Dr Sophie Shotter explains why prevention is key with late-onset adverse events and discusses new thinking on delayed onset nodules
Medical aesthetic practitioners using soft tissue dermal fillers should be conversant with the types of adverse events (AEs) that can occur and their aetiologies. There is much discussion in relation to AEs, particularly in preventing, recognising and managing late-onset AEs that can manifest in some patients a considerable time post-treatment. It is vital that we employ better practices to avoid or mitigate the potential risk for AEs, whilst reporting them for both pharmacovigilance, clinical evaluation and study.
This article will focus on delayed onset nodules (DONs), as these represent a poorly understood and generally neglected group of complications.1
DON is a descriptive term rather than a diagnosis. It is used to describe nodules or areas of induration which can occur from a matter of days, weeks or years after filler treatment.1 DONs can be either inflammatory or non-inflammatory depending on their causative factors.
Inflammatory DONs are often referred to as ‘hot’ nodules because they are characteristically red, painful and swollen. Typically, they most commonly present weeks, or even years following injection. They usually present initially with erythema and other signs of inflammation such as injection-site swelling. Causative factors can include infection, biofilms or foreign body reactions.2
Non-inflammatory DONs or ‘cold’ nodules may be associated with superficial injections, low-grade filler reactions or improper filler placement. They are most commonly seen immediately after injection.2 These nodules will simply present as palpable and sometimes visible product, and are not associated with any erythema, pain or heat.2
DONs can be further categorised by their causative factors. There are a multitude of factors that can impact the incidence, but they can be broadly grouped as patient-related, procedure-related and product-related.3
The likelihood of AEs can increase according to a patient’s medical history, particularly:4
Studies also highlight that some patients may have a genetic predisposition to developing late-onset immune-mediated AEs from dermal fillers.4,5
Poor injection techniques employed during the procedure including incorrect depth or product volume delivery, as well as injecting filler into vascular danger zones, can be procedure-related factors for AEs. Similarly, insufficient preparation of the skin and a lack of aseptic technique can introduce microbial contamination.4,6 The characteristics of the filler product chosen for treatment can be causal factors in AEs, especially when the product is inappropriately placed or is of poor manufacturing quality.4,7 These characteristics may include the concentration of hyaluronic acid, the degree of cross-linking and the particle size which determine its viscosity, elasticity, G-prime and resistance to degradation.4,8
There has notably been some confusion surrounding the molecular weight of hyaluronic acid present in well-evidenced dermal filler brands and its role in inflammation and delayed onset nodule formation.
Pre-clinical studies of hyaluronans have been cited explaining that low molecular weight hyaluronic acid (LMW-HA) is pro-inflammatory and triggers the immune system, whilst high molecular weight hyaluronic acid (HMW-HA) is anti-inflammatory. These studies described LMW-HA as <500 kDa and HMW-HA as >500 kDa.8,9,10
Within filler product marketing, the use of words like ‘low, lower, high and higher’ can be ambiguous in adequately describing the exact molecular content of the HA, so it behoves practitioners to do their own due diligence when choosing products.
All commercially available, cross-linked HA fillers only contain HA of a molecular weight that falls into the described HMW-HA category (ranging from 592-3130 kDa).11 Thus, the argument that late-onset AEs are caused by pro-inflammatory LMW-HA within products can be challenged.
A candidate gene study was performed to evaluate the genetic predisposition of individuals to developing late-onset AEs by assessing human leukocyte antigen (HLA) polymorphisms. The study included 211 patients (89% women, 11% men), of whom 129 experienced late-onset inflammatory AEs to different fillers (the inflammation group) and 82 did not (the reference group). All completed a questionnaire and gave blood samples and an oral swab for HLA testing. Results showed that there was a significant correlation between the combined presence of certain HLA subtypes (HLAs B*08 and DRB1*03) and the occurrence of late-onset cutaneous inflammatory reactions. Patients with this specific genetic profile are at a four-fold increased risk of developing late-onset inflammatory reactions.7
The lead investigator Dr Tom Decates has developed a one-time DNA test to determine if patients carry this genetic combination.12 Although this may not be a practical addition for all patients, there is certainly a niche for it in treatment planning for those who have experienced delayed onset reactions and may be anxious about future treatments.
An in vitro study investigated the potential impact of non-crosslinked HA and cross-linked HA soft tissue fillers on generating immune cell response (which would lead to DONs), with and without bacteria as a stimulating factor. The results showed that HA, regardless of cross-linking, molecular weight or degradation, was not responsible for stimulating an inflammatory immune response on its own. However, the presence of bacteria or bacterial proteins (lipopolysaccharides or heat-inactivated Cutibacterium acnes bacteria) at the site of the injection was sufficient to initiate a hypersensitivity reaction on their own, which would result in a delayed-onset AE.13
The study also found that lower-end molecular weight HA filler products (592 kDa), often undefined as LMW-HA, did not exhibit an increase in activation of T-cells, which previous literature has suggested had a causal role of <500 kDa in inflammatory responses.13
The results presented here indicate that an inflammatory/immune response to HA does not occur in the absence of stimulating factors, and that minimising the presence of bacteria or other stimulating factors may reduce the incidence of these events.13
These are interesting and significant studies that reinforce the understanding of the relevance of procedure-related factors. In particular, these include asepsis to mitigate bacterial contamination and patient-related factors, including a predisposition or systemic immune activation in the occurrence of AEs.13 However, further research is warranted to elucidate the role that the HA filler and its associated degradation products play in the immune response. Confirmation of the bacterial/immune reaction in clinical biopsy samples is needed to further understand the mechanisms identified in this study.13
Correspondingly, another published paper details a retrospective analysis that was conducted on biopsy samples from patients who experienced late-onset inflammatory reactions following soft tissue filler treatments (13 – the inflammation group) and those who did not experience them (16 – the reference group). To exclude contamination from skin microbiota at the time of biopsy from their results, the authors took skin swabs and compared the microbiota with the corresponding biopsies, finding that they differed markedly, thus contamination during the sampling process did not influence their results. The presence of a high level of gram-positive bacteria was found in biopsies of soft-tissue fillers, predominantly in the patients from the inflammation group, which suggests that this bacteria was introduced during the primary filler injection treatment or through bacteraemia.11
It goes without saying that practitioners would rather not be in a situation where they are managing a patient through an adverse event. Therefore, our focus ought to be on prevention, rather than cure, and AEs can be prevented by implementing the best clinical practice, primarily in relation to aseptic injection standards.6
Taking a full patient medical history – including recent dental treatment, any known allergies or immune-suppressant medication – alongside choosing an appropriate soft tissue filler product for the specific area of the face, and knowing the technique for accurate placement of the product using aseptic methods, are crucial ways to minimise the risks.4,9 Combining this with a good understanding of the facial anatomy to avoid vascular ‘danger zones’ and scheduling a post-treatment care plan with your patients are crucial.6
Following recent MRI exploration, we know that soft tissue fillers are retained within the face much longer than previously considered.14 Therefore, I believe we should begin to regard them as surgical implants and follow much stricter aseptic technique protocols. I would advocate for the use of dressing packs, the wearing of surgical gloves, regular hand hygiene, plus hair and ‘bare below the elbow’ standards for infection control, proper attention to skin hygiene, being careful with cannula contamination, optimal clinical waste management, and surface cleaning and disinfection as just some core considerations. Implementing aseptic techniques at all stages of product preparation and during injection must be the primary factor for mitigating the risk of AE occurrence.6
Another potential mitigator of AEs is prophylaxis with antibiotics. The medical disquiet with such proposals lies with the fear of antibiotic resistance, although studies appear to show that there is no increased risk of resistance after a single, intraoperative dose of antibiotics; it is the prolonged use that poses more risk.15,16
Use in this way is further evidenced by a study into antibiotics given during assisted vaginal births. It concluded that women who tear or have a surgical episiotomy during an assisted birth should be given preventive antibiotics as soon as possible after. This is because it significantly reduces the risk of developing an infection compared to delaying antibiotic administration.17 This recommendation, further published by the World Health Organization (WHO), notes, ‘The improved health outcomes for women were clinically significant and outweighed the potential effects on emerging antimicrobial resistance’.18 I am trialling the concept, in consultation with a microbiologist, giving a single, prophylactic dose of 500mg of flucloxacillin to patients.
If a patient has an adverse reaction, you should follow up-to-date published guidance from the Aesthetic Complication Expert Group World and/ or the Complications in Medical Aesthetic Collaborative.19,20 It is neither practical nor fair to expect our primary care colleagues in GP practices or emergency departments to manage AEs related to soft tissue fillers.
Historically, there has been a lack of evidence for the treatments delivered within aesthetic medicine; yet we are now seeing more systemic studies and investigations into potential complications. The true aetiologies of adverse events we see from commonly performed treatments are emerging. With greater understanding comes improved prevention and management protocols.
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