Cutaneous Hypersensitivity Reaction to Injectable ... · Cutaneous Hypersensitivity Reaction to Injectable Hyaluronic AcidGel ... hyaluronic acid can be modified to form a more insol-

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Cutaneous Hypersensitivity Reaction to InjectableHyaluronic Acid GelJASON R. LUPTON, MD AND TINA S. ALSTER, MD

Washington Institute of Dermatologic Laser Surgery, Washington, D.C.

BACKGROUND. Injectable hyaluronic acid gel is a nonanimalbiomaterial used for soft tissue augmentation.OBJECTIVE. The dermal implantation of this naturally occuringpolysaccharide is reported to be well tolerated by patients, witha longer duration in tissue than bovine collagen without anymajor local or systemic side effects. We report a case of anacute hypersensitivity reaction in a woman after her third injec-tion for improvement of melolabial fold wrinkles.

METHODS. An adverse granulomatous-like response to the intra-dermal injection of a modified hyaluronic acid gel is described.RESULTS. The patient developed indurated and erythematouspapulocystic nodules in the melolabial folds bilaterally at thesites of injection.CONCLUSION. Injectable hyaluronic acid gel can be associatedwith severe allergic reactions and patients should be warned ofthis possible treatment side effect.

INJECTABLE HYALURONIC ACID GEL is one ofthe latest biomaterials developed for soft tissue aug-mentation/volume expansion.' Although not currentlyapproved by the U.S. Food and Drug Administration(FDA), it is commonly used in Europe and Canada forcorrection of soft tissue defects and improved facialcontouring. Hyaluronic acid is a naturally occuringpolysaccharide.? a glycosaminoglycan composed ofthe repeating disaccharides D-glucuronic acid and N-acetyl-Dvglucosamine.l-' This compound is a memberof a class of substances forming part of the "groundsubstance" or extracellular matrix of the dermis andfunctions to provide support for other tissues.' Hyalu-ronic acid has natural hydrating functions with an abil-ity to bind large volumes of water. This molecule can bemodified to form an insoluble, cross-linked, high-vis-cosity gel which is suitable for dermal implantation.v'Previous studies have not demonstrated any serious ad-verse effects or allergic reactions to this filler material.This apparent lack of sensitization is thought to be dueto the fact that the product is of nonanimal origin andshould therefore be devoid of any antigenic-stimulatingpeptides.l-" We report the case of a woman developingan acute hypersensitivity reaction at the sites of injec-tion of a modified hyaluronic acid biopolymer gel.

Case Report

A 54-year-old Caucasian woman underwent treatmentfor prominent facial lines and wrinkling with the in-

J.R. Lupton, MD and T.S. Alster, MD have indicated no significantinterest with commercial supporters.Address correspondence and reprint requests to: Tina S. Alster, MD,Washington Institute of Dermatologic Laser Surgery, 2311 M St. NW,Suite 200, Washington, DC 20037, or e-mail: talster@skinlaseLcom.

tradermal injection of a modified hyaluronic acid gel.She was first treated in April 1998 and then again inNovember 1998 with an excellent cosmetic result andwithout any adverse effects. She did not undergo anypretreatment skin testing for evidence of hypersensi-tivity to the injected material. In June 1999 the patientagain sought treatment for recurrent wrinkling of hermelolabial folds and proceeded with her third roundof hyaluronic acid injections. Each treatment sessioninvolved several intradermal injections in a continuousrow along the melolabial folds. She experienced mildbruising and erythema at the injection sites after eachtreatment that resolved within 1-2 days. Two weeksafter the third series of injections, however, the patientdeveloped acute multiple, tender red nodules withinthe treatment areas.

Physical examination showed multiple, discretenodules in the bilateral melolabial folds. The papulo-cystic nodules measured 0.5-1 em in diameter andwere in various stages of development. Some nodulesexuded a coagulated, yellow, stringy material and ap-peared to be secondarily infected with frank pus.Other lesions were more indurated, almost fibrotic,with significant erythema but still with intact overly-ing skin (Figure 1). A bacterial culture of the drainingcystic nodules was obtained but failed to grow out anypathogenic bacteria. The patient declined a diagnosticbiopsy given the location of her eruption.

The patient was treated with minocycline 250 mgby mouth twice a day for 1 week and methylpredniso-lone 4 mg by mouth once a day for 6 days to help re-duce the inflammatory response and prevent perma-nent scarring. The patient also applied warm salinecompresses twice a day to the affected areas and themost purulent and fibrotic nodules were injected withtriamcinolone acetonide 5 mg/cc for symptomatic re-

© 2000 by the American Society jor Dermatologic Surgery, Inc. • Published by Blackwell Science, Inc.ISSN: 1076-0512/00/$15.00/0 • Dermatol Surg 2000;26:135-137

136 LUPTON AND ALSTER: HYPERSENSITIVITY TO HYALURONIC ACID

Figure 1. Initial presentation demonstrating multiple erythema-tous cystic nodules in the bilateral melolabial folds.

lief. The patient rapidly cleared on this regimen, withonly minimal postinflammatory hyperpigmentation atthe sites of the larger, open cystic nodules (Figure 2).Two weeks later the patient returned with recurrentinflammation in the right melolabial fold with earlyeruption of tender, discrete nodules in previously inac-tive sites. The patient was again treated with intrale-sional corticosteroids and warm compresses with rapidresolution of her symptoms.

Discussion

Injectable materials suitable for soft tissue augmenta-tion and volume expansion have been studied formore than 40 years and have included silicone, paraf-fin, and collagen.V Since its approval in the early1980s, however, bovine collagen has been the main-stay of therapy for correction of facial contour defects,atrophic scars, and wrinkles.S? Collagen implants aretemporary fillers and their use has been associatedwith major adverse tissue effects. Approximately 3%of patients will experience an allergic reaction to in-jected bovine collagen with development of circulatingantibodies to the foreign material. 5-9 This reactionusually subsides within 6 months, but has been re-ported to last up to 18 months in some people." Dou-ble skin testing is therefore recommended, but not re-quired, prior to treatment with collagen to monitorfor this allergic response.l?

Localized skin necrosis is another potential side ef-fect associated with collagen injections. Necrosis is es-pecially common in the glabellar area and results fromocclusion of blood vessels during injection.v<? In ad-dition, the beneficial clinical effects obtained with bo-

DermatolSurg 26:2:February 2000

Figure 2. Clinical appearance after treatment, with marked im-provement of cutaneous nodules with residual postinflammatoryhyperpigmentation.

vine collagen implants will usually only last up toabout 6 months before supplemental treatments arenecessary." In response to the need for safer andlonger lasting biomaterials for filling of soft tissue de-fects, a modified hyaluronic acid gel was developed.Two forms of this polymer are currently available.

Hyaluronic acid is a glycosaminoglycan which nat-urally occurs in the skin as part of the extracellularmatrix. It is assembled as disaccharide units contain-ing glucuronic acid alternating with N-acetylglu-cosarnine.l>' Hyaluronic acid has a high molecularweight and because of its water-binding affinity canform a hydrated polymer with a high viscosity. Thehyaluronic acid can be modified to form a more insol-uble, more highly cross-linked molecule for improvedbiocompatibility and longer presence in the tissue."Modified hyaluronic acid gel has an "isovolemic pat-tern" of degradation whereby it can maintain its origi-nal volume over time even with decreasing concentra-tion of implant. The molecule is able to bind morewater as the implant is degraded and therefore canmaintain a somewhat constant volume over time.Eventually the implant is fully degraded and only thenis re-treatment needed.' Thus these bioengineered hy-aluronic acid implants seem to be superior to tradi-tional bovine collagen implants in terms of tissue lon-gevity. Some studies have demonstrated the presenceof modified hyaluronic acid gels in tissue a full year af-ter injection."

Previous studies with both hylan b gel implants andmodified hyaluronic acid gel have shown them to bewell tolerated and safe in patients without any seriousadverse effects.l-" The most common adverse reactionswere self-limited and included bruising, erythema,

Dermetol Surq. 26:2:February 2000 LUPTON AND ALSTER: HYPERSENSITIVITY TO HYALURONIC ACID 137

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edema, and slight discomfort at the treatment sites.Most of these reactions resolved within 1-3 days andthere have been no reported cases of systemic effectsor cutaneous hypersensitivity.' Hyaluronic acid is be-lieved to be nonimmunogenic- and therefore routineskin testing for allergy is not currently recommended.This gel is made in culture by bacterial fermentation,hovyever, and if any impurities are present in its manu-facturing, then these could account for a sensitizationreaction.'

This is the first reported case of a patient develop-ing an acute hypersensitivity reaction to locally in-jected hyaluronic acid gel. Despite previous reports tothe contrary, injectable hyaluronic acid gel may be ca-pable of producing an allergic-type reaction. Even ifthis patient had been skin tested for allergy, no reac-tion would have been elicited since she did not de-velop symptoms until after her third treatment. Asmore patients undergo treatment with injectable hy-aluronic acid it may become possible to estimate theincidence of this adverse reaction and whether this is atrue allergy to some component of the modified hyalu-ronan or merely to impurities present as a result of fer-mentation. Until the issue can be more fully evaluated,patients should be warned of this potential complica-tion. Our patient will continue to be monitored for re-currence of inflammation since this reaction pattern

will likely persist until all of the implanted hyaluronicacid has been fully degraded.

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