Nodules that form after a procedure — how common, when they appear, and what we do

A number with a denominator is better than the word “rare”. We set down what we verified, as it is.

Two things stand out.

First, in the PCL data covering 1,111 treatments there were 0 nodules. The same study reported persistent oedema 4.5%, bruising 2.7% and a temporarily palpable lump 0.45%, so it was not a study that fails to count adverse events. But because these are single-centre retrospective data, “it was not reported” and “it does not happen” are different things.

Second, that the 17.2% for PLLA came down to 1.0% is not because the product changed but because the way of reconstituting it changed. It came about as what had been reconstituted with 5 mL was diluted amply to 9 mL. In one randomised comparison (150 patients) it was 1.3% at a dilution volume of 10 to 12 mL and 8% with the standard protocol. It means this is a risk that can be lowered by technique, and this is why we dilute generously.

Even for the same “something I can feel”, it is an entirely different thing depending on when it appeared. The literature generally divides it into three periods.

The commonest time of onset for a delayed reaction is 3 to 4 months after injection. And an interesting seasonality has been reported — up to 71% of delayed reactions occurred between September and December. It overlaps with the season when viral infections increase.

That said, the timing does not separate them 100%. Among delayed reactions, cases appearing within 24 hours of injection have been reported. So the timing is the first clue, not the conclusion.

The lump felt immediately after a procedure has long been explained as “because it was put in too superficially”. But as a study that checked the actual location by ultrasound came out, the explanation has changed a little.

Schelke LW et al., Dermatologic Surgery 2023;49(6):588 — 27 patients with non-inflammatory nodules were observed with 18 MHz ultrasound.

In all 27 patients the nodule was within the fascial layer. In 14 cases it was confined to the fascia, in 8 it extended into the subcutis, and in 5 there were findings of the product having migrated.

That is, rather than “because it was superficial”, the mechanism is closer to the layer having been taken wrongly so that it pooled inside the fascia, or the product having travelled along the path made by the needle · cannula. So this kind is neither red nor painful, and is only palpable.

What we do at this stage

• Massage — it works best early on. Normal saline or lidocaine in the same amount as was injected is sometimes used along with it
• Watchful waiting — if it is small and in the course of settling, it is better not to touch it
• Hyaluronidase if it is a hyaluronic acid preparation — it can be dissolved and reversed. This is the great advantage of the hyaluronic acid family
• If it persists, aspiration with a 21G needle or removal through a small incision

The polycaprolactone · polylactide families do not dissolve with hyaluronidase. It is because the enzyme acts only on hyaluronic acid. So for this family the layer and the amount at the time of the first injection matter more, and it is also the reason we tell you the layer before we put anything in.

There are cases where a site that had settled down suddenly swells and hardens anywhere from 2 weeks to some months later. It is rare, but this is the side that actually needs attention.

As to the cause, three hypotheses are put forward together — ① the physicochemical structure of the product ② infection · biofilm ③ a change in the host's immune balance. They are taken to be not mutually exclusive but to work in an overlapping way.

The biofilm story — even when the culture is negative

There is one decisive piece of data here.

Bjarnsholt T et al., Dermatologic Surgery 2009;35(Suppl 2):1620 — tissue from long-persisting nodules whose cultures had come back negative was re-examined by Gram stain and fluorescence in situ hybridisation (FISH).

Bacteria were detected in 7 of 8 patients. The bacteria were not scattered but present in the form of aggregates inside the gel and in the tissue between.

The reason this matters is that it means one must not conclude “the culture is negative, so it is not an infection”. A swab rubbed over the surface does not catch bacteria embedded within the tissue, and if antibiotics are used before the specimen is taken, the bacteria will not grow in culture.

Why the bacteria remain has been shown experimentally as well — when a needle passes several times through a contaminated surface, contamination of the product increased 10,000-fold (p<0.001). This is why removing make-up completely, not finishing with alcohol alone, and not passing back and forth many times with one needle actually mean something.

Triggering factors

It is set out that viral infections such as a cold or influenza, dental treatment and other invasive procedures can be a trigger. The recommendation to put off dental treatment for about 2 weeks after a procedure comes from here.

That said, a trial or cohort validating the figure of “2 weeks” we did not find. It is the consensus wording of a 4-member expert panel. Even so, it is a measure that costs nothing, so we include it in our guidance.

The consensus algorithms from several countries agree in broad outline. The order is this.

1. We look at the size and the character. If it is small and in the course of settling, we watch it. If it is over 0.5 cm, painful, red and not improving, we go to the next step
2. We feel whether there is a soft, fluctuant quality. If there is, we check by ultrasound, incise and drain it and send a culture. If it is hard, we consider a biopsy
3. We use antibiotics first. What the consensus documents place first is antibiotics. A macrolide or a tetracycline is used for 2 weeks and the response is watched
4. If it is a hyaluronic acid preparation, after starting antibiotics we use hyaluronidase
5. If it still remains, we consider an intralesional steroid
6. Systemic steroids are restricted to very severe cases

Why we do not use hyaluronidase first

There is a reason we do not dissolve straight away when infection is suspected. The product labelling states that it is not to be used when there is an active infection (cellulitis) — because breaking down hyaluronic acid removes the tissue's barrier to diffusion, so that the infection may spread to the surroundings.

To add it honestly, clinical comparative data showing that hyaluronidase actually spread an infection we did not find. The grounds are these three: ① the contraindication wording on the product label ② the pharmacological mechanism ③ expert consensus. So what has been agreed is not “absolutely contraindicated” but “after antibiotics have been started first”.

That the doses are not standardised

This part is better known than not. It differs from source to source.

There is in fact a survey in Israel that gave 334 injectors the same situation and asked what they would do. 67% chose combination therapy, but the combinations were all over the place, and even the commonest combination came to only 14.7%. The researchers wrote of this that it “demonstrates the ambivalence of the current literature”.

The question we are asked most often is “will it stay for life”. To give the answer first, no.

And most nodules are on the mild side to begin with. In data following adverse events from hyaluronic acid fillers over 5 years, 90% were mild and required no intervention.

These resolution-rate figures do not come from studies with a “no treatment” control group. The authors of the review that collated them also wrote that “because resolution rates vary widely between studies, avoid percentage estimates unless they are specified in the cited literature”. So we use these numbers only as grounds for “most get better”, and we do not tell an individual patient a percentage.

Here it is accurate to write it out separately.

What has evidence

• Aseptic technique, and in particular not passing repeatedly through a contaminated surface with one needle — a 10,000-fold increase in contamination in an in vitro experiment (p<0.001). It is the only data in this field to have shown the mechanism experimentally
• Not finishing with alcohol alone — alcohol needs reapplication during the procedure and has no residual effect. A chlorhexidine-based agent is recommended alongside it
• Starting with make-up completely removed
• Putting off the procedure if there is an active infection · inflammation — for those with frequent herpes labialis, antiviral prophylaxis is recommended
• Using it amply diluted (PLLA) — the 17.2% → 1.0% seen above

Common practice, but we did not find evidence for it

• Avoiding dental treatment for 2 weeks after a procedure — the direction is reasonable, but there are no data validating the figure of “2 weeks”
• Prophylactic antibiotics — they are not recommended anywhere in the five main consensus documents. We do not use them either
• Shaving 3 days beforehand, avoiding contact with tap water after the procedure, the waiting time before resuming make-up — the recommendations themselves are split, from “5 minutes to 24 hours”
• A clinical comparison showing that aseptic technique actually reduced delayed-onset nodules — there is only the in vitro experiment and a survey of injectors' perceptions (61%)

The reason we write it out separately like this is in order to put the effort into the side that has evidence. Doing aseptic technique properly reduces the real risk more than adding to the easy-to-keep practices.

What is verified

• Delayed-onset nodules were 0.33% (2,139 patients), the dermal injection type 0.8% (131 patients), and the PCL family 0 cases in 1,111 treatments
• The timing separates the character — within 2 weeks it is for the most part non-inflammatory, after that a different reaction. The commonest timing is 3 to 4 months
• Early nodules were within the fascial layer in all 27 patients
• A negative culture does not mean there is no infection — bacteria were detected in 7 of 8 patients with culture-negative nodules
• Most get better — granulomas within about 1 year in most cases, and 90% of adverse events are mild
• For PLLA, the dilution volume brought 17.2% down to 1.0%

What is not verified

• There are effectively no randomised controlled trials on the treatment of nodules. The present order is expert consensus, and a review states expressly that even intralesional steroids have no specific trial
• The doses of the agents are not standardised — triamcinolone 5 to 40 mg/mL and hyaluronidase 30 to 300 units, differing from source to source
• For the PDLLA family there is no incidence with a denominator at all. The guideline authors were likewise unable to give a figure
• “No adverse effects were reported” and “there are no adverse effects” are different things — the 0 cases for PCL are also single-centre retrospective data

Lastly we ask one thing only. If some months after a procedure something can be felt or swells, please do not pass it off as unrelated to the procedure, and get in touch with us. The timing itself is the first clue to the diagnosis, and seen early it ends far more simply.

The order in which the bruising and swelling of the days right after a procedure pass is written up in The order in which bruising and swelling pass, and the story of the products by family in The things called ‘collagen boosters’.

Written and reviewed by Lee Chi-Hak, MD, medical director of Miso Clinic in Daegu, South Korea. Every study cited above is given together with its design, its size and the limitations the authors themselves recorded, and where we could not find data, we have said that we could not find any.