Side effects after hyaluronic acid facial injection in adults during COVID- 19 pandemic

Background: Different causes may be responsible for delayed inflammatory reactions after hyaluronic acid injections, among them several mechanisms of SARS- CoV- 2. Aims: The study's objective was to assess the percentage of adverse reactions after hyaluronic acid injections in a cohort of adult patients with a test for SARS- CoV- 2 or vaccinated during the COVID- 19 pandemic. Patients/Methods: An observational, retrospective, comparative, multi- center, non-interventional in a real- life setting study was carried out with patients treated with facial injections of hyaluronic acid from May to September 2021, with a test to discard SARS- COV 2 or that had been vaccinated. Results: Sixty- three patients were included. Seven (11.1%) were vaccinated patients without a test for SaRS- CoV- 2 and 56 (88.9%) with antigenic or PCR screening tests (18 [32.1%] negative and 39 [69.6%


| INTRODUC TI ON
Hyaluronic acid (HA) facial rejuvenation or modeling has recently increased due to its results and safety. 1 However, several factors have been identified that can increase the incidence of side effects, such as skin infections or inflammation, systemic disease, viral diseases such as HIV, HVC, and metabolic or coagulation disorders, among other conditions. Antiviral drugs such as interferon α or ribavirin, 2 or immunization with the influenza vaccine, 3 in combination with HA fillers, can promote the development of side effects. Thus, all these factors should be considered before performing the procedure since it may be necessary to delay or take special precautions when using HA dermal fillers. 4 Immediate or early-onset side effects (occurring up to several days following treatment) include reactions at the injection site-pain, edema, erythema, pruritus, bruising-, infection, hypersensitivity, nodules, asymmetry, facial contour defects, skin discoloration, vascular effects, and tissue necrosis. 5 Delayed adverse reactions (occurring weeks or even years following treatment), in addition to edema, nodules, pain, and infection, include foreign body granuloma, migration, infection, immune reactions, persistent scarring, collected discoloration, and skin affectation. 5 Delayed inflammatory reactions (DIRs) to HA dermal fillers range from 0.02% to 4.25%. [6][7][8][9] Individual immune system reactivity levels play a crucial role; several studies have shown a relationship between the patient's inflammatory and immune status and the development of dermatological alterations. 10 A higher incidence of local complications following HA facial injection has been reported in patients with immunological alterations compared to the immunologically healthy population. 11 The COVID-19 pandemic has forced us to conduct studies on the relationship between HA injections and the development of inflammatory reactions in patients infected with SARS-CoV-2 or following the vaccination. SARS-CoV-2 has been shown to bind and block angiotensin-converting enzyme 2 (ACE2) through the S (spike) protein to access the cell, which could be a potential mechanism for developing a DIR in vaccinated or COVID-19-infected patients who have been injected AH fillers. 12 Protein interaction enhances the pro-inflammatory activation of Th1, promoting a reaction mediated by CD8+ T cells, which represent an essential line of defense against infection and are present in the infiltration developing around HA deposits injected into the skin in the subcutaneous tissue. 13 Recently, it has been observed that SARS-CoV-2-related inflammatory reactions are delayed and mainly occur following vaccination. 13,14 However, in the early days of the pandemic, when no vaccines were available, there was no evidence confirming or not about a higher propensity to increased inflammatory reactions in patients who had been injected HA with facial fillers and would later become infected. The timing of these reactions was also unknown.
The study's objective was to assess the percentage of adverse reactions after hyaluronic acid injections in a cohort of adult patients with a test for SARS-CoV-2 or vaccinated during the COVID-19 pandemic.

| Study design
It was an observational, post-authorization, retrospective, controlled, multi-center, non-interventional study in a real-life setting. It was carried out from May to September 2021 in adult patients (≥18 and ≤70 years of age) treated with a HA facial filler with a positive or negative test for SARS-COV 2 or that had been vaccinated.
The study was conducted following the principles outlined in the current revised version of the Declaration of Helsinki, Good Clinical Practice (GCP), and in compliance with all applicable laws and regulatory requirements.

| Subjects and variables analyzed
The sample included patients treated with HA facial fillers who tested positive or negative for SARS-CoV-2, or vaccinated patients against SARS-CoV-2. General sample data were gathered, and some variables were compared.

Sociodemographic variables included patients' age and gender.
Clinical characteristics included pre-existing conditions and comorbidities, skin type, history of fillers, and previous adverse reactions to HA facial treatments. Treatment-related variables were the type of HA, application site, milliliters injected, the technique, treatment duration, and the attending physician experience.
Safety variables were all HA filler-related AEs. They were classified as mild (when symptoms were temporary and did not affect the subject's daily activities), moderate (when the symptoms were noticeable and moderately affected the subject's daily activities), and severe (when they considerably affected the subject's daily activities).
Treatment tolerability was assessed based on the number and severity of AEs. The resolution of AEs and SAEs was classified as: (i) resolved (when the patient recovered following medical treatment or surgical intervention); (ii) resolved with sequelae (when the AE resulted in permanent or significant disability or incapacity and was classified as a serious AE); (iii) non-resolved (when the patient's condition did not improve, and the symptoms remained unchanged after the study), death (when the event resulted in the death of the subject); (iv) unknown (when the patient's condition was unknown because he/she was lost to follow-up).
As regards COVID-19, the number of patients with compatible symptoms was recorded, as well as the type and severity of symptoms, diagnostic testing performed [antigenic, serological, or polymerase chain reaction (PCR)], and the result obtained. Moreover, the period elapsed after applying the HA facial treatment and the positive diagnostic test were calculated.

| Study procedures
Given the study's observational nature, no additional testing or examinations were conducted to assess safety parameters other than those conducted at the sites where each patient was treated.

| Data management
The investigators included patient data following the questions of a survey designed specifically for the participant doctors in the study. (Table 1) The necessary information was obtained from the medical records at the sites where patients were treated and gathered according to their usual clinical practice. Patients did not have to attend additional visits other than the regular follow-up visits.

| Statistical analysis
Descriptive analyses were conducted based on the nature of each variable. Categorical variables were presented as frequencies and percentages. Continuous variables were presented using central tendency and dispersion measures (mean, standard deviation, and minimum and maximum intervals). Chi-square Tests were performed to assess potential associations, calculating the resulting p-values. A significance level of α = 0.05 was adopted.

| Subjects characteristics
The study included 63 patients, seven (

| Characteristics of the procedure
The area/s of application were: (i) 9 lips (14.3%); (ii) jaw 3 (4.8%); (iii) dark circle 5 (7.9%); (iv) pan-facial 6 (9.5%); (v) upper third 4 (6.3%); (vi) middle third 11 (17.5%); (vii) lower third 1 (1.6%); (viii) Combinations 24 (38.1%). The amount injected in 23 (36.5%) patients was 1 mL; 2 mL in 31 (49.2%); 3 mL in 5 (7.9%); 4 mL in 3 (4.8%), and 5 mL in   Mild AEs resolved without sequelae. Serious AEs occurred in two patients (13.3%) with no history of AEs: (a) a patient with a positive test for SARS-CoV-2 presented a severe inflammation (out of the ordinary) at the regional level, which lasted 6 days and presented with panfacial edema, including the eyelids, and who was treated with a dose of parenteral corticosteroids and oral antihistamines for 10 days, resolving with no sequelae; (b) another patient had a severe delayed inflammatory reaction (out of the ordinary), including inflammation at the injection site and periocular edema, which lasted 3 days and was treated with oral corticosteroids for 4 days, had a standard resolution without sequelae. The treatments applied in the 15 AEs are described in Table 2.  However, HA injections for facial rejuvenation are safe in the context of COVID-19 as long as specific criteria are followed to guarantee patient safety. For instance, avoiding treatment immediately before vaccination or refraining from said treatment between the first and second dose of the vaccine and up to a month following immunization, 12 or refraining from applying them when the patient is positive for SARS-CoV-2.

| DISCUSS ION
The study limitations include the low number of patients, the lack of consistent criteria for patient follow-up, and the difficulty in gathering all the data, especially those related to vaccination. On the other hand, the established follow-up period would need longer, which means that some late-onset AEs would have been excluded from the study. Thus, there is a need for future studies including a more significant number of patients with consistent criteria for patient follow-up and data collection and a long follow-up period.

| CON CLUS IONS
The AEs after hyaluronic acid facial injection were higher among patients with a history. The new scenario related to COVID-19 infections or vaccinations would require readapting the criteria for applying hyaluronic acid injections.

AUTH O R CO NTR I B UTI O N S
Petra Vega, Paloma Tejero, Juan Antonio López-Pitalúa, and Hernán Pinto: (1) substantial contribution to conception and design, acquisition of data, analysis, and interpretation of data; (2) drafting the article and revising it critically for important intellectual content; and (3) final approval of the version to be published.

ACK N OWLED G M ENTS
The authors would like to thank all their collaborators, especially Elena Sánchez-Vizcaíno Mengual, and i2e3 Procomms medical writing team.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors have no conflicts of interest or financial ties to disclose.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.