Keywords
COVID-19 vaccine - dermal filler - inflammation
The emergence of vaccines for coronavirus disease 2019 (COVID-19), including two messenger
RNA (mRNA)-based vaccines, the first of their kind, raises risk of possible adverse
events from interaction between the vaccines and facial aesthetic care. In the few
months after the first two vaccines to gain approval in the United States were introduced,
patients with dermal fillers were already reporting postvaccination inflammatory reactions.[1]
[2]
[3]
[4]
Dermal fillers can become inflamed much later after injection, as observed in some
cases after other vaccinations, the flu vaccine being a case in point. Other triggers
include sinus infections, common viral infections, dental work, and systemic inflammatory
conditions, while the inflammation can also occur for no particular reason. The ingredients
injected into the mRNA COVID-19 vaccines, and also the spike protein generated by
the mRNA payloads, introduce to the immune system several novel potential sensitizers
or adjuvants, any of which could result in delayed inflammation of fillers.[1]
[3]
[4]
[5]
[6]
So far, the adverse effects of dermal fillers related to COVID-19 vaccination reported
almost have been hyaluronic acid (HA) components worldwide.[3]
[4]
[7] We report the first case of delayed inflammatory reaction (DIR) after receiving
a second dose of the mRNA COVID-19 vaccination in a patient with a calcium hydroxylapatite
dermal filler.
Case Report
Following institutional guidelines, this study was approved by the Institutional Review
Board (IRB No. 2021–10–017). A 47-year-old female with no medical comorbidities and
allergies visited our emergency room due to midface swelling and pain after 3 hours
following receiving the second dose of the mRNA BNT162b2 COVID-19 vaccine (Pfizer/BioNTech,
NY). The firm mass-like nodules presented on both cheeks, but symptoms such as erythema
and tenderness were much prominent on the left side (
[Fig. 1A]). About 14 years ago, she underwent nonsurgical augmentation on the nasojugal groove
with a calcium hydroxylapatite dermal filler (Radiesse, Bioform Medical, Inc., NC)
at a primary aesthetic clinic. Since then, she has been experiencing mild swelling
in both cheeks once a year on average, but it improved spontaneously within few days.
And, there were no such symptoms within recent months, including after the first dose
of the COVID-19 vaccine 3 weeks ago. At the initial enhanced computed tomography (CT)
scan, it showed abscess-like lesion on both cheeks (
[Fig. 2A]).
Fig. 1 Clinical photographs. (A) Preoperative image. (B) Intraoperative image. (C) Postoperative image after 3 weeks.
Fig. 2 Radiological images. (A) Preoperative image with enhanced computed tomography (CT). White arrows indicate
the abscess-like lesion on both cheeks. (B) Postoperative 1-day image with enhanced CT. White triangles indicate the sequelae
after removing the abscess. (C) Postoperative 1-day image with magnetic resonance imaging. Diffuse soft tissue inflammation
was observed on both cheeks.
The next day, we performed incision and drainage under general anesthesia. During
operation, yellowish pus-like materials bulged out ([Fig. 3A,B]). We conducted the bacterial/fungal/tuberculosis culture, cytology, and biopsy immediately.
The initial treatment was aimed at simultaneously controlling antibacterial and immune
regulation. The first sets of empirical antibiotics were the unasyn, clindamycin,
and netilmicin for wide spectrum coverage until the culture result come out. And then
125 mg intravenous methylprednisolone was applied for 3 days. The C-reactive protein
level, which increased to 7.13 mg/dL the day after surgery, decreased to 0.97 mg/dL
on the third day after surgery, and normalized to 0.29 mg/dL at 7 days after surgery.
Meanwhile, the methicillin-sensitive Staphylococcus aureus was reported at postoperative 7 days; hence we changed antibiotics to the nafcillin
at the following day (
[Fig. 4]). In biopsy, it showed amorphous basophilic foreign materials with inflammatory
cells (
[Fig. 3C]).
Fig. 3 Clinical and histological images. (A, B) Intraoperative photographs: Yellowish foreign materials with pus-like discharge were
observed in both cheeks. (C) Histological image: The amorphous basophilic foreign materials with inflammatory
cells were observed.
Fig. 4 A schematic image for the clinical course during treatment.
Although soft tissue inflammation and fluid collection were observed on the enhanced
CT scan and magnetic resonance imaging the next day after surgery (
[Fig. 2B,C]), her symptoms such as swelling and erythema improved day by day after surgery.
However, the serobloody discharge continued to come out and was maintained by Penrose
drainage for ∼2 weeks. A complete recovery was achieved at 3 weeks after the treatment
(
[Fig. 1C]).
Discussion
The risk of a reaction occurring much after injecting dermal fillers has gone down
from 0.7% before 1999 when methods of production were less advanced, to the more recent
figure of 0.02%, thanks to use of highly purified products. But the use of HA fillers
that include high and low HA chains for better longevity has increased the occurrence
of such adverse events again, as the modification alters the morphology of HA molecules,
potentially affecting their immunogenicity.[3]
[8] The fact that some manufacturers add other substances such as mannitol or dextran
to make the product more hydrophilic increases the risk of antigens triggering an
immune response.[8]
The injectable implant under the commercial name of Radiesse (Bioform Medical, Inc.,
NC) is 30% composed of uniform calcium hydroxylapatite microspheres, sized from 25
to 45 μm in diameter, while 70% is an aqueous gel carrier of carboxymethylcellulose.
The calcium hydroxylapatite serves as a scaffold to promote formation of new tissue
that resembles its environment when injected in the form of small microspheres.[9] The normal reaction of tissue to any foreign body is typically phagocytosis, which
is known as the single most important factor that decides the longevity of the fillers.
Phagocytosis of particles larger than 5 μm requires aggregated macrophages (foreign-body
giant cells), while particles larger than 15 to 20 μm are generally not ingested by
macrophages or transported to the local lymph nodes, failing to phagocytose. Failure
to effectively phagocytose leads to formation of granuloma, while the aggregates of
activated macrophages take on an epithelioid morphology, and there are giant cells
of different types, surrounded by an infiltrate of T-lymphocytes that release cytokines
including tumor necrosis factor-α, interferon gamma, and interleukin-12, which continue
to activate macrophages.[3] The development of bacterial biofilms or colonies of microorganisms contained in
an extracellular matrix that may surround a foreign body may result in a low-grade
chronic infection with idiopathic or injury-induced reactivation. This may cause acute
inflammation accompanied by a quiescent granuloma after a significant period of time
since the patient had the injection.[2] Even in our case, she had been experiencing a low-grade chronic infection for 14
years. However, current symptoms such as obvious erythematous and tenderness were
the first experience after dermal filler injection, and we assumed that the mRNA COVID-19
vaccine (Pfizer/BioNTech, NY) acts as a trigger to induce a DIR.
One possible explanation for COVID-19 spike protein related to DIR with dermal fillers
could be by binding and blocking the receptors of angiotensin-converting enzyme 2
(ACE2). Skin and other tissues maintain immune homeostasis with relatively higher
levels of ACE2 that regulates the production of proinflammatory angiotensin II in
relation to the amount of the metabolites. However, spike proteins and dermal ACE2
receptors interact and activate Th1 for inflammation, helping a CD8+ T-lymphocyte-mediated
reaction.[3]
[5]
[10] Finally, angiotensin II is known to upregulate CD44 glycoprotein, found on the surface
of many mammalian cells, including endothelial cells, fibroblasts, macrophages, keratinocytes,
and lymphocytes. CD44 glycoprotein tends to bind free extracellular HA, offering another
potential locus for inflammatory reaction against the quiescent HA granuloma.[10] Although our patient had not been injected with an HA dermal filler, we deduced
progress of midface infection with a similar mechanism because she also had a quiescent
inflammatory granuloma due to low-grade chronic infection.
Because the COVID-19-related DIR mechanism has not clearly been investigated, treatment
could be quite controversial. Usually, in consideration of inhibited host immune response,
clinicians are reluctant to prescribe oral corticosteroid as a treatment for an active
infection. However, COVID-19 triggers what is apparently a hyperimmune response, for
which corticosteroid can be helpful. Another suggestion that does require further
study would be to administer ACE inhibitors or angiotensin receptor blockers to treat
acute-phase DIR.[5] Meanwhile, if the nodules do not improve and are painful and tender, accompanied
by edema and erythema, surgery and antibiotics treatment are necessary.[3] We performed surgical treatment immediately after visiting the emergency room, and
used antibiotics as regard bacterial infection. Simultaneously, steroid therapy was
applied, but such anti-inflammatory treatment did not adversely affect infection control.
Rather, we felt that the anti-inflammatory treatment improved a patient's symptoms
faster during the arrival of blood concentration of antibiotics. However, antihistamines
are not recommended because their effectiveness is limited.[10]
According to the report from the American Society for Dermatologic Surgery in 2020,
there do not seem to be many postvaccination inflammatory reactions. Only 3 participants
out of 15,184 patients who had at least one shot of mRNA-1273 in the mRNA-1273 COVID-19
vaccine (Moderna, MA) trial developed swelling on the face that was potentially related
to dermal fillers. Moreover, all patients showed no serious adverse event and had
cured spontaneously.[7] Delayed inflammations of dermal fillers in general are also rare and mostly self-limited.[3] In addition to that, individual tendencies, such as HLA-B*08 and DR1*03 haplotypes,
were found to raise the risk of delayed, immune-mediated, adverse reactions to dermal
fillers; as such combinations of human leukocyte antigen subtypes were linked to almost
four times higher probability of adverse reactions.[8]
In conclusion, people should not be dissuaded from COVID-19 vaccination, in consideration
of the morbidity, mortality rates, and the socioeconomic impact of the pandemic. It
should be noted that many DIRs with immunological causes are localized and self-limited
and are often spontaneously resolved. Also, the low probability of DIRs after dermal
fillers indicates that they should not be a deterrent against receiving the COVID-19
vaccines. Meanwhile, providers of aesthetic procedures are to be aware of the potential
risks of such vaccines for patients who already had or seek to receive dermal filler
injections.
