Filler thriller: Complete resolution of a pair of delayed-onset nodules with hyaluronidase

INTRODUCTION

Hyaluronic acid (HA) fillers are commonly utilized cosmetic agents in the treatment of facial aging for their minimally invasive nature. HA fillers offer several advantages over permanent fillers such as reversibility and low incidence of adverse reactions.¹

Although HA filler complications are sparse, the annual incidence has risen with increasing numbers of cosmetic procedures performed.^2,3 Late-onset infections occur roughly two or more weeks post-injection with involvement of atypical organisms such as mycobacteria and are typically managed with incision and drainage (I&D) in conjunction with antibiotic therapy.²

Delayed-onset inflammatory nodules are an uncommon complication that emerges several weeks after injection due to a multifactorial combination of hypersensitivity, infectious etiology, and foreign body reaction.^2-5 One study of 4,702 HA injections (Juvéderm Voluma, 20 mg/mL concentration) performed at a single institution demonstrated 23 (0.5%) cases of delayed-onset nodules.⁶

Biofilm production occurs when densely populated bacterial colonies secrete protective polymers that can render standard-of-care infection treatment ineffective.^2-4 Antibiotic resistance in the setting of negative culture may indicate biofilm involvement.

Granuloma formation involves the isolation of a foreign body that is unable to be enzymatically broken down by circulating immune cells. If the encapsulated material resists degradation, activated macrophages will continue to release inflammatory markers that promote multinucleated giant cell formation and persistent inflammation.^3,4

Hyaluronidase provides a safe, reliable means of noninvasively removing the offending filler through enzymatic digestion once active infection is ruled out.^2,3,5 However, there is no consensus on the indication for hyaluronidase within the treatment algorithm for delayed-onset inflammatory nodules.

CASE REPORT

Patient #1

A 44-year-old female patient who previously received cosmetic HA injections (Pluryal Volume, 23 mg/mL concentration) and intradermal threads for an elective anti-aging procedure presented with recurrent left-sided facial swelling, erythema, and imaging findings of inflammatory nodules along her left mandible for two months. The volume of injected HA is unknown, as her procedure was performed internationally.

Per outside reports, she initially presented for a symptomatic nodule under the left lower lip that began one week following cosmetic procedure. There was no evidence of vascular occlusion. Prior external management over several months included a single localized hyaluronidase injection of unknown concentration into the small left chin nodule approximately eight days post-injection, prednisone with clarithromycin, two trials of broad-spectrum antibiotic regimens, daily drainage, wound packing for 10 days, and two surgical debridements that were ineffective at resolving inflammation. Pathology acquired from an outside facility revealed granulomatous inflammation with multiple negative bacterial cultures. She presented to our facility for further care due to the persistence of her symptoms.

In our emergency department, the patient endorsed intermittent chills over the past week, but no worsening pain, drainage, expanding numbness, dysphagia, dyspnea, or dysarthria. Relevant cranial nerves were intact, with no focal neurologic deficits. Laboratory tests were unremarkable. Physical examination revealed an open packed wound without purulent secretion or surrounding erythema [Figure 1].

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Figure 1:

(a) Initial computerized tomography (CT) coronal imaging demonstrating left premaxillary draining abscesses, soft tissue stranding, and enhancement overlying the left mandibular body with subcutaneous emphysema (red circle). (b) Initial presentation of open packed wound of the left mandible. (c) Post-treatment presentation at two months demonstrating resolution of erythema and swelling with wound closure and scar formation.

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Maxillofacial computerised tomography (CT) imaging demonstrated soft tissue swelling without periosteal reaction and inflammatory enhancement of the left mandible [Figure 1]. Subsequent magnetic resonance imaging (MRI) and ultrasound showed no findings suggestive of osteomyelitis or drainable fluid collection.

Symptomatic granulomatous inflammation and sterile abscesses were thus attributed to local reaction to unabsorbed HA filler.

An area of demarcated fullness measuring 4 × 4 cm was evenly divided into eight sites for injection throughout the extent of the lesion. Injections were administered with a 32-gauge needle into the subcutaneous plane, with sufficient depth to encompass all planes previously treated with filler, including to the level of the periosteum. Guideline-directed therapy consisted of four serial 250-unit hyaluronidase (Hylenex) injections diluted 1:1 with normal saline across a five day inpatient stay, resulting in near-complete symptom resolution without recurrence at one week follow-up [Figure 1].

Patient #2

A 54-year-old female presented with six months of recurrent erythema, swelling, discomfort, cellulitis, and abscesses of the left zygomatic area after undergoing HA filler injections of 0.3 mL (Juvéderm Voluma, 20 mg/mL concentration) into the zygomatic and infraorbital regions.

Initial symptom onset with persistent left cheek swelling and redness was seven days post-filler placement. Her first outside CT maxillofacial scan demonstrated a developing fluid collection concerning for phlegmon versus abscess for which she underwent I&D. She was then prescribed trimethoprim-sulfamethoxazole before discharge. However, she re-presented one month later with multiple persistent firm nodules inferior, inferolateral, and lateral to the wound site. There was no documentation of vascular compromise. Subsequent outside CT scans demonstrated cellulitis and abscess on several occasions. Her overall outside facility treatment course was extensive, including multiple empiric antibiotic regimens, two intraoral I&Ds, two external I&Ds, and three injections of hyaluronidase (130 units each, performed 23- and 43-days post-injection) over six months of waxing and waning symptoms.

Her presentation to our institution included the above symptoms as well as trismus and pain with leftward gaze. In our emergency department, there was noted neutrophil-predominant leukocytosis and physical examination consistent with the above and possible left-sided facial nerve weakness with mild smile asymmetry [Figure 2]. MRI of the face revealed a left premaxillary facial abscess and osteomyelitis [Figure 2]. Cultures yielded no growth. Tissue sample demonstrated an abscess with inflammation for which she received vancomycin and ceftriaxone.

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Figure 2:

(a) Initial magnetic resonance imaging coronal and axial imaging demonstrating stable left premaxillary facial abscess with features of subjacent malar eminence-anterior zygomatic arch osteomyelitis (red circle). (b) Delayed-onset nodule with erythema and percutaneous drainage before treatment. (c) Post-treatment presentation at one month after four total hyaluronidase injections dosed to filler-related vascular occlusion guideline standards.

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The demarcated area of induration and erythema was measured as 6 × 8 cm in the greatest dimension and divided into 1 × 1 cm grids to account for the extent of the inflammation. Injections were made into the subcutaneous plane using a 25-gauge cannula to dissolve all planes in which filler was placed up to the level of the periosteum. Guideline-directed treatment consisting of 1500 units of hyaluronidase (Hylenex) mixed in a 1:1 dilution with bacteriostatic saline was injected in equal aliquots into each of the gridded sections. She then received two additional 150-unit hyaluronidase injections each administered in a similar fashion before discharge following symptomatic improvement. A final same-dose hyaluronidase injection was administered one week later, with resolution of inflammation and swelling, and the remainder of only a small residual deficit indicative of a closed percutaneous fistula with slight concavity of the zygomatic facial contour [Figure 2].

DISCUSSION

An erythematous, painful nodule that emerges one week after HA filler injection suggests possible infection with a skin-borne pathogen.² However, a negative culture and resistance to standard of care I&D with antibiotic treatment instead favors a diagnosis of delayed-onset granulomatous inflammation.^2,3 There is no current consensus on the etiology of inflammatory delayed-onset nodules, which is considered multifactorial due to hypersensitivity, infection, and/or foreign body reaction.^2-5 Of note, both patients experienced symptom onset within seven days post-injection. Previous studies have demonstrated an average onset of delayed-onset nodules approximately one to three months post-injection.⁷ The subacute time presentation of our patients may indicate an initial type IV hypersensitivity reaction with further complication by factors such as biofilm production and/or foreign body reaction as the weeks and months progressed; such cases have been reported to resolve spontaneously, with monotherapy of corticosteroids, antibiotics, or hyaluronidase, or a combination of modalities.⁷

Prior treatment with infection treatment protocol and corticosteroid therapy was insufficient in resolving inflammation for both patients. Furthermore, numerous failed antibiotic regimens with pathology demonstrating the absence of active infection did not lead to further treatment with hyaluronidase. In patient #1, absorbable polydioxanone (PDO) intradermal threads present a theoretical risk for delayed hypersensitivity reactions. However, a recent systematic review of 59 studies involving 14,222 patients undergoing facial or neck thread lifts reported no cases of delayed hypersensitivity from absorbable threads.⁸ All six documented instances of foreign body granuloma or chronic inflammatory response occurred with non-absorbable barbed threads. Therefore, it is unlikely that the patient’s PDO threads were the primary cause of her presentation, though a contributory role alongside the filler reaction cannot be fully excluded.⁸

No consensus has been reached on the role of hyaluronidase in the treatment algorithm for inflammation related to delayed-onset inflammatory nodules. While the literature mentions hyaluronidase as an alternative treatment option for this complication, specific dosing or frequency recommendations are not provided for this therapeutic modality.^2,3 In a multi-institutional consensus panel comprising 25 plastic surgeons, surveyed participants unanimously agreed on a treatment plan that recommended anti-inflammatory medications such as prednisolone or colchicine with optional antibiotics as the best-suited therapy for inflammatory nodules.⁵ Filler removal was briefly mentioned as an alternative treatment option without specific recommendations.

Given the severity of our patients’ filler-related complications and the well-established safety profile of hyaluronidase at higher concentrations, we proceeded with guideline-directed management of vascular occlusion caused by cosmetic fillers, which recommends complete implant removal with hyaluronidase.² Enzymatic digestion of the cosmetic filler was effective in resolving the ongoing inflammatory process; we therefore recommend hyaluronidase specifically dosed to vascular occlusion management levels as an option for management of delayed-onset filler nodules.

CONCLUSION

HA fillers are ubiquitous in the cosmetic world, favored for their reliability and established safety profiles. Delayed-onset nodules present similarly to standard infection but should be considered with negative culture and poor response to I&D with antibiotic treatment. There is a current lack of dissolution guidelines for granulomatous inflammation and sterile nodule formation. In such instances, injectors should consider hyaluronidase therapy at vascular-occlusion dosing as a potential option for minimally invasive implant dissolution.