Nodule Formation Associated With Botulinum Neurotoxin Type A Injections: Potential Triggers in 23 Patients

Summary:

The formation of nodules at injection sites following botulinum neurotoxin type A (BoNTA) treatment has recently been reported. This complication can cause significant distress for patients, primarily due to the uncertainty surrounding its etiology and progression, as well as the lack of established management strategies. However, this complication has not been thoroughly studied. In this retrospective series, we detailed 23 female participants aged between 35 and 65 years who developed nodules at the injection sites after receiving BoNTA. All participants experienced the formation of nodules within 24 hours of the procedure. We investigated potential triggers for this reaction, including infection, vaccination, and the diluent composition used in the injections. Notably, all patients had received the COVID-19 vaccine and booster before their BoNTA treatment. Management strategies implemented included oral antibiotics, oral serratiopeptidase, topical or systemic steroids, and oral antihistamines. The resolution times for the nodules after treatment ranged from a few days to 1 month. This complication may indicate an immediate hypersensitivity reaction. The potential association between this complication and the COVID-19 vaccination warrants further investigation. It is important to counsel patients about the benign nature of these complications.

Botulinum neurotoxin type A (BoNTA) injections are the most popular cosmetic procedure worldwide, achieving high efficacy rate, patient satisfaction, and a good safety profile. Uncommon adverse effects associated with BoNTA injections have been reported.¹ These include allergic reactions at the injection sites as well as systemic hypersensitivity.^2,3 Granuloma formation at the injection sites has also been documented.⁴ Recently, Anabtawi et al⁴ noted the occurrence of nodule formation at BoNTA injection sites in 3 patients. Such complications can cause significant distress for patients and aesthetic providers due to their unclear etiology, progression, and the lack of established management strategies. In this study, we included patients who developed nodular eruptions at BoNTA injection sites. We provided details on the clinical presentation, course, and management of this complication, while also attempting to identify potential triggering factors.

CASE SERIES PRESENTATION

We conducted a retrospective review of nodular lesions that developed at BoNTA injection sites in aesthetic practices after the COVID-19 pandemic and vaccination (May 2023–December 2024). We studied the patient’s medical history, particularly regarding infections and vaccinations; the type of BoNTA and reconstitution diluent used; clinical features and course of the eruptions; management provided; and outcomes.

We report on 23 Pakistani female patients, aged 35–65 years, who developed erythematous nodules at the injection sites of BoNTA (Table 1) (Figs. 1, 2). (See figure, Supplemental Digital Content 1, which displays patient 18: a 42-year-old woman who developed tender, mildly erythematous nodules [shown with asterisks] at the onabotulinumtoxinA [onaBoNTA] injection sites on the glabella after the procedure, https://links.lww.com/PRSGO/E313.) The nodules were tender in 22 (95.6%) patients. All patients had previously received uneventful BoNTA injections. All patients were treated with onaBoNTA. The toxin (100 international units) was diluted in 2 or 2.5 mL of preservative-free saline (0.9% sodium chloride). The composition of the diluent was the same in all cases, and the ampoules containing the diluent were made of polyethylene. Interestingly, in patients 1–13, there was no recurrence of complications with subsequent BoNTA injections using a different brand of the same diluent. The administered BoNTA doses ranged from 20 to 80 international units. No patients developed systemic symptoms or signs of systemic hypersensitivity.

Table 1.

Clinical Data of Patients Who Experienced Nodule Formation at BoNTA Injection Sites

Patient	H/o COVID-19	H/o COVID-19 Vaccination and Booster	BoNTA Dose, iu	Nodule Distribution	Management	Outcome
1	N	Y	68	Forehead, glabella, jaws, neck	Oral serratiopeptidase and topical betamethasone dipropionate/gentamycin sulphate for 1 wk*	Nodules resolved within 1 wk, with no recurrences noted when using a different brand of the same diluent
2	Y	Y	68	Forehead, glabella, jaws, neck	Oral serratiopeptidase and topical betamethasone dipropionate/gentamycin sulphate for 1 wk	Nodules resolved within 1 wk, with no recurrences noted when using a different brand of the same diluent
3–12	N	Y	68	Forehead, glabella, jaws, neck	Oral serratiopeptidase and topical betamethasone dipropionate/gentamycin sulphate for 1 wk	Nodules resolved within 1 wk, with no recurrences noted when using a different brand of the same diluent
13	N	Y	60	Forehead, glabella, and crow’s feet	Topical Fucidin for 2 d	Nodules resolved within 1 wk, with no recurrences noted when using a different brand of the same diluent
14	Y	Y	64	Forehead, glabella, crow’s feet, and neck	Topical prednicarbate, oral prednisolone, and serratiopeptidase	Nodules resolved in 2 wk
15	Y	Y	20	Forehead	Oral serratiopeptidase and loratadine for 2 wk	Nodules resolved in 2 wk
16	Y	Y	60	Forehead, glabella, and crow’s feet	Oral antibiotic, prednisolone, serratiopeptidase, and loratadine for 4 wk	Nodules resolved in 4 wk
17	N	Y	20	Forehead	Oral antibiotic, prednisolone, serratiopeptidase, and loratadine for 4 wk, and then I&D	Nodules resolved in 4 wk
18	Y	Y	80	Forehead, glabella, crow’s feet, and neck	None	Nodules resolved in 4 mo
19	N	Y	20	Forehead	Oral antibiotic, prednisolone, and serratiopeptidase	Nodules resolved in 3 wk
20	N	Y	50	Forehead and glabella	Oral antibiotic, prednisolone, and serratiopeptidase	Nodules resolved in 3 wk
21	N	Y	60	Forehead andcrow’s feet	Oral prednisolone	Nodules resolved in 3 d
22	N	Y	60	Forehead and crow’s feet	Oral prednisolone	Nodules resolved in 3 d
23	N	Y	56	Forehead, crow’s feet, and lower cheeks	Oral prednisolone	Nodules resolved in 3 d

^*Serratiopeptidase has anti-inflammatory, analgesic, and wound healing properties.

H/o, history of; iu, international units; I&D, incision and drainage; N, no; Y, yes.

Fig. 1.

Patient 3: A 65-year-old woman developed tender, erythematous nodules at the onaBoNTA injection sites on the jawline and neck after the procedure.

Fig. 2.

Patient 5: A 54-year-old woman developed tender, pink erythematous nodules (shown with asterisks) at the onaBoNTA injection sites. A, On the forehead and glabella. B, On the jawlines and neck.

All patients had received COVID-19 vaccination, specifically BNT162b2 (Pfizer–BioNTech) or Sinopharm, along with 2 booster doses. Only 5 (21.7%) patients had experienced a COVID-19 infection, and there were no cases of active infection at the time of the BoNTA injections. Additionally, there were no other infections, and no new drugs were started in the few weeks before the BoNTA injections. There were no other known triggers of the immunologic system, such as bee or wasp sting, before the formation of nodules.

The implemented management approaches (Table 1) were effective, with resolution times ranging from a few days to 1 month. Patient 18 received expectant therapy, with nodule resolution during 4 months. Subsequent BoNTA injections did not lead to a recurrence of this complication in patients.

DISCUSSION

Eruptions secondary to BoNTA injections have been rarely reported.¹ Cases of local or systemic hypersensitivity are uncommon.^2,3 Most such hypersensitivity reactions have been attributed to the immunogenicity of complexing proteins or stabilizers such as gelatin in the BoNTA formulation.² A handful of reports describe nodular eruptions with granuloma pathology—as reviewed by Anabtawi et al.⁴ The nodular eruptions in 3 patients reported by Anabtawi et al⁴ started between 2 days and 3 weeks after BoNTA injections. The authors suggested a type IV hypersensitivity leading to granuloma formation but did not include pathology evaluation.

The clinical features observed in our patients, particularly the appearance of nodules within 24 hours, indicate an immediate (type I) hypersensitivity reaction. Delayed (type IV) hypersensitivity that can lead to granuloma formation occurs more slowly and usually takes more than 72 hours to develop. Complexing proteins in the onaBoNTA formulation might be involved in nodule formation in our patients. We investigated whether the diluent, ampoule material, and excipients in the onaBoNTA formulations could trigger an immune response. All injections used a preservative-free saline diluent, consistent across the board. However, the polyethylene ampoules containing this diluent may release particulate matter into the solution during storage and handling, such as during needle insertion.⁵ This raises a theoretical risk of an immune response to these particulates. Nonetheless, in patients 1–13 (Table 1), the nodules did not recur when a different brand of the same diluent packaged in identical polyethylene ampoules was used. Additionally, the excipients included in the onaBoNTA formulation, such as human albumin and mannitol, which may serve a stabilizing function, have extremely low immunogenicity.⁶

We investigated the patients’ histories before the BoNTA injections to determine whether triggers of immunologic activation might be involved in the development of nodules. We did not identify any instances of new drugs; stings, such as those from bees or wasps; or infections.⁶ Additionally, there were no cases of active COVID-19 infection at the time of the BoNTA injections.

Importantly, all patients had received the COVID-19 vaccine. One case reported by Ming Ng et al⁷ noted the development of nodular lesions 1 day after BoNTA injections; the patient had received the COVID-19 vaccine approximately 3 months before. Similarly, Guo et al⁸ documented 2 cases of subacute hypersensitivity reaction to BoNTA injections following COVID-19 vaccination. Although the authors of these reports speculated that a foreign body reaction may have led to granuloma formation, no pathological evaluations provided support for this hypothesis. Hamed Azzam et al⁹ indicated that the BNT162b2 COVID-19 vaccine may reduce the efficacy of BoNTA injections, as it stimulates the immune system; mRNA vaccines such as BNT162b2 can lead not only to short-lived humoral responses but also to systemic reactogenicity and the emergence of cross-reactive antibodies capable of targeting self-tissue.¹⁰

Our series is limited by the sample size and lack of pathology. Most patients opted for immediate treatment and declined to undergo a biopsy. Aesthetic providers should be aware of this benign complication and provide appropriate counseling to patients. An expectant approach is appropriate when lesions are asymptomatic, particularly because nodular lesions may resolve spontaneously. If the patient decides to pursue treatment, the implemented management strategies including combinations of oral antibiotics, oral serratiopeptidase, topical or systemic steroids, and oral antihistamines can be effective. Additionally, it is important to investigate a potential link between this complication and prior COVID-19 vaccination in powered controlled studies.

CONCLUSIONS

We report an intriguing presentation of nodule formation at BoNTA injection sites, occurring within 24 hours of the procedure. This complication may suggest an immediate hypersensitivity reaction. Healthcare providers should recognize this benign complication and inform patients that it can be effectively treated.

DISCLOSURE

The authors have no financial interest to declare in relation to the content of this article.

ETHICAL APPROVAL

This study was exempt from ethical approval because the investigators recorded and disclosed anonymized information. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki for medical research involving human subjects.