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An Interesting Reaction to a High- and Low-Molecular Weight Combination Hyaluronic Acid

Goodman, Greg J. MD, FACD

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doi: 10.1097/DSS.0000000000000257
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A previously healthy 49-year-old white woman had a history of a basal cell carcinoma of the right upper lip repaired with a V–Y advancement flap in 1997. She required improvement in this scar and the volume deficit on the right side of her upper lip. There was a secondary defect in the right lower cheek region where the flap was raised (Figure 1).

Figure 1:
Upper lip scar and lower face before HA filler.

On 13th January 2010, 2 mL of hyaluronic acid filler (Voluma, Allergan Inc Irvine Cal) (VOL) was injected into prejowl sulci, marionette regions, and nasolabial grooves (especially on the right side where the greatest volume deficit was apparent) through a single entrance point. At that appointment, 0.8 mL of another hyaluronic acid product (Juvederm Ultra, Allergan Inc, Irvine Cal) (JU) was injected into the upper lip.

Three months later, full facial fractionated carbondioxide laser (Deka SmartXide, Firenze, Italy) was performed to facial rhytides and a preexisting scar on the upper lip.

A further month passed and the patient represented with firm swelling in all regions injected with VOL. This was firm to hard large, asymptomatic, nontender swellings with no signs of infection or inflammation. In house, ultrasound of the prejowl sulcus confirmed the presence of a swollen soft tissue region where the bulk of the VOL had been injected but well in excess of the volume originally injected (Figure 2).

Figure 2:
Upper lip, marionette and pre jowl sulcus 10 weeks after HA filler.

The swelling subsided within 2 months. The volume continued to decrease and objectively had completely disappeared after a further 4 months (Figure 3).

Figure 3:
Upper lip, marionette and pre jowl sulcus 8 months after HA filler.

On August 17, 2010, 0.05 mL each of VOL, JU, and Juvederm Ultra Plus (JU-UP) were injected into the left forearm for intradermal allergy testing (Figure 4A). The tests remained negative except for visible product evident at the VOL site that was positive but not until the review at 2 months (October 13, 2010). The VOL site showed significant reaction with redness surrounding the injection site with no reaction being evident at the other sites (Figure 4B). At this visit, 0.05 mL of JUVx+ was injected into the prejowl sulcus on the right side.

Figure 4:
(A) Test sites on left forearm. (B) Positive voluma reaction site 2 months after injection.

On December 15, 2010, the patient was again reviewed and the intradermal reaction to VOL had completely settled, and there were no reactions to the forearm tests for JUVx and JUV nor in the prejowl sulcus after JUV injection+.


The hyaluronic acid (HA) material in this product range is derived from bacterial fermentation by Streptococcus equus.1

HA-based fillers are usually well tolerated.2 Lumps can occur with excess product and are reversible with hyaluronidase.1 Lumps are the result of product placement and are of temporary cosmetic concern only. The more concerning situation involves infective and inflammatory nodules with or without true granuloma formation.

However, our case does not demonstrate objective signs of an infective process just significant and unexplained swelling 3 months after injection that in fact further improved the cosmetic result. Hence, treatment was deemed unnecessary and observation all that was required.

There was also a prolonged delay of 2 months before a positive reaction to intradermal skin testing. This positive intradermal test reaction lasted about 2 months, which mirrored the length of time it took for the facial product to disappear after the treatment reaction began.

This would seem to represent a very specific delayed hypersensitivity reaction, which did not involve cross-reaction with the other HA products tested from the same company. These all tested consistently negative from the intradermal forearm injections and the facial injections.

Native hyaluronic acid consists of long chains of linked disaccharides moieties. Manufactured HA with crosslinking would take on a different and presumably specific 3 dimensional structure as it is folded by the crosslinking chemicals. Although most HA fillers are derived from high-molecular-weight, such as Juvederm (HMW) HA (∼≥1 MDa), the 20-mg/mL highly cohesive, high-viscosity gel uses a mix of low-molecular weight (LMW; <1 MDa) and HMW HA polymer chains as its raw material source. The low concentration, 20-mg/mL smooth, cohesive HA filler (VOL) has a combination of high cohesivity and high viscosity and consequently a high lift capacity, a combination not observed with most other HA gels. Whether this difference in preparation may relate to its immunologic properties as seen in this case remains uncertain.

The unique 3 dimensional configuration on manufacture of the HA may extend to uniqueness in its breakdown products as they unfold. These structural differences may be product-specific and either these structures alone or together with any adhered proteins or bacterial remnants from initial manufacture may be enough to induce the low-grade allergenicity seen here.

Therefore, the take-home points from this patient's experience would be as follows:

  1. That not all reactions to hyaluronic acid require treatment and may be self limiting.
  2. A reaction such as this may produce more rapid degradation of the product. In this case, complete dissolution occurred within 6 months of the reaction developing.
  3. Intradermal testing has shown a very specific allergy to Voluma (Vycross technology) but not Juvederm products (Hyalcross technology). This may allow hyaluronic acid to still be injected in patients with a specific allergy. Intradermal skin testing is worthwhile in cases such as this.


1. Rzany B, Becker-Wegerich P, Bachmann F, Erdmann R, et al.. Hyaluronidase in the correction of hyaluronic acid-based fillers: a review and a recommendation for use. J Cosmet Dermatol. 2009;8:317–23.
2. DeLorenzi C, Weinberg M, Solish N, Swift A. The long-term efficacy and safety of subcutaneously injected large-particle stabilized hyaluronic acid-based gel of non-animal origin in esthetic facial contouring. Dermatol Surg. 2009;35:313–21.
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.