Etiology of Delayed Inflammatory Reaction Induced by Hyaluronic Acid Filler

Abstract

The etiology and pathophysiology of delayed inflammatory reactions caused by hyaluronic acid fillers have not yet been elucidated. Previous studies have suggested that the etiology can be attributed to the hyaluronic acid filler itself, patient's immunological status, infection, and injection technique. Hyaluronic acid fillers are composed of high-molecular weight hyaluronic acids that are chemically cross-linked using substances such as 1,4-butanediol diglycidyl ether (BDDE). The mechanism by which BDDE cross-links the two hyaluronic acid disaccharides is still unclear and it may exist as a fully reacted cross-linker, pendant cross-linker, deactivated cross-linker, and residual cross-linker. The hyaluronic acid filler also contains impurities such as silicone oil and aluminum during the manufacturing process. Impurities can induce a foreign body reaction when the hyaluronic acid filler is injected into the body. Aseptic hyaluronic acid filler injections should be performed while considering the possibility of biofilm formation or delayed inflammatory reaction. Delayed inflammatory reactions tend to occur when patients experience flu-like illnesses; thus, the patient's immunological status plays an important role in delayed inflammatory reactions. Large-bolus hyaluronic acid filler injections can induce foreign body reactions and carry a relatively high risk of granuloma formation.

Keywords

hyaluronic acid filler - delayed inflammatory reaction - filler complication - delayed hypersensitivity

Introduction

Hyaluronic acid filler injections are a widely used minimally invasive aesthetic technique.[1] Although these injections are relatively low-risk procedure, they can cause significant adverse vascular and nonvascular complications.[2] Among the nonvascular complications, delayed inflammatory reactions have been a serious problem that are characterized by swelling and areas of induration presenting at least 2 weeks after the filler injection.[3] However, the etiology and pathophysiology of delayed inflammatory reactions have not yet been fully elucidated.[4] [5] Further, there is variation in the terminology between articles, such as “delayed-onset reaction,”[5] “delayed inflammatory reaction,”[4] [6] “delayed type hypersensitivity reaction,”[4] “delayed-onset tissue nodule,”[7] “nonantibody-mediated edema,”[8] and so on. Additionally, various studies have proposed that delayed inflammatory reaction results from biofilm, nodule, and/or granuloma.[9] [10] However, nodules and granulomas may represent the progressive phenomena of a delayed inflammatory reaction rather than the etiology. The authors discuss the etiology of delayed inflammatory reactions based on previous studies, including reviewing the role of hyaluronic acid filler itself, patient's immunological status, infection, and injection technique.

The Hyaluronic Acid Filler

Hyaluronic acid fillers are composed of high-molecular weight (MW) hyaluronic acids chemically cross-linked using substances such as 1,4-butanediol diglycidyl ether (BDDE).[11] Different products in the market, such as Nonanimal-Stabilized hyaluronic acid (HA), Cohesive Polydensified Matrix (CPM), Resilient HA, Safe Transparent Optimized Reliable Manufacturing, and Vycross Technology, have different manufacturing processes.[12] However, these processes usually involve reactions with BDDE, washing, and autoclaving. Although the manufacturing processes are similar, the final products differ significantly depending on the cross-linking time, temperature, and hyaluronic acid concentration.[13] Therefore, different products can induce different tissue reactions in humans, some of which are described below.

1,4-Butanediol Diglycidyl Ether

As previously described, hyaluronic acid fillers are composed of hyaluronic acids linked using a cross-linker, with the modification degree describing the percentage of hyaluronic acid disaccharide monomer units bound to a cross-linker molecule.[14] However, BDDE does not cross-link two hyaluronic acid disaccharides properly and they exist as fully reacted cross-linkers, pendant cross-linkers, deactivated cross-linkers, and residual cross-linkers.[11] Deactivated type is BDDE that has nonreacted HA but hydrolyzed form and residual type is native form. The Food and Drug Administration recommends a residual level of unreacted BDDE level of <2 ppm for safety. Therefore, unreacted BDDE, similar to residual BDDE, usually does not exist in high amounts in the final hyaluronic acid product. However, problems remain with the pendant and deactivated types. The deactivated cross-linker, 1,4-butanediol di-(propan-2,3-diolyl) ether (BDPE), is known for its major impurities.[15] In addition, there is a much higher proportion of the pendant type than the fully reacted type in hyaluronic acid fillers.[16] To describe these hyaluronic acid filler modifications, previous studies have proposed terms that can characterize hyaluronic acid hydrogels cross-linked with BDDE.[17] [18]

1. The degree of modification (MoD) is the stoichiometric ratio of the sum of mono- (pendant type) and double-linked (fully reacted type) BDPE residues and hyaluronic acid disaccharide units. MoD percentage increases with the increase in cross-link modifications seen when compared with the acetyl group.

2. The cross-linker ratio indicates the fraction of double-linked cross-linker residues compared with all linked cross-linkers and represents a measure of cross-linker efficiency.

3. The degree of cross-linking (CrD) is the stoichiometric ratio of double-linked BDPE residues and hyaluronic acid disaccharide units.

According to a previous study, CPM-2 had 9.8% MoD and 1.06% CrD,[19] as shown in [Fig. 1].

Fig. 1 Schematic diagram of degree of cross-linking. Total degree of modification is 9.8% (schematically 10%) and degree of cross-linking is 1.06% (schematically 1%). BDPE, 1,4-butanediol di-(propan-2,3-diolyl) ether; CrD, degree of cross-linking; CrR, cross-linker ratio; MoD, degree of modification.

There is no evidence that pendant BDDE and deactivated BDDE (BDPE) are linked to delayed inflammatory reactions; however, the purity of an ideal hyaluronic acid filler product should be as high as possible for safety.

Impurities Inside Hyaluronic Acid Filler

Our previous study revealed the presence of impure particles in hyaluronic acid filler products.[19] Stainless steel is commonly found in the machinery during manufacturing.[20] Aluminum particles may exist during the manufacture of prefilled glass syringes.[21] Aluminum can induce an enhanced humoral immune response.[22] Silicone oil, which is used as a lubricant in prefilled syringes, can also be detected inside the hyaluronic acid filler[19] and form particles.[23] Silicone oil can act as an adjuvant and promote immunological tolerance and induce an antibody response.[24] Thus, silicone oil may augment the delayed inflammatory response caused by hyaluronic acid fillers.[24] According to the United States Pharmacopeia[26] and the European Pharmacopeia,[27] the threshold for particle levels in prefilled syringes are 6,000 and 600 per container for particles ≥10 and ≥25 μm, respectively. That means particles which are bigger than 10 μm should not exceed 6,000 inside 1 mL of prefilled syringe. But there are more particles detected in 1 mL of HA filler products according to a previous study.[19] Although there is no direct evidence that impurities inside the hyaluronic acid filler cause a delayed inflammatory reaction, the hyaluronic acid filler product should be as pure as possible and not contain a large amount of impurities ([Table 1]).

Table 1 Hyaluronic acid filler products with variable counts of insoluble particles[19]

	Larger than 10 µm (count/syringe)				Larger than 25 µm (count/syringe)
	First	Second	Third	Average	First	Second	Third	Average
Lorient No 6	1,204	1,340	1,196	1,246	88	72	88	82
A	76,520	79,792	76,588	77,633	812	1,044	876	910
B	11,468	10,460	10,804	10,910	312	312	236	286
C	16,264	16,816	17,084	16,721	936	916	936	929
D	121,244	120,184	118,140	119,856	6,156	6,600	6,008	6,254
E	27,912	29,712	28,180	28,601	120	84	96	100
F	28,892	25,780	25,480	26,717	896	756	820	824
G	46,408	43,516	40,568	43,497	992	1,100	1,092	1,061
Control	44	32	36	37	20	4	12	12

Molecular Weight of Hyaluronic Acid

High-MW hyaluronic acid has weight greater than 1,000 kDa[7] and is known to inhibit inflammation because CD44 receptors produce anti-inflammatory cytokines.[27] [28] The MW of hyaluronic acid used in the production of soft tissue fillers ranges from 500 to 6,000 kDa. The sodium salt of hyaluronan often occurs as a disaccharide with an MW of approximately 401 Da.[29] Hyaluronic acid fragments below 1,000 kDa are proinflammatory and can initiate an inflammatory response by activating Toll-like receptors 2 and 4.[30] Some studies have suggested that the Vycross technology hyaluronic acid filler may have a higher risk of delayed inflammatory reactions because of its low-MW hyaluronic acid composition.[31] However, although hyaluronic acid fillers usually contain a high-MW hyaluronic acid, it is degraded by hyaluronidase and reactive oxygen into 20-kDa fragments.[7] Thus, it is reasonable to assume that the periphery of the implanted hyaluronic acid filler can be degraded by hyaluronidase and that low-MW fragments of hyaluronic acid could induce an inflammatory response. However, the low-MW hyaluronic acid-induced inflammatory response is closely related to infection and the patient's immune status.[7] Moreover, the MW appears to have no impact on the inflammatory or immune response to fillers, regardless of hyaluronic acid cross-linking.[32] Further evaluation is required to determine the influence of MW on delayed inflammatory reactions.

Manufacturing Process

In addition to BDDE, impurities, and low-MW hyaluronic acid, various substances can be present in the hyaluronic acid filler product. One such substance is raw hyaluronic acid. Hyaluronic acid fillers are usually derived from raw hyaluronic acid powder,[34] which is derived from bacteria, but its purity varies.[34] Different hyaluronic acid fillers can be used to produce different purities. In addition, because hyaluronic acid is produced from fermented streptococcal species, there may be some endotoxins present in the hyaluronic acid filler products. Therefore, the hyaluronic acid filler product should be purified such that the endotoxin concentration is <20 units per syringe.[36] During the manufacturing process, sodium hydroxide is used to create an ether linkage in the hydroxyl chain.[37] Thus, this highly alkaline solution should be removed during washing. There is no evidence that impurities induce delayed inflammatory reactions; however, an ideal hyaluronic acid filler product should be as pure as possible ([Fig. 2]).

Fig. 2 Possible hyaluronic acid filler impurities. BDPE, 1,4-butanediol di-(propan-2,3-diolyl) ether; MW, molecular weight.

Patient's Immunological Status

Hyaluronic acid is a natural component of the human tissue.[14] Even if hyaluronic acid is produced using bacteria, as is the case for most fillers, the hyaluronic acid molecule is identical and independent of the species and will not be recognized as a foreign material when implanted in the body. During the cross-linking process, it is important not to modify the hyaluronic acid molecule to such an extent that it is no longer recognized as hyaluronic acid, as this may lead to foreign body reactions.[37] The foreign body reaction is the final stage of inflammation and wound healing after implantation.[38] The purpose of a foreign body granulomatous reaction is to encapsulate and isolate foreign materials that cannot be removed immediately by enzymatic breakdown or phagocytosis.[10] However, the incidence of foreign body granuloma after hyaluronic acid filler injection has been reported to be 0.02 to 0.4%.[39] Therefore, after injection, the extent of foreign body reaction varies due to factors such as the hyaluronic acid itself, patient's immunological status, and injection volumes.

Additionally, the occurrence of nodules and granulomas cannot be used to predict which patients are at risk.[40] Delayed inflammatory reactions can occur without nodule formation. Therefore, in addition to nodule or granuloma formation, patient status is also important for delaying inflammatory reactions.

Delayed inflammatory reactions tend to occur in patients with flu-like illnesses.[41] Type IV hypersensitivity reactions initiated by T lymphocytes following hyaluronic acid injection and influenza infection may play a role in late-onset nodules.[41] However, a recent article reported that there was no T-cell activity in biopsies from areas with delayed inflammatory reactions.[42] Evidence suggests that viral and bacterial infections act as immunological trigger.[43] A recent study described that viremia and postvaccination status with a heightened immune status, and virulent bacteria seeding the surface of the filler in bacteremia, would likely induce a significant immune response.[7] Another study reported that patients with human leukocyte antigen subtypes B*08 and HLA subtype-DRB1*03 have an increased risk of delayed inflammatory reactions.[44]

With the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) virus, numerous vaccines have become available globally.[45] Reports of delayed inflammatory reactions to hyaluronic acid fillers have increased in after COVID-19 vaccination[46] and infections.[47] [48] It has been suggested that the COVID-19 spike protein acts as a trigger for the formation of a delayed inflammatory reaction.[49] Spike protein interactions with angiotensin-converting enzyme receptors cause a proinflammatory helper T cell 1 response and promote CD8⁺ T cell-mediated reactions.[49] Anti-inflammatory drugs or steroids have been used for delayed inflammatory reaction.[13] [48] [50] However, because the COVID-19 vaccine is related to angiotensin-converting enzyme (ACE) 2 receptor, ACE inhibitors such as lisinopril have been proposed for the management of delayed inflammatory reactions.[51] Doses of 5 to 10 mg of lisinopril have been used, with early resolution of swelling within 24 hours in multiple cases.[52] Antihistamines are not beneficial for the management of delayed inflammatory reactions.[47] [53] [54] Thus, steroids or 10 mg lisinopril seem to be promising treatments for delayed inflammatory reactions associated with COVID-19 vaccines.

Infection

The pathogenicity of any implanted surface bacteria affects the patient's immune response, and the patient is more likely to tolerate and implant normal skin commensal bacteria than true pathogens.[7] Thus, aseptic and clean practices should address recontamination during injection procedure.[43] To prevent infection, it is important to check patient's infection history, with previous filler injection history. It is also very important to remove patient's makeup completely before filler injection procedure. There is a risk of bacterial contamination with every needle passing through the skin; however, rapid degradation and phagocytosis may address the invading bacteria.[55] Chlorhexidine gluconate and isopropanol are the preferred antiseptic solutions.[43] Chlorhexidine use has been suggested to contribute to the very low incidence of infection in minimally invasive cosmetic procedures such as filler injections.[56] Thus, during hyaluronic acid filler injections, an aseptic environment should be maintained using an antiseptic solution.

Bolus Injection

The association between a large volume of hyaluronic acid filler and delayed inflammatory reaction is controversial.[43] Larger boluses can cause mechanical irritation and trigger inflammatory reactions.[57] Ideal fillers should be nontoxic, biocompatible, reversible, and safe.[58] As previously described, even if hyaluronic acid is produced using bacteria, the hyaluronic acid molecule is identical and independent of the species and will not be recognized as a foreign material when implanted in the body. However, because the hyaluronic acid filler is cross-linked with a cross-linker, the filler can be recognized as a foreign body by the immune system.[40] Once the filler is recognized as a foreign body, phagocytosis occurs; however, this is related to the longevity of the filler.[59] Particles larger than 5 μm generally require aggregated macrophages (foreign body giant cells) to be phagocytosed, and particles larger than 15 to 20 μm are generally not ingested by macrophages or transported to the local lymph nodes.[60] The body's response varies with the composition of the filler; hyaluronic acid generates more lymphocytic infiltrate, while calcium hydroxyapatite generates more macrophages.[10] The intensity of the reaction depends on the immunological inertness of the injected material.[39] Before 1999, the reported rate of delayed inflammatory response to hyaluronic acid fillers was 0.7%.[61] With manufacturing improvements to increase the purity of hyaluronic acid products, the rate has decreased to approximately 0.2%.[10] However, impurities still exist, as described earlier, and even a large bolus injection increases the risk of foreign body reactions to form multinucleated giant cells.[62] [63] When large amount of filler is injected, patient's immune response prolong for a longer time, which increases the possibility of biofilm formation. Thus, a large bolus volume of hyaluronic acid filler has a greater risk of causing foreign body reactions and other complications.[64] The term “tissue integration” refers to the “pattern of distribution within the biological tissue and, specifically, the way the filler material entangles itself in dermal fibers.”[65] Although there are differences between the layers and filler products, foreign body reactions do not occur or minimal cell infiltration occurs when the hyaluronic acid filler is properly integrated into the tissue.[66] Research in humans has also shown no inflammation or foreign body reaction when 0.2 mL of hyaluronic acid filler is injected intradermally.[67] Another study showed that the level of inflammatory reaction depends on the hyaluronic acid filler product.[68] Thus, when tissue integration is properly performed, no foreign body reaction occurs, and when there are no signs of inflammation, the hyaluronic acid filler degrades slowly within a year.[69]

Conclusion

The etiology of the delayed inflammatory reaction induced by hyaluronic acid fillers is uncertain. However delayed inflammatory reactions are related to foreign body reactions and recurrent inflammation around the injected hyaluronic acid filler. Thus, the injected filler should be as pure as possible without impurities. In addition, stringent aseptic techniques should be practised during hyaluronic acid filler injection.

Conflict of Interest

None declared.

Authors' Contributions

Conceptualization and writing: W.L.; Review, editing, and supervision: S.S-D., N-K.R., and J.C. All authors have read and agreed to the published version of the manuscript.

• References

• 1 The aesthetic society's cosmetic surgery national data bank: Statistics 2019. Aesthet Surg J 2020; 40 (Suppl. 01) 1-26
• 2 DeLorenzi C. Complications of injectable fillers, part I. Aesthet Surg J 2013; 33 (04) 561-575
• 3 Koh IS, Lee W. Filler-induced hypersensitivity inflammation and granuloma. In: Filler complications. 1st ed.. Singapore: Springer; 2019: 41-51
• 4 Chung KL, Convery C, Ejikeme I, Ghanem AM. A systematic review of the literature of delayed inflammatory reactions after hyaluronic acid filler injection to estimate the incidence of delayed type hypersensitivity reaction. Aesthet Surg J 2020; 40 (05) NP286-NP300
• 5 Kokoska RE, Lima AM, Kingsley MM. Review of delayed reactions to 15 hyaluronic acid fillers. Dermatol Surg 2022; 48 (07) 752-757
• 6 Artzi O, Cohen JL, Dover JS. et al. Delayed inflammatory reactions to hyaluronic acid fillers: a literature review and proposed treatment algorithm. Clin Cosmet Investig Dermatol 2020; 13: 371-378
• 7 Goodman GJ, McDonald CB, Lim A. et al. Making sense of late tissue nodules associated with hyaluronic acid injections. Aesthet Surg J 2023; 43 (06) NP438-NP448
• 8 Urdiales-Gálvez F, Delgado NE, Figueiredo V. et al. Treatment of soft tissue filler complications: expert consensus recommendations. Aesth Plast Surg 2018; 42 (02) 498-510
• 9 Ibrahim O, Overman J, Arndt KA, Dover JS. Filler nodules: inflammatory or infectious? A review of biofilms and their implications on clinical practice. Dermatol Surg 2018; 44 (01) 53-60
• 10 Funt DK. Treatment of delayed-onset inflammatory reactions to hyaluronic acid filler: an algorithmic approach. Plast Reconstr Surg Glob Open 2022; 10 (06) e4362
• 11 De Boulle K, Glogau R, Kono T. et al. A review of the metabolism of 1,4-butanediol diglycidyl ether-crosslinked hyaluronic acid dermal fillers. Dermatol Surg 2013; 39 (12) 1758-1766
• 12 Micheels P, Sarazin D, Tran C, Salomon D. Effect of different crosslinking technologies on hyaluronic acid behavior: a visual and microscopic study of seven hyaluronic acid gels. J Drugs Dermatol 2016; 15 (05) 600-606
• 13 Choi SC, Yoo MA, Lee SY. et al. Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents. J Biomed Mater Res A 2015; 103 (09) 3072-3080
• 14 Tezel A, Fredrickson GH. The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 2008; 10 (01) 35-42
• 15 Guarise C, Barbera C, Pavan M, Panfilo S, Beninatto R, Galesso D. HA-based dermal filler: downstream process comparison, impurity quantitation by validated HPLC-MS analysis, and in vivo residence time study. J Appl Biomater Funct Mater 2019; 17 (03) 2280800019867075
• 16 Yang B, Guo X, Zang H, Liu J. Determination of modification degree in BDDE-modified hyaluronic acid hydrogel by SEC/MS. Carbohydr Polym 2015; 131: 233-239
• 17 Wende FJ, Gohil S, Nord LI, Helander Kenne A, Sandström C. 1D NMR methods for determination of degree of cross-linking and BDDE substitution positions in HA hydrogels. Carbohydr Polym 2017; 157: 1525-1530
• 18 Kenne L, Gohil S, Nilsson EM. et al. Modification and cross-linking parameters in hyaluronic acid hydrogels–definitions and analytical methods. Carbohydr Polym 2013; 91 (01) 410-418
• 19 Lee W, Rho NK, Yang EJ. Determination of hyaluronic acid dermal filler impurities using SEM/EDS analysis. Polymers (Basel) 2023; 15 (07) 1649
• 20 Langille SE. Particulate matter in injectable drug products. PDA J Pharm Sci Technol 2013; 67 (03) 186-200
• 21 Bohrer D, do Nascimento PC, Binotto R, Becker E. Influence of the glass packing on the contamination of pharmaceutical products by aluminium. Part III: Interaction container-chemicals during the heating for sterilisation. J Trace Elem Med Biol 2003; 17 (02) 107-115
• 22 Moon SH, Shin EC, Noh YW, Lim YT. Evaluation of hyaluronic acid-based combination adjuvant containing monophosphoryl lipid A and aluminum salt for hepatitis B vaccine. Vaccine 2015; 33 (38) 4762-4769
• 23 Cua M, Martin D, Meza P. et al. Method to determine syringe silicone oil layer heterogeneity and investigation of its impact on product particle counts. J Pharm Sci 2020; 109 (11) 3292-3299
• 24 Melo GB, Shoenfeld Y, Rodrigues EB. The risks behind the widespread use of siliconized syringes in the healthcare practice. Int J Retina Vitreous 2021; 7 (01) 66
• 25 United States Pharmacopeia and National Formulary. United States Pharmacopeial Convention, Inc.: 2021; Rockville, MD.
• 26 Pharmaeuropa. European Pharmacopoeia. Strasbourg, France: Council of Europe; 2019
• 27 Nikitovic D, Kouvidi K, Karamanos NK, Tzanakakis GN. The roles of hyaluronan/RHAMM/CD44 and their respective interactions along the insidious pathways of fibrosarcoma progression. BioMed Res Int 2013; 2013: 929531
• 28 Hamilton SR, Fard SF, Paiwand FF. et al. The hyaluronan receptors CD44 and Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. J Biol Chem 2007; 282 (22) 16667-16680
• 29 Fundarò SP, Salti G, Malgapo DMH, Innocenti S. The rheology and physicochemical characteristics of hyaluronic acid fillers: their clinical implications. Int J Mol Sci 2022; 23 (18) 10518
• 30 Rayahin JE, Buhrman JS, Zhang Y, Koh TJ, Gemeinhart RA. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater Sci Eng 2015; 1 (07) 481-493
• 31 Corduff N, Juniarti L, Lim TS. et al. Current practices in hyaluronic acid dermal filler treatment in Asia Pacific and practical approaches to achieving safe and natural-looking results. Clin Cosmet Investig Dermatol 2022; 15: 1213-1223
• 32 Hee CK, Messina DJ. In vitro inflammatory and immune response to uncrosslinked hyaluronic acid (HA) and HA fillers. J Immunol Regen Med 2022; 17: 100065
• 33 Lee W. Hyaluronic acid filler property and hyaluronidase. In: Safe filler injection techniques. 1st ed.. Singapore: Springer; 2022: 11-17
• 34 Sze JH, Brownlie JC, Love CA. Biotechnological production of hyaluronic acid: a mini review. 3 Biotech 2016; 6 (01) 67
• 35 US Food and Drug Administration. Summary of safety and effectiveness data 2006. Accessed March 3, 2023 at: https:// www.accessdata.fda.gov/cdrh_docs/pdf5/P050047b.pdf
• 36 Yang E-J. Physical properties and rheological approach for hyaluronic acid fillers. In: Won L. ed. Minimally Invasive Aesthetic Surgery Techniques. 1st ed.. Singapore: Springer; 2022
• 37 Edsman K, Nord LI, Ohrlund A, Lärkner H, Kenne AH. Gel properties of hyaluronic acid dermal fillers. Dermatol Surg 2012; 38 (7 Pt 2): 1170-1179
• 38 Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol 2008; 20 (02) 86-100
• 39 Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, Duffy DM. Foreign body granulomas after all injectable dermal fillers: part 1. Possible causes. Plast Reconstr Surg 2009; 123 (06) 1842-1863
• 40 Lee JM, Kim YJ. Foreign body granulomas after the use of dermal fillers: pathophysiology, clinical appearance, histologic features, and treatment. Arch Plast Surg 2015; 42 (02) 232-239
• 41 Turkmani MG, De Boulle K, Philipp-Dormston WG. Delayed hypersensitivity reaction to hyaluronic acid dermal filler following influenza-like illness. Clin Cosmet Investig Dermatol 2019; 12: 277-283
• 42 Decates TS, Velthuis PJ, Jhingoerie R, Gibbs S, Bachour Y, Niessen FB. No association found between late-onset inflammatory adverse events after soft tissue filler injections and the adaptive immune system. J Cosmet Dermatol 2023; 22 (02) 458-463
• 43 Philipp-Dormston WG, Goodman GJ, De Boulle K. et al. Global approaches to the prevention and management of delayed-onset adverse reactions with hyaluronic acid-based fillers. Plast Reconstr Surg Glob Open 2020; 8 (04) e2730
• 44 Decates TS, Velthuis PJ, Schelke LW. et al. Increased risk of late-onset, immune-mediated, adverse reactions related to dermal fillers in patients bearing HLA-B*08 and DRB1*03 haplotypes. Dermatol Ther 2021; 34 (01) e14644
• 45 Al Ghafri TS, Al Balushi L, Al Balushi Z. et al. Reporting at least one adverse effect post-COVID-19 vaccination from primary health care in Muscat. Cureus 2021; 13 (08) e17055
• 46 Kalantari Y, Aryanian Z, Mirahmadi SM, Alilou S, Hatami P, Goodarzi A. A systematic review on COVID-19 vaccination and cosmetic filler reactions: a focus on case studies and original articles. J Cosmet Dermatol 2022; 21 (07) 2713-2724
• 47 Rowland-Warmann MJ. Hypersensitivity reaction to Hyaluronic Acid Dermal filler following novel Coronavirus infection - a case report. J Cosmet Dermatol 2021; 20 (05) 1557-1562
• 48 Shome D, Doshi K, Vadera S, Kapoor R. Delayed hypersensitivity reaction to hyaluronic acid dermal filler post-COVID-19 viral infection. J Cosmet Dermatol 2021; 20 (05) 1549-1550
• 49 Munavalli GG, Guthridge R, Knutsen-Larson S, Brodsky A, Matthew E, Landau M. “COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment”. Arch Dermatol Res 2022; 314 (01) 1-15
• 50 Savva D, Battineni G, Amenta F, Nittari G. Hypersensitivity reaction to hyaluronic acid dermal filler after the Pfizer vaccination against SARS-CoV-2. Int J Infect Dis 2021; 113: 233-235
• 51 Sloan B. July 2021: Lisinopril for delayed inflammatory responses to hyaluronic acid fillers after COVID-19 vaccinations. J Am Acad Dermatol 2021; 85 (01) 34
• 52 Munavalli GG, Knutsen-Larson S, Lupo MP, Geronemus RG. Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation. JAAD Case Rep 2021; 10: 63-68
• 53 Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Plast Surg Nurs 2015; 35 (01) 13-32
• 54 Bhojani-Lynch T. Late-onset inflammatory response to hyaluronic acid dermal fillers. Plast Reconstr Surg Glob Open 2017; 5 (12) e1532
• 55 Saththianathan M, Johani K, Taylor A. et al. The role of bacterial biofilm in adverse soft-tissue filler reactions: a combined laboratory and clinical study. Plast Reconstr Surg 2017; 139 (03) 613-621
• 56 Alam M, Cohen JL, Petersen B. et al. Association of different surgical sterile prep solutions with infection risk after cutaneous surgery of the head and neck. JAMA Dermatol 2017; 153 (08) 830-831
• 57 Winslow CP. The management of dermal filler complications. Facial Plast Surg 2009; 25 (02) 124-128
• 58 Born TM, Airan L, Motakis D. Soft-tissue fillers. Plast Surg (Oakv) 2013; 2: 39-54
• 59 Bentkover SH. The biology of facial fillers. Facial Plast Surg 2009; 25 (02) 73-85
• 60 Doshi N, Mitragotri S. Macrophages recognize size and shape of their targets. PLoS ONE 2010; 5 (04) e10051
• 61 Artzi O, Loizides C, Verner I, Landau M. Resistant and recurrent late reaction to hyaluronic acid-based gel. Dermatol Surg 2016; 42 (01) 31-37
• 62 Williams GT, Williams WJ. Granulomatous inflammation–a review. J Clin Pathol 1983; 36 (07) 723-733
• 63 Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all injectable dermal fillers: part 2. Treatment options. Plast Reconstr Surg 2009; 123 (06) 1864-1873
• 64 Signorini M, Liew S, Sundaram H. et al; Global Aesthetics Consensus Group. Global Aesthetics Consensus: avoidance and management of complications from hyaluronic acid fillers-evidence- and opinion-based review and consensus recommendations. Plast Reconstr Surg 2016; 137 (06) 961e-971e
• 65 Dugaret AS, Bertino B, Gauthier B. et al. An innovative method to quantitate tissue integration of hyaluronic acid-based dermal fillers. Skin Res Technol 2018; 24 (03) 423-431
• 66 Choi MS, Kwak S, Kim J. et al. Comparative analyses of inflammatory response and tissue integration of 14 hyaluronic acid-based fillers in mini pigs. Clin Cosmet Investig Dermatol 2021; 14: 765-778
• 67 Flynn TC, Sarazin D, Bezzola A, Terrani C, Micheels P. Comparative histology of intradermal implantation of mono and biphasic hyaluronic acid fillers. Dermatol Surg 2011; 37 (05) 637-643
• 68 Micheels P, Besse S, Flynn TC, Sarazin D, Elbaz Y. Superficial dermal injection of hyaluronic acid soft tissue fillers: comparative ultrasound study. Dermatol Surg 2012; 38 (7 Pt 2): 1162-1169
• 69 Sheptulin V, Fedorov A, Prause J, Fay A, Grusha Y. Hyaluronic acid gel biodegradation after intrapalpebral and intraorbital injection in experimental study. Ophthal Plast Reconstr Surg 2019; 35 (06) 558-561

Publication History

Received: 03 June 2023

Accepted: 26 August 2023

Accepted Manuscript online:
29 September 2023

Article published online:
07 February 2024