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Repeated redness and swelling of the skin after injecting hyaluronic acid, is hyaluronic acid fake?

Hey guys, today we are going to learn about a complex complication case.Soft tissue filler injection with hyaluronic acid (HA) is one of the most popular treatment methods in reversible, non-invasive and relatively low-risk procedures, which can provide aesthetic improvement. In 2020, HA filler injection is the second most common non-surgical treatment in the world, with more than 4 million patients, second only to botulinum toxin injection.

HA is considered safe and biologically inert for use as a soft tissue filler because it occurs naturally in mammalian tissues. However, with the increasing demand for noninvasive cosmetic procedures and the resulting availability of new hyaluronic acid fillers, a number of adverse reactions have been reported. Complications after filler injection are different, which can be roughly divided into early events (occurring a few days after injection) or delayed events (occurring several weeks to several years after injection) according to the incidence related to filler injection.

Delayed hypersensitivity reactions, also known as type IV hypersensitivity reactions, are T-cell mediated and usually occur 48 to 72 hours after injection, although they may follow an asymptomatic period of weeks to months. The incidence of delayed hypersensitivity reactions following HA soft tissue filler injections has been reported to be approximately 1.13%. With the emergence of COVID-19 pandemic, people began to worry about the interaction between HA soft tissue filler and Covid-19 infection or vaccination. Because some studies have reported delayed hypersensitivity to soft tissue fillers after COVID-19 infection or vaccination, today we learn from the case of repeated delayed hypersensitivity to HA fillers after the booster dose of Pfizer-BioNTech COVID-19 vaccine reported by Korean doctors.

Case report

A 61-year-old woman, who had no allergies or basic diseases except hypertension, went to the emergency room in January 2022. She is taking lercanidipine, a dihydropyridine calcium channel blocker (10 mg per day) for the treatment of hypertension. In June 2021, she injected HA soft tissue filler (Cleviel Contour;; PharmaResearch Co., Ltd) to improve the appearance. There were no complications in the first two doses of vaccination. and the mRNA COVID-19 vaccine (Comirnaty;; Pfizer-BioNTech). A few days after intensive vaccination, she was diagnosed with COVID- 19, but the infection passed without obvious symptoms. In mid-December 2021 she received a booster dose of the mRNA COVID-19 vaccine (Comirnaty; Pfizer-BioNTech). A few days after intensive vaccination, she was diagnosed with COVID- 19, but the infection passed without obvious symptoms.

In mid-January, about one month after the booster immunization, the nasolabial groove became red and swollen, and gradually spread to the whole face (Figure 1A). The white blood cell (WBC) count and C-reactive protein (CRP) level representing serum inflammation were continuously evaluated. At the time of visit, her WBC increased to 11,400/mm 3, but her CRP was normal, which was 0.5 mg/dL. The results of a computed tomography (CT) scan of the skin were evaluated and showed poorly demarcated soft tissue density suggestive of cellulitis (Figure 1B). She was admitted through the emergency room with an intravenous first-generation cephalosporin (cefazolin, 2 grams every 8 hours), primarily because of symptoms suggestive of possible cellulitis. Three days later, because the effect of antibiotics was not obvious, intravenous corticosteroids (dexamethasone, 5 mg every 24 hours) were added. After that, the symptoms subsided (fig. 1C). A week later, she was discharged from hospital after taking gradually reduced oral corticosteroids. After 2 weeks, the symptoms disappeared without sequelae (Figure 2). Her WBC and CRP levels decreased to 7,900/mm 3 and 0.1 mg/dL respectively.

Figure 1: The first delayed hypersensitivity event. (a) Photographs taken by the patient on the day of the visit. (b) Contrast-enhanced facial computed tomography showed unclear soft tissue density, suggesting cellulitis. (c) Photographs of patients taken three days after hospitalization.

Figure 2: Symptoms improved after 2 weeks in hospital, with no sequelae.

About four months later, in May, 2022, erythema swelling appeared again in nasolabial groove and chin, which was similar to the previous events but more limited (Figure 3A). Subsequent contrast-enhanced CT scans showed unclear soft tissue density, enhancement, skin thickening and subcutaneous fat infiltration, suggesting that cellulitis was accompanied by inflammatory injection granuloma or abscess formation (Figures 3B and c). As in previous events, symptoms subsided through surgical drainage and intravenous and oral corticosteroids and antibiotics (Figure 3D). The treatment reduced her WBC level from 16,500/mm 3 to 7,800/mm 3. The CRP level decreased from 8.6 mg/dL to 0.5 mg/dL.

Figure 3: Recurrent delayed hypersensitivity events

(A)Photographs taken by the patient on the day of recurrence. Erythema and swelling of nasolabial groove and chin appeared again, which was more limited than previous events. (B, C) Contrast-enhanced facial computed tomography showed more uneven patterns and unclear soft tissue density, indicating that cellulitis and abscess formation were aggravated. (D) Photographs of patients taken 2 days after surgical drainage. Improved erythema and swelling can be seen.


According to reports, the delayed inflammatory reaction associated with COVID-19 usually subsides spontaneously within a few days or weeks. In mild and severe cases, various treatment methods, including hyaluronidase and oral, intralesional or intravenous steroids, have been applied and achieved remarkable results. Mild to moderate reactions were treated with hyaluronidase at a dosage of 10 units per 1 ml of hyaluronic acid filler, or 30 to 300 units were saved per knot. Secondary treatment includes the use of intralesional steroids alone or in combination with 5- fluorouracil. Antibiotics can be added when symptoms suggest infection, and further surgery, such as incision and drainage, is needed when fluctuating masses are found.

Some studies questioned the use of immunomodulators such as corticosteroids during the COVID-19 pandemic, for fear that it would inhibit the immune response needed to prevent infection. However, short-term or low-dose steroids used to treat general delayed hypersensitivity can be safely used without increasing the risk of SARS-CoV-2 infection. Other doctors have introduced a new low-dose lisinopril therapy, which is an oral angiotensin converting enzyme inhibitor (ACE-I), and was previously used to treat hypertrophic scars, keloids and several inflammatory skin diseases.

In this study, the author successfully treated a patient with repeated delayed hypersensitivity to HA soft tissue filler after COVID-19 vaccination by combining intravenous and oral corticosteroids and antibiotics with surgical drainage. I was worried that COVID-19 infection would worsen, but we confirmed the safety of corticosteroid administration through literature review before prescribing, and no further deterioration of infection was observed. Unfortunately, this patient can't use ACE-I, because she has been taking lercanidipine regularly as an antihypertensive drug, and lisinopril can't be added for fear of hypotension.

Several studies have been carried out and molecular studies are under way, but the exact mechanism related to delayed hypersensitivity between HA filler and COVID-19 vaccine is still unknown. However, there are several reasons to conclude that delayed hypersensitivity occurs in this case. First of all, one month after COVID-19 vaccination corresponds to delayed hypersensitivity. In addition, the swelling and redness around the filler injection and the existence of abscess were similar to those reported before. This is also supported by the rapid relief of symptoms through appropriate antibiotics and corticosteroids. Considering that there are no other specific events near the onset of symptoms, it can be reasonably concluded that this is a delayed hypersensitivity reaction caused by COVID-19 vaccine to HA filler. In addition, this case report has the significance of recurrent cases that have not been reported before.

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