key: cord-1029091-34rrg9ja authors: Luciena, Cegatto Martins Ortigosa; Lenzoni, Fabiano; Suárez, Maria Victória; Duarte, Artur Antônio; Prestes-Carneiro, Luiz Euribel title: Hypersensitivity reaction to hyaluronic acid dermal filler after vaccination against COVID-19: A series of cases in São Paulo, Brazil date: 2022-01-19 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2022.01.024 sha: 29e44aee600b656c2f279e2266067bbcaadec6f7 doc_id: 1029091 cord_uid: 34rrg9ja Brazil ranked second in the world for the number of aesthetic procedures in 2019. Five case reports of delayed hypersensitivity reaction to hyaluronic acid dermal filler against COVID-19 vaccines are presented. Additional vaccination for new variants, including omicron, will be necessary, therefore aesthetic professionals should be aware of this possibility and advise patients accordingly. Introduction Brazil ranks third for the number of patients infected with SARS-CoV-2 coronavirus and second for the mortality rate worldwide, however, vaccination is changing the scenario quickly. In São Paulo, in December 15, 2021, 78.0% of the population was fully vaccinated (Vacinômetro Governo do Estado de São Paulo). According to the International Society for Aesthetic Surgery (ISAPS), in 2019 Brazil ranked second for the number of aesthetic procedures (Global Survey 2019). Dermal fillers using hyaluronic acid (HA) have become popular for enhancing facial features in recent years (Batista, 2017) . It has been reported that after COVID-19 vaccination, 3 patients may present a delayed hypersensitivity reaction (DHR) in the area where HA was previously applied Savva et al., 2021) ). We report five cases of DHR to HA dermal filler after administration of the Pfizer and AstraZeneca vaccines against COVID-19. A healthy 35-year-old woman had a medical history of HA fillers. About 7.0/8.0 mL of HA (Restylane Classic and Restylane Lyft, Galderma) was applied to her lips, nasojugal furrow, malar, and chin regions, at three different times. The first application took part in 2016 in these four indicated areas, and the last application occurred in April 2020 only in the lips and nasojugal furrow regions. Persistent intermittent delayed swelling occurred and she was followed up by her dermatologist. On August 6, 2021, she received her first AstraZeneca COVID-19 vaccine. Twenty-four hours later, she presented induration and edema in her lips and chin, where HA was previously applied, and was diagnosed with DHR to HA dermal filler after vaccination. She was prescribed with prednisone 20 mg twice a day for 7 days. After 2 days of steroids use, the edema in the lips and chin region improved, but they appeared in the other regions of HA application: malar region and nasojugal sulcus. For this reason, prednisone was maintained for a further 7 days, with progressive reduction until 14 days of treatment. Although an improvement was obtained, she still remained with mild lip edema. Cushing syndrome developed and the corticosteroid was presented with DHR to HA dermal filler, characterized by pain and mild edema in the lips where HA was applied. She was prescribed loratadine 10 mg daily for 2 days with complete resolution in 72 hours and no relapse ( Figure 1C ). In September 2021, 2.0 mL of HA (Restylane lift, Galderma) was applied to the mandibula (jaw angle) and chin and 1.0 mL (Vital Light, Galderma) to the lips of a healthy 56-year-old women. Forty-eight hours after receiving the COVID-19Pfizer-BioNTech vaccine, she presented with DHR characterized by induration and edema in the mandible and chin where HA was applied. She was treated with oral prednisone 20 mg twice a day for 3 days with complete resolution (Figure 1, D1) . She developed herpes simplex virus in her lips immediately after vaccination. She was treated with valaciclovir 500 mg twice a day for 5 days and oral prednisone 20 mg twice a day for 3 days with complete resolution (Figure 1, D2 ). In May 2020, 2.0 ml of HA (Revanesse® Versa) was applied to the nasolabial folds and lips of a healthy 43-year-old woman without any complications. In May 2021, the procedure was repeated only on her lips with 1.0 mL of HA (Revanesse® Versa). Fifteen days later, she received the second dose of the COVID-19 AstraZeneca vaccine. One week later she presented with edema, erythema, increase in the temperature of her lips, fever, the sensation of fatigue, and purpuric lesions of the extremities. She was treated with ibuprofen 40 mg/day and prednisone 40 mg/day, and her symptoms reduced after 1 week. Prednisone was progressively decreased and stopped after 3 weeks ( Figure 1E ). All these case reports showed a hypersensitivity reaction to HA dermal filler more than 24 hours after vaccination for COVID-19, characterized by a delayed or type IV hypersensitivity reaction, a cell-mediated hypersensitivity triggered by T lymphocytes (Turkmani et al., 2019; ; Rowland-Warmann 2021; Savva et al., 2021) ). However, several published reports suggested that other causes than COVID-19 vaccines may be involved in the etiology of DHR to HA dermal filler such as viral infections and trauma, filler volume, repeat treatments, intramuscular implantation, and the different properties of HA fillers (Turkmani et al., 2019) . In 2020, 21.0% of the entire population of Brazil lived in São Paulo state, estimated to be 213,930,425 inhabitants according to the Brazilian Census (Instituto Brasileiro de Geografia e Estatística). Since 1973, the vaccine culture in Brazil has been string and at the end of 2021, Brazil was one of the most vaccinated countries for COVID-19. In the country, more than 51% of the population is women and 57.7% are more than 30 years of age and are potential clients for aesthetic procedure. Noteworthy that nowadays there is a increasing demand for men for aesthetic procedures too. In 2019, HA was applied in 398,830 procedures in the country (Global Survey, 2019). It is still not known which patients will progress to DHR after vaccination against COVID-19, how long the application of HA is most likely to produce a reaction as well as the wait time after COVID-19 vaccine for HA dermal filler. Treatment with HA in our case reports varied from weeks to months before vaccination, and although most reactions resolved after a few days some are recalcitrant with periods of improvement, worsening, and recurrence months after the application of the vaccine. Treatment can be expectant, but in most cases, treatment involves antihistamines, oral corticoids, and application of hyaluronidase or lisinopril (Munavalli et al., 2021(a,b) ). Corticosteroids down-regulates the immune response to vaccines and produce an array of side effects. In our case reports, case 1 evolved with Cushing Syndrome and case 4 evolved with herpes simplex virus after treatment with prednisone. However, case 2 was treated with lisinopril, a new therapeutic tool to treat DHR to dermal HA fillers following COVID-19 vaccination. Lisinopril is an oral angiotensin-converting enzyme inhibitor (ACE-I), which decreased the cutaneous HA filler-related inflammatory reaction and edema in patients vaccinated to COVID-19. ACE-I has also been previously reported to have therapeutic value in the treatment of other cutaneous disorders, and different mechanisms are proposed to explain the anti-inflammatory 7 properties of ACE-I. Furthermore, it was suggested that lisinopril can be used not only to treat DHR but also to minimize de risk of DHR after the second dose of the COVID-19 vaccine if the reaction occurred previously (Munavalli et al. 2021 (b) )) Waves of new variants are now appearing; the omicron variant carries about 50 mutations not seen in combination before (World Health Organization). Extra protection against the virus will likely require new vaccine formulations, raising questions on whether booster doses will need to continue indefinitely, increasing the possibility of DHR in patients previously treated with HA. We suggest that countrywide, a large number of women vaccinated for COVID-19 who had previously had HA applied experienced DHR, which has gone unreported. In Brazil, adverse event following immunization (AEFI) of COVID-19 surveillance actions are aimed at moderate and severe events and must be immediately notified in an online available file "Post-vaccination adverse event notification/investigation form" to the Ministry of Health Surveillance Department, Communicable Disease Surveillance Department, General Coordination of the National Immunization Program. The case will be addressed to the Epidemiological Surveillance Center (GVE) of São Paulo state, investigated and clarified so as not to jeopardize the immunization program and the epidemiological safety of the entire population. It is noteworthy that from the five cases reported only one patient was notified to GVE. As vaccination for COVID-19 rolls out to members of all eligible adult demographics and DHR to dermal fillers could become among the most common AEFI, doctors should obtain informed consent from the patients that a hypersensitivity reaction might take place after HA fillers and COVID-19 vaccination. State of Plastic Surgery in Brazil International Survey on Aesthetic/Cosmetic Procedures Performed in 2019. Number of worldwide non-surgical procedures by country Instituto Brasileiro de Geografia e Estatistica (IBGE) COVID-19/SARS-CoV-2 virus Spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment Oral angiotensinconverting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation Hypersensitivity reaction to HyaluronicAcid Dermal filler following novel Corona vírus infection -a case report Hypersensitivity reaction to hyaluronic acid dermal filler after the Pfizer vaccination against SARS-CoV-2 Delayed hypersensitivity reaction to hyaluronic acid dermal filler following influenza-like illness World Health Organization. Classification of Omicron (B.1.1.529): SARS-CoV-2 529)-sars-cov-2-variant-of-concern We conclude that, mainly in Brazil, our report is important so that aesthetic professionals are aware of this event, notify health care authorities of this possible reaction, and advise patients of this possibility. The authors declare no funding sources for this publication. The patients gave their written consent for their images and clinical details to be used for this publication. Ethical approval was not sought for the current manuscript because it was not required.