Erythema multiforme in COVID‐19 patients and following COVID‐19 vaccination: manifestations, associations and outcomes

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Dear Editor:

Erythema multiforme (EM) is a delayed‐type hypersensitivity reaction linked to infectious agents in 90% of cases and medications or vaccination in less than 10% of cases.

A 19‐year‐old male presented with a 48‐h history of an itchy rash. Examination revealed erythematous papules and plaques with central dusky erythema and crusting on the bilateral upper extremities. There was no involvement of the palms, soles or oral mucosa. He had no fever, cough or medications. Prednisone 20 mg and cetirizine 10 mg daily were started. After 3 days, he developed fever, shortness of breath and dry cough; and a SARS‐CoV‐2 test was positive. He was started on remdesivir and dexamethasone. After 5 days, the rash started to improve, and after 2 weeks, it completely resolved.

EM in patients with COVID‐19 has been reported in 23 publications (Fig. 1), including 36 cases with 19 males (53%). Four articles reported EM after COVID‐19 vaccination (Fig. 1). The details of these manuscripts are summarized in Table 1. Among patients with EM and COVID‐19, 16.7% (6/36) patients were less than 18‐year old, 19.4% (7/36) patients were 18–40 years old and 63.9% (23/36) patients were more than 40 years old. Eleven patients (30.6%) took no medications before EM; however, 25 patients (69.4%) reported exposure to medications before. Drugs to which patients were exposed before EM were HCQ in 20 cases (55.5%), azithromycin in 14 cases (38.9%) with 13 of them receiving HCQ in addition to azithromycin and lopinavir/ritonavir in 12 patients (33.3%), all in combination with HCQ. EM occurred before any classic COVID‐19 symptoms only in 5/36 patients (13.9%), four of them under 23 years. Three patients (8.3%) presented with EM and COVID‐19 symptoms simultaneously. However, in most of the patients (78%), EM started after COVID‐19 symptoms. Four patients (11.1%) had only mucosal involvement, five patients (13.9%) had mucosal and skin involvement, but most of the patients (27 patients, 75%) had only skin lesions. Thirty‐five of 36 patients survived, and only a 72‐year‐old woman died. Interestingly, her skin lesions were the first manifestation of infection. ¹ Therefore, we believe EM is not associated with worse outcomes. EM following vaccination is rare, with eight reported cases: three after Moderna (37.5%), four after Pfizer (50%) and one after CoronaVac (12.5%) (Table 1). In another study, three of 414 cases of dermatological presentations were EM after the first dose of the Moderna vaccine. ² This rarity makes it hard to establish a causal link. Infection with SARS‐CoV‐2 may have a role in the pathogenesis of EM. ³ The underlying mechanism is not clear. ⁴ EM may result from the interaction with the virus itself, antiviral immune response and medications. EM can rarely be the presenting sign of COVID‐19, and EM is not associated with worse outcomes. Further studies are needed to elucidate the exact relationship between infection, medications and erythema multiforme in the setting of COVID‐19.

Figure 1.

Literature search and article selection for the cases of Erythema multiforme in COVID‐19 patients.

Table 1.

Reported cases of EM in patients with COVID‐19 and related to vaccination

EM related to the COVID‐19 infection
Sample size for case reports or case series	Age (years) and sex	Medication type for COVID‐19	Latency of EM after positive COVID‐test (days)	Involved areas	Infectious work‐up result other than positive COVID‐19 test	Treatment for EM	Reference
1 of 4	63Y F	Lopinavir/ritonavir, HCQ, azithromycin, ceftriaxone, corticosteroids	16 days after COVID‐19 symptoms	In all patients, skin lesions begun as erythematous papules in upper trunk.	Not performed	Systemic corticosteroids	[5]
2 of 4	77Y F	Lopinavir/ritonavir, HCQ, azithromycin, corticosteroids	16 days after COVID‐19 symptoms		Negative for HIV, EBV, CMV, VZV, HSV, M. pneumoniae, syphilis	Systemic corticosteroids
3 of 4	58Y F	Lopinavir/ritonavir, HCQ, azithromycin; ceftriaxone, corticosteroids	24 days after COVID‐19 symptoms		Not performed	Systemic corticosteroids
4 of 4	58Y F	Lopinavir/ritonavir, HCQ, azithromycin	19 days after COVID‐19 symptoms		Negative EVB for HIV, EBV, CMV, VZV, HSV, M. pneumoniae, syphilis. HSV PCR found in vesicle swab	Systemic corticosteroids
1	11Y F	None	Presented with EM	Elbows, knees, thighs, arms, forearms, legs, ankles, dorsal feet, dorsal hands	MD	None	[6]
1 of 2	17Y M	Vitamin C	15 days after COVID‐19 symptoms.	Palms	A negative syphilitic serology	None	[7]
2 of 2	29Y M	HCQ and azithromycin	12 days after COVID‐19 symptoms.	Palms	A negative syphilitic serology	None
1	95Y F	HCQ	COVID‐19 infection and EM developed simultaneously	Trunk and extremities	Serological study on parvovirus B19 infection showed negative IgM and positive IgG.	Topical corticosteroids	[8]
1	22Y F	Metronidazole, ceftriaxone, meropenem, ribavirin and HCQ	COVID‐19 infection and EM developed simultaneously	Oral and face	None	Oral valaciclovir	[9]
1	25Y F	None	EM appeared on the day 2 of the disease course	Both palms	None	None	[10]
1	37Y F	HCQ, azithromycin and oseltamivir	10 days after COVID‐19 symptoms.	Ventral/dorsal sides of hands, elbows, lips and oral mucosa	HSV, EBV, CMV, HbsAg, Anti HCV and Mycoplasma antibodies were within normal limits.	Oral methylprednisolone	[11]
1 of 2	82Y M	HCQ, ceftriaxone and ertapenem	30 days after COVID‐19 symptoms.	Generalized involvement of trunk and limbs	None	Prednisone	[12]
2 of 2	48Y M	HCQ, ritonavir, lopinavir, ceftriaxone and azithromycin	3 weeks after COVID‐19 symptoms.	Generalized involvement of trunk and limbs	None	Prednisone
1	23Y M	None	Presented with multiple painful mouth ulcers with no respiratory symptoms	Mouth, arms/legs, penis	Both CMV IgM and anti‐EBV IgM were negative.	Intravenous fluids and analgesia	[13]
1	55Y F	HCQ	12 days after COVID‐19 treatment	trunk and upper limbs, without mucosal involvement	HSV and Mycoplasma pneumoniae were negative.	Treatment with HCQ was discontinued.	[14]
1	6Y M	None	Presented with cheilitis, conjunctivitis and skin lesions. Respiratory function was normal.	Cheilitis, extremities, conjunctivitis.	Mycoplasma pneumoniae and HSV were negative.	None	[15]
1	72Y F	Paracetamol	EM as the first manifestation of the infection, 10 days before the onset of any respiratory symptoms.	Trunk and upper and lower limbs	None	Methylprednisolone i.v.	[16]
1	46Y M	Azithromycin and HCQ and specific IgE was positive for ampicillin and amoxicillin	48 h after finishing the course of HCQ, therapy, he developed EM	Face and palms, then generalized	IgM for CMV, HSV 1/2 and mycoplasma were all negative.	Prednisone and oral antihistamines	[17]
1	57‐day‐old F	None	Presented with EM and fever, cough and breathlessness.	Face and limbs	Blood culture was sterile.	Intravenous methyl prednisolone and intravenous immunoglobulin G along with antibiotics.	[18]
1 of 3	63Y F	Lopinavir/ritonavir, HCQ, azithromycin	19 days after COVID‐19 symptoms.	Mucosal involvement on Palate	None	None	[19]
2 of 3	58Y F	Lopinavir/ritonavir, HCQ, azithromycin, tocilizumab, corticosteroids	24 days after COVID‐19 symptoms.		None	None
3 of 3	69Y M	Lopinavir/ritonavir, HCQ, azithromycin	19 days after COVID‐19 symptoms.		None	None
1	57Y M	None	5 days after COVID‐19 symptoms.	Mouth, glans penis and conjunctiva	HIV antibodies were negative, CMV and EBV serologies only found IgG, and mycoplasma pneumoniae was negative.	None	[20]
1	13Y M	Paracetamol	7 days after COVID‐19 symptoms.	Left shoulder and conjunctiva	A full sepsis work‐up Was negative. Mycoplasma pneumoniae, EBV, HSV 1 and 2, adenovirus and parvovirus B19 were negative.	None	[21]
1	83Y F	HCQ and azithromycin	While receiving HCQ and azithromycin, an extensive skin rash developed.	Entire trunk with a transition to the shoulders and buttocks	None	Parenteral glucocorticosteroids	[22]
1	20 Y F	None	The rash started 4 days after cervical, axillary and inguinal lymphadenopathy.	Thighs	None	She did not receive any treatment.	[23]
1	1 Y M	Azithromycin	On the second day of illness, the febrile child developed skin rashes.	Soles, trunk and face	None	Ceftriaxone, HCQ, cetirizine, intravenous immunoglobulin, zinc gluconate, albumin and vitamin D, and meropenem were administered during the treatment course.	[24]
1 of 4	64Y F	HCQ, Lopinavir/Ritonavir, IFN‐β, ceftriaxone	Time from hospital admission to EM onset was 14 days.	Generalized targetoid lesions, and facial oedema	None	Methylprednisolone	[25]
2 of 4	79Y M	HCQ, Lopinavir/Ritonavir, IFN‐β, ceftriaxone	Time from hospital admission to EM onset was 28 days.	Generalized targetoid lesions	None	Prednisone, oral
3 of 4	74Y F	HCQ, Lopinavir/Ritonavir, IFN‐β, ceftriaxone	Time from hospital admission to EM onset was 23 days.	Generalized targetoid Lesions, and facial oedema	None	Methylprednisolone
4 of 4	47Y M	HCQ, Lopinavir/Ritonavir, IFN‐β, ceftriaxone, tocilizumab, azithromycin	Time from hospital admission to EM onset was 24 days.	Generalized targetoid lesions	None	Methylprednisolone
4	Age: 60 (40–78) 2 of 4 were F	All of 4 patients had new drugs interference	>10 days after COVID‐19 symptoms.	Targetoid lesions	None	None	[4]
1	19Y M	None	Presented with rash 5 days before COVID‐19 symptoms.	Upper extremities	None	Prednisone, oral and cetirizine, oral	[26]

EM related to the COVID‐19 vaccine
Sample size	Age (years) and sex	Type of vaccine	Latency of EM after COVID‐vaccine (days)	Involved areas	Infectious Work‐up Result or Recent Medication Use	Treatment for EM
1	75Y M	CoronaVac, developed by Sinovac Life Sciences (Beijing, China)	5 days after the second dose	Knees, face and trunk	He denied systemic symptoms, intake of new medications, and had no signs suggesting any infections.	Topical corticosteroids and oral antihistamines	[27]
1	58Y F	BNT162b2 (Pfizer–BioNTech)	Within 12 h of receiving the first BNT162b2 vaccine. A similar eruption occurred 24 h after receiving the second BNT162b2 vaccine.	Palms and soles bilaterally.	Her medical history included rheumatoid arthritis and a multinodular thyroid goitre.	Topical clobetasol	[28]
3	MD	Moderna first dose	MD	MD	MD	MD	[29]
3	MD	BNT162b2 (Pfizer/BioNTech)	MD	MD	MD	MD	[30]

CMV, Cytomegalovirus; COVID‐19, Coronavirus Disease 2019; EBV, Epstein‐Barr virus; EM, Erythema multiforme; HCQ, Hydroxychloroquine; HSV, Herpes simplex virus; MD, Missing data.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.