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Allergic Complications of Hyaluronidase Injection: Risk Factors, Treatment Strategies, and Recommendations for Management

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Abstract

Background

Hyaluronidase is used as a reversal agent for hyaluronic acid fillers and to increase the diffusion of other medications after infiltration. Cases of hyaluronidase allergy have been described in the literature since 1984. However, it is still frequently misdiagnosed. This review aims to summarize the current literature to describe the clinical picture of hyaluronidase allergy and identify any risk factors associated with its development, as well as provide recommendations for management in plastic surgery.

Methods

A digital search of PubMed, Scopus, and Embase databases was performed by two reviewers following the PRISMA guidelines. This search identified 247 articles.

Results

Two hundred forty-seven articles were identified, and 37 of them met the eligibility criteria. One hundred six patients with a mean age of 54.2 years were included in these studies. History of allergy to other substances (timothy grass, egg white, horse serum, penicillin, insect bites, wasp venom, thimerosal, potassium, histamine, phenylmercuric acetate, and nickel) and allergic diseases (asthma, dermatitis, atopy, rhinitis) was reported. A large portion of the patients with a history of repeated exposure (2–4) experienced the symptoms with their second injection. Nonetheless, there was no significant association between time to allergy development and the number of exposures (P = 0.3). Treatment with steroids +/− antihistamines resulted in the rapid and predominantly complete reversal of the symptoms.

Conclusions

Prior injections or sensitization by insect/wasp venom might be the primary factor associated with hyaluronidase allergy development. The time between the repeated injections is not a likely contributor to the presentation.

Level of Evidence III

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References

  1. Lee Y, Jeon YJ, Kang S et al (2022) Social media use and mental health during the COVID-19 pandemic in young adults: a meta-analysis of 14 cross-sectional studies. BMC Public Health 22:995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Arab K, Barasain O, Altaweel A, et al. (2019) Influence of Social Media on the Decision to Undergo a Cosmetic Procedure. Plast Reconstr Surg—Glob Open. 7, https://journals.lww.com/prsgo/Fulltext/2019/08000/Influence_of_Social_Media_on_the_Decision_to.2.aspx

  3. The Aesthetic Society. Aesthetic plastic surgery National Databank Statistics 2020–2021

  4. Ortiz AE, Ahluwalia J, Song SS, et al. (2020) Analysis of US food and drug administration data on soft-tissue filler complications. Dermatol Surg. 46, https://journals.lww.com/dermatologicsurgery/Fulltext/2020/07000/Analysis_of_U_S__Food_and_Drug_Administration_Data.19.aspx

  5. Ortiz-Perez S, Fernandez E, Molina JJ et al (2011) Two cases of drug-induced orbital inflammatory disease. Orbit 30:37–39

    Article  PubMed  Google Scholar 

  6. Kim MS, Youn S, Na CH et al (2015) Allergic reaction to hyaluronidase use after hyaluronic acid filler injection. J Cosmet Laser Ther 17:283–285

    Article  PubMed  Google Scholar 

  7. Olaiya OR, Forbes D, Humphrey S et al (2021) Hyaluronidase for treating complications related to HA fillers: a national plastic surgeon survey. Plast Surg. https://doi.org/10.1177/22925503211019618

    Article  Google Scholar 

  8. Kang SY, Lee SY, Kim JC et al (2022) Delayed hypersensitivity of hyaluronidase: a case report. J Eur Acad Dermatol Venereol. https://doi.org/10.1111/jdv.18133. (Epub ahead of print 10 April 2022)

    Article  PubMed  PubMed Central  Google Scholar 

  9. Taylor IS, Pollowitz JA (1984) A little-known phenomenon: allergic reaction to hyaluronidase. Ophthalmology 91:1003

    Article  CAS  PubMed  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kim J-H, Choi G-S, Ye Y-M et al (2009) Acute urticaria caused by the injection of goat-derived hyaluronidase. Allergy Asthma Immunol Res 1:48–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu L, Liu X, Jian X et al (2018) Delayed allergic hypersensitivity to hyaluronidase during the treatment of granulomatous hyaluronic acid reactions. J Cosmet Dermatol 17:991–995

    Article  PubMed  Google Scholar 

  13. Ebo DG, Goossens S, Opsomer F et al (2005) Flow-assisted diagnosis of anaphylaxis to hyaluronidase. Allergy 60:1333–1334

    Article  CAS  PubMed  Google Scholar 

  14. Andre P, Fléchet M (2008) Angioedema after ovine hyaluronidase injection for treating hyaluronic acid overcorrection. J Cosmet Dermatol 7:136–138

    Article  PubMed  Google Scholar 

  15. Lee A, Grummer SE, Kriegel D, et al. (2010) Hyaluronidase. Dermatol Surg. 36, https://journals.lww.com/dermatologicsurgery/Fulltext/2010/07000/Hyaluronidase.1.aspx

  16. Quantock CL, Goswami T (2007) Death potentially secondary to sub-Tenon’s block. Anaesthesia 62:175–177

    Article  CAS  PubMed  Google Scholar 

  17. Quhill F, Bowling B, Packard RB (2004) Hyaluronidase allergy after peribulbar anesthesia with orbital inflammation. J Cataract Refract Surg. 30, https://journals.lww.com/jcrs/Fulltext/2004/04000/Hyaluronidase_allergy_after_peribulbar_anesthesia.46.aspx

  18. Minning CA Jr (1994) Hyaluronidase allergy simulating expulsive choroidal hemorrhage. Arch Ophthalmol 112:585–586

    Article  PubMed  Google Scholar 

  19. Kirby B, Butt A, Morrison AM et al (2001) Type I allergic reaction to hyaluronidase during ophthalmic surgery. Contact Dermat 44:44–45

    Article  Google Scholar 

  20. Agrawal A, McLure HA, Dabbs TR (2003) Allergic reaction to hyaluronidase after a peribulbar injection. Anaesthesia 58:493–494

    Article  CAS  PubMed  Google Scholar 

  21. Rajalakshmi AR, Kumar MA (2016) Hyaluronidase hypersensitivity: a rare complication of peribulbar block. Indian J Ophthalmol. 64, https://journals.lww.com/ijo/Fulltext/2016/64020/Hyaluronidase_hypersensitivity__A_rare.15.aspx

  22. Park S, Lim LT (2014) Orbital inflammation secondary to a delayed hypersensitivity reaction to sub-Tenon’s hyaluronidase. Semin Ophthalmol 29:57–58

    Article  PubMed  Google Scholar 

  23. Lyall DAM, McQueen M, Ramaesh K et al (2012) A sting in the tale: cross reaction hypersensitivity to hyaluronidase. Eye 26:1490–1490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Borchard K, Puy R, Nixon R (2010) Hyaluronidase allergy: a rare cause of periorbital inflammation. Australas J Dermatol 51:49–51

    Article  PubMed  Google Scholar 

  25. Feighery C, McCoy EP, Johnston PB et al (2007) Delayed hypersensitivity to hyaluronidase (HyalaseTM) used during cataract surgery. Contact Dermat 57:343–343

    Article  CAS  Google Scholar 

  26. Patil B, Agius-Fernandez A, Worstmann T (2005) Hyaluronidase allergy after peribulbar anesthesia with orbital inflammation. J Cataract Refract Surg. 31, https://journals.lww.com/jcrs/Fulltext/2005/08000/Hyaluronidase_allergy_after_peribulbar_anesthesia.13.aspx

  27. Gupta A, Moharana B, Saini R et al (2022) Pretreatment with systemic corticosteroid can mask early symptoms of hypersensitivity reaction to hyaluronidase following peribulbar block. BMJ Case Rep 15:e247208

    Article  PubMed  PubMed Central  Google Scholar 

  28. Park AR, Kim WM, Heo BH (2015) Delayed allergic reaction to secondary administrated epidural hyaluronidase. Korean J Pain 28:153–155

    Article  PubMed  PubMed Central  Google Scholar 

  29. Kim TW, Lee JH, Yoon KB et al (2011) Allergic reactions to hyaluronidase in pain management—A report of three cases-. Korean J Anesthesiol 60:57–59

    Article  PubMed  PubMed Central  Google Scholar 

  30. Delaere L, Zeyen T, Foets B et al (2009) Allergic reaction to hyaluronidase after retrobulbar anaesthesia: a case series and review. Int Ophthalmol 29:521–528

    Article  CAS  PubMed  Google Scholar 

  31. Szépfalusi Z, Nentwich I, Dobner M et al (1997) IgE-mediated allergic reaction to hyaluronidase in paediatric oncological patients. Eur J Pediatr 156:199–203

    Article  PubMed  Google Scholar 

  32. Raichura ND, Alam MS, Jaichandran VV et al (2018) Hyaluronidase allergy mimicking orbital cellulitis. Orbit 37:149–153

    Article  PubMed  Google Scholar 

  33. Leibovitch I, Tamblyn D, Casson R et al (2006) Allergic reaction to hyaluronidase: a rare cause of orbital inflammation after cataract surgery. Graefes Arch Clin Exp Ophthalmol 244:944–949

    Article  CAS  PubMed  Google Scholar 

  34. Escolano F, Parés N, Gonzalez I et al. (2005) Allergic reaction to hyaluronidase in cataract surgery. Eur J Anaesthesiol EJA. 22, https://journals.lww.com/ejanaesthesiology/Fulltext/2005/09000/Allergic_reaction_to_hyaluronidase_in_cataract.16.aspx

  35. Dieleman M, Bettink-Remeijer MW, Jansen J et al (2012) High incidence of adverse reactions to locoregional anaesthesia containing hyaluronidase after uneventful ophthalmic surgery. Acta Ophthalmol (Copenh) 90:e245–e246

    Article  Google Scholar 

  36. Ahluwalia HS, Lukaris A, Lane CM (2003) Delayed allergic reaction to hyaluronidase: a rare sequel to cataract surgery. Eye 17:263–266

    Article  CAS  PubMed  Google Scholar 

  37. Musa F, Srinivasan S, King CM et al. (2006) Raised intraocular pressure and orbital inflammation: a rare IgE-mediated allergic reaction to sub-Tenon’s hyaluronidase. J Cataract Refract Surg. 32, https://journals.lww.com/jcrs/Fulltext/2006/01000/Raised_intraocular_pressure_and_orbital.51.aspx

  38. Halliday L, Sia PI, Durkin S et al (2018) Atypical case of hyaluronidase allergy with orbital compartment syndrome and visual loss. Clin Exp Ophthalmol 46:563–564

    Article  PubMed  Google Scholar 

  39. Mayor R, Gautam P, Agarwal M et al (2016) Hyaluronidase sensitivity: our experience. Indian J Ophthalmol 64:789–790

    Article  PubMed  PubMed Central  Google Scholar 

  40. Griffiths E, Siew L, Pillai P et al (2015) Hyaluronidase—a sting in the tale? Wiley, Blackwell

    Google Scholar 

  41. Proceedings of the RAMI section of ophthalmology meeting, Friday 7th April 2017 in the Killashee House Hotel, Naas. Ir J Med Sci 1971–2018; 187: 7–10

  42. Eberhart AH, Weiler CR, Erie JC (2004) Angioedema related to the use of hyaluronidase in cataract surgery. Am J Ophthalmol 138:142–143

    Article  PubMed  Google Scholar 

  43. Vartanian AJ, Frankel AS, Rubin MG (2005) Injected hyaluronidase reduces restylane-mediated cutaneous augmentation. Arch Facial Plast Surg 7:231–237

    Article  PubMed  Google Scholar 

  44. Murray G, Convery C, Walker L et al (2021) Guideline for the safe use of hyaluronidase in aesthetic medicine, including modified high-dose protocol. J Clin Aesthet Dermatol 14:E69–E75

    PubMed  PubMed Central  Google Scholar 

  45. Bailey SH, Fagien S, Rohrich RJ (2014) Changing role of hyaluronidase in plastic surgery. Plast Reconstr Surg. 133, https://journals.lww.com/plasreconsurg/Abstract/2014/02000/Changing_Role_of_Hyaluronidase_in_Plastic_Surgery.16.aspx

  46. Sharma DSC, Lahiri MA (2021) Use of hyaluronidase in plastic surgery: a review. J Plast Reconstr Aesthet Surg 74:1610–1614

    Article  PubMed  Google Scholar 

  47. Landau M (2015) Hyaluronidase caveats in treating filler complications. Dermatol Surg 41(Suppl 1):S347–S353

    Article  PubMed  Google Scholar 

  48. Hoesly PM, Tolaymat LM, Sluzevich JC et al (2018) Pretibial myxedema successfully treated with intralesional hyaluronidase. JAAD Case Rep 4:874–876

    Article  PubMed  PubMed Central  Google Scholar 

  49. Riedl M, Lumry W, Li H et al (2016) Subcutaneous administration of human C1 inhibitor with recombinant human hyaluronidase in patients with hereditary angioedema. Allergy Asthma Proc 37:489–500

    Article  CAS  PubMed  Google Scholar 

  50. Wasserman RL, Melamed I, Kobrynski L et al (2016) Recombinant human hyaluronidase facilitated subcutaneous immunoglobulin treatment in pediatric patients with primary immunodeficiencies: long-term efficacy, safety and tolerability. Immunotherapy 8:1175–1186

    Article  CAS  PubMed  Google Scholar 

  51. Youssef Z, Pennefather PM, Watts MT (2005) Orbital cellulitis vs allergic reaction to hyaluronidase as the cause of periorbital oedema. Eye 19:691–692

    Article  CAS  PubMed  Google Scholar 

  52. Varma D, Metcalfe TW (2003) Orbital cellulitis after peribulbar anaesthesia for cataract surgery. Eye 17:105–107

    Article  CAS  PubMed  Google Scholar 

  53. Kempeneers A, Dralands L, Ceuppens J (1992) Hyaluronidase induced orbital pseudotumor as complication of retrobulbar anesthesia. Bull Soc Belge Ophtalmol 243:159–166

    CAS  PubMed  Google Scholar 

  54. Zamora-Alejo K, Moore S, Leatherbarrow B et al (2013) Hyaluronidase toxicity: a possible cause of postoperative periorbital inflammation. Clin Exp Ophthalmol 41:122–126

    Article  PubMed  Google Scholar 

  55. Jin C, Focke M, Léonard R et al (2010) Reassessing the role of hyaluronidase in yellow jacket venom allergy. J Allergy Clin Immunol 125:184-190.e1

    Article  CAS  PubMed  Google Scholar 

  56. Keller EC, Kaminer MS, Dover JS (2014) Use of hyaluronidase in patients with bee allergy. Dermatol Surg. 40, https://journals.lww.com/dermatologicsurgery/Fulltext/2014/10000/Use_of_Hyaluronidase_in_Patients_With_Bee_Allergy.14.aspx

  57. Dunn A, Heavner J, Racz G et al (2010) Hyaluronidase: a review of approved formulations, indications and off-label use in chronic pain management. Expert Opin Biol Ther 10:127–131

    Article  CAS  PubMed  Google Scholar 

  58. Knowles S, Printz M, Kang D et al (2021) Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery. Expert Opin Drug Deliv 18:1–13

    Article  Google Scholar 

  59. Trocchi G, Pirrotta L, Scala E et al (2020) A prospective pilot study to evaluate the use of hyaluronidase in patients with hymenoptera venom allergy. Aesthet Med 6:13–18

    Google Scholar 

  60. Decates T, Kadouch J, Velthuis P et al (2021) Immediate nor delayed type hypersensitivity plays a role in late inflammatory reactions after hyaluronic acid filler injections. Clin Cosmet Investig Dermatol 14:581–589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yocum RC, Kennard D, Heiner LS (2007) Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlled clinical trial. J Infus Nurs. 30, https://journals.lww.com/journalofinfusionnursing/Fulltext/2007/09000/Assessment_and_Implication_of_the_Allergic.9.aspx

  62. Rosengren S, Dychter S, Printz M et al (2015) Clinical immunogenicity of rHuPH20, a hyaluronidase enabling subcutaneous drug administration. AAPS J. https://doi.org/10.1208/s12248-015-9782-0. (Epub ahead of print 13 May 2015)

    Article  PubMed  PubMed Central  Google Scholar 

  63. Jung H (2020) Hyaluronidase: an overview of its properties, applications, and side effects. Arch Plast Surg 47:297–300

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Plastic and Reconstructive Surgery, The Ohio State University, Columbus, OH, USA

    Gunel Guliyeva, Maria T. Huayllani & Craig Lehrman

  2. “Cosmetic and Plastic Surgery of Columbus, Inc”, at 41 Commerce Parkway, Westerville, OH, USA

    Casey Kraft

  3. Division of Allergy and Immunology, Department of Otolaryngology, The Ohio State University, 915 Olentangy River Rd, Columbus, OH, 43212, USA

    Monica T. Kraft

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  1. Gunel Guliyeva
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Correspondence to Monica T. Kraft.

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Guliyeva, G., Huayllani, M.T., Kraft, C. et al. Allergic Complications of Hyaluronidase Injection: Risk Factors, Treatment Strategies, and Recommendations for Management. Aesth Plast Surg 48, 413–439 (2024). https://doi.org/10.1007/s00266-023-03348-5

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