Adverse reactions to cosmetic implants after COVID‐19 vaccination: A literature review

As the world's population of people vaccinated with the COVID‐19 vaccine increases, adverse reactions are increasingly being reported. There have been progressive reports of the effects of COVID‐19 vaccination on cosmetic fillers or prostheses, but they have not been reviewed based on their clinical morphologic patterns. This article reviewed the progress of research on adverse reactions to cosmetic implants after COVID‐19 vaccination.


| INTRODUC TI ON
The 2019 pandemic caused by COVID-19 has had an unprecedented impact on global health and economy.Rapidly evolving public health strategies attempted to control the spread of the disease but were insufficient to slow down the spread of the disease.2][3] A study that used Google Trends to assess changes in public interest in elective plastic surgery during the COVID-19 epidemic found that public interest in all cosmetic-related treatments declined dramatically during the phase, but steadily increased again with the release of the COVID-19 vaccine. 4Statistics released by the American Society for Aesthetic Plastic Surgery (ASAPS) reported that, in 2021, surgical procedures increased by 54% and non-surgical procedures were up 44% compared with 2020.The most popular surgical procedures were liposuction and breast augmentation, and the most popular non-surgical procedures were neurotoxins and dermal fillers. 5Pang et al. assessed the level of public interest in facial rejuvenation on Twitter during the COVID-19 pneumonia epidemic by the number of "tweets per day". 6The authors found that after the COVID-19 pneumonia epidemic outbreak, "Botox," "hyaluronic acid", and "cosmetic treatment" increased in popularity, especially for facial beauty.The COVID-19 vaccine was first released by Pfizer BioNTech on December 14, 2020, 7 followed by the Moderna vaccine on December 18, 2020. 8By the end of May 2021, more than 5 billion doses of vaccine had been administered worldwide.This trend suggested an increased chance of the coexistence of cosmetic implants with vaccination.
There have already been reports of adverse reactions caused by the COVID-19 vaccine at previously injected filler or prosthetic implant sites, 1,9,101 including edema, rash, fever, and capsular contracture, but most of them were case reports.In this article, we attempted to investigate and discuss all the adverse reactions of cosmetic implants related to COVID-19 vaccination in the current literature.The review will be discussing two topics including injectable fillers and surgical implants.Although the adverse reactions were generally benign, we still need to unmask these reactions to make a more accurate assessment of vaccine safety.Based on the statistics and information we summarized, it would be instructive for the clinicians to choose vaccine type and prevent the adverse reactions after COVID-19 vaccination, especially the surgery treatment.

| MATERIAL S AND ME THODS
We carried out a narrative review of the English language literature related to any adverse reactions attributed to cosmetic implants associated with COVID-19 vaccination.The terms used for the MEDLINE and PubMed search were as follows: "COVID-19 vaccine*" or "SARS-CoV-2 vaccination*" and "filler*" or "injection*" or "implant*" and "reaction*" or "effect*" or "event*".The search included original articles (i.e., case reports, case series, registry-based observational studies, and randomized controlled trials) published from March 31, 2020 (inception date) to October 15, 2022.
There were no restrictions in terms of gender, race, or geographic area.In addition, we reviewed references from relevant original papers and review articles to identify further eligible studies not covered by the original database search.Studies describing adverse reactions to cosmetic implants after at least one dose of COVID-19 vaccination were included.In these manuscripts, the association between adverse reactions to implants and the COVID-19 pneumonia vaccine was supported by temporal and topographical criteria and lacked any other triggers (i.e., infection or new medications) or biological plausibility.The criteria for exclusion were as follows: (1) studies without a clear description of symptoms in clinical presentation; (2) studies involving pediatric populations; (3) articles written in languages other than English; and (4) review articles, conference abstracts, and expert opinions.For all eligible studies, we retrieved data on authors and year of publication, study design, sample size, population characteristics (age, sex, preexisting implant, and/ or allergy status), type of implant, timing to onset after the first or booster dose of vaccine, medications management, and outcomes (Figure 1).These data were extracted from the articles: the author, year of publication, age and sex of the patient, filler substance, injection site, symptoms and signs, onset time, vaccine (dose), reaction side, infarction site, treatment, and prognosis.We were only able to analyze the data captured in these articles, some of which had incomplete reporting.

| RE SULTS
A total of 97 articles were found through PubMed and Medline®.
After screening titles and abstracts, the remaining 47 articles underwent full-text assessments for eligibility.And 23 articles were excluded based on the exclusion/inclusion criteria.Finally, a total of 24 studies were included in the review, containing a total of 68 patients (Figure 1).
The present study classified vaccine-related adverse reactions to plastic surgery implants into two categories: (1) injectable filler implants and (2) surgical prosthetic implants.

| Characteristics of patients with injectable filler implants
A total of 16 articles related to the adverse reactions of injectable fillers in our study containing a total of 56 patients, as shown in Table 1.

| Characteristics of patients with surgical prosthetic implants
A total of eight articles related to the adverse reactions of surgical prosthetic implants in our study contained a total of 12 patients, as shown in Table 2. From the table, we can find that all the adverse reactions occurred with breast implants except for one 39-year-old male patient who had an adverse reaction on the nasal silicone implant after rhinoplasty.
The mean age of the patients with breast implants was 50.In the era of the COVID-19 pneumonia epidemic, people may pay more attention to their faces on virtual platforms and spend more time comparing themselves to others, leading to a decrease in body and facial satisfaction. 11,12ter the launch of the first two approved vaccines in the United States, postoperative inflammatory reactions have been reported.

| Statistics of all patients
Worldwide so far, the majority of dermal fillers reported to cause adverse reactions after COVID-19 vaccination have been HA com-

ponents. Munavalli et al. first reported DIRs to HA dermal filler in-
jections after COVID-19 vaccination. 13e current reports related to prosthetic implants are mainly breast implants.Richard J. Restifo first reported in May 2021 that a 34-year-old female patient who had previously undergone bilateral breast augmentation and received two vaccinations of Pfizer vaccines 5 months later. 14There was only a male patient who was 39-year-old and underwent silicone rhinoplasty 8 years ago developing DIRs within 6 days after the first dose of the Pfizer vaccine. 15cording to the data retrieved from a national cross-sectional registry-based study, cutaneous adverse reactions associated with COVID-19 vaccination were more common in women than in men, accounting for 80%-90% of reported cases, 16 which is similar to our findings.[22][23][24][25][26][27] With waves of new variants emerging, [28][29][30][31][32][33][34][35] of which the omicron variant carries about 50 mutations not seen in combination before (World Health Organization 2021), [36][37][38][39][40] new vaccines may formulate.It generates the discussion of the need to continue booster doses indefinitely, which will inevitably increase the risk of DIRs in patients with implants. 41

| Causes of adverse reactions
Acute or type I hypersensitivity reactions begin within minutes to hours after allergen contact, 42  The incidence of DIRs is also related to different materials.
Estimates for the overall incidence of DIRs to dermal fillers vary from 0.02% up to 4.25%. 47DIRs associated with HA fillers are as high as 4.25%. 48A recent report speculated that HA-based fillers with low-molecular weight-degraded products have higher proinflammatory activity. 49And structural modifications of HA fillers during crosslinking have been reported to enhance the resistance of the product to enzymatic breakdown, thereby increasing the longevity of the filler material, but also leading to an increase of DIRs. 13wever, further studies are still needed to study the details of DIRs incidence.
Theoretically, any implant or external material, such as breast implants or artificial joints, used in body tissues could also lead to autoimmune or inflammatory reactions.1][52][53][54][55][56] For example, it had been reported that a series of cases had acute or delayed hypersensitivity in previously filled areas after different types of vaccination in 2008. 24The most common filler in these cases was also HA.Other materials include hydroxyapatite and acrylamide, etc. 57

| Mechanism of DIRs to implants
The pathological mechanism of DIRs after vaccination may be multifactorial.One potential mechanism of DIRs to HA fillers in COVID-19-related cases is binding and blocking the angiotensin-2 converting enzyme receptor (ACE2), [58][59][60][61][62][63] which is targeted by the SARS-CoV-2 viral spike protein to gain access to cells.The interaction of spike protein with ACE2 facilitates a pro-inflammatory, local Th1 cascade that promotes a CD8+ T cell-mediated reaction to incipient granulomas, which previously formed around residual HA particles.Moreover, in human and murine models, implantation of dermal HA fillers is known to stimulate angiogenesis and retain neovascularization. 64Thus, around the injection site, ACE2 may be higher than baseline in dermal and subcutaneous levels, which sets the stage for DIR-triggered occlusion due to vaccination or active COVID-19 pneumonia infection during the peri-injection period.
Furthermore, the threshold for inflammatory reactions triggered by vaccines, reactions, or other stimuli is lower in genetically predisposed individuals. 65recent report showed that patients with HLA subtypes B*08 and DRB1*03 were at higher risk of developing DIRs after filler injections, associated with a predisposition to autoimmune and/or granulomatous disease.66 Abnormalities in acute phase reactants, C-reactive protein, fibrinogen, and low complement levels may also play a role through autoimmune mechanisms.42,67 In addition, HA begins to degrade 3-5 months after injection, which may result in breakdown products and body's exposure to unknown antigens that can also stimulate the immune system when paired with additional triggers.42,68 We postulate a similar mechanism of pathological progression leading to skin infection after receiving other fillers, as there are similar inflammatory granulomatous manifestations.Some studies have shown that injection of components of the mRNA vaccine or spiking proteins produced by the mRNA payload introduces several new potential sensitizers or adjuvants to the immune system, any of which could lead to DIRs of filler materials.13,[69][70][71][72][73] DIRs may represent a peak in the population antibody response to new coronavirus, although there are no available data to confirm at present.74 Certainly, as case reports and studies on the pathophysiology of DIRs increase, the relationship between vaccination against COVID-19 pneumonia and DIRs to fillers will become clearer.
With regard to surgical prosthetic implants, local and systemic reactions such as capsule contracture also belongs to DIRs.The safety of silicone breast implants has been under debate since their invention.A recent study showed that patients with 27 HLA DR and HLA DQ positive haplotypes were overrepresented among women with systemic symptoms after silicone breast implant surgery. 17,75 susceptible individuals, disturbances in the modulation of key cytokines may be responsible for the persistence of the inflammatory reaction, which locally leads to capsular contracture and may systemically trigger autoimmune disease. 76The abundance of immunologically active cells around the capsule is very similar to the DIRs caused by injectable fillers.

| Diagnosis and treatment
DIRs include erythema, granuloma, swelling, edema, etc. 47,48 They can occur anywhere on the body surface, mainly dermal and subcutaneous. 77When the nodules are small in size (less than 0.5 cm) and there is no pain or just mild pain, conservative treatment with close observation is recommended. 78If the presence of a fluctuating mass is noted, imaging tests such as ultrasound should be used to observe the cyst and needle aspiration should be performed, followed by a complete bacteriological examination to look for aerobe, anaerobic bacteria, mycobacterium or fungus that may cause the disease.Systemic antibiotic therapy can be administered while waiting for results.In the experience of experts, bacterial cultures are usually negative.Hyaluronidase injections must be given under antibiotic cover.Biopsies can also be performed if it does not get cured after treatment.Blood tests showing inflammatory markers such as C-reactive protein can also be helpful for diagnosis. 53,79,80ere is no clear consensus on the management of different reactions and there lacks of evidence to guide treatment.Except conservative treatment, appropriate pharmacological treatment may accelerate the relief of symptoms, of which antihistamines are of limited value. 77,81Non-inflammatory nodules resulting from HA injections can be dissolved with hyaluronidase (HYAL). 82In more severe cases of DIRs, it is controversial which intervention to perform first.Since the DIRs are widely considered to be immunologic, the use of corticosteroids is a reasonable first-line treatment, and treating with antibiotics and hyaluronidase may also be considered. 74The most common treatment is a 5-to 7-day course of oral prednisone (20-40 mg daily). 68Steroids can be used to treat immune nodules, but systemic steroid therapy may also interfere with the immune response needed to fight infection or develop immunity.Other adjuvant therapies include topical NSAIDs, alone or in combination with 5-FU.
Hyaluronidase (on average 10 units per 0.1 mL of HA), oral clarithromycin (1-to 4-week course), and intralesional triamcinolone acetonide (ILK).The typical dose for ILK is 5-10 mg/ml.This is injected into the nodules at 2-to 4-week intervals as needed with regular assessment for atrophy. 68r fluctuating masses due to infection, surgical treatment such as incision and drainage should be used in conjunction with antibiotic therapy. 47Munavalli et al. proposed an oral angiotensinconverting enzyme inhibitor (ACE-I) for the treatment of DIRs after vaccination. 13,83tients with breast implants suddenly presenting with unilateral or bilateral breast swelling and discomfort should be thoroughly interviewed regarding recent vaccination and infection of COVID-19 pneumonia.In the cases we counted, seroma, swelling, and pain were the most common symptoms.If patients with breast prosthesis develop seroma after COVID-19 vaccination, we can make a differential diagnosis of other possible diseases such as breast implant-associated anaplastic large cell lymphoma (ALCL). 84The available cases showed that symptoms were not significantly correlated with the timing of implant surgery and the texture of implants.The implant should be removed as soon as possible in cases where conservative treatment has failed.

| Prevention and recommendations
As the number of reports of adverse reactions increase, patients may be hesitant to accept the vaccine if they see adverse reactions. 42At this critical juncture for public health in our society, the benefits of vaccination in preventing potentially fatal diseases far outweigh the deficiencies of vaccines, physicians should strive to encourage vaccination, dispel misconceptions, and help patients complete the vaccination process on time.Moreover, a complete past and personal history of the patient should be obtained and the patient should be given full information before cosmetic treatment. 85Patients who have received prosthetic implants or filler injections may choose a vaccine with a relatively low incidence of adverse reactions and be closely monitored for any immune reactions associated with the implant after receiving the vaccine.If adverse reactions occur after the first dose of the vaccine, we can take preventive measures such as pretreatment with antihistamines or corticosteroids before the patient receives the second or third dose. 86As for the general people, Rice et al. 42 recommends they need to wait at least 4-8 weeks after vaccination before receiving cosmetic implants because it takes 3 weeks for the immune response to peak.The Waiting time interval may be longer for those at risk for autoimmune disease, those taking chemotherapy or immunomodulatory drugs, and those with a history of allergy to implants to minimize the risk of reactions.Filler dilution is another feasible approach, and there is evidence that diluting polylactic acid and hyaluronic acid with saline, sterile water, or lidocaine reduces the risk of adverse events and DIRs. 87According to the results of our study, there was a large time span ranging from 15 days to 14 years, so we cannot make reasonable recommendations about the time interval.
When dealing with recurrent DIRs, some experts recommend treating in the same way as the initial event.However, others indicate that they would make some adjustments such as increasing the hyaluronidase dosage or using a steroid/5-FU/lidocaine mixture. 7,47r future cosmetic injection or implant surgery, we can choose different fillers, implant materials, or fat grafts as an alternative treatment.

| LI M ITATI O N S A N D E X PEC TATI O N S
Although temporal relationships and experience with other vaccines may suggest causality, accurate estimation of the risk and prevalence of vaccine-implant cross-reactivity are unknown.Therefore, it is very challenging to confirm that adverse reactions to implants are caused by the COVID-19 vaccines and not by coincidence.Most of the current studies are case reports, subject to publication bias, which do not allow the drawing of general conclusions with high levels of evidence, including estimating the incidence of adverse reactions of different implant materials.Many cases of chronic dermatologic episodes are not published because interest in common and non-serious reactions is waning.The incidence of DIRs was not
5 years (34-76 years); three patients had bilateral breast discomfort, three patients had unilateral breast discomfort, and the rest of the patients were unknown; the texture of the breast implants was smooth in four patients, textured in three patients, and unknown in the rest; the time interval between vaccination and implant surgery ranged from 2 months to 12 years; 50% (six) patients received Pfizer vaccines (three patients with 1 dose, three patients with 2 doses), and 16.7% (two) patients received 1 dose of AstraZeneca vaccines, and the rest patients unknown.The time interval between vaccination and the onset of adverse reactions ranged from 2 to 19 days, and the symptoms were mainly pain, swelling, lymphadenopathy, capsular contracture, and fever.Eight patients improved after surgical removal of the prosthesis, and the rest recovered after conservative treatments such as NASID and cryotherapy.

There was 95 .
6% (65/68) patients showing delayed inflammatory reactions (DIRs) more than 24 h after COVID-19 vaccination.The most common were adverse reactions to HA after vaccination with Pfizer (44.9%, 22/49) or Moderna (38.8%, 19/49) COVID-19 pneumonia vaccines.Among the cases of surgical prostheses, there were also more patients (50%, 6/12) who had adverse reactions after the Pfizer vaccination.Notably, only in the two cases of botulinum toxin injection, the vaccine was given before the botulinum toxin.All other patients were treated with fillers or surgery prior to vaccination and subsequently developed adverse reactions.
and they are immunoglobulin Emediated.While delayed or type IV hypersensitivity reactions occur TA B L E 2 Cases of surgical prosthetic implants.to months caused by T-lymphocytes.43,44Our results showed that adverse reactions to HA after vaccination with Pfizer or Moderna COVID-19 pneumonia vaccines were most common.It is interesting to note that in one of these cases, there was no reaction to the first two doses of the AstraZeneca vaccine but presented adverse reactions after the third dose was changed to the Pfizer vaccine.And in another case, the situation was similar when the first two doses were Sputnik vaccine, with the third dose changing to Moderna vaccine.The mechanism may be the first two doses activated the immune system in these two cases.It has been suggested that DIRs may be associated with viral infections, dental procedures, and vaccinations.13,45In addition, there was a significant association between the type of vaccines and the occurrence of adverse reactions: A retrospective cross-sectional study evaluated the incidence of adverse reactions in patients who received Pfizer mRNA vaccine, AstraZeneca DNA vaccine, or inactivated COVID-19 vaccine in Iraq and found that out of 843 respondents, only 215 (25.5%) individuals reported not suffering any adverse reactions.46Systemic reactions and skin reactions including erythema and rash were more frequent in subjects who received the AstraZeneca or Pfizer vaccines (84.5% and 75.3%, respectively) (p< 0.05).Therefore, immunogenic triggering due to vaccination may play a role in the development of local inflammatory responses at the filler site, resulting various of adverse reactions.

F I G U R E 1 Screening flow chart. TA B L E 1 Cases of injectable filler implants. Citation Case Age (years) Filler/Texture Time since implant surgery Vaccine (dose) Onset of symptoms (after vaccination) (days) Reaction side Symptoms Treatment Previous allergy or relapse
table we can find that 87.5% (49/56) of the patients were injected with HA (hyaluronic acid), and other injectable fillers that have been reported to cause adverse reactions so far include calcium hydroxyapatite, PMMA (methyl methacrylate), liquid silicone, PCL