Novel mRNA technology used for SARS-CoV-2 vaccine development on such a large scale simultaneously in many countries can be considered as the breakthrough in the history of medicine. Since our full understanding of clinical response to mRNA vaccines remains unknown, the following years will bring more publications on systemic and local effects of the vaccines against Covid-19. Data available so far from the published and completed COVID vaccine trials (mRNA vaccine by Pfizer Biotech, mRNA vaccine by Modern and the vaccine by AstraZeneca) included reporting of adverse events, in which cutaneous AEs were also noted. The Modern trials revealed three cases of hypersensitivity reactions to previously injected HA dermal fillers. Symptoms were described as moderate, the study participants received methylprednisolone and diphenhydramine and quickly recovered [1, 2].

Blumenthal et al [3] described the range of after-vaccine cutaneous reactions, which were present locally, at injection sites but also in distant locations. They confirmed hypersensitivity reaction which was explained as delayed-type or T-cell–mediated hypersensitivity. They were also able to perform skin-biopsy in one patient with a delayed local reaction. Skin-biopsy showed superficial lymphocytic infiltrates with some mastocytes and eosinophil’s in the area.

Delayed inflammatory reactions (DIR) associated with HA fillers within the skin have been reported in previous years with an incidence estimated at 0.8% [4]. The precise mechanism of action for the delayed reaction is unknown, it is most likely immune-mediated. It has not yet been explained why DIR affects only some filler-treated patients. Decades et al revealed that human haplotype B∗08 or DRB1∗03 could be responsible for considerable increase in chances of immune-mediated AEs. In the past DIR to fillers following infections (dental, active sinusitis or viral illness) have been also reported [5].

Patient presented here is a 63-year-old female. She received two HA fillers injections (2 mL) two years ago (2019) – 1 mL which was injected into the nasolabial folds area and the following one, 6 weeks later in the marionette lines region. 4 months after the last HA filler injection, the patient presented to the office with severe oedema in the perioral area and nodules that were not seen but could be easily palpated, especially from the side of the oral cavity. The symptoms appeared at the time of mild throat infection but as tenderness and oedema continued to increase she returned to the clinic asking for the treatment. The patient refused hyaluronidase injection so she was prescribed Clarithromycin 500 mg bid for 10 days and received single injection of Dexaven (Dexamethasoni phosphas, 8 mg). She called the clinic the following day informing that the oedema completely disappeared and the nodules were still palpated but much smaller than the other day. She didn’t present to the clinic for a check-up until recently. In the course of two years none aesthetic treatment was done, the patient hasn’t gone any severe illness, she has no allergies. She received the first Pfizer vaccine dose in June and didn’t have any side effects. A second vaccination was done in July, followed by mild arm pain. Twenty-four hours later, she noted a mild swelling in the nasolabial folds area, followed few hours later by swelling of the whole perioral area. She could palpate small nodules in the reported area. She started to take OTC antihistaminic drug but with no effect. After 48h from the onset of the symptoms she appeared at the clinic (Figure 1, 2). The patient refused oral corticosteroids because she was afraid to suppress the response to the vaccine. At this time her antihistaminic medication was stopped and lisinopril 5 mg once daily was prescribed. An improvement was noted within approx. 10 hours of lisinopril treatment. Over a period of 24 hours, swelling diminished (Figure 3,4). Lisinopril was stopped 2 days later.

Figure 1, 2: 1, 2 48h from the onset of the symptoms.

Figure 3, 4: 24h after initiating the treatment

Another patient is a healthy 56-year-old female who had midface correction with HA filler (2 mL) placed over 10 months ago in a different clinic. She reports no allergies, no inflammatory reaction following filler injection. She received the first Pfizer vaccine dose in July 2021 and reported only mild arm pain after the injection. A second dose of vaccine was done on 8/2/2021. 48 hours later, she noted swelling of the cheeks, redness, oedema and rash (Figure 5). Her primary care physician prescribed her Prednisone 40 mg for 7 days and referred her to our clinic. She started the treatment immediately and by 48 h she noted marked improvement bilaterally (Figure 6). Residual swelling resolved completely 72 hours after starting the medication so no further action was needed.

Figure 5: 48 h after second dose of vaccine.

Figure 6: 48h after initiating Prednisone 40 mg.

Modifications in filler manufacturing processes in recent years have led to receiving products that are more resistant to degradation processes. Nowadays HA dermal fillers can last even few years in some facial locations (tear trough, cheeks, lips) thus increasing a risk of DIR. An explanation for DIR to HA fillers in COVID-19 associated cases is not known as we do not know the mechanism behind this process. It is most likely blocking the angiotensin-2 converting enzyme receptors by the SARS-CoV-2 spike protein when the virus enters the cell. [6] It has been reported that ACE2 can be found in all tissues. Li et al. [7] showed that angiotensin-converting enzyme receptors are present in the skin in more extent when compared to other body organs. ACE2 is responsible for transformation of the angiotensin II into its anti-inflammatory metabolites. Angiotensin II is a strong proinflammatory agent and stimulates inflammatory reaction, being responsible for increasing levels of TNF-α, IL-6 and IL-8 and stimulating immune response in the affected area. When ACE2 is inactivated level of angiotensin II increases, stimulating inflammatory reaction [8].

In the cases presented here, inflammatory reaction occurred rapidly within 24 to 48 hours after the second dose of COVID-19 vaccination (Pfizer). This is very short time comparing to classic immune-mediated hypersensitivity to dermal fillers.

In the first case angiotensin-converting enzyme inhibitor (Lisinopril 5 mg) was used in order to decrease level of angiotensin II. Other authors [9] have described similar cases where they used lisinopril 5-10 mg daily to resolve the problem. Lisinopril – the ACE-I blocks the production of angiotensin II. It has a quick onset of action (the effects were seen within hours after administration). Additionally, it can also increase sodium level and water outflow which helps to cease swelling. This method of treating hypersensitivity to HA filler symptoms seems to be very effective and safe comparing to immunosuppressive mode of action of oral corticosteroids but needs further evaluation.

In the second case presented here the inflammatory reaction was suppressed with orally administered corticosteroids. The situation was resolved very quickly but we do not know whether using corticosteroids in a short time after vaccination or during Covid-19 infection may or may not affect host immune response.

Another group of patients with hypersensitivity to HA filler that has to mentioned are those where inflammatory process develops in response for the native Covid-19 infection which may be a trigger factor. These might be more difficult to manage and probably would take longer to heal [10].

Therapeutic management of DIR associated with HA fillers following Covid-19 or vaccination against SARS-CoV-2 cases should be focused either on suppressing the inflammatory response by corticosteroids or decreasing the level of proinflammatory angiotensin II by ACE-I which seems to be a promising and effective way of treatment but it needs further evaluation. Complex cases would probably need combined treatment (corticosteroids, antibiotic and hyaluronidase; steroids injected into lesions alone or in combination with 5-FU may be considered in cases not responding to first line therapy.

In lieu of the fact that most of the adult population has been or will be vaccinated against SARS-CoV-2 we should expect to see more DIR cases related with HA filler injections. To the best of my knowledge, there are no official guidelines how to approach DIRs or the recurrent DIRs occurring after native Covid-19 infection or after vaccination against Covid-19. It is important to inform the patients about possible adverse events, to avoid HA filler administration immediately after the vaccination and in the time between first and second dose of the vaccine. It needs to be emphasized that previous HA filler treatment is not a contraindication for vaccination against Covid-19 [11].

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