Received: 22 February 2022 | Revised: 20 April 2022 | Accepted: 24 May 2022 DOI: 10.1111/jocd.15117 ORIGINAL ARTICLE Inflammatory immune-­mediated adverse reactions induced by COVID-­19 vaccines in previously injected patients with soft tissue fillers: A case series of 20 patients Jaume Alijotas-­Reig MD, PhD1,2 | Victor García-­GImenez MD3,4 | Peter J. Velthuis MD, PhD5 | Frank B. Niessen MD, PhD6 | Tom S. Decates MD, PhD5 1 Systemic Autoimmune Disease Unit, Service of Internal Medicine, Vall Abstract d’Hebron University Hospital, Barcelona, Background: Adverse events (AE) after COVID-­19 vaccines, particularly, but not Spain 2 Department of Medicine, Faculty of solely, with those messenger RNA (mRNA)-­based vaccines, have rarely been reported Medicine, Universitat Autònoma de in patients previously treated with dermal fillers (DF). Barcelona, Barcelona, Spain 3 Objective: To evaluate the morphology, clinical characteristics, the timing of presen- Europe Medical Centre, Barcelona, Spain 4 tation, and outcomes of inflammatory AE appeared in patients injected with DF, after Sociedad Española de Medicina y Cirugía Cosmética, Barcelona, Spain anti-­COVID-­19 vaccination. 5 Department of Dermatology, Erasmus Methods: Descriptive study of a case series of 20 consecutive patients collected after Medical Center, Rotterdam, The Netherlands the occurrence of AE in previously filled areas post COVID-­19 vaccination. 6 Department of Plastic Surgery, Results: From January 2021 to July 2021, we analyzed 20 AE reactions triggered by Amsterdam UMC, Vrije Universiteit, COVID-­19 vaccines in the previously mentioned cohort. They were vaccinated with Amsterdam, the Netherlands Pfizer/Biontech (11; 55%), Moderna (5; 25%), Astra-­Zeneca (3; 15%), and Sputnik (1; Correspondence 5%). The most common manifestations were oedema/swelling, angioedema, ery- Jaume Alijotas-­Reig, Systemic Autoimmune Diseases Unit, Service thema, skin induration, and granuloma. Less common reactions included myalgia of Internal Medicine, Vall d'Hebron and lymphadenopathy. In 13/20 (65%) cases, the AE appeared after the first dose of University Hospital, Barcelona, Spain. Email: jalijotas@vhebron.net vaccine. These inflammatory AE appeared more rapidly after the second dose than after the first one. In 13/20 (65%) cases, the symptomatology subsided with anti-­ Funding information None inflammatory/antihistaminic drugs, while spontaneously in 3/20 (15%). The manifes- tations are ongoing.in the remaining four cases (20%). Conclusion: Although probably rare, both RNA-­based and adenovirus-­based anti-­ COVID-­19 vaccines can cause inflammatory bouts in patients previously treated with DF. In these cases, caution should be paid on subsequent vaccine doses, considering a tailored risk/benefit for any case before next vaccination. KEYWORDS adverse reactions, COVID-­19, inflammation, SARS-­CoV-­2, soft tissue fillers This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC. J Cosmet Dermatol. 2022;00:1–7.  wileyonlinelibrary.com/journal/jocd | 1 2 | Alijotas-­Reig et al. 1 | I NTRO D U C TI O N All patients gave their informed consent that was registered in the medical history. In addition, special informed consent was signed Interest is growing worldwide in medical treatments with der- in patients (five) when images—­photographs—­were used. IRB is not mal fillers (DF) to prevent or reduce skin aging, both on medical required in this study because only clinical data, and no experimen- grounds and for aesthetic and cosmetic purposes.1 Initially, reports tal samples were used. Finally, all data used were anonymized. 2 on adverse events (AE) were lacking ; however, severe late-­onset inflammatory—­mainly local/regional but also systemic—­reactions are also being reported in 1%–­5% of cases.3–­5 To trigger these immune 3 | R E S U LT S reactions, DF may act as a T-­cell-­directed antigen, as a superantigen or act as an adjuvant. An immunological adjuvant is a substance that All cases were female and all but one were Caucasian. The mean enhances the antigen-­specific immune response, preferably without age was 45.30 years (range: 21–­71 years). Four cases 8, 10, 18, and triggering one on its own.6 Vaccines can also act as adjuvants, and 20 have allergic history, and cases 18 and 19 had been diagnosed of inflammatory local or systemic complaints have been reported.7 As Hashimoto's disease. of this article submission, the number of COVID-­19 disease contin- The four previously mentioned anti-­COVID-­19 vaccines were ues to rise worldwide. Angiotensin-­converting enzyme 2 (ACE2) used, being the BNT162b2 (Comirnaty®, Pfizer) the most frequent is a major target for SARS-­CoV-­2 and essential for virus anchoring in 11/20 cases (55%) followed by mRNA-­1273 (Moderna TX, Inc.) and intracellular invasion.8 ACE2 is ubiquitously expressed in all tis- 5/20 (25%), ChAdOx1 nCoV-­19 (Astra-­Zeneca) 3/20 (15%) and 1/20 sues of the human body. Interestingly, the skin is moderately high in (5.%) (Sputnik V, Gamaleya Center). expression of ACE2.9 ACE2 may act as an inflammatory regulator, All 20 cases were previously injected with DF, 19 in facial area and inhibiting proinflammatory cascade via angiotensins II-­VII. As such, 1 in both the facial and buttocks area plus also having breast implants. blockade of dermal ACE could provoke a proinflammatory pathway DF used in patients of this cohort were: hyaluronic acid (HA), fluid sil- 10 activation causing local inflammation. With the pandemic's intrin- icone (FS), polymethyl methacrylate (PMMA) microspheres and with sic need to vaccinate people worldwide, the possibility of having poly-­alkyl-­imide (PAI). In more detail, the DF used were as follows: people filled with DF and also vaccinated will rise. Thus, a plausible 14/20 with HA, 2/20 HA + SMG, 1/20 HA and methacrylate, 1/20 hypothesis is that the COVID-­19 vaccine could target the possibility cases with PMMA, 1/20 with FS and 1/20 with poly-­alkyl-­imide (PAI). of having AE to fillers. The FDA brief on the Moderna® vaccine al- (Table 1). Three cases (15%) had experienced inflammatory late-­onset ready reported reactions to prior DF after vaccination.11 Pfizer also AE related to DF before COVID-­19 vaccination. Two of them were on launched a similar preliminary warming, later followed by other com- low-­dose prednisone plus tacrolimus, and one was taken full-­dose of panies manufacturing COVID-­19 vaccines.12 Recently, Munavalli allopurinol plus prednisone. All 20 cases experienced inflammatory et al13 reported the first 4 patients previously filled who developed signs in previously implanted areas, having only two patients pre- cutaneous adverse reactions after COVID-­19 vaccination. sented with systemic but transitory symptoms. Herein, we report a series of 20 cases with prior facial/breast In 13/20 (65%) cases, the AE appeared after the first dose of filler injections complicated with inflammatory adverse reactions vaccine and in 7/20 (35%) after second one. The mean lapse time be- after COVID-­19 vaccination. tween the vaccine injection and the occurrence of the inflammatory signs in previous filled areas was 10 days (1–­56 days). Interestingly, AE possibly triggered by COVID-­19 vaccine in previous filled areas 2 | M ATE R I A L A N D M E TH O DS presented more rapidly after the second dose than after the first one (mean: <4 days vs. > 11 days). Three patients received no treatment A case series of 20 patients were recruited from Barcelona (Spain) and clinical signs subsided. Fourteen were treated with antihista- and Amsterdam (the Netherlands). All had previously injected with mines in possible combination with non-­steroidal anti-­inflammatory DF, and one of them has breast prosthesis. drugs and prednisone, or both, with good responses in all but one of An oriented survey was delivered to the patients. The major them. An increase in dosage was needed in the three cases already questions were as follows: age, ethnicity, smoking habit, medical treated with prednisone plus tacrolimus or allopurinol. Clinical im- history, previous autoimmune disorders, COVID-­19 vaccine type, provement, but no full remission with continuous local manifesta- previous dermal filler/s, area/s injected, previous AE, lapse time, tions, was observed in these three cases (Table 1A and B). Finally, post-­vaccine AE, lapse time between vaccination and AE; main AE: photography of 5 cases can be seen in attached Figures 1 and 2. edema, skin induration, granuloma, lymphadenopathy, panniculitis, fever, systemic complaints—­malaise, feverish, arthralgia, myalgia, skin rash—­treatment response, relapses, and biopsy. 4 | DISCUSSION All patients were vaccinated with one of the following anti-­ COVID-­19 vaccines: BNT162b2 (Comirnaty®, Pfizer); mRNA-­1273 We report a cohort of consecutive 20 patients that experienced in- (Moderna TX, Inc.); ChAdOx1 nCoV-­19 (Astra-­Zeneca) and (Sputnik flammatory bouts in the previously filled areas with DF after receiv- V, Gamaleya Center). ing anti-­SARS-­CoV-­2 vaccine. In patients treated with biomaterials TA B L E 1 Type of vaccines, clinical findings, treatment response, and follow-­up of these 20 patients A Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Alijotas-­Reig et al. Vaccine Pfizer x1 Pfizer x1 Pfizer x1 Pfizer x2 Sputnik x2 Pfizer x1 Pfizer x2 A-­Z x1 Moderna x1 A-­Z x1 Previous filler HA HA FS HA HA Methacryl HA HA PAI HA a Area filled Facial Facial Breast Facial Lips Facial Facial Facial Facial Lips Previous AE No No No No No Yes No No No No Post-­vaccine AE lapse time (days) 7 8 14 10 8 10 1 35 7 14 Edema Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Induration Yes Yes Yes Yes Yes Yes Yes No No No Granuloma Yes Yes No Yes Yes Yes No No No No Lymphadenopathy No No Yes No No No No No No No Fever Yes No ND No No No No No No No Systemic complaints No No No Myalgia No No Arthralgia No No No Treatment response Yes Yes Yes No No Partial Yes Yes Yes Yes Type of treatment Prednisone Anti-­H1 Prednisone NSAD Prednisone ↑Tacrolimus Prednisone NSAD Anti-­H1 Anti-­H1 Anti-­H1 Anti-­H1 Anti-­H1 Anti-­H1 ↑Prednisone Anti-­H1 Anti-­H1 Relapse No No No Yes Yes No No No No No B Case 11 Case 12 Case 13 Case 14 Case 15 Case 16 Case 17 Case 18 Case 19 Case 20 Vaccine A-­Z x1 Pfizer x1 Pfizer x1 Moderna Pfizer x1 Moderna Moderna Moderna x2 Pfizer x2 Pfizer x2 x2 x1 x1 Previous filler HA /FS HA HA HA HA HA HA HA HA/Methacryl HA/FS Area filled NSLF Lips Facial Lips Lips Facial Lips Cheeks Facial Lips Previous AE Yes No No No No No No No Yes No Post-­vaccine AE lapse time (days) 56 3 4 3 3 1 2 5 7 14 Edema Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Induration No No Yes No No No No No Yes Yes Granuloma Yes No No No No No No No Yes Yes Lymphadenopathy Yes No No No No No No No No No Fever No No No No No No No No No No Systemic complaints No No No No No No No No No No Treatment response No Yes ND Yes Yes ND ND Yes No Not fully Type of treatment ↑Tacrolimus Prednisone -­-­ Anit-­H1 Prednisone -­-­ Anti-­H1 Prednisone Allopurinol NSAD ↑Prednisone Erythromycin Anti-­H1 Prednisone Anti-­H1 Relapse Yes No No No ND No No No Yes No Abbreviations: FS, fluid silicone; HA, Hyaluronic acid; Methacryl, polymethyl-­Methacrylate; ND, not done; NP, not performed; NSLF, nasolabial folds; Predni, prednisone. a | It was her last prostheses. The patient had been previously filled in facial and buttocks areas, with HA, polymethyl methacrylate and FS. 3 4 | Alijotas-­Reig et al. F I G U R E 1 Inflammatory, immune-­mediated reactions in previously filled patients after receiving an anti-­COVID-­19 vaccine. (A) A 59-­year-­old woman, with history of heavy and recurrent facial immune reaction related to previously polymethyl methacrylate injection, treated with low-­t acrolimus dose plus low-­prednisone dose. 10 days after first shot of Pfizer–­Biontech vaccine, she presented with heavy facial oedema that initially provoke a total eye closure, nasolabial folds induration and inflammatory nodules in supraciliary areas and the upper lip. (Case 6). (B) Palm and digital red-­purplish erythema of left hand of patient 1A. Right hand had the same kind of lesion. This skin changes appear with relapses. (Case 6). (C) A 21-­year-­old healthy woman, treated with hyaluronic acid on lips 5 months before COVID-­19 vaccination, presented with grave oedema in the prior injected areas a few days after the second dose of Moderna. She was put on prednisone, and the lip swelling disappeared in a few days with no relapses until now. (Case 17). (D) A 50-­year-­old woman, with history of heavy and recurrent facial and buttocks inflammatory immune reaction related to previously hyaluronic acid, polymethyl-­methacrylate and fluid silicone injections. She was asymptomatic taken hydroxychloroquine, antihistamines, and allopurinol when she was vaccinated. 14 days after the first dose of Pfizer–­Biontech vaccine, she presented a severe inflammatory reaction in face and breasts with associated axillary lymphadenopathy. Prednisone was added, and a rapid improvement was achieved or DF, infections and vaccines may act as adjuvants and eventually increases immunological reactions of the body, and especially, per- 7 provoking activation of the immune system. Along these lines, in manent fillers remain in the immune memory of T-­cells and mac- 2008, Alijotas-­Reig J et al5,14,15 already reported a series of cases rophages for decades, causing a foreign-­body reaction in certain of human adjuvant-­like disease induced or triggered by synthetic patients. This looked like this in our patients. They were effectively DF. Vaccines can also act as adjuvants, and inflammatory local or treated with such and such immunosuppressive drugs. Thus, the 7 systemic complaints have been reported. Acute or delayed AE in most probably if not true trigger for these inflammatory AE was areas previously filled with DF appeared after different vaccination COVID-­19 vaccination. Some of these AE appeared few days to have also been reported.11–­13,16,17 The most filled material in these 2 weeks after vaccination, but in two cases the lapse-­time was reported cases was HA but also others like calcium-­hydroxylapatite longer, up to 56 days. Other previously commented small series or acrylamides, like our cases, reflecting that HA is the most used reported similar data.13,16–­18 The proper explanation for these dif- filler from far. Our patients showed no clinical nor microbiologi- ferences is elusive to us. The genetic background, previous sensi- cal evidence of acute SARS-­CoV-­2 infection. Thus, a vaccination tization, the role played for resident immune cells, and the degree Alijotas-­Reig et al. | 5 F I G U R E 2 Inflammatory, immune-­mediated reactions in previously filled patients after receiving an anti-­COVID-­19 vaccine. (A) A 52-­year-­old healthy women with HA in zygomatic areas, cheekbones, and lips injected 30 and 52 days before the first and second doses of Sputnik vaccine. Bilateral oedema and painful inflammatory nodules appeared in zygomatic areas, cheekbones, and nose 2 weeks later. She was put on local cold packs and non-­steroidal anti-­inflammatory drugs, but clinical complaints did not remit (case 5). (B,C) A 48-­year-­old otherwise healthy women, with history of HA injections in malar areas. She was injected with two doses of Pfizer–­Biontech vaccine. 10 days after receiving the second shot, prominent inflammatory signs in the face appeared with big nodule on malar left side. She was put on non-­ steroidal anti-­inflammatory drug plus antihistamines with a slow improvement over weeks (case 4) of immune stimulation provoked by the vaccine could explain it. TA B L E 2 Preliminary recommendations on patients filled, Three patients were already on treatment with prednisone, tacroli- inflammatory adverse reactions and COVID-­19 vaccines mus, and allopurinol, because of chronic and recurrent AE before Q1: The patient has already been treated with dermal fillers/ vaccination. In addition, in these 3 cases, the protective role of prosthesis months or years before and had no known problems anti-­COVID-­19 vaccine is doubtful but sufficient to trigger inflam- and wants to be vaccinated: A1: The patient can be vaccinate. matory bouts. It is challenging that the patient with breast involve- Q2: The patient has been fully vaccinated without notifying any ment also had previously and repeatedly been filled in other areas, problem and requests to be treated with fillers/prosthesis: but only suffered market inflammatory signs in breast, and slight A2: The patient can be filled I implanted. signs in the face and buttocks. Q3: The patient has been vaccinated, has been treated with dermal fillers/prosthesis with no complaints and wants to be vaccinated Why have only a few cases of all vaccinated and filled people (next doses): finally develop these AE? Probably by the similar ground that only A3: The patient can receive additional doses. 1%–­4% of filled cases will develop an intermediate or delayed in- Q4: The patient has already been treated with dermal fillers/ flammatory, immune-­mediated AE: the genetic background. In prosthesis, presented some type of delayed inflammatory reaction or adverse effect related to filler and wants to be these manner, our team19 recently reported that the HLA-­B*08 and vaccinated for the first time: DRB1*03 haplotype is related to high risk to develop subacute or A4: Currently, there is no sufficient data to answer this question. It must late-­onset inflammatory, immune reaction to DF. In some instances, individualize the counseling. Probably the patient can receive vaccine. suspected allergic reactions to polyethylene glycol, a common ex- Q5: The patient was treated with dermal filler/prosthesis weeks, months or years before and had no known problems. After the cipient in vaccines, should be considered in certain cases). However, first or second dose of COVID-­19 vaccine, adverse reactions of the relationship between polyethylene glycol and inflammatory inflammatory type appear in the filled/implanted areas: bouts in prior filled areas has not been previously reported. In 16 of A5: We suggest avoid or delay the next dose of vaccine. According our cohort patients, the clinical complaints abated spontaneously to the clinical follow-­up, comorbidities and personal risk, re-­ evaluate and reconsider this recommendation. in 3 and in 13 after treatment. Interestingly, three cases on treat- ment before vaccination keep on treatment and are still symptom- Note: These recommendations have the endorsement of the Sociedad atic. Patient number 20 presents still local clinical manifestations. Española de Medicina y Cirugia Cosmética. Abbreviations: A, answer; Q, Question. Although Gotkin et al20 stated that the relationship between DF 6 | Alijotas-­Reig et al. and AE in filled patients remains unclear, we should be mindful ORCID that causality could be present. Special attention will have to be Jaume Alijotas-­Reig https://orcid.org/0000-0002-9212-3619 paid in those cases with previous inflammatory AE related to DF. Unfortunately, the accurate estimation of risk and prevalence of REFERENCES vaccine-­f iller cross reactivity is unknown. More data on this topic 1. American Sociey for Dermatologic Surgery. ASDS members per- are warranted. Meanwhile, we cannot assemble a solid recom- formed nearly 14 milluions treatments in 2019. 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