Demand for non-surgical cosmetic procedures is rapidly growing. These include the use of hyaluronic acid (HA) dermal fillers for volume replacement, skin rejuvenation and soft tissue augmentation (Cohen et al, 2015). HA dermal fillers are biodegradable gels and are the most widely used dermal filler in the US, Europe and Australia (Zhang et al, 2020). The use of HA dermal filler is considered safe, and Düker et al (2016) acknowledge complication rates in fewer than 3% of procedures. A number of adverse events have been recognised with the use of these dermal fillers, including inflammatory and non-inflammatory nodules; overcorrection or undesired aesthetic outcomes; discolouration at the injection site; transient and persistent oedema; foreign body reactions; bacterial infections; tissue necrosis secondary to vascular occlusion or compression; and visual impairment or vision loss (Cohen et al, 2015). An important benefit of HA dermal filler is that it can be dissolved with hyaluronidase in the event of adverse outcomes (Wu et al, 2018).
Hyaluronidase is an endogenous endoglycosidase that catalyses the glucosaminidic bond between C1 of the glucosamine moiety and C4 of glucuronic acid to hydrolyse hyaluronic acid into monosaccharides (Murdoch, 2015). The enzyme's pharmacodynamics have led to its usage in medicine for over 60 years in the fields of ophthalmology, dermatology and pain medicine (Murdoch, 2015). Subsequently, Brody (2005) pioneered its use in the resolution of dermal filler complications. However, hyaluronidase has its own set of risks that are frequently overlooked in the aesthetic speciality due to scant reports of complications (Andre and Fléchet, 2008). The most serious concern is allergic reactions, which was first reported by Taylor and Pollowitz in 1984. Allergic reactions to hyaluronidase, including anaphylaxis, have been reported in 0.1% of ophthalmology procedures (Andre and Fléchet, 2008). It is imperative that medical practitioners relying on hyaluronidase for procedures in the aesthetics field be knowledgeable about the risks involved with this medication.
Review aim
This integrative literature review will aim to present evidence for the safety of hyaluronidase administration in the aesthetic field. The purpose of this integrative literature review is to provide updated information regarding the safe use of hyaluronidase in patients receiving HA dermal filler complication management and explore necessary considerations for the potential use of hyaluronidase prior to administering HA treatments.
Method
Search strategy
The search strategy aimed to find published studies using medical and nursing academic databases and a search of CINAHL and OVID was undertaken. The database searches used a blend of keyword and medical subject headings (MeSH) combinations to locate studies consistent with the review aims. The MeSH and keywords used are detailed in Table 1. Furthermore, the author conducted a university library search after limited results were acquired through CINAHL and OVID. This proved to be an effective method for comprehensively locating literature on the topic, with most search strategies yielding duplicate articles to those already identified.
Table 1. Keyword and MeSH search terms
| Combination | Keyword | MeSH |
|---|---|---|
| 1 | ‘Hyaluronidase’ | ‘Hyaluronidase’/‘Hyaluronoglucosaminidase’ |
| 2 | ‘Hypersensitivity reactions; anaphylaxis’, ‘severe allergic reaction’ or ‘anaphylactic shock’ | ‘Hypersensitivity, immediate’, ‘anaphylaxis’ or ‘drug sensitivity’ |
| 3 | ‘Hyaluronic acid’ or ‘dermal filler’ | ‘Hyaluronic acid’ or ‘dermal filler’ |
Inclusion criteria
All studies considered for this integrative literature review included patients with HA filler complications who were treated with hyaluronidase. All ages, genders, aesthetic settings and healthcare providers were eligible. Animal studies were not considered. Studies that were supportive of the use of hyaluronidase in the aesthetic field or investigated the outcome of hyaluronidase in the correction of HA filler adverse events were included. This review considered studies that used quantitative, qualitative or mixed methods. Case reports and case series, as well as experimental and non-experimental designs, were included. Although mixed method studies were considered, no mixed method or qualitative studies were included in this review, due to a lack of literature on this phenomenon. The inclusion and exclusion criteria are available in Table 2.
Table 2. Inclusion and exclusion criteria
| Included | Excluded |
|---|---|
| The use of hyaluronidase for hyaluronic acid dermal filler adverse events | No full-text available |
| Primary studies descriptive of adverse outcomes with the use of hyaluronidase | Setting other than aesthetics |
| English language | Studies presented in Rzany et al's (2009) review |
| Full-text articles | Duplicate articles |
| Primary literature | Secondary/tertiary literature |
| All date ranges | Animal studies |
Study inclusion
Following the search, 625 citations were found. Records were then excluded due to the following reasons: discipline other than aesthetics; secondary/tertiary papers; textbook/chapter; non-English languages; duplicates; animal studies; and hyaluronidase not discussed/used. The search yielded a total of 17 eligible records: 13 case studies and four cohort studies.
Findings
The studies in this integrative literature review were subjected to thematic analysis to identify and investigate recurring themes or important concepts. The coding was performed manually and followed Braun and Clarke's (2006) thematic analysis guide. Theory-driven coding around the question: ‘What are the risks of hyaluronidase use in dissolving HA dermal filler?’ was used for all included articles. Once coding was complete, they were collated into theme groups. These themes were reviewed against the data and research question. The two themes that were identified and will be presented are ‘hyaluronidase adverse effects and treatment’ and ‘intradermal skin tests’.
Hyaluronidase reactions and treatment
This theme identified six of the included articles that described negative or positive reactions to hyaluronidase. Two patients were reported to have immediate hyaluronidase reactions (Andre and Fléchet, 2008; Kim et al, 2015). Andre and Fléchet's (2008) patient contacted their clinic, concerned with ‘swelling’ of her face, and was later diagnosed with angioedema that progressed from around the mouth to the upper face in 15 minutes. The authors noted that there was no presence of tongue swelling or breathing difficulty (Andre and Fléchet, 2008). Kim et al (2015) noted that erythematous oedema was present after their patient's dissolving procedure of HA filler overcorrection with hyaluronidase. Furthermore, Wu et al (2018) reported sensitisation to hyaluronidase the day after their patient's fourth treatment, with the patient developing sudden pain and swelling of the face and facial nodules, presenting the need for HA filler correction with hyaluronidase. However, their face became red and enlarged again.
It is unclear if Saptura and Kapoors' (2020) patient suffered any reactions; however, they mentioned that their patient experienced swelling. These authors noted that antibiotic cover was not used after the dissolving treatment due to there being no signs of infection. However, at a 10-day patient review, it was explained that there had been a complete resolution of swelling (Saptura and Kapoor, 2020). Of the six articles presented for this theme, two papers expressed that no patients had a reaction to hyaluronidase treatment. The retrospective cohort study by Ors (2020) reported no hyaluronidase allergies in all 16 of their patients. Additionally, Zhang-Nunes et al (2021) reported no reactions in their nine participants, where each person received 14 injections of varying doses of hyaluronidase (seven injection sites per forearm) to compare the dosing required to dissolve HA dermal filler. The remaining 11 records made no mention of positive or negative reactions to hyaluronidase reactions.
Hyaluronidase treatments were described in four of the included records. Andre and Fléchet (2008) and Kim et al (2015) both detailed the treatments for hyaluronidase reactions in their patients. Andre and Fléchet (2008) administered 4mg betamethasone to a patient and, within 2 hours, reported rapid resolution of the angioedema and they discharged her with prednisolone 40mg three times daily for 3 days. These authors noted that the patient's angioedema resolved to a natural look ‘a few days later’, at which time, HA filler was performed (Andre and Fléchet, 2008). Kim et al (2015) detailed that their patient was prescribed antibiotics for 7 days without improvement, at which time, she reported to their clinic. Kim et al (2020) conducted a biopsy from the focal nasolabial fold plaque lesion, and the patient was treated with systemic corticosteroid, antihistamine and topical steroid cream, which improved the erythematous oedema in 4 days. Conversely, Wu et al (2018) made no mention of treatment for hyaluronidase reaction; however, it is noted that their patient was diagnosed with a hyaluronidase allergy and was not treated with hyaluronidase again for the HA filler complication. This resulted in palpable nodules at a 6-month review.
Intradermal skin testing
Four of the included records described intradermal skin testing. Andre and Fléchet (2008) proposed a skin test to eliminate the risk of allergic reaction prior to the administration of hyaluronidase. However, the patient refused. The authors did not disclose if a skin test was conducted after their patient developed a reaction (Andre and Fléchet, 2008). Kim et al (2015) conducted intradermal skin testing for both HA filler and hyaluronidase and used normal saline as a negative control and histamine 0.1% as a positive control after their patient's reaction post-hyaluronidase administration. Their patient had a positive result for hyaluronidase sensitivity, as they developed a wheal and flare response in 30 minutes, with further exacerbation of the skin testing symptoms at 2 days (Kim et al, 2015). Wu et al (2018) conducted intradermal skin testing after a routine blood test proved normal. The skin test revealed a positive result for hyaluronidase, with the patient developing a 3cm area of erythema at the test site 24 hours later, which resolved after 1 week, resulting in hyperpigmentation of more than 2cm (Wu et al, 2018). Further blood workup ‘indicated hyaluronidase-specific T cell’ development and ‘exhibited Th1-or CD8 + T cells dominant immune response’ and the patient was diagnosed with delayed allergic hypersensitivity to hyaluronidase (Wu et al, 2018). In Zhang-Nunes et al's (2021) prospective randomised trial, intradermal skin testing was implemented as the control group, with each test forearm having a hyaluronidase intradermal implantation site. The remaining 13 records included in this review did not mention intradermal skin testing for hyaluronidase.
Discussion
Analysis of the studies identified the successful resolution of HA filler complications with the use of hyaluronidase in the majority of the captured literature. However, there was a lack of reporting, particularly those relating to patient allergies and details of hyaluronidase treatment. It is acknowledged that most of the included records primarily focused on the outcome of the HA filler complication, rather than the details of hyaluronidase use. However, over 80% (n = 14) of the included studies lacked patient allergy information and particulars on hyaluronidase preparation, dosing and observed reactions (including no reactions). Furthermore, a thorough capture of the patient's clinical presenting features was lacking in Wu et al's (2018) case report.
Interestingly, Warren (2017) was the only author to mention reporting any complication with their national drug administration, in this case, the Medicines and Healthcare products Regulatory Agency (MHRA). A search of the Australian Therapeutic Goods Administration (TGA) (2021a) adverse event database from 1 January 1971 to 1 September 2021 yielded 64 notifications. In 44 of these cases, hyaluronidase was suspected as the sole medicine cause, and no deaths were reported (TGA, 2021a). Facial and periorbital oedema were the most common reactions, with most concurrent medications (i.e. fentanyl, midazolam, ropivacaine) consistent with periorbital surgery. It should be noted that hyaluronidase was the only medicine reported in 45% of the cases. There were two reported cases that appeared to be related to aesthetic practice. One patient received concurrent abobotulinumtoxinA therapy, resulting in hypersensitivity and oedema, although HA filler was not mentioned. In the other case, hyaluronidase was used off-label, resulting in anaphylaxis and cardiac arrest. As these reactions were reported voluntarily by an unknown population, it is not always possible to estimate the frequency or to demonstrate a causal association to drug exposure. However, adverse event databases serve a significant purpose in keeping patients safe through identifying trends, unsafe practices and monitoring the therapeutic safety of a drug (TGA, 2021b). Practitioners should strive to report all adverse events to their national drugs administration (for example, the MHRA).
Hyaluronidase is available in many variants, including, more recently, a human recombinant variant (Murdoch, 2015). The human recombinant version has been cited as being a promising development in the potential minimisation of hyaluronidase-related reactions (Yocum et al, 2007; Murdoch, 2015). A double-blind, placebo-controlled, single-dose study with 100 subjects reported no positive allergic reactions to the human recombinant variant (Yocum et al, 2007). Zhang-Nunes et al (2020) conducted their prospective randomised experimental blinded trial using a human recombinant variant and reported no allergic reactions to the hyaluronidase. Other studies evaluating the use of human recombinant hyaluronidase report no immediate hypersensitivity reactions; however, delayed localised sensitivities (for example, injection site erythema and itching) have been reported (Yocum et al, 2007; Raghavan et al, 2016).
» Aesthetic practitioners are encouraged to report adverse events to their national drugs administration in an effort to maintain patient safety and identify trends in hyaluronidase use «
Hypersensitivity reactions are classified into four groups, based on the timing of onset and severity of the symptom complex: local reaction; immediate hypersensitivity; delayed hypersensitivity; and anaphylaxis (Limsuwan and Demoly, 2010). Three patients, with a possible fourth, were reported to have a drug reaction to hyaluronidase in this review. These are detailed in Table 3.
Table 3. Hyaluronidase drug reactions captured
| Hypersensitivity type | Reaction |
|---|---|
| Local reaction | Alluded localised injection site swelling (Saptura and Kapoor, 2020) |
| Immediate hypersensitivity | Angioedema of face (Andre and Fléchet, 2008) |
| Delayed hypersensitivity | Angioedema and erythematous/swollen nodules immediately after fourth treatment (Wu et al, 2018) Focal erythematous plaque (Kim et al, 2015) |
| Anaphylaxis | Nil reported |
The management of adverse drug reactions varies from conservative management to emergency life-saving measures. Localised hyaluronidase reactions typically include redness, swelling and injection site pain (Murdoch, 2015). Table 4 lists the most common signs and symptoms of allergic reactions. As demonstrated by the case studies presented by Andre and Fléchet (2008) and Wu et al (2018), angioedema can result from immediate hypersensitivity-type reactions. Angioedema should be managed with H1 antihistamines and adjunctive systemic corticosteroids (0.5–1mg/kg/day) in severe presentations (Limsuwan and Demoly, 2010). Andre and Fléchet (2008) and Wu et al (2018) reported successful treatment of hyaluronidase-induced angioedema in the outpatient setting with the use of antihistamines and corticosteroids, with full resolution of oedema within 3 days. Murdoch (2015) also advised aesthetic practitioners to use corticosteroids in the treatment of moderate allergic reactions. In the event of anaphylaxis, evidenced by systemic involvement (more than two body systems), measures such as alerting emergency services and administering epinephrine should be initiated as soon as possible (Limsuwan and Demoly, 2010).
Table 4. Signs of allergic reactions
| Signs of anaphylaxis (severe allergic reaction) | Signs of mild to moderate allergic reaction |
|---|---|
|
|
There is a marked lack of patient allergy information mentioned in the captured literature, particularly in cases where hyaluronidase adverse reactions were encountered or with the management of HA filler complications with hyaluronidase. The Aesthetic Complications Expert (ACE) Group guideline for the use of hyaluronidase in aesthetic practice acknowledges the increased risk of allergic reaction to hyaluronidase in patients with a history of bee- or wasp-sting allergies and considers this a relative contraindication for use (King et al, 2018). However, there was no mention of bee-sting allergy as a contraindication in HA filler or hyaluronidase procedures by Global Aesthetics Consensus, another expert group (Signorini et al, 2016). Furthermore, the absence of bee- or insectsting allergies as a contraindication in hyaluronidase product information suggests that the allergic risk to these patients is unknown. Gmachl and Kreil (1993) discovered hyaluronidase in the venom of snakes, scorpions, bees and wasps. Tan et al (2016) expressed concern that patients who are allergic to these bites and stings may also be allergic to hyaluronidase products. Keller et al (2014) discussed the use of hyaluronidase in patients with bee-sting allergies and concluded that hyaluronidase is an allergenic substance in 10–15% of cases. However, anaphylactic reactions remain rare.
Hypersensitivity reactions are also likely to occur in patients without reported allergies. Hyaluronidase hypersensitivity in ophthalmology cases has rarely been reported, with an estimated incidence of 0.1% (Andre and Fléchet, 2008; Keller et al, 2014). HA dermal filler protocols that include insect-sting allergies as a contraindication may give aesthetic practitioners false confidence in using hyaluronidase in patients without this allergy. The risks of HA dermal filler and hyaluronidase treatment should be considered against the outcomes of aesthetic treatment in all patients, with a focus on informed patient consent to all relative risks and well-educated aesthetic practitioners to manage complications that arise. Furthermore, there is confusion in the literature as to whether intradermal skin testing for hyaluronidase sensitivity should be conducted prior to its administration (Keller et al, 2014).
Intradermal skin tests investigate the skin's reaction to a potential allergy by injecting a small amount of a specific drug or allergen and monitoring for immediate or delayed signs of an allergic reaction (Australasian Society of Clinical Immunology and Allergy (ASCIA), 2016). A positive reaction is defined as an increase in wheal and red flare dimensions (ASCIA, 2016). The test should be conducted with positive and negative controls, as the test reactions can be considered invalid (ASCIA, 2016). The test results should be read at 15 and 20 minutes; however, delayed skin test readings after intradermal injection may be observed up to 96 hours later (ASCIA, 2016). This is an important consideration for hyaluronidase, because false-negative rates may be higher in these patients.
Limsuwan and Demoly (2010) emphasised that intradermal skin tests should be performed in a specialist environment and should not be performed within 4 weeks of an allergic reaction. Interestingly, Kim et al (2015) and Wu et al (2018) conducted intradermal tests after their patients' reaction as a diagnostic method to confirm hyaluronidase allergy. Keller et al (2014) asserted that if patients are anaphylactic to bee stings, then hyaluronidase intradermal testing should be performed by an immunologist; however, if a patient has an unknown or large reaction to bee stings, then an aesthetic clinic intradermal test should be performed in non-emergent (non-vascular compromised) situations.
Sensitisation to hyaluronidase appears to also occur. Wu et al (2018) reported the development of pain and swelling of the face on their patient's fifth treatment with hyaluronidase. This has also been reported in ophthalmology literature with subsequent cataract surgeries of the opposite eye inducing angioedema resulting from a delayed hyaluronidase allergy (Andre and Fléchet, 2008; Delaere et al, 2008; Park and Lim, 2013). Patients seeking aesthetic procedures are usually self-referred and privately funded, which may lead to procedures at multiple clinics over their cosmetic journey. Conducting intradermal skin testing results prior to HA filler treatment may place the patient at a higher risk of sensitisation to hyaluronidase with each subsequent use. Rzany et al (2009) highlighted the importance of not performing intradermal tests, as they are not a reliable indicator of allergy. Throughout aesthetic literature, intradermal testing has not been routine, and this is evident in the captured studies, with more than 75% of the studies not reporting intradermal skin tests.
If a patient is identified as having an actual or potential sensitivity to hyaluronidase, conservative management HA filler complications can be considered, including watchful waiting, natural degradation of the HA filler, medication management (i.e. antibiotics for infective complications, oral steroids for delayed HA filler sensitivity) and needle aspiration; however, excision should only be considered as a last resort (Convery et al, 2021). Persistent non-infectious late-onset inflammatory nodules from HA filler usually resolve within 1 year, even without treatment (Convery et al, 2018). However, if hyaluronidase use in the correction of HA filler is decided not to be given, then the effects on the patient's psychological wellbeing needs to be evaluated. Unfavourable HA filler reactions have a significant impact on quality of life (QoL), even when compared to chronic inflammatory illnesses such as psoriasis and atopic dermatitis (Düker et al, 2016). Although, Düker and et al (2016) included all injectable products, including permanent fillers, and excluded complications associated with overcorrection in their trial, the insights into the QoL of these patients is valuable for those that are not suitable for hyaluronidase procedures. Düker et al (2016) found that 75% of subjects' QoL was affected, with over 37% of these having a large or very large impact on their QoL. The biggest impact was on the patients' self-confidence. After sensitisation to hyaluronidase, Wu et al (2018) were required to manage their patient's multiple cutaneous granulomatous reactions conservatively. Unfortunately, the patient suffered post-inflammatory hyperpigmentation, and the nodules were slightly palpable at 6 months. The authors did not detail any psychological impacts affecting the patient's QoL in their case report.
Practitioners have a responsibility to guide patients through difficult times and providing emotional support may significantly benefit the patient (Convery et al, 2021). Furthermore, the risk of psychological distress and physical harm from hyaluronidase treatment must be weighed against the benefits of using hyaluronidase in HA filler complications (i.e. vascular occlusion or vision impairment/loss) and emerging or persistent complications (i.e. inflammatory lesion, granuloma or suspected HA filler delayed hypersensitivity reaction).
Implications for practice
It is hoped that the information provided in this review will assist in evidence-based protocols for the use of hyaluronidase in aesthetic practice. Furthermore, this research provides evidence for patient selection protocols in HA filler procedures, particularly those with previous allergies. Intradermal testing for diagnosis of suspected hyaluronidase allergy or prior to the use of hyaluronidase in patients with previous anaphylaxis of insect stings should be performed by an immunologist.
Recommendations for practice
Antihistamine and corticosteroid as first-line drug management of moderate allergic reactions in aesthetic clinics is recommended if reaction is localised to one system. Informed consent for hyaluronidase should be obtained concurrently with HA filler consent prior to procedures. Furthermore, aesthetic practitioners are encouraged to report adverse events to their national drugs administration in an effort to maintain patient safety and identify trends in hyaluronidase use. It may be advisable to refer patients with previous moderate-to-large reactions to an immunologist for hyaluronidase allergy testing prior to administration of HA filler. It is recommended that every practitioner considers the risks and benefits of administering or withholding hyaluronidase and creating a collaborative agreement for treatment with their patient.
Recommendations for education
Education on the use of antihistamine and corticosteroid medications in the event of large hypersensitivity should focus on aesthetic practitioners monitoring for signs of anaphylaxis and initiating anaphylaxis protocols upon detection. Furthermore, education on the safe use of antihistamine and corticosteroid treatment in the treatment of hyaluronidase reactions should take place. Practitioners need to be well educated in their practice environment, emergency protocols and equipment.
Recommendations for research
Studies and case reports should strive to thoroughly report interventional drugs, including brand, dosage and reconstitution medium, as well as adverse reactions or lack of drug reactions. This will ensure that future research can be compared and contrasted, providing succinct synthesis of phenomena. To establish the basis for evidence-based practice, international large-scale, multi-centre clinical studies are required to validate the off-label use of hyaluronidase, including an evaluation of the comparative risks between variants of hyaluronidase. Further research is required to understand the risks that hyaluronidase poses to those who have allergies to insect stings, and treatment protocols should be developed for these patients. It is evident that further research on the safety of intradermal testing of hyaluronidase outside of specialist facilities is needed.
Conclusion
HA-based dermal filler procedures are rapidly growing across the world. Although rare, complications can occur, and hyaluronidase has been advocated widely as a first-line drug to reverse many adverse reactions. Rzany et al (2009) concluded from their review that hyaluronidase is safe; however, they acknowledged that allergic reactions can occur. At the time, there was little evidence supporting hyaluronidase in the use of HA filler adverse reactions.
Adverse reactions to hyaluronidase are rare, and, when they do occur, can vary from mild to severe. Sensitisation to hyaluronidase can also occur and this needs to be considered when using hyaluronidase. This review identified the need to have antihistamine and corticosteroid available as first-line drug management, to ensure the safe management of moderate allergic reactions to the enzyme. Hyaluronidase in patients with previous allergies or allergies to insect stings remains unclear; however, the practitioner should always be prepared to initiate anaphylaxis protocols. If a patient has a confirmed anaphylaxis allergy to insect stings, then hyaluronidase should only be administered in an appropriate clinical environment with an appropriately confident and competent medical practitioner.
The safety of conducting intradermal skin tests prior to hyaluronidase remains questionable. Concerns regarding incorrectly administered testing and sensitisation to hyaluronidase were raised in this review. However, the risk of adverse reactions to hyaluronidase needs to be weighed against the risk of not treating HA filler complications, both physically and psychologically. In most HA filler complications, treatment with hyaluronidase remains beneficial, despite the rare risk of sensitivity.
Key points
- Adverse reactions to hyaluronidase are rare, and, when they do occur, can vary from mild to severe. However, most reactions can be safely treated with conservative management or antihistamine and corticosteroid treatment
- Hyaluronidase use in patients with insectsting allergies remains unclear; however, the practitioner should always be prepared to initiate anaphylaxis protocols. If a patient has a confirmed anaphylaxis allergy to insect stings, then hyaluronidase should only be administered in an appropriate clinical environment, with an appropriately confident and competent practitioner
- The safety of conducting intradermal skin tests prior to hyaluronidase remains questionable, as testing can easily be incorrectly administered and sensitisation to hyaluronidase can occur
- The risk of adverse reactions to hyaluronidase needs to be weighed against the risk of not treating hyaluronic acid-based filler complications. Hyaluronidase may remain the beneficial outcome in most situations, despite the rare risk of hyaluronidase sensitivity
- To establish the basis for evidence-based practice, international large-scale, multi-centre clinical studies are required to validate the off-label use of hyaluronidase, including an evaluation of the comparative risks between variants of hyaluronidase.
CPD reflective questions
- When considering hyaluronic acid dermal filler complications, do you think about the risks of hyaluronidase treatment itself?
- If treating a patient with hyaluronidase who immediately showed signs of drug sensitivity, what would be your steps to manage this?
- What is your practice relating to intradermal skin testing for hyaluronidase?