Article Type: Review Article

Accepted Article
CONSENSUS STATEMENT ON PREVENTION AND MANAGEMENT OF

ADVERSE EFFECTS FOLLOWING REJUVENATION PROCEDURES WITH

HYALURONIC ACID BASED FILLERS

WG Philipp-Dormston1, D Bergfeld2, BM Sommer2, G Sattler3, S Cotofana4,5, P Snozzi6,

U Wollina7, KPJ Hoffmann8, C Salavastru9, K Fritz9,10

1
Hautzentrum Köln (Cologne Dermatology), Schillingsrotter Str 39-41, 50996 Köln, Germany
2
Sommerclinics, Goethestraße 26-28, 60313 Frankfurt am Main, Germany
3
Rosenparkklinik, Heidelberger Landstrasse 18+20, 64297 Darmstadt, Germany
4
Institute of Anatomy, Paracelsus Medical University Salzburg & Nuremberg, Salzburg, Austria
5
Department of Anatomy, Ross University School of Medicine, Roseau, Commonwealth of Dominica, West Indies
6
Smoothline, Bahnhofplatz 2, 8001 Zürich, Switzerland
7
Academic Teaching Hospital of Technical University of Dresden, Friedrichstrasse 41, 01067 Dresden, Germany
8
St. Josef-Hospital Bochum, Abteilung für Ästhetisch Operative Medizin und Kosmetische Dermatologie,

Gudrunstraße 56, 44791 Bochum, Germany

9
Department of Paediatric Dermatology, Colentina Clinica Hospital, Carol Davila University of Medicine and

Pharmacy, Bucharest, Romania

10
Dermatology and Lasercenters Reduitstr. 13, D -76829 Landau, Germany

RUNNING HEADER: ‘AE PREVENTION & MANAGEMENT FOLLOWING HA

FILLER-BASED USE’

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/jdv.14295
This article is protected by copyright. All rights reserved.
 CORRESPONDING AUTHOR:
Accepted Article Dr med Wolfgang G Philipp-Dormston

Hautzentrum Köln (Cologne Dermatology)

Schillingsrotter Str 39-41

50996 Köln, Germany

Telephone: +49 0221 398 00 200

Fax: +49 0221 398 00 201

Email: [email protected]

SOURCES OF FUNDING:

The organization of the consensus conference and scientific funding was supported by

Pharm-Allergan GmbH, Frankfurt, Germany and Galderma Laboratorium GmbH,

Düsseldorf, Germany.

CONFLICTS OF INTEREST:

Dr Philipp-Dormston has been study investigator and member of the scientific advisory

boards of Allergan, Biofrontera, Galderma, L’Oreal, Leo and Merz and received honoraria

and scientific support by these companies. There is no conflict of interest or influence

regarding this publication by any means.

Dr. Snozzi has been a member of the scientific advisory board of Allergan and reports

personal fees and non-financial support from Allergan, Merz and Galderma outside of this

submitted work.

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 Dr. Sommer reports personal fees from Pharm-Allergan, non-financial support from
Accepted Article Galderma, and personal fees from Merz Pharmaceuticals outside of the submitted work.

Dr. Hoffmann worked as a consultant running studies and workshops for Allergan and

Galderma.

Dr Wollina, Dr Bergfeld, Dr Sattler, Dr Salavastru, Dr Fritz and Dr Cotofana have no conflict

of interests relevant to this manuscript to declare.

ABSTRACT

Facial fillers play an important role in the correction of facial changes associated with ageing.

They offer quick treatments in the outpatient setting with minimal subsequent downtime that

provide predictable, natural-looking, long-lasting results. Hyaluronic acid soft tissue

injectables have established their role as the fillers of choice for patients over the last 2

decades. Hyaluronic acid fillers are rarely associated with adverse reactions, and those that

do occur tend to be mild and temporary. However, as with all injected or implanted

biomaterials, adverse events can occur and patients must be fully informed of potential risks

prior to undergoing treatment. A panel of experts from Germany (D), Austria (A) and

Switzerland (CH) developed recommendations and this paper provides the ‘DACH

Consensus Recommendations’ from this group specifically on the use of hyaluronic acid

fillers. The aim is to help clinicians recognise potential risks and to provide guidance on how

best to treat adverse events if they arise. Contra-indications to hyaluronic acid fillers are also

detailed and ways to prevent adverse events occurring are discussed. Hyaluronic acid-based

products are claimed by some to be very close to fulfilling many of the requirements of an

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 ideal tissue augmentation agent, nevertheless, the potential benefits of treatment must be
Accepted Article carefully weighed against the risk of potential adverse events.

INTRODUCTION

Facial aging is a dynamic process involving facial bones, retaining ligaments of the face,

muscles of facial expression and mastication, facial fat compartments and the skin. The onset

and the progression of this process varies between individuals and each of the involved

structures change at a different pace and severity. The clinical appearance can be generally

characterised by loss of facial volume, increased facial vasculature, pigment alterations, and

development of lines and wrinkles. These effects are due to epidermal thinning, dermal

atrophy and actinic changes associated with loss of dermal collagen1. According to the

Plastic Surgery Report 2014, released by the American Society of Plastic Surgeons2 the

numbers of cosmetic minimally-invasive procedures increased by 154% during the last 14

years, whereas the numbers for cosmetic surgical procedures decreased by 12%. During the

same period the numbers of soft tissue fillers applications alone, increased by 253%. The

increased popularity of such minimally-invasive procedures are that they are quick, available

in the outpatient setting with minimal subsequent downtime, and they provide predictable,

natural and long-lasting results. Facial fillers play a key role in the correction of age-related

facial changes and there is an array of non-, semi- and permanent dermal and sub-dermal

fillers available that can be biodegradable, reversible or non-reversible3,4.

Hyaluronic acid (HA) based fillers have become the most popular category of filler product.

They have been shown to last longer and require less product to achieve the same cosmetic

effect as collagen for treatment of nasolabial folds5,6,7,8,9.

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 HYALURONIC ACID (HA)
Accepted Article HA is a naturally occurring linear polysaccharide that is a component of all connective

tissues. It is a glycosaminoglycan comprising regular repeating non-sulfated disaccharide

units of glucuronic acid and N-acetylglucosamine10. It has no species or tissue specificity so

there is limited potential for causing immunologic reactions. HA acts as a lubricant and

moisturiser as it is highly hydrophilic. When water is drawn into the HA matrix, it creates a

swelling pressure, or turgor, that enables the HA complex to withstand compressive forces. It

has proved useful as a filler in treating some of the signs of ageing since it moisturises the

skin and returns some of its elasticity and tone, producing natural, healthy-looking facial

skin1. Over time, HA fillers are broken down by natural biological processes and removed

from the body.

Most HA fillers used in clinical practice are of bacterial origin and stabilised by crosslinking.

Unmodified HA has a half-life of only 24-48 hours, rendering it is unsuitable as a dermal

filler, but synthetic HA crosslinking improves stability, elastoviscosity and longevity that can

reach or exceed one year11. In most market-leading products, the crosslinking agent used is

1,4-butanediol diglycidyl ether (BDDE). Its stability, biodegradability and safety record

spanning >15 years make it the industry standard12.

The first HA filler was developed by Balazs in 198913 and HA-derived fillers have been

available in Europe since 199614. There are now several HA fillers available, with many

others in development. HA fillers can vary significantly in terms of properties, due to

differences in HA concentration, amount of crosslinking, visco-elasticity and particle sizes.

Thus, it is important to select the product that offers optimum outcomes for the particular

facial area being treated.

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 The uniform structure of HA throughout all living species means that adverse immune
Accepted Article reactions are rare. However, despite claims from manufacturers that fillers are non-toxic and

non-immunogenic, or that complications are very uncommon, adverse effects (AEs) do occur.

Implanted or injected biomaterials in contact with the blood can trigger a variety of AEs

which may appear early or late, ranging from local to systemic effects15. Thus, patients

should be fully informed that unforeseen AEs may occur prior to treatment. Currently there

is a general lack of reliable clinical data regarding the positive and negative aspects of

treatment. The American Society for Dermatologic Surgery (ASDS) has developed

consensus guidelines on the use of injectable fillers (Guidelines of Care Task Force, 2008).

These guidelines do not stipulate standards of care but are intended as an evolving document

presenting how physicians commonly use injectable soft tissue augmentation products in

patients16.

Our aim is to provide updated consensus recommendations on the use of HA fillers to help

clinicians recognise potential risks and indicate how best to treat AEs if they arise. The

‘DACH guidelines’ are not intended to replace specialist training and valuable experience,

but have been developed to support aesthetic clinicians. However, each patient must be

assessed individually, acknowledging that their particular requirements may vary from those

proposed in a standard treatment algorithm.

CONSENSUS PANEL

The need for consensus guidelines was recognised in 2014. During the 2015 annual meeting

of the German Society for Aesthetic Botulinum Toxin Therapy (Deutsche Gesellschaft für

Ästhetische Botulinumtoxin-Therapie), leading society members defined the criteria for the

HA AEs to be included in the guideline and an expert panel was appointed to develop the

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 treatment algorithm. After defining the Standard Operating Procedures (SOP), a 1-year
Accepted Article period of interactive scientific exchange and voting in a second approach approval followed,

leading into the results of this publication. The panel of experts comprised members from

Germany (D), Austria (A) and Switzerland (CH) and they developed the ‘DACH Consensus

Recommendations’ specifically on the use of HA fillers.

ADVERSE EFFECTS

General Filler Adverse Effects

AEs following any filler treatment can be broadly categorised as being attributable to the

following:

• Injectable material

• Injection technique

• Individual patient immunologic responsiveness

Adverse reactions to any type of surgical intervention/replacement therapy can be divided

into immediate-to-short term (<2 weeks after treatment) or delayed (>2 weeks after

treatment). Most immediate-to-short term AEs tend to be related to injection technique and

method of filler delivery and usually comprise haematoma, redness and/or swelling, and pain

and/or tautness. Allergic or anaphylactic reactions can also occur rarely, due to patient

hypersensitivity to one of the injectable materials, inflammation or infection at the injection

site and systemic effects (e.g. influenza-like symptoms, nausea and dizziness). Delayed, and

often chronic reactions with formation of foreign body granulomas are thought to be related

to late immunological reactions (e.g. Type-IV hypersensitivity reactions) or biofilm

formation17,18,19,20,21,22,23. A biofilm is a dormant bacterial infection, probably introduced

during injection or related to a regional or systemic infection (e.g. dental infections), that

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 forms a structured community of micro-organisms surrounded by a protective barrier
Accepted Article comprising a self-developed polymeric matrix24,25. These colonies adapt and maintain their

integrity by evading the host’s immune system through reduced metabolism and growth rates,

as well as being antibiotic resistant and protected from phagocytosis by the extra-polymeric

barrier. Once established, biofilms are extremely difficult to completely eradicate24.

Although biofilms are not usually associated with non-permanent fillers, the prolonged

longevity of HA fillers of up to 36 months26 suggests they may also pose a risk for biofilm

complications similar to permanent fillers25,27. Bjarnsolt28 and Christensen20 both showed that

bacteria could be detected in almost any late-onset tissue filler lesions by means of

fluorescence in situ hybridation, even though standard cultures where negative. In another

large study, a single shot of antibiotics at the time of implantation of a PMMA filler reduced

the incidence of late inflammatory reactions from 7% to 2% (p=0.03)29. Furthermore, Alhede

et al showed that in a mouse model the injection of contaminated HA (with as little as 10-30

bacteria) were sufficient to cause biofilm formation (microcolonies on the skin contain up to

100,000 bacteria). A single-shot of antibiotics at the time of injection prevented biofilm

formation whereas a single-shot of antibiotics done 10 days after injection had no influence23.

Patient Consent

HA fillers are considered very safe, with most AEs being mild and temporary30. However,

even if a patient has previously been treated with facial fillers without complications, it is

vital to inform them that there is a rare but possible risk of an immunologic reaction or a

vascular accident after HA treatment. All patients should sign an informed consent document

pre-treatment and should be informed about all possible HA-specific complications.

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 Importance of Product Selection
Accepted Article Soft tissue injectable fillers are deemed to be medical products rather than pharmaceuticals.

It is essential to choose products from a reputable company that ideally should also be

manufacturing pharmaceuticals that adheres to the highest standards by testing their products

before marketing in methodologically rigorous clinical trials. There is a wide range of fillers

available that have different properties suitable for different indications, so selection should

be based on a detailed understanding of the various products and their rheological properties.

Adverse Event Prevention

It is essential to obtain a detailed patient clinical history pre-treatment to determine any

history of HA hypersensitivity, or to any other treatment component (e.g. local anaesthetic or

crosslinker), evidence of skin inflammation or infection at the injection site (e.g. acne),

tendency to develop hypertrophic scars, auto-immune disease (e.g. diabetes, multiple

sclerosis, systemic lupus erythematosus), signs of streptococcal infection (e.g. repeated bouts

of angina, acute articular rheumatism), dental procedures that could potentially spread

pathogens, or use of anti-coagulant concomitant medication etc.

AE prevention is important and we recommend adhering to the following pre-treatment:

• Detailed knowledge of important anatomical structures and vessels

• Detailed knowledge of the specific target injection sites

• Detailed knowledge of the injectable material and its properties

• Ensure formal sterile surgical preparation to prevent the introduction of bacteria and

potential subsequent biofilms

• Administer injections slowly and react quickly to patient pain or occurrence of any

unexpected reactions

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 • Use aspiration if possible, although it should be noted that although aspiration is
Accepted Article important it does not provide 100% avoidance of intravascular injection. In high risk

zones, a blunt cannula can also be used

Furthermore, a recent publication has demonstrated that mannitol, which has a long and well-

established safety profile in both the food and pharmaceutical industry, can help prevent

some of the potential AEs associated with HA fillers. Mannitol has both hydrating and anti-

oxidant properties that make it an ideal excipient for use with HA fillers. The free-radical

scavenging properties of mannitol help reduce the inflammation and swelling associated with

the HA injection procedure and prevent the degradation of injected HA by free radicals31.

Potential Adverse Events

Localised Injection Site Reactions: Most AEs associated with HA fillers comprise localised

injection site reactions resulting from an acute inflammatory response to tissue damage and

introduction of foreign material. Although frequent, they are generally mild and temporary30,

comprising bruising at the injection site, redness, slight pain, and swelling6. Swelling can

occur due to the water-retaining effects of hydrophilic HA and it is important not to make

treatment adjustments or repeat injections too early since there might be underlying swelling

or haematoma which might lead to over-correction if re-injections are done too early.

Furthermore, volume augmentation with highly viscous HA injected into the deep tissue

layers can migrate due to compression of the material from the superficial layers above.

Treatment: These initial localised complications are best managed with the application of

pressure and ice (an exception is for the complication of vascular occlusion or compression,

where pressure and ice are contraindicated). Redness and swelling should resolve within 1-2

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 days post-injection, but may last ≥3 days in some individuals. Swelling can be treated with
Accepted Article homoeopathic or bromelain-containing drugs, while swelling occurring 1-3 weeks post-

injection without signs of inflammation or skin discolouration due to HA can be treated with

hyaluronidase or steroids if necessary (see Table 1).

Hyaluronidase is an enzyme that is able to rapidly counteract the effects of HA treatment

within a few hours by breaking down HA molecules at the cross-link points; however,

significantly, it does not seem to have any effect on the body’s own HA30,32. Gentle massage

increases the effect of the enzyme by ensuring sufficient dispersal. Hyaluronidase products

are either of ovine, bovine, or human recombinant origin. There is a risk of allergic reaction

within 30 minutes of administration and therefore all patients should be kept under

observation following treatment. Special caution should be undertaken before injecting a

patient with a known hypersensitivity to hymenoptera venom as these patients have a higher

incidence of allergic reactions to hyaluronidase. It is known that bee venom (Apis mellifera)

shares 30% sequence identity with human hyaluronidases, which could suggest potential

cross-reactivity between hyaluronidase used in the clinic and hyaluronidase in bee

venom, i.e. patients with bee venom allergy could be at an increased risk of an

allergic reaction to the hyaluronidase used in facial filler treatment 33 . However, the

clinical significance of hyaluronidase in terms of allergic reactions to venoms has

not been clearly established as insufficient information is currently available. The

risk of a reaction to hyaluronidase in a patient having a history of hymenoptera

allergy is minimal but, in cases of concern or when planning the treatment of a

delayed adverse reaction, hyaluronidase skin testing of the patient can be

conducted 34 . Furthermore, using human recombinant hyaluronidase may reduce the risk

of hypersensitivity reactions. All physicians are recommended to ensure they have

hyaluronidase supplies readily available in case of emergency and to make themselves

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 familiar with the product information detailed in the package insert35.
Accepted Article
Vascular Obliteration: The most serious immediate onset reaction associated with HA filler

treatment is vascular obliteration. This is due to intra-vasal injection or vascular

compression, thrombosis or embolisation following inadvertent interruption of the vascular

supply and subsequent development of injection site ulcers36, 37, 38, especially when injecting

in the high risk glabellar area39. This is a rare AE and is in general associated with typical

treatment indications, but it can potentially occur in any facial treatment area. It is more

commonly reported from Asia where nose augmentation is a more frequent procedure. Cases

of necrosis after administering HA injections into the nasolabial folds have been reported40.

The nasal ala is deemed a danger zone and injections of patients who have a history of open

rhinoplasty should be performed with maximum caution or avoided. Although inadvertent

intra-arterial injection of fillers is rare, the potential risk should always be considered.

Blindness secondary to filler injections into the glabellar region is a rare complication, but it

can occur if injection into an artery causes retrograde flow proximal to the central retinal

artery's branching point, with the filler then being carried forward with the blood flow,

eventually causing obstruction32,41. Thus, irreversible vision loss should be added to the list of

potential complications associated with injection of cosmetic facial fillers, regardless of

where the filler is injected in the face42,43.

Treatment: We recommend avoidance of critical anatomical areas, aspiration, slow injection

technique and avoidance of excessive quantities of HA, with close attention paid to any pain

or discolouration (i.e. skin whitening or livedo reticularis). In high risk zones, a blunt cannula

of at least 25 gauge can be used. Most authors use high doses of hyaluronidase for the

affected tissue, with repeated injections until there is a visible improvement/normalisation of

the capillary refilling, combined with acetylsalicylic acid32,44. Carruthers et al presented a

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 technique for treating vascular occlusion, which left untreated may potentially lead to
Accepted Article blindness or stroke. This technique comprises retro- or peri-bulbar injection of hyaluronidase.

Inadvertent canalization of facial vessels can cause embolic occlusion of retinal vasculature

and the retina is only able to withstand a maximum of 90 minutes of hypoxia so, in the

absence of an ophthalmologist, this technique may be used in an emergency to reverse this

very serious complication45.

Skin necrosis is a rare but potentially disastrous and disfiguring complication following HA

filler injection and there is no standard treatment option for HA-related skin necrosis46.

Avoidance can be achieved through adopting a meticulous technique, but if necrosis should

occur then mainstays of treatment include prompt recognition, immediate treatment with

hyaluronidase, oral acetylsalicylic acid (aspirin), and warm compresses32. There have been

recommendations in the literature that nitroglycerin paste may be useful in the early treatment

of patients presenting with ischaemic complications following dermal filler treatment, and

half of the participants in the consensus panel do use nitroglycerin in this way. However,

Hwang et al found that no significant improvement in perfusion was noted in animal model

after applying nitroglycerin paste to treat filler-associated skin ischaemia and indeed

concluded that it could worsen the ischaemia as well as leading to other adverse effects47.

Meanwhile Kang et al reported on a patient who experienced tissue necrosis of the glabellar

area after receiving filler injections that was successfully treated using platelet-rich plasma48.

Other secondary treatment options for necrosis include intra-arterial infusion of

hyaluronidase which has been used in peripheral arterial occlusive diseases with no

significant complications32. In a case study of ophthalmic artery occlusion by injected HA

filler, intra-arterial infusion of hyaluronidase was shown to be able to recanalise the

ophthalmic and facial arteries faster than conservative treatment without surgical

intervention46. Administration of ancillary vasodilating agents such as prostaglandin E1 can

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 also be beneficial32. In severe, persistent cases, hyperbaric oxygen should be administered to
Accepted Article aid the survival of compromised tissue by delivering oxygen deep into the skin49,50.

Haematomas and Ecchymoses: These occur due to extravasation of blood after insertion of

a needle into the skin and inadequate prevention of bleeding. A number of factors can

facilitate the occurrence of haematomas and ecchymoses, including alcohol consumption,

anti-platelet-aggregating drugs (e.g. acetylsalicylic acid, clopidogrel or ticagrelor),

ticlopidine, vitamin E or non-steroidal anti-inflammatory drugs pre-treatment3.

Treatment: Treatment comprises discontinuation of the intake of those drugs (if possible

based on the indication for the drugs), or refraining from alcohol for some days pre-treatment.

Firm pressure immediately post- procedure is important; ice-pack application may also prove

beneficial. Vitamin K creams, heparin and arnica can also provide relief, however

spontaneous resolution usually occurs, taking on average 2 to 7 days3.

Tyndall Effect: If HA injections are administered too close to the skin’s surface, this can

cause bluish translucent lines through the skin that resemble a bruise (Tyndall effect). This

occurs as a result of light scattering of the shorter-wavelength blue light by the HA filler

particles35.

Treatment: We recommend hyaluronidase injected into the exact same area as the HA filler.

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 Lumps and Nodules: Lumps and nodules are a common complication following filler use
Accepted Article and are associated with significant patient morbidity. They are commonly categorised as

either non-inflammatory or inflammatory. Non-inflammatory nodules are typically seen

immediately post-implantation and are usually secondary to improper filler placement or an

underlying, deep haematoma. Inflammatory nodules may appear anywhere from days to

months after treatment and can result from varied aetiologies, including infection,

hypersensitivity reactions, or sterile abscesses.

Treatment: Lumps or nodules occurring a few days after injection may be due to infection

and should be treated with antibiotics, with incision and drainage if necessary. Persistent

swelling 1-3 weeks post-injection may be filler material-dependent and is best treated with

hyaluronidase to disperse the material. New swelling occurring 1-3 weeks or later after

injection may be due to either filler migration or reaction to HA and should be treated with

hyaluronidase and then steroids if necessary. A single knot appearing a few days or weeks

after treatment may be due to chronic inflammation or a possible biofilm. Treatment should

comprise antibiotics, followed by hyaluronidase if no response, and finally steroids if

necessary. Emergence of multiple knots a few days or weeks post-treatment may be due to a

biofilm or possible chronic immunological reaction and should be treated with antibiotics,

followed by hyaluronidase if necessary, and then with steroids if there is no treatment

response or there is histological proof of a granuloma. In our combined experience of treating

more than 500 documented cases of delayed inflammatory reactions following treatment with

a variety of HA fillers, the authors of this publication have found that broad-spectrum

antibiotics in conjunction with hyaluronidase injections into persistent inflammatory

indurations appear to be an effective treatment regimen in the majority of cases. This

suggests that biofilms play a significant role in the emergence of these inflammatory reaction

AEs.

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 Interestingly, with the accepted high safety and efficacy levels of filler procedures, a new
Accepted Article clinical situation has emerged in which some patients, in the quest for physical perfection,

become addicted to multiple sequential cosmetic injections, thereby increasing the risk of

AEs, particularly skin granulomatous reactions. In such cases, histopathology is the best way

to achieve accurate diagnosis51.

Hypersensitivity: Until recently, it was believed there were no cases of HA hypersensitivity.

However, local and systemic, acute and chronic hypersensitivity cases have been observed

after HA injection. These comprise angioedema-like swelling, nettle-type rash reaction,

induration and papulocystic nodules, as well as abscess formation with spontaneous

rupture52,53,54,55. Long-term follow-up is necessary to assess the safety and reversibility of

such AEs3.

Treatment: Treatment options for patients presenting with delayed HA hypersensitivity

reactions range from simple observation to local treatment with corticosteroids. Lesions that

fail to resolve with conservative therapy may be best treated with systemic corticosteroids,

intravenous antihistamines, although occasionally surgical intervention may be required.

Infection: Infection following filler treatment is uncommon56, but may be caused by

bacterial, viral (most commonly herpes simplex), and Candida species. Rarely, patients may

present with signs and symptoms of infection, i.e. multiple red, tender lumps and if these

signs are observed, prompt action is necessary to avoid development of a persistent biofilm.

A single abscess would indicate contamination through the skin during treatment, while

multiple, simultaneous abscesses may indicate contamination in the syringe prior to

treatment35.

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 Treatment: Patients with a history of cold sores may be pre-treated with acyclovir,
Accepted Article famciclovir, or valacyclovir to reduce the severity and duration of cutaneous herpes

infections. In cases of infection, abscesses should controlled with incision and drainage, a

course of antibiotics, and if necessary, hyaluronidase. When there is evidence of a biofilm,

bacteria are irreversibly bound to the implant material and the only course of action is its

complete removal which, in the case of HA fillers, can be achieved with hyaluronidase,

together with concomitant use of antibiotics to prevent biofilm spread. For acute infections

(e.g. cellulitis, abscess) the antibiotic therapy should cover common bacteria such as

Staphylococcus aureus or S. pyogenes, therefore a potential recommendation is

amoxicillin/clavulanic acid or in case of a known allergy to penicillin, clindamycin can be

used. For a delayed onset inflammation where a biofilm is suspected, the use of a marcolide

antibiotic with anti-inflammatory action (e.g. clarithromycin) proves good results. A

combination with a chinolone antibiotic (e.g. 3rd or 4th generation) is also used by some of

the authors but depends on an individual risk-benefit-analysis for each case. The therapy

should cover microorganisms such as S. epidermidis, Psuedomonas acnes or P. aeruginosa

but often also needs to cover rarer bacteria.

Potential AEs associated with HA fillers and their recommended treatment, as suggested by

these DACH Consensus Guidelines, are summarised in the treatment algorithm (Table 1).

CONCLUSION

The properties of an ideal filler are that it is safe (i.e. non-allergenic and non-immunogenic),

non-carcinogenic, non-teratogenic, and non-migratory. Currently, there is no filler available

that fulfils all these criteria. However, manufacturers of HA-based products claim their

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 products are close to fulfilling many of the requirements of an ideal tissue augmentation
Accepted Article agent39.

The versatility of HA-derived products expands the physician's treatment options for

aesthetic procedures. Its low risk of immune reactions makes HA products the cornerstone of

injectable fillers, which are indisputably gaining ground in the search for the ideal

implant57,58,59. Nevertheless, the potential benefits that patients may receive from HA-derived

fillers must be carefully weighed against risk of potential AEs.

Cosmetic treatment with HA fillers has been considered relatively safe, with the occurrence

of serious AEs being rare, but as their use continues to expand worldwide, an increasing

number of AEs to these products have been reported. Despite a variety of physicians in a

wide range of medical specialties being authorised to perform HA injections, including

dentists, currently there is no standardisation of treatment options for dealing with AEs. As

such, there is now an urgent need for publication of specific guidelines for AE management60.

Funt et al recognised this need to provide guidance to physicians and conducted a review of a

variety of dermal fillers, including HA, to provide physicians with a background to the

aetiology of filler-related complications, as well as structured, clear guidance on their

treatment and avoidance49. Furthermore, a multinational, multidisciplinary group of experts

in cosmetic medicine convened the Global Aesthetics Consensus Group to review the

properties and clinical uses of HA products (i.e. Hyalacross™ and Vycross™) and to develop

updated consensus recommendations for the management of early and late complications

associated with HA fillers61. These ‘DACH Consensus Guidelines’ are intended to

complement other published guidance to inform clinicians how best to recognise and prevent

potential risks and provide recommendations on how to manage AEs if they occur62.

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 ACKNOWLEDGMENTS
Accepted Article We thank Pharm-Allergan GmbH, Frankfurt am Main and Galderma Laboratorium GmbH,

Düsseldorf for financial research support for this publication. Medical writing support for this

manuscript was provided by Debbie Jordan, with funding from Pharm-Allergan.

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Accepted Article Time Clinical Signs Possible Cause Recommended Therapy

During injection Whitening/blanching of the skin and pain, Vascular occlusion (intravascular Hyaluronidase, warmth, anticoagulation, if necessary further rheological
followed by livedo /extravascular, complete / partial) and surgical procedures

Immediately after Swelling Injection trauma, haematoma Depending on trauma pressure, cooling
injection
Immediately to a few Angioedema-like swelling (mainly in the lip Allergic or anaphylactic reaction Observation: if no muco-cutaneous involvement usually will resolve in
hours after injection area) approximately 1 to 2 hours. If persisting or muco-cutaneous involvement:
intravenous antihistamines/steroids, if necessary emergency procedures
Immediately to a few Neurological symptoms, e.g. impairment of Retrograde embolisation of central Emergency treatment at neurological / ophthalmic stroke unit, e.g. systemic
hours after injection vision ateries with ischemia, e.g. ophthalmic anti-ischemia treatment,
artery retrobulbar Hyaluronidase injection when required
First day up to 2 weeks Swelling without discolouration Injection trauma, hygroscopic effect Observation: maybe homoeopathic drugs or bromelain-containing drugs
First day up to 2 weeks Swelling with dark or livid discolouration Haematoma Heparin-/ Vitamin K-containing creams

First day up to 2 weeks Livedo (reddish- or blue-mottled discoloration) Vascular obliteration (intravascular Hyaluronidase, warmth, anticoagulation, if necessary further rheological
/extravascular, complete / partial) and surgical procedures
Few days after injection Newly developed redness and swelling (with Infection Antibiotics for sufficient duration
signs of inflammation)

Few days after injection Newly developed fluctuating single process Abscess Incision, drainage, antibiotics
(with signs of inflammation)

1-3 weeks after Persisting swelling without signs of Injection material-dependent: swelling Hyaluronidase
injection inflammation or skin discolouration due to hygroscopic effect, wrong injection
site or overdose
1-3 weeks after New swelling without signs of inflammation or Migration of injection material or reaction Hyaluronidase, if no response steroids
injection skin discolouration to injection material

Few days or weeks after Single knot / swelling / induration (possible Chronic inflammation, possible biofilm Antibiotics, if no response hyaluronidase in addition, steroids if no response
treatment slight redness) to the previous

Few days or weeks after Multiple knots / swelling / indurations Possible biofilm (look for signs of previous Antibiotics, if no response hyaluronidase in addition
treatment (possible slight redness) infection, dental treatment etc.). Also (steroids or other immunosuppressives only if no response to the previous
consider chronic immunological reactions or if histopathological proof of granuloma)
(granuloma) / chronic systemic diseases

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