COVID-19, Coronavirus Vaccines, and Possible Association with Lipschütz Vulvar Ulcer: A Systematic Review

Data Source

The study was recorded on the International Prospective Register of Systematic Reviews of the National Institute for Health Research (PROSPERO CRD42023376260) and undertaken in accordance with the Joanna Briggs Manual and the second edition [4] of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA). Three databases, i.e., Excerpta Medica, the National Library of Medicine, and Web of Sciences, were explored in September 2022 and updated on January 15, 2023, without any restriction for original articles or letters using the following terms entered in separate pairs: “genital ulcer” OR “Lipschütz ulcer” OR “non-sexually acquired genital ulcer” OR “ulcus pseudovenereum” OR “ulcus vulvae (acutum)” AND “coronavirus disease 2019” OR “COVID 19” OR “SARS-CoV-2” OR “severe acute respiratory syndrome coronavirus 2.” The search strategy for each database is given in the online supplementary material. Google Scholar, personal files, and the bibliography of each identified article were also screened. Cases published uniquely as abstracts were not included.

Selection Criteria—Diagnostic Criteria

Of interest were acute episodes of Lipschütz ulcer temporally associated with a COVID-19 or a vaccination against SARS-CoV-2 and a latency of four weeks or less [5]. The Lipschütz ulcer was categorized as intra-infectious in cases exhibiting both COVID-19 and genital disease simultaneously. On the other hand, it was categorized as postinfectious in cases with the onset of the genital disease after recovery from COVID-19. Cases of Lipschütz ulcer in patients without any symptom of COVID-19 but uniquely with a positive test were considered intra-infectious. In the case of post-vaccination ulcer, the time latency from vaccination against SARS-CoV-2 to the onset of Lipschütz ulcer was calculated. Cases heralded by an infection other than COVID-19 or by a vaccination against a microorganism other than SARS-CoV-2 with a latency of four weeks or less were not included. The diagnosis was made in previously healthy and apparently immunocompetent subjects with rapid onset of a few, painful, rather large genital ulcers. Sexual inactivity was not a prerequisite for the diagnosis [1, 2]. Patients with a sexually transmitted disease, laboratory findings consistent with an acute Epstein-Barr virus infection, Behçet’s disease, Crohn’s disease, cancer, cutaneous drug reactions, or trauma were excluded.

A positive microbiologic testing was a sine qua non for the diagnosis of COVID-19. Its severity was classified into five stages, as suggested by the National Institutes of Health [5]: (1) asymptomatic (without symptoms and signs), (2) mild (any symptom or sign such as malaise, headache, fever, cough, sore throat, or myalgia without shortness of breath, dyspnea, or abnormal chest imaging), (3) moderate (evidence of lower respiratory tract disease by clinical assessment or imaging, and oxygen saturation on room air ≥ 94%), (4) severe (respiratory rate > 30/min, oxygen saturation on room air < 94%, or pulmonary infiltrates > 50%), and (5) critical (hypercapnia, septic shock, or multiple organ dysfunction).

Data Extraction—Reporting Comprehensiveness—Data Synthesis

Data were extracted using a piloted form. For each episode of Lipschütz ulcer temporally related to COVID-19 or an immunization against SARS-CoV-2, the following information was sorted: demographics; medical history; temporal relationship between coronavirus disease 2019 or immunization against it and first symptoms and signs of genital ulcer; clinical features of Lipschütz ulcer such as local clinical features, urinary symptoms, treatment with systemic corticosteroids, and disease duration (defined as recovery time of ulcers); and the possible existence of an acute Epstein-Barr virus serology test.

For each episode of Lipschütz ulcer temporally related to COVID-19, information about microbiology testing and features of coronavirus disease was also collected. For each episode of Lipschütz ulcer heralded by a vaccination against SARS-CoV-2, information about the type of vaccine and dose (first, second, or third) was collected. The corresponding authors of original reports were contacted to obtain missing information.

Reporting comprehensiveness was stratified as satisfactory, good, or excellent according to our standard procedure [2].

Two authors separately performed the literature search, the selection of eligible studies, data extraction, and evaluation of reporting comprehensiveness in duplicate. Any disagreements were discussed, and a senior author was involved for any remaining discrepancies.

Pairwise deletion was employed to deal with missing values. Continuous variables are shown as median with interquartile range and were analyzed using the Wilcoxon-Mann–Whitney test. Categorical variables are shown as proportions. Dichotomous categorical data were compared using the Fisher test, and ordered categorical data were compared using the Wilcoxon-Mann–Whitney test. A two-sided P < 0.05 was used to denote significance. GraphPad Prism 9.5.1 (GraphPad Software, San Diego, California, USA) was used for statistics.

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