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Cutaneous reactions to COVID-19 vaccines: A review

Open AccessPublished:February 16, 2022DOI:https://doi.org/10.1016/j.jdin.2022.01.011

      Background

      The increasing number of reports on cutaneous reactions following COVID-19 vaccination has led to growing concerns among certain groups.

      Objective

      We reviewed the published reports of cutaneous lesions after COVID-19 vaccination.

      Methods

      We conducted a literature search for original and review articles published between January 1, 2020, and September 27, 2021.

      Results

      Eleven cutaneous reactions associated with COVID-19 vaccines were determined; the most prevalent reactions were local injection site reactions, delayed local reactions, urticaria, angioedema, and morbilliform eruptions. There were more reports on skin reactions following the administration of messenger RNA-based vaccines than on those following the administration of adenoviral vector or inactivated whole-virus vaccines, in part, due to their higher administration rate. Most reported skin reactions occurred after the first vaccine dose.

      Limitations

      A reporting bias could not be excluded, and skin biopsy results were not available for most included individuals. Moreover, given that the included trials focused on vaccine efficacy, there was a lack of details concerning cutaneous reactions and participant information.

      Conclusion

      Not all cutaneous reactions observed after COVID-19 vaccination are hypersensitivity reactions. Different cutaneous reactions may reflect underlying immune responses to the vaccines. A large majority of COVID-19 vaccination reactions were mild and self-limiting, and people should be encouraged to complete their vaccination regimen.

      Key words

      Abbreviation used:

      SCAR (severe cutaneous adverse reactions)
      • Most common cutaneous reactions were transient local reactions. No serious sequelae were reported.
      • Different cutaneous reactions may reflect underlying immune responses to vaccines. Most reactions were minor and should not discourage vaccination. The majority of cutaneous reactions occurred after mRNA-based vaccine administration, which could be due to its widespread use.

      Introduction

      As COVID-19 mass vaccination is underway, increasing reports of adverse reactions associated with the vaccines are emerging. Anecdotal reports regarding novel formulations of messenger RNA (mRNA)-based vaccines are being inflated by social media, generating alarming misconceptions about vaccination.
      • Chirumbolo S.
      Vaccination hesitancy and the “myth” on mRNA-based vaccines in Italy in the COVID-19 era: does urgency meet major safety criteria?.
      ,
      • Hotez P.
      • Batista C.
      • Ergonul O.
      • et al.
      Correcting COVID-19 vaccine misinformation: lancet Commission on COVID-19 Vaccines and Therapeutics Task Force Members.
      Therefore, understanding the spectrum of adverse reactions to COVID-19 vaccines is crucial in creating awareness of the importance of vaccination in the general population.
      Although systemic adverse effects are important, cutaneous effects are the immediate reason for dissuading vaccine administration. We reviewed the published reports of cutaneous reactions to COVID-19 vaccines and described these reactions in relation to clinical practice. We reported the prevalence of cutaneous reactions to different types of COVID-19 vaccines and the clinical severity of the reactions.

      Materials and methods

      For this review, we searched PubMed, OVID, EMBASE, MEDLINE, and Google Scholar for original and review articles written in English and published from January 1, 2020, to September 27, 2021. We used the key words “cutaneous,” “skin,” “rash,” “morbilliform,” “sweet syndrome,” “pityriasis rosea,” “pityriasis-rosea-like,” “pemphigus,” and “bullous pemphigoid” in combination with “COVID-19 vaccination,” “2019-nCOV,” “novel coronavirus,” “human coronavirus 2019,” “hCoV-19,” and “SARS-CoV-2.” We reviewed the published reports of cutaneous reactions to all COVID-19 vaccines approved by the World Health Organization; we included Gam-COVID-Vac (Sputnik V; Gamaleya National Research Center of Epidemiology, Health Ministry of the Russian Federation) and BBV152 (Covaxin; Bharat Biotech International Ltd), given their global availability. We eliminated articles that were not relevant to cutaneous manifestations (Table I). We extracted the following data from the included studies: skin reactions, type of vaccine, administration dose (first or second dose), median duration between vaccine administration and the eruption of lesions, clinical outcomes, and skin biopsy results (Table I).
      Table ISummary of the types of COVID-19 vaccines and cutaneous reactions
      mRNA-based vaccinesAdenoviral vector vaccinesInactivated whole-virus vaccine
      BNT162b2mRNA-1273Sputnik VVaxzevria/CovishieldAd26.COV2.SCoronaVacCovaxinSinopharm
      First doseSecond doseNRFirst doseSecond doseNRFirst doseSecond doseFirst doseSecond doseSingle doseFirst doseSecond doseFirst doseSecond doseFirst doseSecond doseNR
      Pain31942737012,78412,3850NRNR88554379644310354054853
      Swelling2562620105117640NRNR342189130012126
      Redness195251056312610NRNR25218950008153
      Delayed local reaction566206111600NRNR1000000000
      Urticaria503801541910000001300000
      Angioedema232201121200000000000000
      Morbilliform eruption19501480000000000000
      Herpes zoster11801520000000010000
      Bullous eruptions640640000000000000
      Filler reactions330660000000000000
      Chilblains530330000000000000
      Sweet syndrome301000002000000000
      Pityriasis rosea340110000001100000
      Erythema multiforme720010000000000000
      Dermal hypersensitivity reactions001101000000000000
      Lichen planus110000000000000000
      Pityriasis rosea-like eruptions111000000000000000
      Papulovesicular eruptions002001000000000000
      Severe cutaneous adverse reactions000000001010000000
      Facial pustular neutrophilic eruptions000110000000000000
      Generalized annular eruptions000000000010000000
      NR, Not reported.

      Results

      We summarized the findings of 75 articles: 7 randomized controlled trials, 1 registry-based study, 1 prospective cohort study, 4 retrospective studies, 21 case series, and 41 case reports. In total, 125,713 patients were included, and 48,740 cutaneous reactions were described (Supplementary Table I, available via Mendeley at https://data.mendeley.com/datasets/vbjbrr7ynh/1).
      The median age of individuals in whom cutaneous reactions developed after COVID-19 vaccination was 49.3 years; however, in 99% (48,387/48,740) of the cases, the age was not reported. Among the 48,740 reported cutaneous reactions, 45 (0.1%) occurred in men, 310 (0.6%) occurred in women, and 48,385 (99.3%) did not report their sex. Table I presents these findings. Skin reactions occurred in 28,655 (58.8%) cases after the first dose, 19,987 (41%) cases after the second dose, and 98 (0.2%) cases in which the dose was undocumented.
      A total of 213,198 COVID-19 vaccine doses were administered in the included articles; 91,111 doses of mRNA-1273 (Moderna, Inc; National Institute of Allergy and Infectious Diseases), 63,030 of BN-T162b2 (Comirnaty; Pfizer/BioNTech Manu-facturing GmbH and Fosun Pharma), 31,465 of Gam-COVID-Vac, 21,895 of Ad26.COV2.S (Janssen Pharmaceuticals Com-panies of Johnson & Johnson), 2362 of BBIBP-CorV (Sinopharm; China National Biotec Group Co, Ltd and Beijing Institute of Biological Products Co, Ltd), 1798 of Vero cell (CoronaVac; Sinovac Research and Development Co, Ltd), 676 of AZD1222 (ChAdOx1-S; Covishield/Vaxzevria; AstraZeneca and University of Oxford), and 596 of BBV152. However, in 265 cases, the vaccine type was not documented (Table I).
      Among the 48,740 reported cutaneous reactions, 38,472 (78.93%) occurred after the aministration of mRNA vaccines, 8920 (18.3%) after the aministration of adenoviral vector vaccines, and 1333 (2.74%) after the aministration of inactivated whole-virus vaccines (Table II). The vaccine name was not recorded in 15 (0.03%) cases. However, taking into consideration the total doses of mRNA vaccines (154,141 doses) and inactivated whole-virus COVID-19 vaccines (4756 doses) administered in the included studies, the prevalence of cutaneous reactions reported with mRNA vaccines (38,472/154,141; 25%) was lower than that with inactivated whole-virus COVID-19 vaccines (1333/4756; 28.3%). Table III provides the details of these findings. Cutaneous reactions occurred more commonly after the first dose (28,655/48,740; 58.8%) than after the second dose (19,987/48,740; 41%).
      Table IIPrevalence of cutaneous reactions following COVID-19 vaccination
      mRNA-based COVID-19 vaccinesAdenoviral vector COVID-19 vaccinesInactivated whole-virus COVID-19 vaccines
      Reported cutaneous reactions38,47289201333
      Total vaccine doses given154,14154,0364756
      Prevalence of cutaneous reactions38,472/154,141 = 25%8920/54,036 = 16.5%1333/4756 = 28.3%
      Fifteen reported cases of cutaneous reactions did not have their types of vaccines recorded.
      Table IIISummary of the 10-most common cutaneous reactions to COVID-19 vaccines and survival data
      Cutaneous reactionsNumber of reported reactionsVaccine nameDoseMedian age, ySexClinical outcome
      Local injection site reactions46,943BNT162b2: 6895 mRNA-1273: 29,808

      Covishield/Vaxzevria: 157

      Ad 26.COV2.S: 8757

      CoronaVac: 116

      Covaxin: 13

      Sinopharm: 1197
      Dose 1: 27,533

      Dose 2: 19,348

      NR: 62
      NRNRNo serious sequelae reported
      Delayed local reactions898BNT162b2: 118 mRNA-1273: 771

      Covishield/Vaxzevria: 1

      NR: 8
      Dose 1: 669

      Dose 2: 222

      NR: 8
      51.57 M: 128 F

      763 NR
      No serious sequelae reported
      Urticaria440BNT162b2: 88 mRNA-1273: 345

      CoronaVac: 7
      Dose 1: 205

      Dose 2: 232

      NR: 3
      34.53 M: 16 F

      421 NR
      No serious sequelae reported
      Angioedema277BNT162b2: 45 mRNA-1273: 232Dose 1: 135

      Dose 2: 142
      42.52 M: 6 F

      269 NR
      No serious sequelae reported
      Morbilliform eruptions46BNT162b2: 24 mRNA-1273: 22Dose 1: 33

      Dose 2: 13
      552 M: 1 F

      43 NR
      No serious sequelae reported
      Herpes zoster39BNT162b2: 19 mRNA-1273: 17

      Covaxin: 1

      NR: 2
      Dose 1: 27

      Dose 2: 10

      NR: 2
      6013 M: 15 F

      11 NR
      No serious sequelae reported
      Bullous eruptions20BNT162b2: 10 mRNA-1273: 10Dose 1: 12

      Dose 2: 8
      7910 M: 10 FNo serious sequelae reported
      Filler reactions18BNT162b2: 6 mRNA-1273: 12Dose 1: 9

      Dose 2: 9
      470 M: 9 F

      9 NR
      No serious sequelae reported
      Chilblains14BNT162b2: 8 mRNA-1273: 6Dose 1: 8

      Dose 2: 6
      702 M: 2 F

      10 NR
      No serious sequelae reported
      Pityriasis rosea11BNT162b2: 7 mRNA-1273: 2

      CoronaVac: 2
      Dose 1: 5

      Dose 2: 6
      392M: 4F

      1 NR
      No serious sequelae reported
      NR, Not reported.
      We classified the most commonly reported cutaneous reactions associated with COVID-19 vaccines into the following 11 classes:
      • 1.
        Local injection site reactions: Local injection site reactions included pain, redness, and swelling, which occur within 7 days after vaccination.
        • Polack F.P.
        • Thomas S.J.
        • Kitchin N.
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
        • Baden L.R.
        • El Sahly H.M.
        • Essink B.
        • et al.
        Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
        • Ramasamy M.N.
        • Minassian A.M.
        • Ewer K.J.
        • et al.
        Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
        • Wu Z.
        • Hu Y.
        • Xu M.
        • et al.
        Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
        On average, these reactions started on the first day after vaccination, regardless of the dose.
        • Polack F.P.
        • Thomas S.J.
        • Kitchin N.
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
        ,
        • Baden L.R.
        • El Sahly H.M.
        • Essink B.
        • et al.
        Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
        The median duration of these reactions was 2 to 3 days. These were the most common skin reactions associated with the COVID-19 vaccines (96%). For the 8 vaccines that were studied, the most common local injection site reaction was pain (36,883/48,740; 75.7%), followed by redness (4497/48,740; 9.2%) and swelling (5563/48,740; 11.4%). Most (58.7%) reactions occurred after the first dose. Younger individuals tended to have a higher incidence than older individuals. However, the median age and sex of the individuals were not documented.
        • Polack F.P.
        • Thomas S.J.
        • Kitchin N.
        • et al.
        Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
        ,
        • Baden L.R.
        • El Sahly H.M.
        • Essink B.
        • et al.
        Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      • 2.
        Delayed local reactions: Delayed local reactions are local reactions with onset at ≥7 days after vaccination.
        • Baden L.R.
        • El Sahly H.M.
        • Essink B.
        • et al.
        Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
        ,
        • McMahon D.E.
        • Amerson E.
        • Rosenbach M.
        • et al.
        Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.
        ,
        • Baeck M.
        • Marot L.
        • Belkhir L.
        Delayed large local reactions to mRNA vaccines.
        These reactions were characterized by erythema, pruritus, induration, tenderness near the injection site, and a presentation mimicking cellulitis,
        • Baden L.R.
        • El Sahly H.M.
        • Essink B.
        • et al.
        Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
        ,
        • McMahon D.E.
        • Amerson E.
        • Rosenbach M.
        • et al.
        Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.
        ,
        • Blumenthal K.G.
        • Robinson L.B.
        • Camargo C.A.
        • et al.
        Acute allergic reactions to mRNA COVID-19 vaccines.
        ,
        • Lindgren A.L.
        • Austin A.H.
        • Welsh K.M.
        COVID arm: delayed hypersensitivity reactions to SARS-CoV-2 vaccines misdiagnosed as cellulitis.
        and these accounted for 1.7% of the reported skin reactions. Nearly all the reported delayed local reactions (889/898; 99%) occurred after mRNA vaccination. Most (74.9%) of the delayed local reactions occurred after the first dose. The median age of individuals who experienced these reactions was 51.5 years. The median duration of the onset of delayed local reactions following COVID-19 vaccination was 7 days.
      • 3.
        Urticaria: Urticaria is characterized by pruritic erythematous wheals or plaques.
        • McMahon D.E.
        • Amerson E.
        • Rosenbach M.
        • et al.
        Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.
        ,
        • Robinson L.B.
        • Fu X.
        • Hashimoto D.
        • et al.
        Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines.
        ,
        • Bianchi L.
        • Biondi F.
        • Hansel K.
        • Murgia N.
        • Tramontana M.
        • Stingeni L.
        Skin tests in urticaria/angioedema and flushing to Pfizer-BioNTech SARS-CoV-2 vaccine: limits of intradermal testing.
        A total of 440 (0.9%) urticarial reactions were reported. Most (97.9%) of the urticarial reactions occurred after mRNA vaccination. Among 19 individuals for whom the age and sex were documented, the median age was 37.9 years (women: 17/19, 89.5%; men: 2/19, 10.5%). The median duration of the onset of urticarial eruptions after COVID-19 vaccination was 22 hours.
      • 4.
        Angioedema: Angioedema is characterized by submucosal or subcutaneous swelling.
        • McMahon D.E.
        • Amerson E.
        • Rosenbach M.
        • et al.
        Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.
        ,
        • Robinson L.B.
        • Fu X.
        • Hashimoto D.
        • et al.
        Incidence of cutaneous reactions after messenger RNA COVID-19 vaccines.
        ,
        • Bianchi L.
        • Biondi F.
        • Hansel K.
        • Murgia N.
        • Tramontana M.
        • Stingeni L.
        Skin tests in urticaria/angioedema and flushing to Pfizer-BioNTech SARS-CoV-2 vaccine: limits of intradermal testing.
        It accounted for 0.5% of the reported skin reactions following COVID-19 vaccination. All the reported cases of angioedema occurred after mRNA vaccination. A total of 50.2% and 49.8% of the angioedema cases occurred after the first and second doses, respectively. Among 3% of cases for which the age and sex were documented, the median age was 40.4 years (women, 6/8, 75%; men: 2/8, 25%). The median duration of the onset of angioedema eruptions following COVID-19 vaccination was 12 hours.
      • 5.
        Morbilliform eruption: Of the reported skin reactions after COVID-19 vaccination, morbilliform eruption represented 0.09%. All the reported cases occurred after mRNA vaccination. A total of 72% and 28% of the morbilliform eruptions occurred after the first and second doses, respectively. The median age of individuals who reported a morbilliform eruption was 55 years. The median duration of the onset of morbilliform eruptions following COVID-19 vaccination was 3 days.
      • 6.
        Herpes zoster: Herpes zoster accounted for 0.08% of the reported skin reactions. Most (69.2%) cases occurred after the first dose. The median age of individuals who experienced herpes zoster following COVID-19 vaccination was 60 years. The median duration of the onset of herpes zoster following COVID-19 vaccination was 4 days.
      • 7.
        Bullous eruptions: The reported bullous eruptions included bullous pemphigoid (18/20; 90%), pemphigus vulgaris (1/20; 5%), and bullous fixed drug eruption (1/20; 5%). Bullous eruptions accounted for 0.04% of the reported skin reactions following COVID-19 vaccination. All the reported bullous eruptions occurred after mRNA vaccination, and most (60%) occurred after the first dose. The median age of individuals in whom bullous eruptions developed after COVID-19 vaccination was 79 years (men: 50%; women: 50%). The median duration of the onset of bullous eruptions following COVID-19 vaccination was 7 days.
      • 8.
        Filler reactions: Filler reactions refer to delayed inflammatory reactions to hyaluronic acid-based fillers. They manifest as erythema, painful induration, tissue hardening, and edema.
        • Munavalli G.G.
        • Guthridge R.
        • Knutsen-Larson S.
        • Brodsky A.
        • Matthew E.
        • Landau M.
        COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment.
        ,
        • Michon A.
        Hyaluronic acid soft tissue filler delayed inflammatory reaction following COVID-19 vaccination—a case report.
        Filler reactions accounted for 0.04% of the reported skin reactions following COVID-19 vaccination. All the reported filler reactions occurred after mRNA vaccination. In total, 50% occurred after the first dose and 50% after the second dose. The median age of individuals who experienced filler reactions was 47 years; 50% of them were women, whereas 50% did not report their age or sex. The median duration of the onset of filler reactions following COVID-19 vaccination was 1 day.
      • 9.
        Chilblains: Chilblains accounted for 0.03% of the reported skin reactions. All the reported cases of chilblains occurred after mRNA vaccination, and most (64%) occurred after the first dose. The median age of individuals who experienced chilblains was 70 years. The median duration of the onset of chilblains following COVID-19 vaccination was 3 days.
      • 10.
        Pityriasis rosea: In total, 0.023% of the reported skin reactions following COVID-19 vaccination were attributed to pityriasis rosea. Most (90%) occurred after mRNA vaccination and after the second dose (60%). The median age of individuals who experienced pityriasis rosea was 39 years; among them, 40% were women, 20% were men, and 40% did not report their age or sex. The median duration of the onset of the eruptions of pityriasis rosea following COVID-19 vaccination was 5.5 days.
      • 11.
        Severe cutaneous adverse reactions (SCARs): SCARs following COVID-19 vaccination were very rare and accounted for 0.004% (2 cases) of the reported skin reactions.
        • Dash S.
        • Sirka C.S.
        • Mishra S.
        • Viswan P.
        COVID-19 vaccine-induced Stevens–Johnson syndrome.
        ,
        • Lospinoso K.
        • Nichols C.S.
        • Malachowski S.J.
        • Mochel M.C.
        • Nutan F.
        A case of severe cutaneous adverse reaction following administration of the Janssen Ad26.COV2.S COVID-19 vaccine.
        Nonetheless, they posed a significant risk of morbidity and mortality in affected patients. The reported SCARs included acute generalized exanthematous pustulosis and Stevens-Johnson syndrome. The 2 reported cases occurred after the administration of adenoviral vector vaccines. The median age of individuals who experienced SCARs was 67 years, and both were men. The median duration of the onset of SCARs following COVID-19 vaccination was 3 days. Both the patients recovered, with no serious sequelae.
      Other less-common cutaneous reactions reported following COVID-19 vaccination included erythema multiforme (0.02%),
      • McMahon D.E.
      • Kovarik C.L.
      • Damsky W.
      • et al.
      Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study.
      • Sechi A.
      • Pierobon E.
      • Pezzolo E.
      • 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.
      • Kim M.J.
      • Kim J.W.
      • Kim M.S.
      • Choi S.Y.
      • Na J.I.
      Generalized erythema multiforme-like skin rash following the first dose of COVID-19 vaccine (Pfizer-BioNTech).
      • Saibene A.M.
      • Alliata A.
      • Cozzi A.T.
      • et al.
      Erythema multiforme major following SARS-CoV-2 vaccine.
      • Bonino C.B.
      • Arias N.M.
      • Rico M.L.
      • et al.
      Atypical erythema multiforme related to BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine.
      • Lavery M.J.
      • Nawimana S.
      • Parslew R.
      • Stewart L.
      A flare of pre-existing erythema multiforme following BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine.
      • Gambichler T.
      • Scholl L.
      • Dickel H.
      • Ocker L.
      • Stranzenbach R.
      Prompt onset of Rowell’s syndrome following the first BNT162b2 SARS-CoV-2 vaccination.
      • de Las Vecillas L.
      • López J.
      • Morchón E.
      • Rodriguez F.
      • Drake M.
      • Martino M.
      Viral-like reaction or hypersensitivity? Erythema multiforme minor reaction and moderate eosinophilia after receiving Pfizer-BioNTech BNT162b2 (mRNA-based SARS-CoV-2 vaccine).
      Sweet syndrome (0.012%),
      • Sechi A.
      • Pierobon E.
      • Pezzolo E.
      • 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.
      ,
      • Torrealba-Acosta G.
      • Martin J.C.
      • Huttenbach Y.
      • et al.
      Acute encephalitis, myoclonus and Sweet syndrome after mRNA-1273 vaccine.
      • Darrigade A.S.
      • Théophile H.
      • Sanchez-Pena P.
      • et al.
      Sweet syndrome induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine.
      • Baffa M.E.
      • Maglie R.
      • Giovannozzi N.
      • et al.
      Sweet syndrome following SARS-CoV2 vaccination.
      • Capassoni M.
      • Ketabchi S.
      • Cassisa A.
      • et al.
      AstraZeneca (AZD1222) COVID-19 vaccine-associated adverse drug event: a case report.
      dermal hypersensitivity reactions (0.01%),
      • McMahon D.E.
      • Kovarik C.L.
      • Damsky W.
      • et al.
      Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study.
      lichen planus (0.006%),
      • Hiltun I.
      • Sarriugarte J.
      • Martínez-de-Espronceda I.
      • et al.
      Lichen planus arising after COVID-19 vaccination.
      ,
      • Merhy R.
      • Sarkis A.S.
      • Kaikati J.
      • El Khoury L.
      • Ghosn S.
      • Stephan F.
      New-onset cutaneous lichen planus triggered by COVID-19 vaccination.
      papulovesicular eruptions (0.006%),
      • McMahon D.E.
      • Kovarik C.L.
      • Damsky W.
      • et al.
      Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: a registry-based study.
      pityriasis rosea-like eruptions (0.004%),
      • Cyrenne B.M.
      • Al-Mohammedi F.
      • DeKoven J.G.
      • Alhusayen R.
      Pityriasis rosea-like eruptions following vaccination with BNT162b2 mRNA COVID-19 vaccine.
      ,
      • Carballido Vázquez A.M.
      • Morgado B.
      Pityriasis rosea-like eruption after Pfizer-BioNTech COVID-19 vaccination.
      generalized annular lesions (0.002%),
      • Song E.J.
      • Wong A.J.
      Widespread annular eruption after Ad26.COV2.S COVID-19 vaccine.
      facial pustular neutrophilic eruptions (0.004%),
      • Merrill E.D.
      • Kashem S.W.
      • Amerson E.H.
      • et al.
      Association of facial pustular neutrophilic eruption with messenger RNA-1273 SARS-CoV-2 vaccine.
      and flares of underlying autoimmune skin conditions (0.002%).
      • Krajewski P.K.
      • Matusiak Ł.
      • Szepietowski J.C.
      Psoriasis flare-up associated with second dose of Pfizer-BioNTech BNT16B2b2 COVID-19 mRNA vaccine.
      All the cases resolved, without serious sequelae.

      Discussion

      The increasing number of reports of cutaneous reactions following mRNA vaccination has led to misinformation in the media.
      • Chirumbolo S.
      Vaccination hesitancy and the “myth” on mRNA-based vaccines in Italy in the COVID-19 era: does urgency meet major safety criteria?.
      ,
      • Hotez P.
      • Batista C.
      • Ergonul O.
      • et al.
      Correcting COVID-19 vaccine misinformation: lancet Commission on COVID-19 Vaccines and Therapeutics Task Force Members.
      Misleading claims arise from relatively short clinical trials and the novel mechanisms of mRNA vaccines. We sought to explore the skin reactions occurring after COVID-19 vaccination.
      Local injection site reactions were more commonly observed in younger individuals than in older individuals.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ,
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      To date, no serious sequelae have been reported in individuals with local injection site reactions. By providing proper vaccine guidance, recipients can be mentally prepared for the possible occurrence of cutaneous reactions and, therefore, more likely to complete their second dose.
      In observational studies, delayed local reactions were the most commonly reported cutaneous reactions following COVID-19 vaccination. Nearly all of these reactions occurred after mRNA vaccination, with a few occurring after DNA vaccination.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      ,
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      ,
      • Wu Z.
      • Hu Y.
      • Xu M.
      • et al.
      Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
      ,
      • Blumenthal K.G.
      • Robinson L.B.
      • Camargo C.A.
      • et al.
      Acute allergic reactions to mRNA COVID-19 vaccines.
      ,
      • Lindgren A.L.
      • Austin A.H.
      • Welsh K.M.
      COVID arm: delayed hypersensitivity reactions to SARS-CoV-2 vaccines misdiagnosed as cellulitis.
      ,
      • Zhang Y.
      • Zeng G.
      • Pan H.
      • et al.
      Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
      • Folegatti P.M.
      • Ewer K.J.
      • Aley P.K.
      • et al.
      Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.
      • Baeck M.
      • Marot L.
      • Belkhir L.
      Delayed large local reactions to mRNA vaccines.
      • Johnston M.S.
      • Galan A.
      • Watsky K.L.
      • Little A.J.
      Delayed localized hypersensitivity reactions to the Moderna COVID-19 vaccine: a case series.
      • Lieberman P.
      • Simons F.E.
      Anaphylaxis and cardiovascular disease: therapeutic dilemmas.
      • Liu X.
      • Lee S.
      • Lohse C.M.
      • Hardy C.T.
      • Campbell R.L.
      Biphasic reactions in emergency department anaphylaxis patients: a prospective cohort study.
      • Abi Zeid Daou C.
      • Natout M.A.
      • El Hadi N.
      Biphasic anaphylaxis after exposure to the first dose of Pfizer-BioNTech COVID-19 mRNA vaccine.
      • Wenande E.
      • Garvey L.H.
      Immediate-type hypersensitivity to polyethylene glycols: a review.
      • Sellaturay P.
      • Nasser S.
      • Ewan P.
      Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).
      • Sellaturay P.
      • Nasser S.
      • Islam S.
      • Gurugama P.
      • Ewan P.W.
      Polyethylene glycol (PEG) is a cause of anaphylaxis to the Pfizer/BioNTech mRNA COVID-19 vaccine.
      • Kounis N.G.
      • Koniari I.
      • de Gregorio C.
      • et al.
      Allergic reactions to current available COVID-19 vaccinations: pathophysiology, causality, and therapeutic considerations.
      • Bellomo R.G.
      • Gallenga C.E.
      • Caraffa A.
      • Tetè G.
      • Ronconi G.
      • Conti P.
      Anaphylaxis is a rare reaction in COVID-19 vaccination.
      Interim clinical considerations for use of COVID-19 vaccines currently approved or authorized in the United States. Centers for Disease Control and Prevention.

      Park HJ, Montgomery CJ, Boggs LN. Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria. Preprint. Posted online April 14, 2021. Mil Med. https://doi.org/10.1093/milmed/usab138

      Guidance for differentiating anaphylaxis from acute stress response for vaccine providers and emergency departments. Melbourne Vaccine Education Centre.
      • Gold M.S.
      • MacDonald N.E.
      • McMurtry C.M.
      • et al.
      Immunization stress-related response—redefining immunization anxiety-related reaction as an adverse event following immunization.
      • Turner P.J.
      • Ansotegui I.J.
      • Campbell D.E.
      • et al.
      COVID-19 vaccine-associated anaphylaxis: a statement of the World Allergy Organization Anaphylaxis Committee.
      • McNeil M.M.
      • Weintraub E.S.
      • Duffy J.
      • et al.
      Risk of anaphylaxis after vaccination in children and adults.
      • Paul E.
      • Steptoe A.
      • Fancourt D.
      Attitudes towards vaccines and intention to vaccinate against COVID-19: implications for public health communications.
      • Haas E.J.
      • Angulo F.J.
      • McLaughlin J.M.
      • et al.
      Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data.
      • Dagan N.
      • Barda N.
      • Kepten E.
      • et al.
      BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting.
      The mechanism of these reactions is not fully understood. The skin biopsy results of these individuals support the speculation of T-cell−mediated hypersensitivity as the mechanism of delayed injection site reactions.
      • Zhang Y.
      • Cao W.
      • Xiao M.
      • et al.
      Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia.
      Delayed hypersensitivity reactions are expected to occur sooner and more robustly after the second vaccine dose than after the first dose owing to prior sensitization. However, most delayed local reactions to the first dose did not recur with the second dose.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      ,
      • McMahon D.E.
      • Amerson E.
      • Rosenbach M.
      • et al.
      Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases.
      ,
      • Wei N.
      • Fishman M.
      • Wattenberg D.
      • Gordon M.
      • Lebwohl M.
      “COVID arm”: a reaction to the Moderna vaccine.
      Another hypothesis is related to the delayed appearance of the spike protein; mRNA vaccines require the translation of their mRNA to generate endogenously produced viral spike proteins to which the immune response is generated. Similarly, antigen production in adenoviral vector-based vaccines is delayed because the vaccine is delivered within a viral envelope, and host cells start producing spike proteins in a manner similar to that after the administration of an mRNA vaccine.
      • Grobusch M.P.
      • Schnyder J.
      • Garcia-Garrido H.M.
      • et al.
      Delayed large local reaction to the adenovirus-vectored (ChAdOx1) vaccine.
      The immune response generated after the first dose can moderate the subsequent reaction to the second dose. The timing of a delayed local reaction onset coincides with that of the immune system's detection of the spike protein generated by the vaccine's mRNA at the injection site.
      • Ewer K.J.
      • Barrett J.R.
      • Belij-Rammerstorfer S.
      • et al.
      T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial.
      ,
      • Meinberger D.
      • Koch M.
      • Roth A.
      • et al.
      Analysis of IgM, IgA, and IgG isotype antibodies directed against SARS-CoV-2 spike glycoprotein and ORF8 in the course of COVID-19.
      Delayed local reactions to COVID-19 vaccines may reflect the protective immune response stimulated by the vaccine. Given the similarities in the appearance and timing of onset, these delayed local reactions are misdiagnosed as cellulitis.
      • Lindgren A.L.
      • Austin A.H.
      • Welsh K.M.
      COVID arm: delayed hypersensitivity reactions to SARS-CoV-2 vaccines misdiagnosed as cellulitis.
      ,
      • Blumenthal K.G.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      It is important to recognize these reactions to avoid unnecessary antibiotic prescriptions for presumed cellulitis.
      Morbilliform eruptions following COVID-19 vaccination were increasingly being reported. The biopsy results demonstrated spongiosis and dermal perivascular lymphocytic infiltrate and were similar to the histochemical results found in the cases of COVID-19–associated cutaneous reactions. They also tended to recur with the second vaccine dose. All these suggested that morbilliform eruptions following COVID-19 vaccination reflect the underlying immune responses generated by the vaccines. Ohsawa et al
      • Ohsawa R.
      • Sano H.
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      Clinical and histopathological views of morbilliform rash after COVID-19 mRNA vaccination mimic those in SARS-CoV-2 virus infection-associated cutaneous manifestations.
      suggested that immunity to SARS-CoV-2 would have been established if morbilliform eruptions had developed in patients after they received the initial dose of the vaccine and, therefore, suggested considering omitting the second dose of COVID-19 vaccines.
      Following BNT162b2 vaccination, herpes zoster developed in few patients with autoimmune diseases.
      • Furer V.
      • Zisman D.
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      • Rimar D.
      • Paran Y.
      • Elkayam O.
      Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series.
      In immunocompromized patients, herpes zoster following COVID-19 vaccination may be similar to immune reconstitution inflammatory syndrome. The virus's reactivation might have been due to the paradoxical worsening of a latent infection unmasked by the host's inflammatory response to the COVID-19 vaccine. Nonetheless, there are few reports of herpes zoster after COVID-19 vaccination in healthy individuals.
      • Bostan E.
      • Yalici-Armagan B.
      Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence?.
      • Eid E.
      • Abdullah L.
      • Kurban M.
      • Abbas O.
      Herpes zoster emergence following mRNA COVID-19 vaccine.
      • Lee C.
      • Cotter D.
      • Basa J.
      • Greenberg H.L.
      20 Post-COVID-19 vaccine-related shingles cases seen at the Las Vegas Dermatology clinic and sent to us via social media.
      Preclinical trials of COVID-19 vaccines demonstrated a transient duration of lymphopenia within the first few days after vaccination.
      • Folegatti P.M.
      • Ewer K.J.
      • Aley P.K.
      • et al.
      Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.
      ,
      • Mulligan M.J.
      • Lyke K.E.
      • Kitchin N.
      • et al.
      Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.
      The timing of herpes zoster onset corresponds with that of lymphopenia; therefore, it is conceivable that the transient duration of lymphopenia after COVID-19 vaccination can trigger herpes zoster.
      To date, 15 cases of delayed filler reactions after COVID-19 vaccination have been reported across 3 observational studies. Adipose tissue, where most fillers are injected, has a high expression of angiotensin-converting enzyme 2 receptors. Coincidentally, these receptors are targeted by the SARS-CoV-2 spike protein, and the resulting interactions may instigate an inflammatory cascade. This may explain the delayed reaction to hyaluronic acid fillers observed after COVID-19 vaccination. Munavalli et al
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • Brodsky A.
      • Matthew E.
      • Landau M.
      COVID-19/SARS-CoV-2 virus spike protein-related delayed inflammatory reaction to hyaluronic acid dermal fillers: a challenging clinical conundrum in diagnosis and treatment.
      ,
      • Munavalli G.G.
      • Knutsen-Larson S.
      • Lupo M.P.
      • Geronemus R.G.
      Oral angiotensin-converting enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced cutaneous inflammation.
      proposed the use of lisinopril to treat delayed filler reactions after COVID-19 vaccination, which was deemed beneficial. The authors theorized that blocking the production of angiotensin II reduces the angiotensin-converting enzyme 2 substrate; thus, angiotensin-converting enzyme inhibitors can promote an anti-inflammatory response.
      There are reported cases of pityriasis rosea eruption following COVID-19 vaccination. One of the hypotheses regarding this association is that a high cytokine response to the vaccine distracts the T-cell–mediated control of latent infections, such as human herpes virus 6 and 7 and, hence, the reactivation of the latent viruses.
      • Drago F.
      • Ciccarese G.
      • Rebora A.
      • Parodi A.
      Pityriasis rosea following human papillomavirus vaccination.
      • Watanabe T.
      • Kawamura T.
      • Aquilino E.A.
      • et al.
      Pityriasis rosea is associated with systemic active infection with both human herpesvirus-7 and human herpesvirus-6.
      • Drago F.
      • Broccolo F.
      • Rebora A.
      Pityriasis rosea: an update with a critical appraisal of its possible herpesviral etiology.
      In contrast, pityriasis rosea-like eruptions following COVID-19 vaccination may have a different pathophysiology. These have been postulated to be a manifestation of a delayed hypersensitivity response to the vaccine.
      • Wilkin J.K.
      • Kirkendall W.M.
      Pityriasis rosea-like rash from captopril.
      This literature review had some limitations. First, the focus of the included clinical trials was predominantly on vaccine efficacy; therefore, there was a lack of details regarding cutaneous reactions and participant information. Second, most of the included individuals did not undergo skin biopsy; it was challenging to differentiate causality from causation for some of the cutaneous manifestations without histologic results. Third, a reporting bias could not be excluded.
      In conclusion, this review presents a spectrum of cutaneous reactions following COVID-19 vaccination. Most reactions were self-limiting and should not discourage vaccination. We observed that cutaneous reactions following mRNA-based vaccination were more commonly reported than those after inactivated whole-virus vaccination. This might have been due to the widespread use of mRNA-based vaccines. However, the safety of COVID-19 vaccines should continue to be monitored. Accurate and transparent communication with the communities about the adverse events associated with COVID-19 vaccines and their possible causes is important in increasing vaccine acceptance.Further studies with histopathological findings are needed to establish the causality of the skin reactions following vaccinations.

      Conflicts of interest

      None disclosed.

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