Dr Beata Cybulska details the formation, pathophysiology and treatment of granulomas following dermal filler injections
Granulomas are a delayed, poorly understood and distressing complication of dermal filler injections. Histologically, they represent a foreign body type of reaction with giant cells and macrophages infiltrating tissues. Granulomas are classified into three types: cystic, nodular and sclerosing, which clinically present as red, firm papules, nodules or plaques occurring months or years after filler injections. Filler dependent factors such as volume and particle size, as well as the presence of biofilm, have been suggested as possible causes. Treatment is often empirical, hence good differential diagnosis is essential in choosing the right treatment pathway. Overcorrection using dermal fillers, hypersensitivity reaction and infections ought to be considered before embarking on treatment, which consists of antibiotics and hyaluronidase in the first instance, followed by intralesional or systemic steroids. Surgical excision is recommended as the last resort. Investigations that may be of assistance in making the diagnosis and assist with the management include blood tests such as: white blood count (WBC) and C-reactive protein (CRP). Out of the imaging methods available, the use of ultrasound (USS) is most useful. Biopsy and histology offer confirmatory diagnosis. Culture is often unhelpful as a negative result does not exclude possibility of the presence of biofilm. Counselling the patient and adopting preventative measures such appropriate filler choice and prevention of infection should be part of every case of dermal filler injections.
Granulomas following dermal filler injections are challenging for aesthetic practitioners to manage and can be distressing to the individuals affected by them.1,2 Granulomas can develop months or years after deposition of the dermal filler in the dermis and may occur after both permanent and semi-permanent dermal filler use, including hyaluronic acid (HA), bovine collagen, silicone, paraffin, polyacrylamide gel, poly-lactic acid microspheres and calcium hydroxyapatite.1-8 Frequency of granuloma occurrence has been reported as 0.02-0.4% after HA and 0.04%-0.3% after bovine collagen injections.3,4,5
Granuloma formation is a non-allergic, chronic inflammatory response, characterised by foreign body types of reaction in the dermis following injection of dermal filler or other foreign material.3,4 A granuloma is defined as a tumour composed of immune cells such as macrophages, activated and fused into multinucleated giant cells, consisting of more than 20 nuclei and arranged in an irregular and random way.9,10
Formation of granuloma occurs in stages involving:
As the neutrophil infiltration and adsorption of host proteins to the foreign material occur, monocytes circulating in the blood migrate to the surrounding tissues and differentiate into macrophages. Where the particle volume is greater than the macrophage volume, macrophages aggregate, forming giant cells and secrete factors, which activate fibroblasts, influencing the development of fibrous capsule around the foreign body material and formation of the foreign body giant cell (FBGC).3,9,10
It is not fully understood why small filler particles or silicone fluid trigger granuloma formation, both of which are easily phagocytosed by macrophages.11 One hypothesis that was put forward by Lemperle et al in 2006 suggests that macrophages act as memory cells and remember small phagocytosed particles. Triggered by systemic infection, they initiate FBGC formation and the development of granuloma.12 The authors were of the opinion that volume, purity and physical characteristics of the injected dermal filler such as particle size, smoothness, charge and hydrophilicity play a role in this process. Bentkover hypothesised that the main cause of FBGC reaction is the size of the filler particles, which prevents them from being phagocytosed.13 Granulomas have been linked to biofilms, which are defined as a structured community of microorganisms encapsulated within a self-developed, polymeric matrix, irreversibly adherent to a living or inert surface.14 In 2007, Christiansen hypothesised that biofilms form when bacteria is introduced during filler injections or are seeded in the filler during bacteriaemic episodes.14 Once present, they remain dormant for months or years on the surface of the filler and become a target of a delayed immune response, resulting in granuloma formulation. Many biofilms are almost impossible to culture using current microbiology culture technology.15 They live in a quiescent state, resulting in a low-grade infection associated with low-grade host response. Activation of biofilms may be triggered by dental manipulation, trauma or other factors, leading to local or systemic infection, as well as granulomatous, inflammatory response. Biofilm populations can shift from active to dormant depending on exogenous threats. When bacterial proteins turn off cell metabolism and the cell becomes dormant, it becomes antibiotic resistant, as well as difficult, if not impossible, to culture.3,15,16,17
Patients with chronic sinusitis, chronic dental problems, or other infections may have a greater tendency to develop an infection after a filler is injected in the periorbital area or central face. These patients may also be prone to formation of a biofilm around or in the implant, caused by injection trauma around the site of a previous filler injection. Many problems that were previously assumed to be foreign body granulomas or allergic reactions, on the basis of negative bacterial cultures, are now thought to be due to biofilms.3,15,16,17
Diagnosis and management of dermal filler granulomas is complex. In order to offer satisfactory treatment and resolution, it is very important to take good medical and aesthetic history and thoroughly examine the patient. Investigations may assist with making correct diagnosis although, in reality, they are rarely carried out and treatment is empirical. It is therefore essential to understand the pathophysiology of granulomas and differentiate them from other causes of nodular lesions caused by dermal fillers, as their management differs depending on the presence or absence of inflammatory features.
Presentation and symptoms
Cystic, nodular, bluish, indurated plaques with congested capillaries that are bigger than the injected volume of filler and develop simultaneously at different sites.
Evenly sized, whiter in colour and harder than granulomatous nodules.
Erythema, oedema, indurated papule, nodule with or without itching.
Erythema, swelling, oedema, induration and/or tenderness.
Filler dependent: type and volume of filler used.
Subject dependent: infection and biofilm.
Injector dependent: attention to skin cleanliness and patient selection.
Injector dependent: poor injection technique (overcorrection or too superficial injection), lack of massage.
Subject dependent: lack of massage (L-polylactic acid).
Filler dependent: HA or bovine type collagen.
Subject dependent: bacterial, viral, fungal, parasitic infections. Injector dependent: poor patient selection, poor skin cleansing.
Delayed by months or years after filler injection.
Early – up to two weeks after filler injection.
One month after filler injection with spontaneous resolution after one year.
|Early or delayed.|
Figure 1: Differential diagnosis of granuloma3,16
Medical history should constitute part of every aesthetic consultation. In cases of delayed complications such as suspected granuloma formation, more specific questions about onset, presence of inflammatory features such as pain and redness, history of dermal filler injections, type and volume of injected filler and sites, presence of skin infections, as well as skin conditions or immunocompromised state should be enquired for. Pre-existing skin infection in or close to the injected area may worsen and result in complications. Patients with ongoing skin infections caused by bacteria like streptococci and staphylococci resulting in impetigo; those with excessive Propionibacterium acnes or parasitic mite infection such as demodex folliculorum associated with rosacea; yeast infections; extensive pityrosporum folliculitis; viral infections such as herpes virus simplex (HSV) or perioral human papilloma virus infection (HPV); should not have dermal filler injections until the infection is treated. In the presence of sinusitis, periodontal disease, ear, nose or throat infections, or dental abscesses, dermal fillers should not be injected. There is evidence that these infections might invade the implanted filler and may result in biofilm formation, which in turn may trigger hypersensitivity reaction.16
Patients with chronic sinusitis, chronic dental problems, or other infections may have a greater tendency to develop an infection after a filler is injected in the periorbital area or central face
Dermal filler granulomas have been classified into three types based on their histological features: cystic (HA, bovine collagen), nodular lipogranuloma with ‘Swiss cheese pattern’ (silicone, polyacrylamide) and sclerosing.11 Mixed pattern granulomas have also been identified.1 Clinically, granulomas present as red, firm papules, nodules or plaques, which may occur months or years after filler injection.16
Corticosteroids (triamcinolone acetate – Kenalog)
Melting with laser
Figure 2: Treatment options for granulomas
It is sometimes difficult to distinguish between granulomas and nodules due to other causes or an abscess. Diagnosis of nodules complicating dermal filler injections is complex and difficult in those with no clear history of dermal filler injection. It is, however, very important to get the correct diagnosis in order to achieve a successful outcome. Granulomas ought to be differentiated from nodules caused by poor injection technique, an infection or delayed hypersensitivity reaction (Figure 1). Establishing possible causes of dermal filler nodules impacts on treatment options and outcomes. Investigations which may assist in diagnosis include: blood tests: C-reactive protein, white blood count (WBC), erythrocyte sedimentation rate (ESR), microscopy and culture, in situ hybridisation, computerised tomography (CT scan), magnetic resonance imaging (MRI), skin biopsy and histology.11,18 Cassuto and Sundaram (2013) advocate the use of ultrasound (USS) imaging in cases of persistent nodules to assist with location of the implanted material.19
Treatment of dermal filler nodules is often empiric without full evaluation of possible causes and variable satisfaction rates due to a misunderstanding of the pathophysiology. A problemfocused approach in the diagnosis and treatment has been recommended.17,19-21 Common causes such as infection, before rare causes such as hypersensitivity to filler material, ought to be considered, as should poor injection technique, before filler dependent factors are blamed (Figure 1). Painful nodular lesions with inflammatory features ought to be treated promptly with broad spectrum antibiotics in spite of negative culture when biofilm is suspected (Figure 2). If HA filler was injected, intralesional hyaluronidase and extraction of the nodule content using a 16G needle and negative pressure, followed by administration of intralesional 5 fluorouracil (5 FU), laser lysis and, as a last resort, surgical excision can be carried out. Antibiotic therapy is the first step in the management of cases suspected of infection origin, in spite of negative culture. Intralesional steroids used before antibiotics can prolong the problem.
|HA Filler||Non HA Filler|
|Small amounts of intralesional steroids|
5 FU 0.5ml of 50mg/ml + 0.3ml of 10 mg/ml triamcinolone + 0.2 ml of 2% lidocaine with adrenalin
Fractional laser (eyelids and lips)
Figure 3: Management of non-inflammatory dermal filler nodules. Palpable, visible, nodules appearing two to four weeks after injection
Painless granuloma with no inflammatory response can be treated with intralesional steroids in the first instance, followed by 5 FU and surgical excision21 (Figure 2). Such lesions are not urgent and the patient can be reviewed in two weeks. Polymethylmethacrylate fillers can be melted with laser energy first, before pouring them out of the area as demonstrated by Cassuto et al.22 In some cases it may be necessary to use intralesional steroids to reduce the lump whilst continuing to administer antibiotics. Injections of steroids ought to be performed carefully due to the risk of localized atrophy. High dose triamcinolone (35-40mg) mixed with 2% lidocaine is recommended using a 0.5mlto 1ml insulin syringe with a 30G needle for intralesional injections. Smaller needle diameter helps to avoid steroid-induced atrophy. As granulomas spread in a finger-like pattern, best injection technique involves injecting small amounts on the periphery, moving towards the centre. Other agents include bleomycin, colchicine, cyclosporine, immiquimod or etanercept, which is traditionally used to treat rheumatoid arthritis and psoriasis.23-26 Isotretinon can be used alone or in combination with steroids.27
Systemic treatment is recommended in recurrent granulomas when localised treatment is not effective. Higher doses of steroids are used in such cases, e.g. oral prednisolone 30mg/day starting dose followed by 60mg/day of maintenance dose has been suggested to prevent recurrence of granulomas.1 Oral antibiotic minocycline alone or combined with oral or intralesional steroids has been indicated as effective in the treatment of inflammatory granulomas and silicone granulomas.20
Surgical excision offers a cure by removing the foreign body, as well as biofilm, however it is not without complications. In particular, scarring and deformities can occur because of potential invasive growth of granulomas and irregular borders making their complete removal impossible.4 In addition, in silicone-induced granulomas, surgery carries a risk of abscess or a fistula. Localised sclerosing granulomas can be excised with subsequent correction of deformities using fat grafts or flaps.3 Incision and drainage of a sterile abscess has been indicated as effective.6
Red, indurated area occurring any time after filler injection
Sterile abscess, red, indurated area occurring several months to years after filler injection
Broad spectrum antibiotics:
Ciprofloxacin or clarithromycin 500mg bd PO + moxifloxacin 400mg od PO x four weeks.
If poor response switch to clindamycin 600mg bd P.O. + tetracycline 500mg bd PO.
If good response, extract nodule material using 16G needle and negative pressure. Consider: injections of 0.5 cc of 5FU monthly x 4; laser lysis, incision and washing out cavity with antibiotics or surgical excision.
Intralesional or systemic steroids: triamcinolone, betamethasone or prednisolone.
If no response add: 5 FU, bleomycin, colchicine, cyclosporine.
If still no response, consider surgical excision using flap technique or fat grafting.
Clean skin thoroughly before injection, avoid injecting through oral or nasal mucosa, use prophylactic antibiotics if facial infection present two weeks prior to treatment.
Limit filler volume, avoid intramuscular injection, select microspheres with smooth surfaces for use in patients with multiple filler injections.
Figure 4: Management of inflammatory dermal filler nodules28
|Clean surfaces||Clean patient’s skin||Clean hands||Clean instruments|
Figure 5: Aseptic technique
Dermal filler related granulomas may be prevented by meticulous cleansing and disinfecting the skin, sterile injection technique, prophylactic antibiotics, as well as using smaller gauge needles to minimise trauma and access for bacteria. Patients should be advised to avoid makeup immediately before and after injection. Overcorrection with dermal filler, injecting too large a volume of the wrong type of filler for the tissue type, and lack of even redistribution of the filler due to lack of massage, should be avoided. Correct injection technique with placement of needle at the appropriate depth before injecting and discontinuing injecting before retraction of the needle is recommended.
Granulomas are rare, however they are complex and difficult to manage delayed complications of dermal filler injections. Understanding their pathophysiology is essential in differential diagnosis and appropriate management. Use of a sterile and correct injection technique, as well as high quality dermal filler that is appropriate for the tissue type, are important factors in the prevention of these challenging, and often distressing for the patient, filler complications.
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