | 1 | Oral pain, Pain, Vulval ulceration | 3 | Yes | ||
| 5 | 13 | Pfizer/BioNTech | - | Genital ulceration, Oedema peripheral | 1 | Yes | ||
| 6 | 13 | Pfizer/BioNTech | 2,3 | Pain, Vulval ulceration | 2 | Gram stain negative Herpes simplex test negative | Yes | Ulceration occurred after second dose and recurred upon re-exposure (third dose) |
| 7 | 14 | Pfizer/BioNTech | 3 | Vulval ulceration | 2 | Yes | ||
| 8 | 12 | Pfizer/BioNTech | 2 | Vulval ulceration | - | Yes | ||
| 9 | 13 | Pfizer/BioNTech | - | Bladder catheterisation, Dysuria, Vaginal ulceration, Vulvovaginal pain | 3 | Bacterial and viral cultures negative, Blood test normal Mononucleosis heterophile test negative | No, identified through diagnostic criteria | Urination got so painful causing urine retention and making bladder catheterization necessary |
| 10 | 13 | Pfizer/BioNTech | 2 | Genital pain, Malaise, Pyrexia, Vulval ulceration | 1 | Yes | Diagnosis made by senior gynecologist Pain worsened, suspected infection | |
| 11 | 16 | Janssen | - | Genital ulceration, Influenza like illness, Pyrexia, Vaginal ulceration, Vulvovaginal pain | 2 | Yes | Patient was screened for cancer after LU diagnosis | |
| 12 | 14 | Pfizer/BioNTech | 2 | Genital ulceration, Pain, Pyrexia, Sexually transmitted disease | 2 | SARS-CoV-2 test STD tests negative | No, identified through diagnostic criteria | PmHx: irritable bowel syndrome No history of vulvovaginal ulcers |
| 13 | 16 | Moderna | 2 | Condition aggravated, Genital ulceration, Vulvitis | 2 | Yes | Patient experienced a flare-up of LU causing nerve pain in the genitalia. Developed vulvitis | |
| 14 | 12 | Pfizer/BioNTech | - | Vulval ulceration | - | Yes | ||
| 15 | 13 | Pfizer/BioNTech | 2 | Genital ulceration | 4 | Blood test Culture | Yes | Not sexually active No STDs PmHx: drug allergy (cephalosporines) |
| 16 | 14 | Pfizer/BioNTech | - | Vulvovaginal ulceration | 2 | Yes | PmHx: depression and anxiety | |
| 17 | 16 | Pfizer/BioNTech | - | Genital ulceration, Pain, Urinary retention | 4 | Negative for all STDs Mononucleosis heterophile test negative Sexually transmitted disease test negative | Yes | Not sexually active “Horrible vaginal ulcers unable to urinate tremendous pain” |
| 18 | 14 | Pfizer/BioNTech | - | Chills, Chromaturia, Dysuria, Gait disturbance, Genital ulceration, Loss of personal independence in daily activities, Pain, Pyrexia, Urinary tract infection, Vaginal ulceration, Vulvovaginal pain | 2 | STD tests negative SARS-CoV-2 test negative | Yes | External vaginal irritation without visible signs two days after vaccination. On day three two lesions on the inner side of each labia minora, painful to the touch. On day four experienced greatly increased pain and problems urinating. |
| 19 | 14 | Pfizer/BioNTech | - | Vaginal ulceration | 1 | Yes | PmHx: ADHD, insomnia | |
| 20 | 15 | Pfizer/BioNTech | 2 | Pyrexia, Vulval ulceration | 0 | Yes | ||
| 21 | 14 | Pfizer/BioNTech | 2 | Genital ulceration | 0 | SARS-CoV-2 test | Yes | LU beginning hours after administration of the second vaccine dose, increasing in pain, swelling and severity. |
| 22 | 13 | Pfizer/BioNTech | 2 | Dysuria, Genital pain, Night sweats, Pyrexia, Vulval disorder, Vulval ulceration, Vulvovaginal swelling | 2 | Chlamydia test negative Epstein-Barr virus test negative Herpes simplex test negative HIV test negative SARS-CoV-2 test negative Staphylococcus test negative Treponema test negative Pregnancy test negative | Yes | Not sexually active Noticed three or four “red/purple bumps” on her right labia majora, painful, progressed to a “sore” at the base of her right labia near the introitus. Vulva continued to swell |
| 23 | 14 | Pfizer/BioNTech | - | Bladder catheterisation, Dysuria, Genital pain, Pain, Vulval ulceration, Vulvovaginal pain | 2 | Culture | Yes | Genital pain developed on day two, bilateral aphthous vulvar ulcers noted on the third day after vaccination causing extreme pain. Patient required bladder catheterization |
| 24 | 13 | Pfizer/BioNTech | 1,2 | Vaginal ulceration | - | STD tests negative | No, identified through diagnostic criteria | Not sexually active Genital ulcers occurred after the first and second vaccine dose |
| 25 | 12 | Pfizer/BioNTech | - | Erythema, Pyrexia, Tenderness, Vulval disorder, Vulval ulceration, Vulvovaginal pain, Vulvovaginal swelling | 3 | SARS-CoV-2 test negative Urine analysis | Yes | Significant pain and swelling of labia |
| 26 | 12 | Pfizer/BioNTech | - | Abdominal pain upper, Feeling cold, Pyrexia, Vaginal ulceration | 1 | Yes | ||
| 27 | 14 | Pfizer/BioNTech | 2 | Amenorrhoea, Condition aggravated, Fatigue, Pyrexia, Vaginal ulceration, Vulvovaginal pain, Vulvovaginal swelling | 2 | Tests negative for any virus or bacteria | No, identified through diagnostic criteria | |
| 28 | 12 | Pfizer/BioNTech | - | Discharge, Swelling, Vulval ulceration | 3 | Yes | ||
| 29 | 14 | Pfizer/BioNTech | 2 | Chills, Myalgia, Pyrexia, Vulval oedema, Vulval ulceration, Vulvovaginal pain | 1 | Blood test | Yes | Diagnosis made by a gynaecologist and dermatologist. Auto-immune reaction ruled out by a rheumatologist |
| 30 | 12 | Pfizer/BioNTech | - | Pyrexia, Vulval ulceration | 2 | Yes | ||
| 31 | 15 | Pfizer/BioNTech | 2 | Malaise, Pain, Pyrexia, Vaginal ulceration | 1 | Bacterial test negative Herpes simplex test negative | Yes | Bilateral painful vaginal ulcers Ulcer consistent with LU |
| 32 | 13 | Pfizer/BioNTech | - | Burning sensation, Dysuria, Vaginal ulceration | 2 | Blood test | Yes | LU in vaginal area, extremely painful to urinate |
| 33 | 13 | Pfizer/BioNTech | 2 | Dysuria, Vaginal ulceration, Vulvovaginal pain | 2 | Blood test normal Urine analysis normal | Yes | Vaginal pain and dysuria within one week of the second vaccine dose |
| 34 | 15 | Pfizer/BioNTech | 2 | Dysuria, Fatigue, Pain, Pyrexia, Vaginal ulceration | 2 | Epstein-Barr virus negative Blood test normal Urine analysis normal | Yes | |
| 35 | 14 | Pfizer/BioNTech | - | Genital ulceration, Pain | 2 | Herpes simplex test negative | Yes | Painful genital ulcers, looked most consistent with LU |
| 36 | 12 | Pfizer/BioNTech | - | Vulval ulceration | 2 | Herpes virus test performed | Yes | |
| 37 | 15 | Pfizer/BioNTech | - | Genital ulceration | 2 | Yes |
Abbreviations: SARS-CoV-2: Severe Acute Respiratory Syndrome CoronaVirus 2; STD: Sexually transmitted disease; LU: Lipschütz ulcer; PmHx: Past medical History; ADHD: Attention Deficit Hyperactivity Disorder
Information on the management of the reported episode was available in 15 of the 37 cases (41%). In most cases a combination of topical or systemic corticosteroids and local anaesthetic was applied. Sitz baths were also prescribed in some cases.
In terms of seriousness and severity, two patients required bladder catheterisation, but several other reports described very painful urination or severe dysuria as well as difficulties walking due to the ulcerations.
Nine publications, reporting on 15 adolescent patients experiencing VAU after COVID-19 vaccination were identified in the medical scientific literature (Table 5). The published case reports showed remarkable consistency with the case reports identified in VigiBase with respect to age range, clinical details, and time to onset following vaccination with only two occurrences after dose 1, one with the Pfizer BioNTech vaccine and the only case following the AstraZeneca vaccine.
Table 5Published case reports of acute Vulval Aphthous Ulceration/Lipschütz Ulcers (VAU) in 12- to 17-year-old females shortly after COVID-19 vaccination.
| Case Report | Age [years] | COVID-19 vaccine | Dose number | Time-to-onset [days] | Sexually active | Investigations | Symptoms | Notes | Management and Outcome |
|---|---|---|---|---|---|---|---|---|---|
| Drucker et al, 2021 1 | 14 | Pfizer/BioNTech | 2 | 2 | No | Negative tests for COVID-19, CMV, EBV, HSV infections. | Within 12h severe fatigue, body aches, insomnia. Day 2-burning pain at introitus. Progression over 3d to exquisitely painful labia minora ulceration | No recent fever or URTI. No personal or FH autoimmune disease. Von Willebrand's Disease, on oral contraceptives for bleeding control. VAU/LU diagnosed. | Topical local anaesthetic and oral analgesia. Recovered after 10 days |
| Hsu et al, 2022 2 | 12 | Pfizer/BioNTech | 2 | 2 | No | HSV-1 & HSV-2 (PCR), Trichomonas/Gardnerella/Candida (DNA probe), EBV (antibody panel), respiratory viral panel, SARS-CoV-2 (PCR) negative. | Subjective fevers, fatigue and malaise for 24h following the vaccination. | Initially treated for suspected urinary tract infection (nitrofurantoin, fluconazole, phenazopyridine). | Topical corticosteroid and local anaesthesia, oral analgesia. |
| 14 | Pfizer/BioNTech | 2 | 3 | ? | SARS-CoV-2 (PCR), EBV (serologies), HSV (PCR) negative. | Onset of painful vulvar ulcerations approximately 48 hours after vaccination. Low-grade fevers, severe vulvar pain and ulceration. Symptom onset three days after vaccination. | Second episode of genital ulceration. First episode several months previously following fever, headaches, and body aches (COVID-19 negative). Rheumatologic investigations normal. | Recovered over the course of two weeks. Topical corticosteroid and local anaesthesia, local analgesia. After three days changed to oral corticosteroid and local anaesthesia. Recovering after four weeks. Information not reported. | |
| Popatia et al, 2021 3 | 12 | Pfizer/BioNTech | 2 | 3 | No | Negative tests for HSV. | Day 1 - fever Day 2-3 painful ulcers and oedema of right labia majora and minora | No H/O oral or vulval ulceration | Topical corticosteroid and local anaesthesia, oral analgesia. Resolved over 10 days |
| Scott et al, 2022 4 | 15 | Pfizer/BioNTech | 1 | 3 | No | Neisseria gonorrhoeae and Chlamydia trachomatis PCR negative | Low grade fever lasting for 48 hours post vaccination. Patient noticed sore on her vagina on day three after vaccination. | Three days after receiving her second vaccine dose (21 days after dose 1) the patient reported recurrent pain and a new ulcer on the right labia was noted. | Daily sitz baths, oral analgesics, topical anaesthetics, and topical steroids. Upon follow up one week after the first episode patient reported no more pain and the ulcer resolved. |
| Wojcicki et al, 2021 5 | 16 | Pfizer/BioNTech | 2 | 1 (within 24h) | No | Negative tests for COVID-19, CMV, HSV 1&2, syphilis, HIV and recent CMV infections. ANA negative. | Initial – fever, fatigue, myalgias, lesions in vaginal area. Progression over 5d -lesions R labium became exquisitely painful and necrotic. | Misdiagnosed as Bartholin's abscess, antibiotic treatment ineffective. VAU/LU diagnosed by gynaecologist. H/O recurrent oral ulceration, one oral aphthous ulcer developed while VAU/LU resolving. | Topical corticosteroid and local anaesthesia, oral analgesia. Resolving after two weeks |
| Frederiks et al, 2022 6 | 12 | Pfizer/BioNTech | 2 | 3 | No | HSV-1/2 (swab), VSV (PCR), bacterial and fungal (microscopy and culture), mycoplasma, streptococcal, HIV, celiac disease serologies, all negative, EBV, CMV serologies, past infection. | Day 1 - myalgia Day 3 - painful vulval ulcers two each side labia minora, difficulty voiding and constipation | Did not meet local clinical and epidemiological criteria for COVID-19 infection testing | Oral paracetamol and opioid analgesia, laxatives, topical corticosteroids and local anaesthesia. Almost recovered at 10 days. |
| Wijaya et al, 2022 7 Case 1 | 16 | Pfizer/BioNTech | 2 | 3 | No | Chlamydia, gonorrhoea, genital swab (culture), HSV-1/2, CMV, VSV serologies, enterovirus, adenovirus (PCR) all negative | Day 1 - fever, headache, lethargy Day 3 - vulval pain, partially symmetrical vaginal ulcers, urinary retention needing IDC | Initial diagnosis genital herpes simplex, treated with famciclovir. | Oral predinisolone, improvement at 2 weeks, dose reduced, asymptomatic and further improved at 4 weeks. |
| Wijaya et al, 2022 7 Case 2 | 14 | Pfizer/BioNTech | 2 | 4 | No | Urine, genital swab (cultures), HSV-1/2, CMV, VSV (serologies), enterovirus, adenovirus (PCR) all negative | Day 1, fever, myalgia, lymphadenopathy. Day 4, vulval pain, bilateral vulval ulcers on labia minora, urinary retention needing IDC | History of monthly oral ulcers | Oral prednisolone. Recovered after one week |
| Wijaya et al, 2022 7 Case 3 | 19 | AstraZeneca | 1 | 3 | - | No investigations as recovered quickly | Sudden onset painful vulvar ulcers with appearance of vulvar aphthosis | - | Ibuprofen for analgesia, recovered over one week. |
| Moncada-Madrazo et al, 2022 8 Case 1 | 16 | Pfizer/BioNTech | 2 | 2 | No | CBC and metabolic panel normal, bacterial & fungal cultures negative | Day 1 - fever Day 2 - vulval ulcers, discomfort, irritation and dysuria | - | Local anaesthetic and barrier protection creams. Recovered within 10 days. |
| Moncada-Madrazo et al, 2022 8 Case 2 | 16 | Pfizer/BioNTech | 2 | 3 | No | CBC and metabolic panel normal, bacterial & fungal cultures negative | Day 1 - fever Day 3 - vulval ulcers, pain and dysuria. | - | Local anaesthetic and barrier protection creams. Recovered within 10 days. |
| Lawson et al, 2022 9 Case 1 | 12 | Pfizer/BioNTech | 2 | 2 | - | EBV and CMV tests negative | Vulval pain and multiple vulval aphthous ulcers | Oral lesions present. No history of COVID-infection or recent exposure, no recent symptomatic viral illnesses | Recovered within three weeks. |
| Lawson et al, 2022 9 Case 2 | 14 | Pfizer/BioNTech | 2 | 2 | - | Declined investigations | Vulval pain and multiple vulval aphthous ulcers | No history of COVID-infection or recent exposure, no recent symptomatic viral illnesses | Recovered within three weeks. |
| Lawson et al, 2022 9 Case 3 | 15 | Pfizer/BioNTech | 2 | 2 | - | EBV and CMV tests negative | Vulval pain and multiple vulval aphthous ulcers | No history of COVID-infection or recent exposure, no recent symptomatic viral illnesses | Recovered within three weeks. |
Abbreviations: VAU/LU, vulval aphthous ulceration/Lipschütz ulcers; h, hours; d, days, w, weeks; CMV, cytomegalovirus; HSV, herpes simplex virus; EBV, Epstein Barr virus; HIV, human immunodeficiency virus; ANA, antinuclear antibody; URTI, upper respiratory tract infection; H/O, history of; FH, family history; IDC, indwelling catheter; VSV, vesicular stomatitis virus
Case series assessment
Applying the Bradford Hill criteria in our case series, a strength of association was found through the statistically significant prominence of vulvovaginal ulceration in combination with COVID-19 vaccine in VigiBase. With few case reports, an expected time to onset is not known, but the time to onset, within one week, is consistent across the VAU VigiBase reports as well as the published reports. The reports also show consistency in that similar descriptions are reported from several countries. There is some coherence with other observations as VAU has been reported following COVID-19 infection
34
, 37
, 38
, 39
. The reports show specificity for causal agent and reported adverse effect. COVID-19 vaccine is the only suspect agent in the majority of reports. Genital and vulvovaginal ulceration are not specific terms as they can have various aetiologies but reports with evidence for VAU suggest a specific underlying pathology. A dose response is suggested as 16 of the 19 VAU VigiBase reports with this information and 13 of the 15 published adolescent case reports with this information all indicate onset after the second vaccine dose and three of the VigiBase reports after the third dose. Biologic plausibility is not at this point fulfilled as a mechanism is only hypothesised. To our knowledge there is no evidence of analogy as VAU has not been reported with other vaccines, and we are not aware of any experimental evidence of a causal association. In summary, six of the nine Bradford Hill criteria are fulfilled each lending weight to a causal association.Discussion
Ninety-four international reports of ulceration described as genital, vulval and/or vaginal in adolescent females within a week of COVID-19 vaccination included 37 with evidence that the ulcers were VAU and that the COVID-19 vaccination may have been the trigger. In a few cases this evidence was further emphasized by a positive rechallenge.
Neither the European Summaries of Product Characteristics (SmPCs) nor the US FDA drug label for the two mRNA-based COVID-19 vaccines from Moderna and Pfizer/BioNTech as well as the viral vector-based vaccine from Janssen describe genital ulcerations as sADRs to the vaccine. However. hypersensitivity reactions are noted to occur with unknown frequency
28
, 29
, 30
, 31
, 32
, 33
.Up to December 2022, we have identified 15 case reports published in the scientific literature for genital ulcerations following COVID-19 vaccine administration in adolescent patients
1
–59. Twelve of the patients were reported to be sexually inactive prior to vaccination and occurrence of the reported episodes, with no information provided for the other three. The ulcers occurred at a median of two days after vaccination, ranging from one to six (Table 5) and usually occurred after the second dose. There was marked consistency between these reports and the 37 VigiBase reports identified as VAU.Non-sexually acquired acute genital ulcers can have a variety of underlying causes such as viral infections, autoimmune disorders, adverse reactions to medicines, etc (see Table 1)
15
,16
. Location and appearance differ between different forms of genital ulceration. Differential diagnosis, therefore, requires a range of diagnostic tests potentially causing physical and mental stress for the patients. However, for some forms of genital ulceration aetiology and pathophysiology are unclear. The pathophysiology of VAU for example is poorly understood. To our knowledge, there are no published reports about the occurrence of VAU following immunization with other vaccines. However, viral infections, especially EBV, mycoplasma pneumoniae, cytomegalovirus, influenza A and B, and adenovirus infections are known triggers34
. Hypotheses for mechanisms include a type III hypersensitivity reaction caused by immune complex deposition leading to microthromboses and genital tissue necrosis34
, 35
, 36
, as well as virus-provoked cytolysis following the systemic spread of virus-infected lymphocytes via auto-inoculation34
. We have identified four literature cases describing the occurrence of LU in adolescent girls following COVID-19 infection34
,37
, 38
, 39
. A potential mechanism for COVID-19 infection-induced mucosal ulceration is increased cytokine and TNF-alpha levels triggering neutrophils to disrupt the mucosa40
. Huppert in her related editorial commented that the pathogenesis of complex oral and vulval aphthosis is still uncertain but likely involves a cell-mediated immune response. She observed that aphthosis can be triggered by a long list of factors such as local trauma, viral infections and drugs and thus a viral disease such as COVID-19, or a vaccine that elicits a strong immune response, is a plausible trigger for vulvar aphthosis10
.As of January 2023, there were 2298 reports of oral aphthous ulcers following COVID-19 vaccination in VigiBase with an expected number compared with all other vaccine reports of 2178. The high background prevalence of this disorder makes causality assessment difficult. However, there are published case reports of an association with COVID-19 infection
40
and vaccination41
. Two of 13 patients with non-vaccine related VAU had concomitant oral aphthae and the majority had a history of oral aphthosis.36
Deep, complex oral aphthoses with occasional vulvar manifestations have been described42
However, oral aphthosis was not mentioned in any of the 37 LU VigiBase case reports we have described although this may have been under-reported. Of the 15 VAU literature cases (Table 5) one patient developed oral lesions in addition to the VAU, two had a history of oral ulceration and one of these developed a lesion as she was recovering from VAU.In the analysed case series, all patients but one had received the mRNA-based COVID-19 vaccines. The lack of reports concerning other vaccine types in the analysed age group does not necessarily mean that they would not be observed after administration of non-mRNA vaccines as only mRNA vaccines were approved for this age group during the study period.
Especially in adolescent patients, the experience of genital ulcerations can be traumatic and can create unnecessary distress for the patients and their parents or guardians who may have concerns regarding, for example, sexual abuse
1
,3
,18
. We would like to explicitly mention the case report of COVID-19 infection-related VAU presented by Krapf and colleagues34
. The patient's perspective is expressed illustrating the impact of the reported event on the health-related quality of life of the patient and her parents. Furthermore, LU can be easily misdiagnosed as herpes simplex virus (HSV) infection if exclusion testing is not performed properly, potentially resulting in unsuccessful HSV treatment17
. In VigiBase, there were 14 reports containing the PT “Genital herpes”, following COVID-19 vaccination in the age group 12 to 17 with varying degrees of documentation. One of these reports, concerning a 15-year-old female patient, illustrates the diagnostic problem: she experienced several painful genital lesions one day after receiving the second dose of the Pfizer/BioNTech vaccine. The lesions were presumed to be genital herpes even though the test result was negative, and the patient was unsuccessfully treated with aciclovir.Case reports were also fundamental to characterising VAU as a clinical entity. Huppert states that “By continuing to publish similar case reports, we share our experience and are better able to provide supportive care, avoid extensive diagnostic workups, and offer reassurance about the self-limited nature of most cases of vulvar aphthosis”
10
. Correct recognition of VAU may not affect the outcome of this generally self-limiting condition. However, knowing the cause of distress may relieve the psycho-social burden on patients and their parents or guardians. We therefore deem it important to raise awareness of the possibility for VAU to occur following COVID-19 vaccination.The editorial by Dr Huppert discussing published case reports of VAU following COVID-19 vaccination also makes a strong case for frontline providers submitting case reports as valuable additions to the medical literature. Dr Huppert goes on to say that a collection of high-quality case reports can inform hypotheses which can be tested in larger studies and can sometimes be synthesized into evidence to inform decision-making. National and international pharmacovigilance databases are collections of case reports of sADRs of medicines and vaccines. Although the reports are of variable quality, aggregation of cases and application of causality assessment criteria for case series allows the information they contain to be complementary and to some extent compensates for missing data in some reports. These reports can be used to generate hypotheses and in some cases these alone have led to regulatory decision making
43
. Submitting case histories to national databases allows for more timely detection of signals of unexpected adverse reactions and is often required by journals prior to publication. The case series we have presented shows that submitting well-documented reports is highly desirable to enable accuracy of diagnosis and exclusion of alternative aetiologies for a suspected medicine or vaccine-related condition. It is possible that many of the reports we excluded from in-depth analysis in our case series because of insufficient diagnostic documentation, were VAU, as few indicated alternative aetiologies for the ulceration.The main limitation of the presented study is the nature of the case reports submitted to VigiBase which generally describe observations which have arisen from an unexpected or unwanted event. The information comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. Furthermore, underreporting is usual as the submitted reports are mostly unsolicited. The volume of reports for a particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the adverse effects and other factors.
Another limitation was the lack of VAU or LU as official MedDRA PTs. This complicated report identification and potentially reporting itself.
Conclusion
Vulvovaginal ulcerations following COVID-19 vaccination have been reported disproportionately more often than expected in the WHO global pharmacovigilance database, VigiBase. Of the 94 cases of vulvovaginal ulceration reported in the female adolescent age group there was evidence that at least 37 were VAU. Reports of VAU frequently described severe symptoms. Urine retention and the necessity for bladder catheterization was reported in two cases. The events occurred mostly following the 2nd dose, with a consistent median time to onset of two days. The reports are consistent with fifteen published case reports for adolescent females.
VAU can be perceived as a traumatic experience, especially in adolescent patients. There is furthermore a risk that the ulcers will be misdiagnosed resulting in avoidable investigation and treatment burdens.
We communicate this signal to support the small number of published case reports and raise awareness of the possibility of VAU occurring in a temporal association with COVID-19 vaccination. Furthermore, the case series illustrates the value of well-documented case reports for rare adverse events that are difficult to study more formally and their submission to national pharmacovigilance databases to expedite recognition of previously unexpected adverse reactions.
Declaration of Competing Interest
All authors declare that they have no conflicts of interest.
Acknowledgements
The authors are indebted to the national centres who make up the WHO Programme for International Drug Monitoring and contribute reports to VigiBase. However, the opinions and conclusions of this study are not necessary those of the various centres nor of WHO.
References
- Vulvar Aphthous Ulcer Following Pfizer-BioNTech COVID-19 Vaccine - A Case Report.J Pediatr Adolesc Gynecol. 2021; 35 (Oct 28): 165-166
- Acute Genital Ulceration After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination and Infection.J Pediatr. 2022; 246 (Apr 9): 271-273
Popatia S, Chiu YE. Vulvar aphthous ulcer after COVID-19 vaccination. Pediatr Dermatol. 39(1):153–4.
- Vulvar Aphthous Ulcers in an Adolescent After Coronavirus Disease 2019 (COVID-19) Vaccination.Obstet Gynecol. 2022; 140 (May 5): 514-517
- Vulvar Aphthous Ulcer in an Adolescent After Pfizer-BioNTech (BNT162b2) COVID-19 Vaccination.J Pediatr Adolesc Gynecol. 2021; 35 (Oct 25): 167-170
- Lipschütz ulceration in a 12-year-old girl following second dose of Comirnaty (Pfizer) COVID-19 vaccine.Int J Womens Dermatol. 2022; 8 (Dec): e066
- Acute Vulvar Aphthous Ulceration After COVID-19 Vaccination: 3 Cases.J Low Genit Tract Dis. 2022; 26 (Apr): 186
- To keep in scope: vulvar aphthous ulcers after COVID-19 vaccination.J Pediatr Adolesc Gynecol. 2022; 35 (Apr 1): 235
- Post COVID-19 Vaccination Vulvar Aphthous Ulcers: An Unpopular Case Series.J Pediatr Adolesc Gynecol. 2022; 35 (Apr 1): 226
- Adolescents with Vulvar Ulcers: COVID-19 disease, COVID-19 Vaccines, and the Value of Case Reports.J Pediatr Adolesc Gynecol. 2022; 35 (Jan): 109-111
VigiBase, the WHO global database of reported potential side effects of medicinal products [Internet]. Uppsala Monitoring Centre; Available from: https://who-umc.org/vigibase/vigibase-services/
US Food and Drug Administration C for DE and. US Food and Drug Administration. Adverse Event Reporting System (FAERS) - Public Dashboard. FDA [Internet]. 2021 Oct 22 [cited 2022 Sep 14]; Available from: https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard
US Centres for Disease Control and Prevention. US Centres for Disease Control and Prevention. Vaccine Adverse Event Reporting System (VAERS). [Internet]. [cited 2022 Sep 14]. Available from: https://vaers.hhs.gov/
Health Canada. MedEffect Canada [Internet]. 2011 [cited 2022 Sep 14]. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-canada.html
- How to identify common pediatric vulvar conditions.Contemp OBGYN J [Internet]. 2022; 67 (Jun 28 [cited 2023 Jan 13]Available from:)
- Pediatric and Adolescent Gynecologic Emergencies.Obstet Gynecol Clin North Am. 2022; 49 (Sep): 521-536
- Lipschütz's acute vulvar ulcer: a systematic review.Eur J Pediatr. 2020; 179 (Oct): 1559-1567
- Lipschütz Ulcer: An Unusual Diagnosis that Should Not be Neglected.Rev Bras Ginecol E Obstetrícia RBGO Gynecol Obstet. 2021; 43 (May): 414-416
Moise A, Nervo P, Doyen J, Kridelka F, Maquet J, Vandenbossche G. Ulcer of Lipschutz, a rare and unknown cause of genital ulceration. Facts Views Vis ObGyn. 10(1):55–7.
Sidbury R. Acute genital ulceration (Lipschütz ulcer). [Internet]. Moise LL, Corona R, editors. UpToDate; 2020 [cited 2022 Jan 18]. Available from: https://www.uptodate.com/contents/acute-genital-ulceration-lipschutz-ulcer
- Clinical Immunology Review Series: An approach to the patient with recurrent orogenital ulceration, including Behçet's syndrome.Clin Exp Immunol. 2009; 156 (Apr): 1-11
- Effects of anti-SARS-CoV-2 vaccination on safety and disease exacerbation in patients with Behçet syndrome in a monocentric cohort.Int J Rheum Dis. 2022; 25 (Sep): 1068-1077
Craven J. Regulatory Affairs Professionals Society. COVID-19 vaccine tracker. [Internet]. 2022 [cited 2022 Aug 9]. Available from: https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker
Ritchie H, Mathieu E, Rodés-Guirao L, Apple C, Giattino C, Ortiz-Ospina E, et al. COVID-19 vaccinations [Internet]. Our World In Data; 2022 [cited 2022 Jan 27]. Available from: https://ourworldindata.org/covid-vaccinations?country=∼OWID_WRL
- Comirnaty COVID-19 vaccine: EMA recommends approval for children aged 5 to 11 [Internet].European Medicines Agency, 2021 ([cited 2022 Jan 27]. Available from:)
- Ulcus vulvae acutum Lipschütz: a systematic literature review and a diagnostic and therapeutic algorithm.J Eur Acad Dermatol Venereol. 2020; 34 (Jul): 1432-1439
- Causal Association in Pharmacovigilance and Pharmacoepidemiology.Drug Saf. 2002; 25 (May 1): 467-471
- Summary of Product Characteristics for Comirnaty [Internet].European Medicines Agency, 2022 ([cited 2022 Jan 18]. Available from:)
- Summary of Product Characteristics for Jcovden (previously COVID-19 vaccine Janssen) [Internet].European Medicines Agency, 2022 ([cited 2022 Aug 15]. Available from:)
- Summary of Product Characteristics for Spikevax (previously COVID-19 vaccine Moderna) [Internet].European Medicines Agency, 2021 ([cited 2022 Jan 18]. Available from:)
- Drug Label Information for Comirnaty (covid-19 vaccine, mrna injection, suspension) [Internet].US Food and Drug Administration, 2022 ([cited 2022 Sep 15]. Available from:)
- Drug Label Information for Janssen COVID-19 vaccine (ad26.cov2.s injection, suspension) [Internet].US Food and Drug Administration, 2022 ([cited 2022 Sep 15]. Available from:)
- Drug Label information for Spikevax (covid-19 vaccine, mrna injection, suspension). [Internet].US Food and Drug Administration, 2022 ([cited 2022 Sep 15]. Available from:)
- Reactive non-sexually related acute genital ulcers associated with COVID-19.BMJ Case Rep. 2021; 14 (May 5)e242653
- [Lipschütz Ulcers After the AstraZeneca COVID-19 Vaccine].Actas Dermosifiliogr. 2021; (Aug 2;Epub ahaed of print)
- Non–Sexually Related Acute Genital Ulcers in 13 Pubertal Girls: A Clinical and Microbiological Study.ARCH DERMATOL. 2009; 145: 38-45
- COVID-19-related acute genital ulcers.J Eur Acad Dermatol Venereol. 2020; 34 (Jun 26): e655-e656
- Vulvar Aphthous Ulcer in an Adolescent With COVID-19.J Pediatr Adolesc Gynecol. 2021; 34 (Jun): 418-420
- Vulval (Lipschütz) ulcers in young females associated with SARS-CoV-2 infection and COVID-19 vaccination: case series.Arch Dis Child. 2023; (Jan 6;archdischild-2022-325149)
- Minor aphthae associated with SARS-CoV-2 infection.Int J Dermatol. 2020 Jun 18; 59: 1022-1023
- Various painful oral adverse reactions following COVID-19 vaccination: a case series.BMC Oral Health. 2022; 22 (Mar 8): 64
- Recurrent aphthous stomatitis.Dermatol Clin. 2003; 21 (Jan 1): 33-39
- An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making.BMJ Open. 2014; 4 (Jan 1)e004221
Article info
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Accepted:
March 10,
2023
Received in revised form:
March 6,
2023
Received:
November 9,
2022
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In Press Journal Pre-ProofIdentification
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© 2023 Published by Elsevier Inc. on behalf of North American Society for Pediatric and Adolescent Gynecology.
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