Abstract: The outbreak of COVID-19 pandemic has raised urgent vaccine development to prevent viral transmission. Cutaneous adverse events such as erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been observed following COVID-19 vaccination. In this systematic review, we aimed to investigate the clinical features and outcomes of EM/SJS/TEN following COVID-19 vaccination. A comprehensive literature search was conducted in PubMed, Embase, Web of Science, and Cochrane databases up to July 3, 2022. We included studies reporting patients who developed EM, SJS, or TEN following COVID-19 vaccination. A total of 47 studies involving 90 patients with EM and 16 patients with SJS/TEN were reviewed and outlined. EM predominantly occurred after the messenger ribonucleic acid vaccines (70.4%), mostly after the first (47.5%) and second doses (42.4%), with delayed onsets ranging from 1 day to 30 days. SJS/TEN were observed following either the first (55.6%)- or second-dose (33.3%) vaccination, with onset times ranging from 6 hours to 14 weeks. Three EM cases and 1 SJS case showed recurrence upon reexposure to the same vaccines. No mortality was reported. Most patients exhibited improvement or resolution after treatment, with resolution times ranging from 6 days to 8 weeks. In conclusion, EM and epidermal necrolysis, including SJS and TEN, have emerged as potential cutaneous adverse events following COVID-19 vaccine administration. Further research is warranted to elucidate the pathogenesis and casual relationship between COVID-19 vaccines and EM/SJS/TEN.
Get full access to this article
View all access options for this article.
References
1.
NiebelD, NovakN, WilhelmiJ, et al.Cutaneous adverse reactions to COVID-19 vaccines: Insights from an immuno-dermatological perspective. Vaccines (Basel). 2021; 9(9); doi: 10.3390/vaccines9090944
2.
WuPC, HuangIH, WangCW, et al.New onset and exacerbations of psoriasis following COVID-19 vaccines: A systematic review. Am J Clin Dermatol. 2022; 23(6):775–799; doi: 10.1007/s40257-022-00721-z
3.
WuPC, HuangIH, WangCW, et al.Severe cutaneous adverse reactions after COVID-19 vaccination: A systematic review. Allergy. 2023; 78(5):1383–1386; doi: 10.1111/all.15642
4.
McMahonDE, AmersonE, RosenbachM, et al.Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases. J Am Acad Dermatol. 2021; 85(1):46–55; doi: 10.1016/j.jaad.2021.03.092
NewkirkRE, FominDA, BradenMM. Erythema multiforme versus Stevens-Johnson syndrome/toxic epidermal necrolysis: Subtle difference in presentation, major difference in management. Mil Med. 2020; 185(9–10):e1847–e1850; doi: 10.1093/milmed/usaa029
8.
StoneCAJr, RukasinCRF, BeachkofskyTM, et al.Immune-mediated adverse reactions to vaccines. Br J Clin Pharmacol. 2019; 85(12):2694–2706; doi: 10.1111/bcp.14112
SuJR, HaberP, NgCS, et al.Erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis reported after vaccination, 1999–2017. Vaccine. 2020; 38(7):1746–1752; doi: 10.1016/j.vaccine.2019.12.028
11.
SchneckJ, FagotJP, SekulaP, et al.Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: A retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol. 2008; 58(1):33–40; doi: 10.1016/j.jaad.2007.08.039
12.
McMahonDE, KovarikCL, DamskyW, et al.Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: A registry-based study. J Am Acad Dermatol. 2022; 86(1):113–121; doi: 10.1016/j.jaad.2021.09.002
13.
PageMJ, McKenzieJE, BossuytPM, et al.The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021; 372:71; doi: 10.1136/bmj.n71
14.
Bujan BoninoC, Moreiras AriasN, Lopez-Pardo RicoM, et al.Atypical erythema multiforme related to BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Int J Dermatol. 2021; 60(11):e466–e467; doi: 10.1111/ijd.15894
15.
de Las VecillasL, LopezJ, MorchonE, et al.Viral-like reaction or hypersensitivity? Erythema multiforme minor reaction and moderate eosinophilia after the Pfizer-BioNTech BNT162b2 (mRNA-Based) SARS-CoV-2 Vaccine. J Investig Allergol Clin Immunol. 2021; 32(1):77–78; doi: 10.18176/jiaci.0757
16.
GriecoT, MaddalenaP, SernicolaA, et al.Cutaneous adverse reactions after COVID-19 vaccines in a cohort of 2740 Italian subjects: An observational study. Dermatol Ther. 2021; 34(6):e15153; doi: 10.1111/dth.15153
17.
KhalidM, LipkaO, BeckerC. Moderna COVID-19 vaccine induced skin rash. Vis J Emerg Med. 2021; 25:101108; doi: 10.1016/j.visj.2021.101108
18.
LaveryMJ, NawimanaS, ParslewR, et al.A flare of pre-existing erythema multiforme following BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Clin Exp Dermatol. 2021; 46(7):1325–1327; doi: 10.1111/ced.14714
WangC, RademakerM, TateB, et al.SARS-CoV-2 (COVID-19) vaccination in dermatology patients on immunomodulatory and biologic agents: Recommendations from the Australasian Medical Dermatology Group. Australas J Dermatol. 2021; 62(2):151–156; doi: 10.1111/ajd.13593
21.
AkatsukaT, SakaiY, ToyamaT, et al.Cutaneous reactions after coronavirus disease 2019 vaccination: Summary of 20 Japanese cases [Letter]. J Dermatol. 2022; 49(6):e210–e211; doi: 10.1111/1346-8138.16335
22.
BurlandoM, HerzumA, MicalizziC, et al.Cutaneous reactions to COVID-19 vaccine at the dermatology primary care. Immun Inflamm Dis. 2022; 10(2):265–271; doi: 10.1002/iid3.568
23.
CatalaA, Munoz-SantosC, Galvan-CasasC, et al.Cutaneous reactions after SARS-CoV-2 vaccination: A cross-sectional Spanish nationwide study of 405 cases. Br J Dermatol. 2022; 186(1):142–152; doi: 10.1111/bjd.20639
24.
FreemanEE, SunQ, McMahonDE, et al.Skin reactions to COVID-19 vaccines: An American Academy of Dermatology/International League of Dermatological Societies registry update on reaction location and COVID vaccine type [Letter]. J Am Acad Dermatol. 2022; 86(4):e165–e167; doi: 10.1016/j.jaad.2021.11.016
25.
IwasawaO, KamiyaK, KomineM, et al.Case of atypical erythema multiforme following coronavirus disease 2019 vaccination. J Dermatol. 2022; 49(3):e113–e114; doi: 10.1111/1346-8138.16255
KaratasE, NazimA, PatelP, et al.Erythema multiforme reactions after Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273) COVID-19 vaccination: A case series. JAAD Case Rep. 2022; 32:55–58; doi: 10.1016/j.jdcr.2021.12.002
KothariRS, SubramaniD, AsnaniDR, et al.Erythema multiforme after Covishield/ChAdOx1 vaccination. Dermatol Ther. 2022; 35(3):e15289; doi: 10.1111/dth.15289
30.
LeeDS, KimJW, LeeKL, et al.Adverse events following COVID-19 vaccination in South Korea between February 28 and August 21, 2021: A nationwide observational study [Article]. Int J Infect Dis. 2022; 118:173–182; doi: 10.1016/j.ijid.2022.03.007
31.
ManjiKP, MwanikiG, SimbaAA, et al.Erythema multiforme in a young adult following COVID-19 infection and vaccination in Tanzania. BMJ Case Rep. 2022; 15(5); doi: 10.1136/bcr-2021-247168
32.
MassipE, MarcantP, FontG, et al.Cutaneous manifestations following COVID-19 vaccination: A multicentric descriptive cohort [Letter]. J Eur Acad Dermatol Venereol. 2022; 36(4):e253–e255; doi: 10.1111/jdv.17883
33.
Pour MohammadA, MashayekhiF, SeirafianpourF, et al.COVID-19 and COVID-19 vaccine-related dermatological reactions: An interesting case series with a narrative review of the potential critical and non-critical mucocutaneous adverse effects related to virus, therapy, and the vaccination. Clin Case Rep. 2022; 10(4):e05775; doi: 10.1002/ccr3.5775
34.
PouraniMR, Shahidi DadrasM, SalariM, et al.Cutaneous adverse events related to COVID-19 vaccines: A cross-sectional questionnaire-based study of 867 patients. Dermatol Ther. 2022; 35(2):e15223; doi: 10.1111/dth.15223
35.
ScharfC, Di BrizziEV, PelleroneS, et al.Nevocentric erythema multiforme after SARS-COV-2 vaccine. J Eur Acad Dermatol Venereol. 2022; 36(1):e30–e32; doi: 10.1111/jdv.17688
36.
SechiA, PierobonE, PezzoloE, et al.Abrupt onset of Sweet syndrome, pityriasis rubra pilaris, pityriasis lichenoides et varioliformis acuta and erythema multiforme: Unravelling a possible common trigger, the COVID-19 vaccine. Clin Exp Dermatol. 2022; 47(2):437–440; doi: 10.1111/ced.14970
37.
ShakoeiS, KalantariY, NasimiM, et al.Cutaneous manifestations following COVID-19 vaccination: A report of 25 cases. Dermatol Ther. 2022; 35(8):e15651; doi: 10.1111/dth.15651
38.
AkdaşE, ÖğütB, ErdemÖ, et al.Cutaneous reactions following CoronaVac COVID-19 vaccination: A case series of six healthcare workers from a single centre. J Eur Acad Dermatol Venereol. 2021; 35(12):e861–e864; doi: 10.1111/jdv.17592
SaibeneAM, AlliataA, CozziAT, et al.Erythema multiforme major following SARS-CoV-2 vaccine. Clin Case Rep. 2021; 9(10):e04947; doi: 10.1002/ccr3.4947
41.
CastilloJG, GibertPR, Romero AbrioC, et al.Erythema multiforme after the third dose of mRNA-1273. Dermatol Ther. 2022; 35(6):e15497; doi: 10.1111/dth.15497
42.
IbrahimMM. Erythema multiforme after Pfizer-BioNTech covid-19 vaccination in Iraqi patient [Article]. MLU. 2021; 22(1):67–69; doi: 10.37506/mlu.v22i1.3181
43.
KimMJ, KimJW, KimMS, et al.Generalized erythema multiforme-like skin rash following the first dose of COVID-19 vaccine (Pfizer-BioNTech). J Eur Acad Dermatol Venereol. 2022; 36(2):e98–e100; doi: 10.1111/jdv.17757
44.
PetruzziM, GalleggianteS, MessinaS, et al.Oral erythema multiforme after Pfizer-BioNTech COVID-19 vaccination: A report of four cases. BMC Oral Health. 2022; 22(1):90; doi: 10.1186/s12903-022-02124-2
ElboraeyMO, EssaE. Stevens-Johnson syndrome post second dose of Pfizer COVID-19 vaccine: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol. 2021; 132(4):e139–e142; doi: 10.1016/j.oooo.2021.06.019
49.
MansouriP, ChalangariR, Martits-ChalangariK, et al.Stevens-Johnson Syndrome due to COVID-19 vaccination. Clin Case Rep. 2021; 9(11):e05099; doi: 10.1002/ccr3.5099
50.
BattagliniD, BallL, RobbaC, et al.Patients with suspected severe adverse reactions to COVID-19 vaccination admitted to intensive care unit: A case report. Front Med (Lausanne). 2022; 9:823837; doi: 10.3389/fmed.2022.823837
MansouriP, FarshiS. A case of Steven-Johnson syndrome after COVID-19 vaccination. J Cosmet Dermatol. 2022; 21(4):1358–1360; doi: 10.1111/jocd.14756
53.
PadniewskiJJ, Jacobson-DunlopE, AlbadriS, et al.Stevens-Johnson syndrome precipitated by Moderna Inc. COVID-19 vaccine: A case-based review of literature comparing vaccine and drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Int J Dermatol. 2022; 61(8):923–929; doi: 10.1111/ijd.16222
54.
BakirM, AlmeshalH, AlturkiR, et al.Toxic epidermal necrolysis post COVID-19 vaccination – first reported case. Cureus. 2021; 13(8):e17215; doi: 10.7759/cureus.17215
55.
KherlopianA, ZhaoC, GeL, et al.A case of toxic epidermal necrolysis after ChAdOx1 nCov-19 (AZD1222) vaccination. Australas J Dermatol. 2021; 63(1):e93–e95; doi: 10.1111/ajd.13742
MuradMH, SultanS, HaffarS, et al.Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018; 23(2):60–63; doi: 10.1136/bmjebm-2017-110853
58.
MaLL, WangYY, YangZH, et al.Methodological quality (risk of bias) assessment tools for primary and secondary medical studies: What are they and which is better? Mil Med Res. 2020; 7(1):7; doi: 10.1186/s40779-020-00238-8
NaranjoCA, BustoU, SellersEM, et al.A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30(2):239–245; doi: 10.1038/clpt.1981.154
61.
HsuT-J, LiuK-L. Stevens-Johnson syndrome and toxic epidermal necrolysis related to immune checkpoint inhibitors: Two cases and literature review [Case Report]. Dermatol Sin. 2020; 38(4):236–239; doi: 10.4103/ds.ds_24_20
62.
Bastuji-GarinS, RzanyB, SternRS, et al.Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993; 129(1):92–96.
63.
SassolasB, HaddadC, MockenhauptM, et al.ALDEN, an algorithm for assessment of drug causality in Stevens-Johnson Syndrome and toxic epidermal necrolysis: Comparison with case-control analysis. Clin Pharmacol Ther. 2010; 88(1):60–68; doi: 10.1038/clpt.2009.252
KhalilI, LepageV, DouayC, et al.HLA DQB1*0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol. 1991; 97(4):697–700; doi: 10.1111/1523-1747.ep12484029
66.
ChangCJ, ChenCB, HungSI, et al.Pharmacogenetic testing for prevention of severe cutaneous adverse drug reactions. Front Pharmacol. 2020; 11:969; doi: 10.3389/fphar.2020.00969
67.
SalehW, AlharbiH, ChaS. Increased prevalence of erythema multiforme in patients with COVID-19 infection or vaccination. Sci Rep. 2024; 14(1):2801; doi: 10.1038/s41598-024-52099-z
68.
StanleyEA, ZhangL, O’HaraJ, et al.The seven-fold rise in incidence of Stevens-Johnson syndrome & toxic epidermal necrolysis: Associations with COVID-19 and the vaccine. Burns. 2024; 50(1):87–92; doi: 10.1016/j.burns.2023.06.016
69.
DuanL, ZhengQ, ZhangH, et al.The SARS-CoV-2 spike glycoprotein biosynthesis, structure, function, and antigenicity: Implications for the design of spike-based vaccine immunogens. Front Immunol. 2020; 11:576622; doi: 10.3389/fimmu.2020.576622
70.
TanC, ZhengX, SunF, et al.Hypersensitivity may be involved in severe COVID-19. Clin Exp Allergy. 2022; 52(2):324–333; doi: 10.1111/cea.14023
71.
ChenCB, LeeCC, WangCW, et al.Genetic associations of human leukocyte antigen alleles in cutaneous delayed drug hypersensitivity reactions: An updated review. Dermatologica Sinica. 2023; 41(4):183–198; doi: 10.4103/ds.DS-D-23-00082
72.
KounisNG, KoniariI, de GregorioC, et al.Allergic reactions to current available COVID-19 vaccinations: Pathophysiology, causality, and therapeutic considerations. Vaccines (Basel). 2021; 9(3):221; doi: 10.3390/vaccines9030221
73.
RitchieH, MathieuE, Rodés-GuiraoL, et al.Coronavirus pandemic (COVID-19). OurWorldInData.org 2020 Available from: https://ourworldindata.org/coronavirus.
74.
SsentongoP, SsentongoAE, VoletiN, et al.SARS-CoV-2 vaccine effectiveness against infection, symptomatic and severe COVID-19: A systematic review and meta-analysis. BMC Infect Dis. 2022; 22(1):439; doi: 10.1186/s12879-022-07418-y
75.
ChuMT, WangCW, ChangWC, et al.Granulysin-based lymphocyte activation test for evaluating drug causality in antiepileptics-induced severe cutaneous adverse reactions. J Invest Dermatol. 2021; 141(6):1461–1472.e10; doi: 10.1016/j.jid.2020.11.027
76.
HanL, AnC, LiuD, et al.Development of an ELISA assay for the determination of SARS-CoV-2 protein subunit vaccine antigen content. Viruses. 2022; 15(1); doi: 10.3390/v15010062
77.
HungWK, ChiCC, WangSH. AZ arm: Delayed cutaneous reaction to ChAdOx1 nCoV-19 (AZD1222) vaccine. Dermatol Sin. 2022; 40(1):52–53; doi: 10.4103/ds.ds_4_22
78.
BarbaudA. Skin testing in delayed reactions to drugs. Immunol Allergy Clin North Am. 2009; 29(3):517–535; doi: 10.1016/j.iac.2009.04.010
79.
MuikA, LuiBG, WallischAK, et al.Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited human sera. Science. 2022; 375(6581):678–680; doi: 10.1126/science.abn7591
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
