Abstract Hyaluronic acid fillers have been increasingly popular for soft tissue augmentation. Although generally considered safe, early and delayed types of adverse events were reported. We describe an unusual delayed type reaction observed with hyaluronic acid filler in a series of three patients treated for tear trough and periorbital hollow. Patients presented with a unilateral lower eyelid swelling without palpable nodules or tenderness developing months after injection and disappearing in few days. Reaction was triggered by infection in two patients. Temporary lower eyelid swelling is another late complication of periorbital filler injection that was not reported previously. Level of Evidence: 5 Hyaluronic acid (HA) fillers have been increasingly used for soft tissue augmentation and facial rejuvenation since 1996.1 Nowadays they have also become favorite periorbital treatment for the tear trough deformity and periorbital hollow as a noninvasive procedure.2 According to the American Society for Aesthetic Plastic Surgery statistics, 2.5 million procedures were performed using hyaluronic acid fillers in 2016 with a 16% increase compared to 2015, which ranked second in top nonsurgical cosmetic procedures, following botulinum toxin type A.3 As a consequence of this expansion, an increase in the number and possibly the variety of complications can be expected. Because HA has no organ or species specificity, it was thought that immunologic reactions or implant rejection is negligible when introduced to the market.4 However, the incidence of hypersensitivity reactions in 1999 reported is 0.07%, which later decreased to 0.02% in connection with a reduction in protein load of raw material.5 Studies involving HA injections in the periorbital area usually focus on the effectiveness of the treatment rather than complications. Hence the follow-up periods are either not reported or short during which only early complications can be seen, and delayed reactions are unusual to be observed.2,6 We describe 3 patients presented with an unusual delayed type of reaction consisting of temporary (1-3 days) lower eyelid swelling several months after periorbital HA injection without recurrence. CASE REPORTS Patient features are presented in Table 1. All the patients were treated by the author using the same product (Teosyal PureSense Redensity [II] manufactured by Teoxane Laboratories, Geneve, Switzerland). One patient also received additional filler injection with another product (Belotero Balance; Merz Aesthetics, Raleigh, NC). Patients had no history of autoimmune disease or allergic reaction. All but one were naïve to previous filler injections. Emla cream (2.5% lidocaine and 2.5% prilocaine, AstraZeneca, Cambridge, UK) was applied for 30 minutes to anesthetize, and ethanol 70% was used to prepare the skin prior to injection. Patients were instructed not to apply make up on the day of treatment. All the injections were placed preperiosteally using blunt tip 25 G cannulae. This late reaction was similar in all cases. The main feature was only sudden diffuse swelling, without palpable nodules, pain, induration, or tenderness lasting a few days in the lower eyelids where the filler was injected (Figure 1). Temporary purplish discoloration developed in two cases. No accompanying systemic symptoms and signs were observed. Early side effects associated with filler injection including bruising, redness, and swelling were not seen in any of the patients following treatment. No patient had lumpiness. No blood tests were carried out at the time of periorbital reaction. The cosmetic result was satisfactory immediately after treatment, until the reaction. Table 1. Patient Characteristics With Delayed Type Reaction Age (years), gender Involvement Total amount Latency Triggering factor Treatment Complete resolution Follow-up Case 1 41, female Unilateral 1 ml 8.5 months Flu-like illness, pityriasis rosea Dexamethasone 8 mg IM for rosea 3 days 9 months Case 2 40, female Unilateral 1ml 6 months Dental abscess, flu-like illness NSAID for swelling Antibiotic for abscess 2 days 8 months Case 3 43, female Unilateral 2 ml* 3 months Not identified NSAID 3 days 6 months Age (years), gender Involvement Total amount Latency Triggering factor Treatment Complete resolution Follow-up Case 1 41, female Unilateral 1 ml 8.5 months Flu-like illness, pityriasis rosea Dexamethasone 8 mg IM for rosea 3 days 9 months Case 2 40, female Unilateral 1ml 6 months Dental abscess, flu-like illness NSAID for swelling Antibiotic for abscess 2 days 8 months Case 3 43, female Unilateral 2 ml* 3 months Not identified NSAID 3 days 6 months NSAID, nonsteroidal anti-inflammatory drug. *2 syringes were injected in total on 2 occasions with one month interval. View Large Table 1. Patient Characteristics With Delayed Type Reaction Age (years), gender Involvement Total amount Latency Triggering factor Treatment Complete resolution Follow-up Case 1 41, female Unilateral 1 ml 8.5 months Flu-like illness, pityriasis rosea Dexamethasone 8 mg IM for rosea 3 days 9 months Case 2 40, female Unilateral 1ml 6 months Dental abscess, flu-like illness NSAID for swelling Antibiotic for abscess 2 days 8 months Case 3 43, female Unilateral 2 ml* 3 months Not identified NSAID 3 days 6 months Age (years), gender Involvement Total amount Latency Triggering factor Treatment Complete resolution Follow-up Case 1 41, female Unilateral 1 ml 8.5 months Flu-like illness, pityriasis rosea Dexamethasone 8 mg IM for rosea 3 days 9 months Case 2 40, female Unilateral 1ml 6 months Dental abscess, flu-like illness NSAID for swelling Antibiotic for abscess 2 days 8 months Case 3 43, female Unilateral 2 ml* 3 months Not identified NSAID 3 days 6 months NSAID, nonsteroidal anti-inflammatory drug. *2 syringes were injected in total on 2 occasions with one month interval. View Large Figure 1. View largeDownload slide This 43-year-old woman injected for midface and tear trough. Additionally, 1 mL HA filler was used in the periorbital area one month later. She presented with a left sided lower eyelid swelling after 3 months. Purplish discoloration was noted next day. NSAID and cold compress were recommended. Swelling disappeared on the fourth day. (A) Before treatment. (B) Immediately after the last treatment. (C) Delayed lower eyelid swelling is seen without palpable nodules, induration, or tenderness 3 months following the last injection. Figure 1. View largeDownload slide This 43-year-old woman injected for midface and tear trough. Additionally, 1 mL HA filler was used in the periorbital area one month later. She presented with a left sided lower eyelid swelling after 3 months. Purplish discoloration was noted next day. NSAID and cold compress were recommended. Swelling disappeared on the fourth day. (A) Before treatment. (B) Immediately after the last treatment. (C) Delayed lower eyelid swelling is seen without palpable nodules, induration, or tenderness 3 months following the last injection. Redensity [II] is made of cross-linked and non-cross-linked HA (15 mg/g) of nonanimal origin and specifically formulated for periorbital treatment. It is also supplemented with a dermo-restructuring complex (supplemented phosphate buffer containing eight amino acids, three antioxidants, two mineralsm and vitamin B6) and lidocaine 0.3%.6 This report of case series is in accordance with the medical ethics of the Declaration of Helsinki. Case 1 A 41-year-old woman was treated in June 2016 for tear trough deformity. She had previous injections with HA fillers in the other areas of the face without any side effects. Eight and a half months later she had a flu-like illness along with pityriasis rosea (PR) and right lower eyelid swelling with a violate discoloration. Although dexamethasone 8 mg/2 mL IM was used for skin eruption (PR), swelling resolved completely in 3 days. Case 2 A 40-year-old woman was injected for midface and lower eyelids in November 2016. Six months later lower eyelid swelling appeared on the right side concurrent with a flu-like illness and dental abscess on the contralateral side. A nonsteroidal anti-inflammatory drug (NSAID) and antibiotics were prescribed for dental condition. Swelling disappeared the next day. Case 3 A 43-year-old woman underwent filler implantation for midface and tear trough in February 2017. Additionally 1 mL HA filler (Belotero Balance) was used in periorbital area to improve final result one month later. Three months following injection, left sided lower eyelid swelling appeared without any triggering factor. Purplish discoloration was noted next day. NSAID and cold compress were recommended. Patient noted resolution on the fourth day. DISCUSSION Reactions to HA fillers can be divided into two on the basis of timing of the onset: acute and delayed reactions. Injection site reactions (redness, swelling, bruising, etc.), infections, hypersensitivity reactions, noninflammatory nodules, Tyndall effect, and vascular occlusion are the acute events occurring up to days following injection.7 Delayed type of reactions include inflammatory nodules, foreign body granulomas, infections, malar edema, persistent discoloration, cutaneous vasculitis, pseudoabscess, and induration.7-9 The rate of delayed nodules is between 0.02% and 15%.5,9-11 The latency between the injection and the appearance of late reactions was found to be mostly 3 to 5 months after injection with a median of 4 months.9,10 Common to all published reactions is the prolonged course in almost all cases up to 36 months.8-10 The terms “granuloma” and “nodule” have been used interchangeably which might be confusing to the readers. Granuloma is a reaction of the body to get rid of the filler and histologically characterized by inflammatory infiltrate composed of histiocytes and epithelioid cells.12 The fact that the granuloma is a histopathological diagnosis, while nodule is a clinical description was emphasized by some authors.7 Early nodules are characterized by painless, noninflammatory, isolated single lumps and static lesions resulting from poor technique, improper or excessive amount of material. However, the etiology and classification of delayed nodules are less clear cut. Delayed type of reactions suggested to be mediated by macrophages and T lymphocytes.13 Although the exact cause is not clear antigenic stimulation originating from the protein contaminants, breakdown products of the cross-linking,14 biofilm formation, immune system activation, and infections acquired during procedure or colonization secondary to either direct or hematological spread of the infectious agent have been attributed to the formation of delayed type of reactions.5,10,15 Biofilm formation (ie, structured community of bacteria encapsulated with a complex extracellular matrix which is resistant to antibiotics and host’s defense system) is commonly implicated in the formation of delayed nodules but some authors are opposed to this mechanism asserting lack of evidence or sufficient scientific proof.16-18 Recently some studies described a higher rate of long term complications related to a new generation of HA fillers composed of mainly low molecular weight HA chains, and to a lesser degree high molecular weight chains with a high degree of binding to the cross-linking agent. The authors concluded that modifications of HA structure by manufacturing process may increase complications.9,10,19 The filler used in our patients is not a pure HA. Therefore other excipients might have increased the risk of observed adverse reactions. Referring to the lack of similar cases in the literature, the reaction may be pertinent to this filler. Berguiga et al studied 151 patients for efficacy and safety of the same product in periorbital hollow ring and/or tear trough deformity suggesting excellent tolerability and minimal complications. However the mean follow-up time was 3 weeks which is not considered enough to observe the delayed reactions.6 The earliest reaction in our series was 3 months from injection. Several filler related adverse reactions were triggered by infections, dental procedures, or trauma.10,12,13 The adjuvant effect of microbial molecules, namely the nonantigenic activation of the innate and regulatory immunity as well as the expression of various regulatory cytokines can explain the mechanism in these cases.13 Beleznay et al identified an immunologic stimulus immediately preceding the reaction in 39% of patients with delayed inflammatory nodules and a seasonal variation occurring mainly in the fall and winter. The reaction was concurrent with a flu-like illness in two patients in our series.10 Intermittent swelling and edema particularly with lip fillers stimulated by exercise, sun exposure, and menstruation were previously reported with HA injections.20 None of the patients in our group experienced recurrence during follow up. Although the diagnosis could not be verified histopathologically, it was thought as an immunological nongranulomatous (inflammatory) nodule formation because of the short course of reaction as well as concurrent flu-like illness in two patients. Biofilm is also excluded based on the duration or lack of recurrence during follow up. To the best of our knowledge this type of reaction is the first report on filler complications following tear trough and periorbital treatment. No similar reactions were observed regarding other facial areas in previous publications. Case series is not only interesting regarding the location but also the significantly short course, and the character of the reaction (ie, consisting of merely swelling and purplish discoloration without accompanying tenderness, palpable nodules, induration as well as systemic signs and symptoms). The manufacturer was informed about these cases and asked if there were similar cases reported. They reviewed the batch records and confirmed that the products had been released in accordance with the product specification. They noted that this was the first time that such an adverse event was reported. When such a reaction is seen, anti-inflammatory medication (NSAID) rather than systemic antibiotics, steroids (unless necessary for the concomitant problems) or hyaluronidase injection is suggested as a first line treatment. Currently a well-established classification system for the delayed complications is not available. Besides, the nomenclature of late reactions is not uniform and comprehensible. This type of reaction we observed may be included as a “temporary delayed type of reaction” in the classification. This study has some limitations that must be acknowledged. Two patients had concurrent diseases which had to be treated accordingly, other than flu-like illness. For this reason, having said that anti-inflammatory treatment was in common, the treatment approach was not exactly the same in all cases. This may be a confounding factor to draw a certain conclusion regarding the treatment. CONCLUSIONS Filler injections are among the most common procedures in outpatient cosmetic surgery. As the use of them increases it is not unusual to see unprecedented cases. HA is among the safest alternatives due to low risk of immunogenicity for this purpose. However, every HA filler should not be regarded as same in terms of complications since they may have different risk profiles depending on the distinctive characteristics (molecular weight, degree of cross linking, supplemental ingredients, etc.) and host factors. Disclosures The author declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. Funding The author received no financial support for the research, authorship, and publication of this article. REFERENCES 1. André P. Evaluation of the safety of a non-animal stabilized hyaluronic acid (NASHA—Q-Medical, Sweden) in European countries: a retrospective study from 1997 to 2001. J Eur Acad Dermatol Venereol . 2004; 18( 4): 422- 425. Google Scholar CrossRef Search ADS PubMed 2. Goldberg RA, Fiaschetti D. Filling the periorbital hollows with hyaluronic acid gel: initial experience with 244 injections. Ophthal Plast Reconstr Surg . 2006; 22( 5): 335- 341; discussion 341. Google Scholar CrossRef Search ADS PubMed 3. Cosmetic Surgery National Data Bank Statistics. Aesthet Surg J . 2017; 37( suppl 2): 1- 29. 4. Matarasso SL, Carruthers JD, Jewell ML; Restylane Consensus Group. Consensus recommendations for soft-tissue augmentation with nonanimal stabilized hyaluronic acid (Restylane). Plast Reconstr Surg . 2006; 117( 3 Suppl): 3S- 34S; discussion 35S. 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Artzi O, Loizides C, Verner I, Landau M. Resistant and recurrent late reaction to hyaluronic acid-based gel. Dermatol Surg . 2016; 42( 1): 31- 37. Google Scholar CrossRef Search ADS PubMed 10. Beleznay K, Carruthers JD, Carruthers A, Mummert ME, Humphrey S. Delayed-onset nodules secondary to a smooth cohesive 20 mg/mL hyaluronic acid filler: cause and management. Dermatol Surg . 2015; 41( 8): 929- 939. Google Scholar CrossRef Search ADS PubMed 11. Alsaad SM, Fabi SG, Goldman MP. Granulomatous reaction to hyaluronic acid: a case series and review of the literature. Dermatol Surg . 2012; 38( 2): 271- 276. Google Scholar CrossRef Search ADS PubMed 12. 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( 6): 1842- 1863. Google Scholar CrossRef Search ADS PubMed 13. Alijotas-Reig J, Fernández-Figueras MT, Puig L. Inflammatory, immune-mediated adverse reactions related to soft tissue dermal fillers. Semin Arthritis Rheum . 2013; 43( 2): 241- 258. Google Scholar CrossRef Search ADS PubMed 14. Coleman SR; Plastic Surgery Educational Foundation DATA Committee. Cross-linked hyaluronic acid fillers. Plast Reconstr Surg . 2006; 117( 2): 661- 665. Google Scholar CrossRef Search ADS PubMed 15. Marusza W, Mlynarczyk G, Olszanski R et al. Probable biofilm formation in the cheek as a complication of soft tissue filler resulting from improper endodontic treatment of tooth 16. Int J Nanomedicine . 2012; 7: 1441- 1447. Google Scholar PubMed 16. Monheit GD, Rohrich RJ. The nature of long-term fillers and the risk of complications. Dermatol Surg . 2009; 35( Suppl 2): 1598- 1604. Google Scholar CrossRef Search ADS PubMed 17. Sadashivaiah AB, Mysore V. Biofilms: their role in dermal fillers. J Cutan Aesthet Surg . 2010; 3( 1): 20- 22. Google Scholar CrossRef Search ADS PubMed 18. 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Aesthetic Surgery Journal – Oxford University Press
Published: Feb 6, 2018
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