# Oral Lesions in Pediatric Subjects: SARS-CoV-2 Infection and COVID-19 Vaccination
## 1 Introduction  
The first information regarding COVID-19 dates back to the first cases of SARS-CoV-2 infection, reported in December 2019, in Wuhan, Hubei Province in China. Three months later, on 11 March 2020, the World Health Organization (WHO) proclaimed the status of a global pandemic [1]. Various non-drug preventive measures, such as facial masks and social distancing, were adopted to control the spread of infection, later combined with vaccination. COVID-19 vaccines, although associated with Adverse Drug Reactions (ADRs) [2], similar to all medicinal products, have been effective in reducing the risk of viral transmission and infection, preventing severe forms of COVID-19, and decreasing the rate of hospitalization and death [3]. In the early stages of the COVID-19 pandemic, the number of pediatric SARS-CoV-2 positive subjects appeared to be very small [4]. The evidence suggested, at the time, thatpediatric subjects frequently developed an asymptomatic or oligosymptomatic form of SARS-CoV-2 infection [4]. However, subsequent findings revealed that COVID-19 could evolve, in some pediatric cases, into the severe form of the disease. Indeed, cases diagnosed worldwide with a newly characterized syndrome, potentially linked to SARS-CoV-2 infection in children, identified as \"Multisystem Inflammatory Syndrome in Children\" (MIS-C), or \"Paediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19\" (PIMS-TS), have been described [5; 6]. This syndrome shares similar features with other entities already known, also potentially involving the oral cavity, such as Kawasaki Disease (KD), Toxic Shock Syndrome (TSS), Macrophage Activation Syndrome (MAS), and Secondary Hemophagocytic Lymphhohstiocytosis (SHLH) [5; 6]. However, the lower prevalence of severe COVID-19 observed in pediatric subjects compared to adult ones, and the contrasts with infections caused by other respiratory pathogens, has been partially explained by the age-related differences in viral receptor expression, immune function, and comorbidities rate [6]. Indeed, comorbidities are associated with an increased risk of severe disease, hospitalization, and death, even in pediatric subjects, although most of those hospitalized due to COVID-19 did not have comorbidities [6]. Nevertheless, 14,448,622 pediatric SARS-CoV-2 subjects were recorded in the United States until 24 August 2022 [7], representing 18.4% of all cases. Consequently, COVID-19 vaccination may be especially beneficial for pediatric subjects at higher risk of severe disease and is thought to be effective in protecting against post-COVID-19 conditions and MIS-C/PIMS-TS [6]. Accordingly, to date, the European Centre for Disease Prevention and Control recommended the COVID-19 vaccination in 12-17 year-olds in all European countries, registering 26.2% of the pediatric population (<18 years of age) as having received at least one dose (on 25 August 2022) [6], with some countries also recommending booster doses for the same age group [6]. The European Medicines Agency (EMA) approved the mRNA BNT162b2 Comimraty (PfizerBioNTech) and the mRNA-1273 Spikevax (Moderna) vaccines for 6-11 year-olds. Similarly, the Centers for Disease Control and Prevention reported that 38% of the pediatric population (<18 years of age) received at least one dose (on 24 August 2022) [7] and approved the mRNA BNT162b2 Comimraty (Pfizer-BioNTech) vaccine administration in subjects \(\geq\)5 years old. The FDA also authorized the use of the mRNA-1273 Spikevax (Moderna) for children <5 years of age. Therefore, the present systematic review primarily aimed to assess the prevalence and macro-microscopic features of oral lesions following SARS-CoV-2 infection, estimating the degree of association and grading primary oral lesions based on COVID-19 forms in pediatric (<18 years old) subjects.