Covid-19 vaccine associated erythema nodosum: Factors to consider.

Dear Editor,

We read with great interest the letter by Teymour et al. The authors describe a possible case of mRNA‐1273 Covid‐19 vaccine‐associated erythema nodosum (EN) in a 66‐year‐old female. The patient subsequently received the second dose without the reappearance of EN.

We would like to report a further case of EN following the COVID‐19 vaccination. Our patient is a 62‐year‐old non‐obese male with a history of well‐controlled hypertension. He received the first BNT162b2 mRNA vaccine on April 30, 2021. Two weeks post‐vaccination, he noticed several tender nodules in his right ankle. A topical corticosteroid was prescribed for an assumed insect bite. He received his second dose on June 16, 2021; 4 days later, he experienced sudden onset of skin lesions accompanied by malaise and leg pain. Dermatological examination revealed subcutaneous nodules of 1–3 cm in diameter on the anterior lower legs and extensive redness and swelling at the vaccine injection site. Laboratory examinations revealed slightly elevated C reactive protein (10.5 mg/dl). Additional testing did not identify other etiologies for EN. We further assessed this association using the Naranjo adverse drug reaction causality scale. Our patient had a score of 6, suggesting a probable adverse drug reaction. Three weeks later, most of the lesions regressed spontaneously (Figure 1). No skin biopsy was performed due to the typical clinical presentation and contusiform color evolution. No recurrence was observed at the 6‐month follow‐up. The patient is not eligible to receive a third vaccine dose.

FIGURE 1

Contusiform color evolution of nodules, 3 weeks after onset of erythema nodosum

EN is considered a hypersensitivity response to a variety of antigenic stimuli. Precipitating factors include infections, inflammatory diseases, neoplasia, and drugs. However, approximately 50% of cases are idiopathic.

Eight vaccines have been associated with subsequent development of EN: tetanus, diphtheria, and acellular pertussis (DTaP), Bacille–Calmette–Guerin (BCG), hepatitis B, human papillomavirus, malaria, rabies, smallpox, typhoid, and cholera. Time intervals between vaccine administration and the onset of EN are variable. They manifest within 24–48 h following vaccine administration (hepatitis B, typhoid and cholera vaccine, rabies vaccine, DTaP) or 2–4 weeks later (malaria, smallpox, BCG, and papillomavirus vaccine). The pathogenesis of vaccine‐related EN may be linked to the antigen of the infectious disease or adjuvant components.

COVID‐19 vaccine‐associated EN seems to be rare. In a large‐scale study by McMahon et al, out of the 414 subjects, no cases of EN were reported.

To date, there are seven reports of EN temporally associated with receipt of COVID‐19 vaccine (Table 1). , , , , , ,

TABLE 1

Reported cases of COVID‐19 vaccine‐associated erythema nodosum

Author	Patient age/sex	Vaccine	1st dose‐reaction	2nd dose‐reaction	Time	Lab/HP findings
Teymour et al 1	66/F	mRNA‐1273 (Moderna)	Nodules on the bilateral anterior tibia	second inoculation without reappearance	10 days	Unremarkable/compatible with EN
Hali et al 6	66/F	ChAdOx1‐S (AstraZeneca)	NR	nodular lesions of the lower and upper limbs	48 h	↑ESR/septal hypodermitis, no vascular involvement, minimal granulomatous infiltrate
Mehta et al 7	25/F	ChAdOx1 nCoV‐ 19 (Covishield)	Low‐grade fever, joint pains, and painful nodules over legs	No recurrence was observed on receiving 2nd dose after 4 weeks	4 days	↑inflammatory markers/ compatible with EN
Aly et al 8	22/F	BNT162b2 (Pfizer‐BioNTech)	Nodules on both legs	NR	24 h	Normal/NP
Wu et al 9	37/F	BNT162b2 (Pfizer‐BioNTech)	No	Nodules on distal legs	24 h	NR/ septal panniculitis with granulomatous aggregates
Hsu et al 10	27/M	Medigen MVC‐COV1901	Fever, malaise, headache, myalgia, nausea, swelling of the ankles, rash on the legs	NR	72 h	↑CRP/ septal panniculitis, lymphocytic infiltrates, and Miescher's granulomas
Cameli et al 11	64/F	ChAdOx1 nCoV‐19 (AstraZeneca)	Painful, erythematous plaques on both lower limbs	NR	2 days	Normal/NP
Damevska and Simeonovski (present case)	62/M	BNT162b2 (Pfizer‐BioNTech)	Several nodules	Malaise, nodules on lower limbs, Injection ‐site reaction	14 days after the 1st dose, 4 days after 2nd dose	↑CRP /NP

Abbreviations: NP, not performed; NR, not reported.

Our patient, with no history of COVID‐19 infection, had mild EN after his first dose and severe relapse after the second dose. Interestingly, he showed injection site reaction, which has not been reported in the other cases. The absence of coincidental events leads us to support the potential role of the vaccine.

Our case and other mentioned cases are mainly based on a temporal relationship between the vaccine administration and the onset of EN.

However, the causality assessment requires complete information related to an individual case, such as evidence or history for herd immunity to SARS‐CoV‐2, type of vaccine, positive re‐challenge, follow‐up information, other disease and drug interactions, and so on. Apart from clinical judgment, the use of algorithms, such as the Naranjo scale, could be of great assistance when assessing these conditions. ,

We thank Teymour et al for their important case description. Further studies are needed to evaluate the mRNA vaccine as a potential cause of EN. In our opinion, the correct conclusion from the current evidence should be that Covid‐19 vaccine‐associated EN is a rare, benign, and self‐limiting condition.

We would like to emphasize that we have a professional obligation to detect and report cutaneous adverse events related to COVID‐19 vaccines.

CONFLICT OF INTEREST

The authors declare no conflict of interest.