Non-responsive Covid-19 vaccine nodules |

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Non-responsive Covid-19 vaccine nodules

Dr Patrick Treacy shares his novel method for treating non-responsive Covid-19 vaccine-induced nodules using methotrexate

During the Covid-19 pandemic, dermal fillers made world headlines as it was reported that patients who had cosmetic fillers experienced side effects after receiving vaccines that utilised both viral vector and mRNA technology.

Initially, the Moderna mRNA-1273 vaccine trial reported an incidence rate of facial swelling of 0.02% after receiving the vaccine. Later, similar effects were noted from both the Astra Zeneca and the Pfizer/BioNTech Covid-19 vaccine. The exact mechanism was thought to be due to Type IV hypersensitivity causing foreign body granulomas. These problems appeared globally and were initially treated with antihistamines, 5-fluorouracil, hyaluronidase and intralesional steroids. However, the medical world also experienced a cohort of patients unresponsive to any established treatment protocols, and we proceeded to solve the problem.


To evaluate the efficacy of using the immunosuppressant methotrexate to treat Covid vaccine-related delayed onset nodules in 23 patients with moderate facial disfigurement unresponsive to established treatment protocols, including intralesional steroids and hyaluronidase.


We identified a cohort of 23 international patients injected with dermal filler or collagen stimulators who presented with delayed onset nodules after receiving the Covid booster vaccine. Eighteen of these patients were from Ireland, three from the United Kingdom, one each from France, the United States and Dubai.

All of the patients were unresponsive to established treatment protocols, including antihistamines, 5-fluorouracil (5-FU), 5-FU and lidocaine, and intralesional steroids. Some presented with as many as 30-40 nodules in the case of poly-L-lactic acid (PLLA; Sculptra®), and excision of implanted material was considered only used as a last resort. Eighteen of these complications related to both cross-linked and non-cross-linked hyaluronic acid fillers. Fourteen to monophasic HA products (Juvederm®, Allergan, Irvine, CA, USA), (Teosyl®, Clarion Medical Technologies) (Stylage M (Vivacy, Paris), two to the biphasic filler, Restylane®, (Q-MED, Uppsala, Sweden), and three were an unknown product. Five were related to poly-L-lactic acid (PLLA; Sculptra®; Valeant), and two of these patients had been injected nearly two years previously.

All of the hyaluronic acid patients were injected intradermally or supraperiosteally. Two patients received Teosyl® HA filler (0.2 ml in each side) to their tear trough areas with microcannula. Both had received previous hyaluronidase with little effect. None of the patients developed swelling, erythema, or nodules directly after dermal filler injection but presented with hard nodules about two weeks after vaccination.

The patients received various vaccines, including the AstraZeneca vaccine, Pfizer/ BioNTech vaccine, and the Moderna-type vaccine (Moderna, Cambridge, MA). The Moderna and Pfizer/BioNTech vaccines are forms of mRNA vaccine. These vaccines work by teaching immune cells to make a harmless piece of “spike protein”. Unlike the Pfizer/ BioNTech and Moderna coronavirus vaccines, the Oxford/AstraZeneca vaccine is not an mRNA vaccine. Instead, the AstraZeneca vaccine is a viral vector vaccine made from a weakened form of a common cold virus from chimpanzees.


Methotrexate is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. It is particularly used to reduce the activity of the immune system when it mistakenly attacks parts of the body, such as skin and joints, causing illness. Methotrexate is used to treat rheumatoid arthritis, psoriatic arthritis, vasculitis, systemic sclerosis, and severe psoriasis. It initially needs to be closely monitored, requiring blood tests every two weeks until stable and then every three months.


When methotrexate is used for Covid vaccine nodules, it may be taken once a week (or in certain circumstances as three divided doses over 36 hours once a week). Folic acid is normally prescribed to be taken on a different day than methotrexate. Treatment of psoriasis with methotrexate is also prescribed intermittently over a week.

These are unusual dose regimens that may confuse some patients. It is important to clearly explain the dosing schedule to each patient and make sure they have understood the information. Specify on every prescription and the dispensed medicine label the day of the week (written in full) the dose is to be taken.

Healthcare professionals should also check that the patient is taking methotrexate correctly. Serious and sometimes life-threatening or fatal adverse effects can be caused by incorrect methotrexate dosing.


It is imperative that monitoring of renal and liver function tests, full blood count and chest radiography occur before and during treatment. The Best Practice Advocacy Centre (BPAC) recommendations for monitoring methotrexate and management of methotrexate toxicity are outlined in Tables 1 and 2.3Please note that local guidelines may vary.


The risk of serious adverse effects is greater with higher doses and with prolonged methotrexate treatment. Hepatotoxicity may occur without previous signs of gastrointestinal or haematological toxicity. Pulmonary toxicity, including pneumonitis and pulmonary fibrosis, can also occur at any time during therapy. Methotrexate is usually contraindicated in patients with impaired renal function.


These problems appeared centred on hyaluronic acid dermal fillers and poly-L-lactic acid collagen stimulators, which normally rarely cause persistent side effects.

Dermal fillers and collagen stimulators are essentially foreign bodies, and some patients may develop a Type I hypersensitivity reaction after initial or repeated exposure to these injected products when exposed to an immune response to both viral and bacterial infection. This is related to immunoglobulin E (IgE)-mediated immune hypersensitivity.

It is known that IgE stimulates mast cells to degranulate, releasing proteases, heparin, histamine, cytokines, prostaglandins, leukotrienes, and platelet-activating factor, which result in oedema, erythema, pain, and itching characteristic of an allergic response. Reactions can be severe and can last for several weeks.

Delayed hypersensitivity reactions also occur mediated by T lymphocytes rather than antibodies. They typically occur one day after injection but may be seen as late as several weeks after injection and may persist for many months. These are characterised by induration, erythema, and oedema.

The different HAs have varying degrees of hardness (G’), which will influence their suitability for a particular procedure. In general, the greater the G’ of the product, the deeper it should be injected. It should be noted that while more concentrated products with a greater degree of cross-linking have a longer duration of effect, they also increase reactivity in the body and, thus, the risk of inflammation and granuloma formation. Fillers with biodegradable particles that stimulate the body to produce its own collagen have a longer duration of effect; such products include calcium hydroxylapatite (CaHA; Radiesse®; Merz Pharmaceuticals GmbH) and poly-L-lactic acid (PLLA; Sculptra®; Valeant, West Laval, QC, Canada). CaHA consists of synthetic CaHA microspheres suspended in a carrier gel. Injection provides immediate visual improvement with long-term deposition of new collagen surrounding the microspheres, which contributes to an average duration of effect of around 15 months.

Cases of dermal filler swelling resulting from SARS-CoV-2 vaccination with the Moderna-type vaccine (Moderna, Cambridge, MA) had been successfully treated with Lisinopril, an angiotensin-converting enzyme inhibitor (ACE-1) in the United States. ACE-1 treatment has previously been used in the treatment of hypertrophic scars, keloids, and other inflammatory skin disorders and can assist in downregulating CD44 by inhibiting the pro-inflammatory Angiotensin II. Other cases were successfully treated in the United Kingdom and Germany with 0.5 mL of 50 mg/ mL 5-FU, 0.3 mL of 10 mg/mL triamcinolone (or 40 mg/mL triamcinolone, depending on localisation and degree of inflammation), and 0.2 mL 2% lidocaine with adrenalin.


All patients successfully responded to 10mgs of Methotrexate for a three-month period, and all their nodules dissipated. One patient had to stop the treatment in week ten due to moderately severe anergia. The treatment protocol above was submitted and accepted by peer review at both the AIDA Dermatology Conference in Abu Dhabi (May 2022) and the IMCAS World Conference in Paris (June 2022). It has changed the lives of many patients by reducing the gross distress caused by this condition.

Dr Patrick Treacy is the founder of the Ailesbury Clinic, Dublin. Recognised globally as a leading pioneer and expert in aesthetic medicine, he is currently President of the Royal Society of Medicine (London) Aesthetic Faculty and Chairman of the Irish Association of Cosmetic Doctors. He was recently made visiting Professor of Dermatology at Isra University in Pakistan and received an Honorary Fellowship in Cosmetic Surgery from the Australian College of Cosmetic Surgery and Medicine.


1. Sclafani AP, Fagien S.Treatment of injectable soft tissue filler complications. Dermatol Surg. 2009;35(Suppl 2):1672–1680.

2. Michon A. Hyaluronic acid soft tissue filler delayed inflammatory reaction following Covid-19 vaccination-A case report.J Cosmet Dermatol. 2021; 20:2684-2690.

3. Rowland-Warmann MJ. Hypersensitivity reaction to hyaluronic acid dermal fillerfollowing novel coronavirus infection- a case report.J Cosmet Dermatol. 2021; 20:1557-1562.

4.Turkmani MG, De Boulle K, Philipp-Dormston WG. Delayed hypersensitivity reaction to hyaluronic acid dermal fillerfollowing an influenza-like illness. Clin Cosmet Investig Dermatol. 2019; 12:277-283

5. Arron ST, Neuhaus IM. Persistent delayed-type hypersensitivity reaction to injectable non-animal-stabilised hyaluronic acid.J Cosmet Dermatol. 2007;6(3):167–171.

6. Van Dyke S, Hays GP, Caglia AE, Caglia M. Severe Acute Local Reactions to a Hyaluronic Acid-derived Dermal Filler.J Clin Aesthet Dermatol. 2010;3(5):32–35

7. Methotrexate DBLData Sheet 25 August 2017. URL:

This article appears in November 2022

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November 2022
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