key: cord-0767453-xpun6vic authors: Bachour, Yara; Bekkenk, Marcel W.; Rustemeyer, Thomas; Kadouch, Jonathan A. title: Late inflammatory reactions in patients with soft tissue fillers after SARS‐CoV‐2 infection and vaccination: A systematic review of the literature date: 2022-02-23 journal: J Cosmet Dermatol DOI: 10.1111/jocd.14840 sha: a2b89d747f442bc74ee7fd46d729fc15daf493f9 doc_id: 767453 cord_uid: xpun6vic INTRODUCTION: Soft tissue fillers are used for cosmetic and reconstructive purposes, and soft tissue filler procedures are among the most common nonsurgical procedures in the USA. Although soft tissue filler procedures are relatively quick and safe, adverse events such as late inflammatory reactions have been reported with every filler product. Infections and vaccinations have been proposed as potential triggers for late inflammatory reactions (LIRs), and it is therefore not surprising that these adverse events have been reported after SARS‐CoV‐2 infection and vaccination. Therefore, this review aims to give a detailed overview of these cases. MATERIALS AND METHODS: A literature search was undertaken on LIRs in patients with a history of soft tissue filler use after SARS‐CoV‐2 infection or vaccination. This systematic review was reported according to the PRISMA guidelines. We searched the electronic database PubMed from January 2020 to August 2021. Data on patient characteristics, filler characteristics, clinical findings, and treatment options were included. RESULTS: This review included 7 articles with a total of 19 patients with LIRs after SARS‐CoV‐2 infection or vaccination. Three patients with postinfection LIRs and 16 patients with postvaccination LIRs were reported. These LIRS mainly occurred in females who had HA injections for cosmetic purposes. Three patients with postinfection LIRs had symptoms of facial swelling and/or lip angioedema in a matter of weeks. Sixteen patients reported reactions after SARS‐CoV‐2 vaccination (13 following Moderna vaccination and 3 after Pfizer vaccination, after both the first and second doses) from 13 hours up to three weeks. These patients presented with similar clinical symptoms as patients with postinfection LIRs. All patients were treated in a conservative manner. DISCUSSION: This review shows a relationship between LIRs and SARS‐CoV‐2 infection and vaccination. In the case of vaccination, these adverse events have been reported only after Moderna and Pfizer vaccinations. The reported adverse events are generally minor and self‐limiting, and we encourage patients with soft tissue fillers to participate in vaccination programs. Soft tissue fillers are used for aesthetic purposes as well as to restore aesthetics after trauma or cancer. 1 According to the American Society for Aesthetic Plastic Surgery, the use of soft tissue fillers increased by 59% between 2014 and 2018. 2,3 With almost one million procedures performed annually, soft tissue filler procedures are among the most commonly performed nonsurgical treatments in the United States. 2 The popularity of soft tissue fillers has been attributed to their simple use, quick results, and relative safe use. 4 As a result, the increased use of soft tissue fillers has led to an increase in soft tissue filler products. These products are divided according to their biodegradability into temporary, biostimulatory, or permanent fillers. 5, 6 Table 1 shows an overview of soft tissue fillers that have been used in the past and present. Although the use of contemporarily available soft tissue fillers is considered safe, several studies have shown that complications occur with all filler types. 4, [7] [8] [9] [10] [11] [12] [13] Late inflammatory reactions (LIRs) are among the most common complications after filler use. However, the etiology of LIRs is unknown; therefore, they are difficult to treat. 13 Examples of LIRs are erythematous lumps, granulomas, edema, or nodules. Several reports have shown that LIRs occur between weeks and years after filler treatment. According to Marusza et al., these complications occur in 0.01%-4.25% of soft tissue filler procedures. 14, 15 Thus far, the etiopathogenesis of LIRs is still not known. Several hypotheses have been proposed, such as bacterial contamination, foreign body reaction, delayed-type hypersensitivity reaction, and adjuvant-based filler reactions due to triggers such as infection, trauma, or vaccination. 12, 14, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] It is therefore not surprising that in the current COVID-19 pan- 2 | ME THOD In this systematic review, a literature search was performed on soft tissue filler-related LIRs after SARS-CoV-2 infection or vaccination and conducted according to the PRISMA guidelines. 27 A search was performed in the electronic database PubMed with the use of the index term 'filler' (see supplemental data file). Studies from January 2020 to August 2021 were included without language restrictions. Studies on LIRs in soft tissue filler use after SARS-CoV-2 infection or vaccination were identified. We included original patient studies. Here, there was no limitation on the type of filler product or on SARS-CoV-2 vaccinations. The search was executed with the aid of an experienced medical information specialist. Two reviewers considered the eligibility of each article in the subsequent steps: the reviewers inspected the title first and thereafter screened the abstract. In the case of doubt on the eligibility, they reviewed the full text. When a study was included, the extracted data were entered into standardized tables. These data included article, patient, and filler characteristics, such as the date of publication, study design, number of patients, age and sex of patients, type/amount and location sites of the soft tissue fillers, indication for injection, description of The first reports on adverse events in patients with soft tissue fillers following a SARS-CoV-2 infection emerged in January 2021 and were soon followed by several other reports (Table S1a) . Munavalli et al. reported on a 50-year-old woman with a history of HA injections up to 15 days prior to a SARS-CoV-2 infection. 29 Two weeks after her positive PCR test for SARS-CoV-2, she developed lip burning and swelling followed by cheeks and tear trough swelling. The patient's symptoms seemed to worsen over the following days. She was primarily treated with Hylenex (hyaluronidase; unknown manufacturer) injections and showed a transient improvement followed by cheek edema. In the weeks that followed, she received prednisone, doxycycline, Hylenex, microneedling combined with clarithromycin and prednisone, intralesional triamcinolone acetamide and Hylenex, which altogether resulted in a slight improvement. At the last visit, the patient continued to report intermittent mild edema under the eyes. 29 In another case report, a young patient had HA filler treatment in the nose area 5 months prior to SARS-CoV-2 infection. 30 The first adverse events following SARS-CoV-2 vaccination were reported in the preliminary FDA results for the Moderna vaccine (Table S1b) , 26 which showed adverse events in three patients. Two patients with recent filler injections (6 months Again, in all patients, complete resolution of their symptoms was reported. LIRs may emerge from weeks up to months after soft tissue filler injection. To date, it is unclear which patients will develop these complications, as the etiology of LIRs is not completely clear. 13 It has been proposed that immunobiological factors (e.g., bacterial infection, foreign body reaction, delayed-type hypersensitivity reaction, adjuvant-based filler reactions, and genetic predisposition), chemical properties (e.g., electrical charge, surface irregularities, particle size, hydrophilicity/hydrophobicity, molecular weight, and amount of chemical cross-linking), and injection techniques (e.g., level of implantation, filler volume, and repeated treatments) might play a central role in its development. 12, 14, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [39] [40] [41] [42] Based on the clinical presentation of the current cases, we suggest that immunobiological factors might play an important role in the etiology of LIRs after SARS-CoV-2 infection and vaccination. Most authors of the presented studies suggest that these reactions are due to delayed-type hypersensitivity (type IV) reactions initiated by T-lymphocytes and mediated by CD4+ cells. 38 HA is one of the few filler constituents that has proven to evoke a type IV hypersensitivity reaction shown by positive skin testing. 20 However, this concerned only one study. A recent study on patients who experienced LIRs following HA filler injection showed no reaction for general allergic screening (patch test) or intradermal testing. 43 Munavalli et al. treated their patients with lisinopril, which decreased the clinical symptoms. 29, 33 Lisinopril is an angiotensinconverting enzyme inhibitor (ACE-1) that plays a crucial role in SARS-CoV-2 binding properties but is mostly known for its role in the renin-angiotensin system (RAS), which regulates the interstitial fluid volume. The authors therefore propose a novel mechanism of action via ACE-1 29,33 ; via several steps, the reaction is shifted toward an anti-inflammatory reaction that results in an increase in sodium water outflow. This results in a decrease of the swelling. 29, 33, 44 Another theory is adjuvant-based filler reactions. Alijotas-Reig and colleagues postulate that foreign body materials such as breast implants or dermal fillers might trigger the immune system not as antigens but more like adjuvants. 13, 24 By this, they mean that adjuvants can trigger the immune system but without having specific antigenic properties themselves. 25 As a result, the innate and adaptive immune systems can be triggered by adjuvants. These adjuvants mimic molecules such as PAMPs that can trigger the immune system by binding Toll-like receptors (TLRs). This results, for example, in the release of several cytokines and the activation of dendritic cells (DCs) or macrophages. 25 The effects of adjuvants are thought to be mediated by several activities, as described in our former review. 13 Certain triggers, such as infections and vaccinations (e.g., SARS-CoV-2 infection and vaccination), may induce adjuvant activity or act as adjuvants themselves. 24 Last, it has been suggested that some patients are genetically predisposed to develop LIRs, as a recent study has shown that patients bearing HLA subtypes B*08 and DRB1*03 are at a greater risk of developing these complications. 39 These outcomes suggest that these patients might have a lower threshold to, for example, infections, vaccines, or other factors that trigger the immune system. What we can learn from the cases presented in this review is that adverse reactions toward soft tissue filler do occur after SARS-CoV-2 infection and vaccination. The relationship between these factors seems to be possible, as LIRs occur within a few hours up to several weeks after an infection or vaccination. We believe that these adverse events are generally minor and concern tens of patients. However, to prevent these complications, we can learn from these cases, and we make the following recommendations: First, we would advise prevaccination counseling in cosmetic pa- Overall, this review shows that LIRs can occur after SARS-CoV-2 infection and vaccination. In the case of vaccination, these adverse events have been reported only after the Moderna and Pfizer vaccines. The reported adverse events are generally minor and self-limiting, and we encourage patients with soft tissue fillers to participate in vaccination programs. We suggest that a patient's medical history should be thoroughly evaluated for soft tissue filler procedures. We also suggest that patients should be asked about filler injection prior to vaccination and that international registries ensure careful reporting of soft tissue adverse events to give a more detailed overview of these complications. No conflict of interest relevant to this article. Y.B. performed the research, designed the research study, and analyzed the data. Y.B. and J.K. wrote the paper. Y.B., J.K., M.B., and T.R. reviewed the paper. The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data. The data that supports the findings of this study are available in the supplementary material of this article. Clinical data on injectable tissue fillers: a review An overview of permanent and semipermanent fillers Orofacial dermal fillers: foreign body reactions, histopathologic features, and spectrometric studies. 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