When a is no easy task.
Dr. Terrence Keaney
“It’s sometime very difficult to distinguish between the two,” Terrence Keaney, MD, said during the Orlando Dermatology Aesthetic and Clinical Conference. “Classically, an early-onset infection presents as a suppurative mass that’s fluctuant and tender. The challenge with delayed-onset infection is that it often does not tend to be fluctuant. It doesn’t resemble the classic infection you see in regular dermatology practice.”
Dr. Keaney, a dermatologist who is founder and director of SkinDC in Arlington, Va., said that the source of delayed infection could stem from inoculation at the time of injection – primarily via the skin microflora. “There are also rare case reports of mycobacterial infections from watered gauze,” which he said is why he does not use watered gauze in his practice. “This risk reinforces the importance of filler hygiene when you’re using dermal fillers. Isopropyl alcohol is often not enough. A lot of practices use chlorhexidine, avoiding its use around the eyes, to reduce the skin flora. Hypochlorous acid is another safe antiseptic for the face. You also want to be very careful with the needle or cannula tip not to touch your glove and to minimize going in and out of the skin so you’re not seeding the filler with bacteria.”
Other potential sources of a delayed infection described in the literature include a dental abscess, pimple popping, and subsequent injections from acupuncture or hyaluronidase.
When patients present with a nonfluctuant delayed nodule that shows no obvious signs of infection, however, the root cause can stump clinicians. “Is this infectious or not?” asked Dr. Keaney, who is also clinical associate faculty in the department of dermatology at George Washington University, Washington. “Is this a focus on chronic inflammation in response to the product, or is this a collection of chronic bacteria, a biofilm too large to be engulfed by a single cell?” A review of the topic found that three risk factors for the development of biofilms include the surface area of product (large boluses of filler), longevity of the product, and inadequate sterilization technique.
Dr. Keaney said that biofilms create an impaired immune system penetration, which boosts their resistance to antibiotics by 1,000-fold. “These bacteria also have a reduced growth rate, an altered microenvironment, and altered gene expression, so it makes it difficult to clear these biofilms.”
To determine if a delayed nodule is infectious or not, performing a biopsy with polymerase chain reaction (PCR) analysis of tissue samples is ideal. “This would amplify the DNA by electrophoresis,” Dr. Keaney continued. “The problem is, it is often difficult to find labs to perform PCR. Also, you’re likely going to have to biopsy someone’s face. The patient is likely already upset that they have a delayed nodule. Ideally, you would want to avoid having to do a punch biopsy of a patient’s lip, tear trough, temple, or chin. The flip side of the coin is, how do you accurately determine if this is a noninfectious delayed nodule? If it is noninfectious, what is the mechanism of action?”
According to Dr. Keaney, short hyaluronic acid (HA) fragments can act as substrates for cell trafficking and can activate macrophages, dendritic cells, and T cells. In an analysis of immune cell response that used in vitro cell-based assays and was presented during a poster session at the 2018 Anti-Aging Medicine World Congress, researchers found no evidence of inflammatory or immune response to HA used for dermal fillers, regardless of size or formulation. However, physiologic degradation of HA to intermediate/small fragments tends to occur 4-5 months after injection.
“The hypothesis is that proinflammatory HA fragments may prime the immune system for an inflammatory response in the setting of a triggering event,” Dr. Keaney said. “The presence of an inflammatory reaction triggers an immune response to the HA fragments. Possible triggers include infections, dental procedures, and immunizations.”
The American Society for Dermatologic Surgery (ASDS) recently published a guidance regarding SARS-CoV-2 mRNA vaccine side effects in dermal filler patients after three patients developed a reaction to the Moderna vaccine, in clinical trials. “One patient, a 29-year-old, had previous angioedema from a flu vaccine, so the question is: Is it truly a delayed nodule or an immunologic reaction to the ingredients in the vaccine?” Dr. Keaney said. Two other patients, a 51-year-old female and a 46-year-old female, developed facial swelling that were believed to be related to a previous filler injection. Both cases resolved.
“Is the COVID vaccine more of an immunologic trigger than other vaccines?” Dr. Keaney asked. “Are we going to see this more frequently? We may. We just don’t know the denominator. We do not know how many patients in the Moderna or Pfizer vaccine studies had been previously treated with dermal fillers. In patients who have had previous filler treatments, I’m still advising them to get the COVID vaccine if they can.”
Dr. Keaney’s algorithm for treating a delayed nodule that is fluctuant starts with culturing any exudate and beginning a course of empiric antibiotic therapy. “If it’s a nonfluctuant delayed nodule where you’re not sure if it’s related to a biofilm or to an immunologic reaction, there are multiple global consensus papers about this challenging condition in the medical literature,” he said. “Among the papers, there is no consensus treatment, even among consensus panels. They often recommend multiple antibiotic regimens when biofilm is the suspected culprit. For a noninfectious delayed nodule, they recommend prednisone or anti-inflammatory medications. If the nodule is recalcitrant to anti-inflammatory treatments, consider adding empiric antibiotic therapy or dissolve the product.”
In other specialties, the No. 1 priority of a biofilm infection is to get rid of the implant. In orthopedics, for example, the surgeon may remove the artificial joint, Dr. Keaney said. “If that delayed nodule is not responding to comprehensive antibiotic therapy or prednisone anti-inflammatories, you may consider dissolving the filler. The challenge is, there is wide variation in the ability of different hyaluronidase [products] and fillers to dissolve. Another concern is that you may make smaller, more immunogenic HA fragments by dissolving the filler.”
One approach for vascular occlusions introduced by Claudio DeLorenzi, MD, a plastic surgeon in private practice in Kitchener, Ontario, is to dissolve dermal fillers with high-dose pulsed hyaluronidase using up to 1,500 IU every hour. “In the U.S., hyaluronidase comes in 150-200-unit sizes,” Dr. Keaney said. “In my practice, it’s not enough to have one bottle of hyaluronidase. You need around 15-20 bottles to be able to treat for a vascular incident, but if you have a delayed nodule you may also have to use high doses of hyaluronidase.”
Dr. Keaney reported that he is a consultant to and/or an advisory board member for several pharmaceutical companies.