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COVID-19 Vaccines and the Skin

The Landscape of Cutaneous Vaccine Reactions Worldwide

      Keywords

      Key points

      • The most common cutaneous reactions cited in the clinical trial data of COVID-19 vaccines are local injection site reactions.
      • The most common cutaneous reactions cited in nontrial literature are delayed large local reactions.
      • Dermatologic side effects of COVID-19 vaccines range from morbilliform rash and pernio to pityriasis rosea and erythema multiforme.
      • As vaccine reactogenicity reports continue to surface, dermatologists and other health care providers should understand the landscape of the latest cutaneous reactions to guide and address patients’ concerns.

      Introduction

      As of April 22, 2021, the novel coronavirus disease 2019 (COVID-19) has sickened more than 142 million people and taken more than 3 million lives worldwide.
      Although restrictions such as physical distancing are crucial to containment, these measures are only temporary solutions. One silver lining amid this crisis is that the tragedy has become a catalyst. Scientists around the globe have raced to develop a long-term solution to impede viral transmission. On March 13, 2020, just 63 days after the genetic sequence of severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) was published, researchers began testing the first doses of a human COVID-19 vaccine.
      • Tregoning J.S.
      • Brown E.S.
      • Cheeseman H.M.
      • et al.
      Vaccines for COVID-19.
      By December 2, 2020, the United Kingdom became the first country to approve of and distribute the Pfizer-BioNTech BNT162b2 vaccine.
      • Ledford H.
      • Cyranoski D.
      • Van Noorden R.
      The UK has approved a COVID vaccine - here's what scientists now want to know.
      The United States followed suit days later, with the Food and Drug Administration (FDA) issuing Emergency Use Authorizations for both the Pfizer-BioNTech and Moderna vaccines.
      Since then, several COVID-19 vaccines have been authorized and approved for distribution around the globe, with many more in the pipeline. Of significance to dermatologists are the increasing reports of cutaneous reactions associated with these vaccines. The American Academy of Dermatology and the International League of Dermatologic Societies COVID-19 Registry began collecting such cases in late December 2020. The cases submitted ranged from delayed large local reactions to pityriasis-rosea–like eruptions and reactivation of herpes simplex and varicella zoster.
      • 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.
      Mass vaccination is key to achieving herd immunity and ending the pandemic. Therefore, it is critical that providers are aware of and understand the cutaneous side effects among the approved vaccines to better educate patients and provide proper counseling.
      In this article, we evaluate the landscape of dermatologic side effects from COVID-19 vaccines worldwide. We first summarize the latest skin reactions reported in clinical trial data following the administration of 11 different approved COVID-19 vaccines, before describing additional skin findings in reports outside of clinical trials.

      Cutaneous manifestations of COVID-19 vaccination in clinical trials

      As of April 15, 2021, 13 vaccines have achieved regulatory authorization and approval: Pfizer-BioNTech’s BNT162b2, Moderna’s mRNA-1273, Oxford-AstraZeneca’s AZD1222, Gamaleya’s Sputnik V, Johnson & Johnson’s Janssen’s Ad26.COV2.S, Sinovac’s CoronaVac, Sinopharm’s BBIBP-CorV, The Vector Institute’s EpiVacCorona, CanSino’s Convidecia, Bharat’s Covaxin, Sinopharm’s WIBP-CorV, Chumakov’s CoviVac and Anhui Zhifei Longcom’s ZF2001 (Table 1).
      • Craven J.
      COVID-19 vaccine tracker. April 15, 2021.
      Of these vaccines, 11 have published trial data (Table 2).
      Table 1Characteristics of 13 authorized/approved COVID-19 vaccines as of April 21, 2021
      Vaccine Name(s)Manufacturer(s)TypeCountry of OriginTrial Phase with Published DataTrial Time FrameAge Group Tested
      BNT162b2, ComirnatyPfizer-BioNTech, Fosun PharmamRNAUS, GermanyIII7/27/2020—11/14/202016+
      mRNA-1273Moderna, National Institute of Allergy and Infectious DiseasesmRNAUSIII7/27/2020—10/23/202018+
      AZD1222, ChAdOx1 nCoV-19Oxford-AstraZenecaAdenovirusUKI/II4/23/2020—11/4/202018+
      Sputnik V, Gam-COVID-VacGamaleya Research Institute; Health Ministry of the Russian FederationRecombinant adenovirus (rAd26, rAd5)RussiaIII9/7/2020—11/24/202018+
      Ad26.COV2.S, JNJ-78436735Johnson & Johnson’s Janssen BiotechNonreplicating viral vectorThe Netherlands, USI/IIa7/22/2020—11/7/202018–55, 65+
      CoronaVacSinovac BiotechInactivated (formalin with alum adjuvant)ChinaI/IIPhase I: 4/16/2020—4/25/2020

      Phase II: 5/3/2020—5//5/2020
      18–59
      BBIBP-CorVChina National Pharmaceutical Group (Sinopharm); Beijing Institute of Biological ProductsInactivatedChinaI/IIa5/18/2020—7/30/202018–59
      EpiVacCoronaFederal Budgetary Research Institution State Research Center of Virology and BiotechnologyPeptideRussiaI/II
      No data published yet as of April 22, 2021.
      7/27/2020—Present18–60
      Convidicea, Ad5-nCoVCanSino BiologicsRecombinant (adenovirus type 5 vector)ChinaIII4/11/2020—4/16/202018+
      Covaxin, BBV152Bharat Biotech; Indian Council of Medical ResearchInactivatedIndiaI/II9/5/2020—9/12/202012–65
      WIBP-CorVChina National Pharmaceutical Group (Sinopharm); Wuhan Institute of Biological ProductsInactivatedChinaI/II4/12/2020—5/2/202018–59
      CoviVacChumakov Federal Scientific Center for Research and Development of Immune and Biological ProductsInactivatedRussiaI/II
      No data published yet as of April 22, 2021.
      N/AN/A
      ZF2001Anhui Zhifei Longcom Biopharmaceutical; Institute of Microbiology of the Chinese Academy of SciencesRecombinantChina,

      Uzbekistan
      I/IIPhase I: 6/22/2020—7/3/2020

      Phase II: 7/12/2020—7/17/2020
      18–59
      a No data published yet as of April 22, 2021.
      Table 2Cutaneous side effects reported in the trial data of 11 authorized COVID-19 vaccines
      Vaccine name(s)ErythemaSwellingTendernessPainIndurationPruritusOther Skin FindingsSerious Cutaneous Reactions
      BNT162b2, ComirnatyDose 1:

      16–55 y: 5%

      >55 y 5%

      Dose 2:

      16–55 y 6%

      >55 y 7%
      Dose 1:

      16–55 y 6%

      >55 y 7%

      Dose 2:

      16–55 y 6%

      >55 y 7%
      N/ADose 1:

      16–55 y 83%

      >55 y 71%

      Dose 2:

      16–55 y 78%

      >55 y 66%
      N/AN/AN/ANone
      mRNA-1273Dose 1:

      2.8%

      Dose 2:

      8.6%
      Dose 1:

      6.1%

      Dose 2:

      12.2%
      Dose 1:

      10.2%

      Dose 2:

      14.2%
      Dose 1:

      83.7%

      Dose 2:

      88.2%
      N/AN/AAllergic, hand, atopic and contact dermatitis; eczema; exfoliative rash; hypersensitivity; injection site urticaria; erythematous rash; macular rash; maculopapular rash; pruritic rash; vesicular rash; urticaria; papular urticaria (<0.2%)None
      AZD1222, ChAdOx1 nCoV-19Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      3%

      With paracetamol prophylaxis:

      2%

      Group 3

      None
      Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      4%

      With paracetamol prophylaxis:

      2%

      Group 3

      None
      Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      83%

      With paracetamol prophylaxis:

      77%

      Group 3

      Dose 1:

      50%

      Dose 2:

      50%
      Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      67%

      With paracetamol prophylaxis:

      50%

      Group 3

      Dose 1:

      50%

      Dose 2:

      20%
      Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      3%

      With paracetamol prophylaxis:

      0%

      Group 3

      None
      Group 1a, 1b, 2a, 2b:

      Without paracetamol prophylaxis:

      7%

      With paracetamol prophylaxis:

      12%

      Group 3

      Dose 1:

      10%

      Dose 2:

      10%
      One case each of psoriasis, rosacea, vitiligo and Raynaud phenomenon (<0.1%)One case of severe cellulitis
      Sputnik V, Gam-COVID-VacN/AN/AN/AN/AN/AN/AAcneiform dermatitis, allergic rash, alopecia, indeterminate rash, petechial rash, and eczema (<0.1%)None
      Ad26.COV2.S, JNJ-784367357.3%5.3%N/A48.6%N/AN/AN/ANone
      CoronaVac0/14 schedule:

      Dose 1:

      3μg group:

      0.8%

      6μg group:

      None

      Dose 2:

      3μg group:

      None

      6μg group:

      1.7%

      0/28 schedule:

      Dose 1:

      3μg group:

      None

      6μg group:

      0.8%

      Dose 2:

      None
      0/14 schedule:

      Dose 1:

      3μg group:

      0.8%

      6μg group:

      None

      Dose 2:

      3μg group:

      0.8%

      6μg group:

      2.5%

      0/28 schedule:

      Dose 1:

      None

      Dose 2:

      3μg group:

      None

      6μg group:

      0.9%
      N/A0/14 schedule:

      Dose 1:

      3μg group:

      9.2%

      6μg group:

      16.7%

      Dose 2:

      3μg group:

      13.3%

      6μg group:

      11.8%

      0/28 schedule:

      Dose 1:

      3μg group:

      7.5%

      6μg group:

      10%

      Dose 2:

      3μg group:

      2.6%

      6μg group:

      5.9%
      0/14 schedule:

      Dose 1:

      None

      Dose 2:

      3μg group:

      0.8%

      6μg group:

      0.8%

      0/28 schedule:

      None
      0/14 schedule:

      Dose 1:

      None

      Dose 2:

      3μg group:

      0.8%

      6μg group:

      0.8%

      0/28 schedule:

      None
      N/AOne case of acute hypersensitivity with urticaria 48 h after dose 1 (6 μg group)
      BBIBP-CorV1%2%N/A16%N/A2%Unspecified rash in 1 participant (<1%)None
      Convidicea,

      Ad5-nCoV
      Low dose:

      2%

      High dose:

      1%
      Low dose:

      4%

      High dose:

      4%
      N/ALow dose:

      57%

      High dose:

      56%
      Low dose:

      2%

      High dose:

      2%
      Low dose:

      6%

      High dose:

      2%
      One case of buccal ulceration within 14 d

      One case of oral herpes
      None
      Covaxin, BBV152Dose 1:

      3μg group:

      1%

      6μg group:

      1%

      Dose 2:

      None
      N/AN/ADose 1:

      3μg group:

      3%

      6μg group:

      3%

      Dose 2:

      3μg group:

      4%

      6μg group:

      2%
      N/ADose 1:

      3μg group:

      1%

      6μg group:

      1%

      Dose 2:

      3μg group:

      None

      6μg group:

      1%
      One case of mild unspecified rash after dose 2 (3 μg group)None
      WIBP-CorVPhase I

      (0, 28, 56-d group):

      Low dose:

      None

      Medium dose:

      None

      High dose:

      4.2%

      Phase II

      0 and 14-d group:

      Medium dose:

      None

      0 and 21-d group:

      Medium dose:

      None
      Phase I

      (0, 28, 56-d group):

      Low dose:

      4.2%

      Medium dose:

      None

      High dose:

      4.2%

      Phase II

      0 and 14-d group:

      Medium dose:

      None

      0 and 21-d group:

      Medium dose:

      1.2%
      N/APhase I

      (0, 28, 56-d group):

      Low dose:

      20.8%

      Medium dose:

      4.2%

      High dose:

      25%

      Phase II

      0 and 14-d group:

      Medium dose:

      2.4%

      0 and 21-d group:

      Medium dose:

      14.3%
      N/APhase I

      (0, 28, 56-d group):

      Low dose:

      None

      Medium dose:

      None

      High dose:

      None

      Phase II

      0 and 14-d group:

      Medium dose:

      None

      0 and 21-d group:

      Medium dose:

      1.2%
      N/ANone
      ZF2001Phase I

      25 μg group:

      20%

      50 μg group:

      20%

      Phase II

      Two-dose group:

      25 μg group:

      8%

      50 μg group:

      8%

      Three-dose group:

      25 μg group:

      16%

      50 μg group:

      14%
      Phase I

      25 μg group:

      5%

      50 μg group:

      15%

      Phase II

      Two-dose group:

      25 μg group:

      4%

      50 μg group:

      6%

      Three-dose group:

      25 μg group:

      14%

      50 μg group:

      13%
      N/APhase I

      25 μg group:

      20%

      50 μg group:

      55%

      Phase II

      Two-dose group:

      25 μg group:

      3%

      50 μg group:

      5%

      Three-dose group:

      25 μg group:

      12%

      50 μg group:

      12%
      Phase I

      25 μg group:

      10%

      50 μg group:

      25%

      Phase II

      Two-dose group:

      25 μg group:

      3%

      50 μg group:

      5%

      Three-dose group:

      25 μg group:

      9%

      50 μg group:

      7%
      Phase I

      25 μg group:

      20%

      50 μg group:

      35%

      Phase II

      Two-dose group:

      25 μg group:

      6%

      50 μg group:

      9%

      Three-dose group:

      25 μg group:

      19%

      50 μg group:

      17%
      One case of unspecified rash in the phase I trial (50 μg group)

      Three cases of unspecified rash in the phase II trial, 2-dose schedule, 25 μg group

      Four cases of unspecified rash in the phase II trial, 2-dose schedule, 50 μg group

      2 cases of unspecified rash in phase II trial, three-dose schedule, 25 μg group

      One case of unspecified rash in phase II trial, three-dose schedule, 50 μg group
      One case of unspecified grade ≥3 rash (50 μg group)
      Abbreviation: N/A, not applicable.
      The most common adverse cutaneous reactions noted were local injection site reactions such as erythema, swelling, tenderness, pain, induration, and pruritus within 7 days after injection. Mild to moderate injection site pain was the most prevalent event among all 11 COVID-19 vaccine trials, with up to 88% of participants experiencing pain that typically resolved within 24 to 48 hours after onset. Erythema, swelling, induration, and itch were less common, and reported in up to 20%, 15%, 25%, and 35% of participants, respectively (see Table 2). An emerging trend is the higher incidence of these local injection site reactions in the younger population compared with participants age 60 years and older.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      • Polack F.P.
      • Thomas S.J.
      • Kitchin N.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.
      • Xia S.
      • Zhang Y.
      • Wang Y.
      • et al.
      Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.
      Delayed large local reactions, with a typical onset of 8 days or more after vaccination and consisting of erythema, induration, and tenderness, were specifically reported in Moderna’s phase III trial.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      After the first dose, 244 participants (0.8%) in the vaccinated cohort developed mild, delayed injection reactions that resolved over the course of 4 to 5 days.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      After the second dose, 68 participants (0.2%) developed delayed large local reactions.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      There was no mention, however, of whether those who had reactions after the first dose experienced a recurrence after the second dose.
      Although infrequent, a series of other dermatologic manifestations with varying severity have been reported. Less than 0.2% of Moderna’s vaccinated cohort developed rashes, including allergic, atopic and contact dermatitis; eczema; exfoliative rash; hypersensitivity reactions; injection site urticaria; papular urticaria; and vesicular rash, among others (see Table 2).
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      Although specific characteristics such as timing and duration were not reported, none of these skin findings were labeled as severe.
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      Similarly, acneiform and allergic dermatitis, alopecia, petechial rash and eczema were seen in less than 0.1% of Sputnik V’s vaccinated participants.
      • Logunov D.Y.
      • Dolzhikova I.V.
      • Shcheblyakov D.V.
      • et al.
      Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia.
      One participant developed an unspecified rash in the BBIBP-CorV vaccine trial and another developed a mild unspecified rash in the Covaxin trial.
      • Xia S.
      • Zhang Y.
      • Wang Y.
      • et al.
      Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial.
      ,
      • Ella R.
      • Reddy S.
      • Jogdand H.
      • et al.
      Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial.
      Vaccine-related buccal ulceration and oral herpes were also noted in the Convidecia vaccine cohort.
      • Zhu F.C.
      • Guan X.H.
      • Li Y.H.
      • et al.
      Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial.
      Three cases of serious cutaneous reactions were observed among these 11 vaccines. One participant in the CoronaVac trial developed a severe, acute hypersensitivity reaction with urticaria 48 hours after the first dose.
      • 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.
      The rash resolved within 3 days after the administration of chlorphenamine and dexamethasone, and a similar reaction was not observed after the second dose.
      • 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.
      Among the 11 recipients of the ZF2001 vaccine who developed unspecified rashes, 1 case was labeled as severe (grade 3 or higher).
      • Yang S.
      • Li Y.
      • Dai L.
      • et al.
      Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials.
      The AZD1222 trial reported 1 case of severe cellulitis in addition to one case each of vaccine-induced psoriasis, rosacea, vitiligo, and Raynaud phenomenon.
      • Voysey M.
      • Clemens S.A.C.
      • Madhi S.A.
      • et al.
      Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

      Cutaneous manifestations of COVID-19 vaccination in real-world settings

      Dermatologic reactions to COVID-19 vaccines may be largely uncommon among clinical trial participants, but as we enter global mass vaccination, these adverse events will increase and new cutaneous reactions will emerge. In fact, numerous observational reports and case series of COVID-19 vaccine-related dermatoses have been published recently. An increased awareness of these manifestations can help dermatologists to identify potential risks, engage in anticipatory guidance, and initiate appropriate management. Here, we present an overview of the latest nontrial literature on reactive dermatoses to COVID-19 vaccines.

      Delayed Large Local Reactions

      A delayed large local reaction, defined as the onset of an erythematous and edematous patch at the injection site at least 4 days or more after vaccine administration, was the most commonly noted adverse cutaneous event in nontrial literature.
      • 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.
      Across all 6 observational studies, 350 participants experienced at least one episode of delayed large local reaction (Table 3). Of these 350 individuals, 117 (33.4%) received the BNT162b2 vaccine and 233 (66.6%) received the mRNA-1273 vaccine (see Table 3).
      Table 3Reactive dermatoses to authorized COVID-19 vaccines reported in the nontrial literature
      Articles within each morphology group are organized in order of publication date.
      Article ReferenceStudy DesignStudy SizeStudy PeriodVaccine Name(s)Cutaneous ReactionsDose NumberTime to Onset after VaccinationTime to ResolutionIntervention
      Delayed large local reactions
       Fernandez-Nieto et al,

      Fernandez-Nieto D, Hammerle J, Fernandez-Escribano M, et al. Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers. ‘COVID-arm’: a clinical and histological characterization. J Eur Academy of Dermatology and Venereology. 2021;35(7):425-7.

      2021
      Retrospective study at a tertiary referral hospital in Spain47751/11/2021–2/12/2021BNT162b2/Comirnaty103 participants with delayed large local reactionsDose 1:

      49/103 (47.6%)

      Dose 2:

      54/103 (52.4%)
      N/A<8 h:

      23/103 (22.3%)

      8–24 h:

      27/103 (26.2%)

      48–72 h:

      38/103 (36.9%)

      >72 h:

      14/103 (13.6%)
      N/A
       Blumenthal et al,
      • Blumenthal K.G.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      2021
      Case series12N/AmRNA-127312 participants with delayed large local reactions after dose 1

      3 participants with similarly severe reactions, 3 participants with less severe reactions after dose 2
      Dose 1:

      12/12 (100%)

      Dose 2:

      6/12 (50%)
      Dose 1:

      4–11 d (median 8 d)

      Dose 2:

      1–3 d (median 2 d)
      Dose 1:

      2–11 d after onset (median, 6 d)

      Dose 2:

      N/A
      Ice, antihistamines, glucocorticoids (topical, oral or both), antibiotics
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty

      mRNA-1273
      BNT162b2/Comirnaty:

      12 reports of delayed large local reactions

      mRNA-1273

      206 reports of delayed large local reactions
      BNT162b2/Comirnaty:

      Dose 1:

      5/34 (15%)

      Dose 2:

      7/40 (18%)

      mRNA-1273

      Dose 1:

      175/267 (66%)

      Dose 2:

      31/102 (30%)
      BNT162b2/Comirnaty:

      N/A

      mRNA-1273:

      median 7 d after dose 1, median 3 d after dose 2
      BNT162b2/Comirnaty:

      N/A

      mRNA-1273:

      median 4 d after dose 1; median 3 d after dose 2
      Topical corticosteroids, oral antihistamines, pain relievers, antibiotics
       Wei et al,
      • Wei N.
      • Fishman M.
      • Wattenberg D.
      • et al.
      "COVID arm": a reaction to the Moderna vaccine.
      2021
      Case series4N/AmRNA-1273Delayed large local reactionsDose 1Case 1: 8 d

      Case 2: 8 d

      Case 3: 7 d

      Case 4: 10 d
      Case 1: N/A

      Case 2: 3 d

      Case 3: 4 d

      Case 4: 2 d
      Case 1 and 2: topical corticosteroids, oral antihistamine

      Case 3 and 4: None
       Ramos et al,
      • Ramos C.L.
      • Kelso J.M.
      "COVID Arm": very delayed large injection site reactions to mRNA COVID-19 vaccines.
      2021
      Case series12N/ABNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      1 report of delayed large local reaction

      mRNA-1273

      11 reports of delayed large local reactions
      BNT162b2/Comirnaty:

      1 case of delayed large local reaction after dose 2 only

      mRNA-1273

      11 case of delayed large local reaction after dose 1 only
      5–11 d (average 7 d)3–8 d (average 5 d)Topical corticosteroids, ice, oral antihistamines, pain relievers
       Baeck et al., 2021Case report1N/ABNT162b2/ComirnatyDelayed large local reactionDose 1 only6 d5 dN/A
      Morbilliform rashes
       Jedlowski et al,
      • Jedlowski P.M.
      • Jedlowski M.F.
      Morbilliform rash after administration of Pfizer-BioNTech COVID-19 mRNA vaccine.
      2021
      Case report1N/ABNT162b2/ComirnatyMorbilliform rash on lower backDose 1 and dose 2Dose 1 and 2:

      48 h
      Dose 1 and 2:

      24 h
      None
       CDC COVID-19 Response Team and FDA
      Centers for Disease C
      Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States.
      Case series1012/21/2020–1/10/2021mRNA-12734 cases of morbilliform rashDose 15–45 minN/AIntramuscular epinephrine
       CDC COVID-19 Response Team and FDA
      Centers for Disease C
      Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States.
      Case series2112/14/2020–12/23/2020BNT162b2/Comirnaty7 cases of morbilliform rashDose 12–25 minN/AIntramuscular epinephrine
       Ackerman et al,

      Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash after the first dose of Pfizer-BioNTech COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(7):423-5.

      2021
      Case report1N/ABNT162b2/ComirnatyMaculopapular exanthema (30% body surface area)Dose 1 (dose 2 avoided)3 h>1 moCorticosteroids
       Corbeddu et al., 2021Case series11N/ABNT162b2/Comirnaty3 cases of morbilliform rashesDose 2:

      3/3 (100%)
      Dose 2:

      5 hours–3 days
      2–3 dNone
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      9 reports of morbilliform rash

      mRNA-1273

      18 reports of morbilliform rash
      BNT162b2/Comirnaty:

      Dose 1:

      6/9 (67%)

      Dose 2:

      3/9 (33%)

      mRNA-1273

      Dose 1:

      11/18 (61%)

      Dose 2:

      7/18 (39%)
      Dose 1:

      Median of 3 d

      Dose 2:

      Median of 2 d
      Dose 1:

      Median of 4.5 d

      Dose 2:

      Median of 2.5 d
      Topical corticosteroids, oral antihistamines, pain relievers, antibiotics
      Urticaria
       CDC COVID-19 Response Team and FDA
      Centers for Disease C
      Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States.
      Case series1012/21/2020–1/10/2021mRNA-12731 case of urticariaDose 111 minN/AIntramuscular epinephrine
       CDC COVID-19 Response Team and FDA
      Centers for Disease C
      Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States.
      Case series2112/14/2020–12/23/2020BNT162b2/Comirnaty10 cases of urticariaDose 15–54 minN/AIntramuscular epinephrine
       John M. Kelso, 2021Case series4N/AmRNA-12731 case of urticariaDose 1 (dose 2 refused)1 minN/ADiphenhyramine, IV epinephrine, diazepam
       Corbeddu et al., 2021Case series11N/ABNT162b2/Comirnaty2 cases of urticariaDose 1:

      2/2 (100%)
      Dose 1:

      1 hour–2 days
      2–3 dNone
       Park et al,
      • Park H.J.
      • Montgomery J.R.
      • Boggs N.A.
      Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria.
      2021
      Case report1N/ABNT162b2/ComirnatyUrticaria with immediate anaphylaxisDose 1 only3 min2 dIntramuscular epinephrine and diphenhydramine
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty

      mRNA-1273
      BNT162b2/Comirnaty:

      17 reports of urticaria

      mRNA-1273

      23 reports of urticaria
      BNT162b2/Comirnaty:

      Dose 1:

      9/17 (53%)

      Dose 2:

      8/17 (47%)

      mRNA-1273

      Dose 1:

      16/23 (70%)

      Dose 2:

      7/23 (30%)
      BNT162b2/Comirnaty:

      Dose 1:

      9 cases after 24 h

      Dose 2:

      1 case within 24 h,

      7 cases after 24 h

      mRNA-1273

      Dose 1:

      13 cases after 24 h

      3 cases of unknown timing

      Dose 2:

      2 cases within 24 h,

      5 cases after 24 h
      Dose 1:

      Median 5 d

      Dose 2:

      Median 3 d
      Topical corticosteroids, oral antihistamines, pain relievers, antibiotics
      EM
       Gambichler et al., 2021Case report1N/ABNT162b2/ComirnatyRowell’s syndromeDose 11 dN/AOral corticosteroids
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021mRNA-12733 reports of EMmRNA-1273

      Dose 1:

      3/3 (100%)
      N/AN/AN/A
      DIRs to hyaluronic acid dermal fillers
       Munavalli et al,
      • Munavalli G.G.
      • Knutsen-Larson S.
      • Lupo M.P.
      • et al.
      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.
      2021
      Case series2N/ABNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty

      1 report of DIR to hyaluronic acid dermal fillers

      mRNA-1273

      1 report of DIRs to hyaluronic acid dermal fillers
      BNT162b2/Comirnaty:

      Dose 2:

      1/2 (50%)

      mRNA-1273

      Dose 1:

      1/2 (50%)
      BNT162b2/Comirnaty:

      Dose 2:

      24 h

      mRNA-1273

      Dose 1:

      48 h
      BNT162b2/Comirnaty:

      Dose 2:

      24 h

      mRNA-1273

      Dose 1:

      Initiation of lisinopril at 48 h, resolved after 24 h
      BNT162b2/Comirnaty:

      Corticosteroids mRNA-1273: Antihistamines, acetaminophen, lisinopril
       Munavalli et al,
      • Rowland-Warmann M.
      Hypersensitivity reaction to hyaluronic acid dermal filler following novel coronavirus infection – a case report.
      2021
      Case series4N/ABNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty

      2 reports of DIRs to hyaluronic acid dermal fillers

      mRNA-1273

      2 reports of DIRs to hyaluronic acid dermal fillers
      BNT162b2/Comirnaty:

      Dose 1:

      1/2 (50%)

      Dose 2:

      1/2 (50%)

      mRNA-1273

      Dose 1:

      16/23 (70%)

      Dose 2:

      1/2 (50%)
      BNT162b2/Comirnaty:

      Dose 1:

      10 d

      Dose 2:

      2 d

      mRNA-1273

      Dose 1:

      18 h (recurred with dose 2)

      Dose 2:

      24 h
      BNT162b2/Comirnaty:

      Dose 1:

      7 d

      Dose 2:

      Initiation of lisinopril at 72 h, resolved after 24 h

      mRNA-1273

      Dose 1:

      Initiation of lisinopril at 48 h, resolved after 24 h

      Dose 2:

      Initiation of lisinopril at 48 h, resolved after 72 h
      Low-dose lisinopril
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      1 report of DIR to hyaluronic acid dermal fillers

      mRNA-1273

      8 reports of DIR to hyaluronic acid dermal fillers
      BNT162b2/Comirnaty:

      Dose 2:

      1/1 (100%)

      mRNA-1273

      Dose 1:

      3/8 (38%)

      Dose 2:

      5/8 (63%)
      N/AN/AN/A
      Local injection site reactions
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      16 reports of local injection site reactions

      mRNA-1273

      186 reports of local injection site reactions
      BNT162b2/Comirnaty:

      Dose 1:

      8/16 (50%)

      Dose 2:

      8/16 (50%)

      mRNA-1273

      Dose 1:

      117/186 (63%)

      Dose 2:

      69/186 (37%)
      Dose 1:

      Median day 1

      Dose 2:

      Median day 1
      Dose 1:

      Median days 4

      Dose 2:

      Median days 3
      N/A
      Erythromelalgia
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      3 reports of erythromelalgias

      mRNA-1273

      11 reports of erythromelalgias
      BNT162b2/Comirnaty:

      Dose 1:

      1/3 (33%)

      Dose 2:

      2/3 (67%) mRNA-1273

      Dose 1:

      5/11 (45%)

      Dose 2:

      6/11 (55%)
      Dose 1:

      Median day 7

      Dose 2:

      Median day 1
      Dose 1:

      Median days 5.5

      Dose 2:

      Median days 3
      N/A
      Lichen planus
       Hiltun et al., 2021Case report1N/ABNT162b2/ComirnatyLichen planus flareDose 248 hN/ATopical corticosteroids
      Varicella zoster
       Bostan et al., 2021Case report1N/AN/AVaricella zoster flareN/A5 d1 wkOral valacyclovir
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      5 reports of varicella zoster

      mRNA-1273

      5 reports of varicella zoster
      BNT162b2/Comirnaty:

      Dose 1:

      1/5 (20%)

      Dose 2:

      4/5 (80%)

      mRNA-1273

      Dose 1:

      5/5 (100%)
      N/AN/AN/A
      Herpes simplex
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021N/A4 reports of herpes simplex flaresN/AN/AN/AN/A
      Pityriasis rosea
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      3 reports of pityriasis rosea

      mRNA-1273

      1 report of pityriasis rosea
      BNT162b2/Comirnaty:

      Dose 1:

      2/3 (67%)

      Dose 2:

      1/3 (33%)

      mRNA-1273

      Dose 1:

      1/1 (100%)
      N/AN/AN/A
       Busto-Leis et al,

      Busto-Leis J, Servera-Negre G, Mayor-Ibarguren A, et al. “Pityriasis rosea, COVID-19 and vaccination: new keys to understand an old acquaintance”. Journal of the European Academy of Dermatology and Venereology. n/a.

      2021
      Case series2N/ABNT162b2/Comirnaty2 reports of pityriasis roseaDose 224 h,

      7 d
      N/AN/A
      Pernio/chilblains
       Kha et al,
      • Kha C.
      • Itkin A.
      New-onset chilblains in close temporal association to mRNA-1273 (Moderna) vaccination.
      2021
      Case report1N/AmRNA-12731 report of pernio/chilblainsDose 1 and 2Dose 1:

      2 d

      Dose 2:

      3 d
      Dose 1:

      14 d

      Dose 2:

      7 d
      Topical corticosteroids
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty mRNA-1273BNT162b2/Comirnaty:

      5 reports of pernio/chilblains

      mRNA-1273

      3 reports of pernio/chilblains
      BNT162b2/Comirnaty:

      Dose 1:

      3/5 (60%)

      Dose 2:

      2/5 (40%)

      mRNA-1273

      Dose 1:

      3/3 (100%)
      N/AN/AN/A
       Lopez et al,

      Lopez S, Vakharia P, Vandergriff T, et al. Pernio after COVID-19 Vaccination. Br J Dermatol 2021.

      2021
      Case report11/2021BNT162b2Pernio/chilblainsDose 23 d>28 dClobetasol as needed, avoidance of cold exposure
      Petechiae
       McMahon et al,
      • 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.
      2021
      Retrospective review of AAD/ILDS registry of vaccine-related cutaneous reactions41412/24/2020–2/14/2021BNT162b2/Comirnaty

      mRNA-1273
      BNT162b2/Comirnaty:

      1 report of petechiae

      mRNA-1273

      3 reports of petechiae
      BNT162b2/Comirnaty:

      Dose 1:

      1/1 (100%)

      mRNA-1273

      Dose 1:

      1/3 (33%)

      Dose 2:

      2/3 (67%)
      N/AN/AN/A
      Purpura
       Malayala et al,
      • Malayala S.V.
      • Mohan G.
      • Vasireddy D.
      • et al.
      Purpuric rash and thrombocytopenia after the mRNA-1273 (Moderna) COVID-19 vaccine.
      2021
      Case report13/2021mRNA-1273Brown to red purpuric, nonblanchable rashDose 11 dN/AMonitoring of platelet, liver, renal function panels; antihypertensives
      Abbreviations: AAD, American Academy of Dermatology; CDC, Centers for Disease Control and Prevention; DIRs, delayed inflammatory reaction; EM, erythema multiforme; FDA, Food and Drug Administration; ILDS, International League of Dermatologic Societies; N/A, not applicable.
      a Articles within each morphology group are organized in order of publication date.
      Of note, female patients younger than 65 years of age consistently composed the majority of these delayed large local reactions, prompting the question of sex’s role in vaccine response. Notably, women also comprise an overwhelming majority (>70%) of the national and international health care workforce.
      • Alobaid A.M.
      • Gosling C.M.
      • Khasawneh E.
      • et al.
      Challenges faced by female healthcare professionals in the workforce: a scoping review.
      World Health O
      Gender equity in the health workforce: analysis of 104 countries.

      Your health care is in women’s hands. United States Census Bureau.

      Therefore, the observation may reflect a reporting bias, given that vaccination campaigns initially targeted health care professionals and that women may be more likely to visit their doctor. However, the cause is likely multifactorial, because biology is also at play. Women have stronger immune responses to foreign antigens than men, and decades of research have shown that although women exhibit a greater immune response to vaccines, they also experience more adverse events.
      • Klein S.L.
      • Flanagan K.L.
      Sex differences in immune responses.
      • Fink A.L.
      • Klein S.L.
      Sex and gender impact immune responses to vaccines among the elderly.
      • Fink A.L.
      • Klein S.L.
      The evolution of greater humoral immunity in females than males: implications for vaccine efficacy.
      • Fischinger S.
      • Boudreau C.M.
      • Butler A.L.
      • et al.
      Sex differences in vaccine-induced humoral immunity.
      • Flanagan K.L.
      • Fink A.L.
      • Plebanski M.
      • et al.
      Sex and gender differences in the outcomes of vaccination over the life course.
      Although studies varied in their reporting of characteristics, most of the delayed large local reactions were mild and transient, with few recurrences after the second dose. All delayed large local reactions reported in the nontrial literature resolved within 11 days. In the study by McMahon and associates,
      • 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.
      only 11 participants developed reactions after both doses; all were mRNA-1273 vaccine recipients, and reactions after the second dose were frequently smaller in size with an earlier onset at a median of 2 days. Six of the 12 patients who received the mRNA-1273 vaccine in Blumenthal and colleagues
      • Blumenthal K.G.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      had recurrent reactions that were of lesser severity than those after the first dose and also occurred at a median of 2 days. Likewise, of the 11 patients who received the mRNA-1273 vaccine in Ramos and Kelso, 4 developed similar local reactions after the second dose with an onset of 2 to 3 days after injection. Although most delayed large local reaction reports in nontrial literature occurred with the mRNA-1273 vaccine, these findings have also been observed with the BNT162b2 vaccine. Of the 103 patients reported on by Fernandez-Nieto and colleagues

      Fernandez-Nieto D, Hammerle J, Fernandez-Escribano M, et al. Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers. ‘COVID-arm’: a clinical and histological characterization. J Eur Academy of Dermatology and Venereology. 2021;35(7):425-7.

      and who developed delayed large local reactions after the first dose of BNT162b2, one-half experienced similar recurrent reactions after the second dose (onset not reported).
      The morphology of these delayed large local reactions ranged from erythematous targetoid patches to large 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.
      ,

      Fernandez-Nieto D, Hammerle J, Fernandez-Escribano M, et al. Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers. ‘COVID-arm’: a clinical and histological characterization. J Eur Academy of Dermatology and Venereology. 2021;35(7):425-7.

      In 2 studies of mRNA-1273 vaccine recipients, lesion diameters ranged from 5.0 to 19.5 cm, with 7 of the 16 lesions labeled as grade 3 plaques (≥10 cm in diameter).
      • Blumenthal K.G.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      ,
      • Wei N.
      • Fishman M.
      • Wattenberg D.
      • et al.
      "COVID arm": a reaction to the Moderna vaccine.
      Histology of these skin lesions revealed superficial and deep perivascular lymphocytic infiltrates with rare eosinophils and scattered mast cells, confirming a delayed type, T-cell–mediated hypersensitivity reaction.
      • Blumenthal K.G.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      ,

      Fernandez-Nieto D, Hammerle J, Fernandez-Escribano M, et al. Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers. ‘COVID-arm’: a clinical and histological characterization. J Eur Academy of Dermatology and Venereology. 2021;35(7):425-7.

      ,
      Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA vaccines.
      To date, no such findings have been reported with other non-mRNA COVID-19 vaccines and the exact etiology is still unknown. However, a delayed hypersensitivity reaction to polyethylene glycol, an allergen, may be one explanation because both BNT162b2 and mRNA-1273 vaccines contain this excipient.
      • Wei N.
      • Fishman M.
      • Wattenberg D.
      • et al.
      "COVID arm": a reaction to the Moderna vaccine.
      Treatment has not been necessary; most reactions are mild and resolve spontaneously. Although some patients were treated with ice, antihistamines, pain relievers, and glucocorticoids (topical, oral, or both), others received no intervention.
      • 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.
      • Freeman E.E.
      • Saff R.R.
      • et al.
      Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2.
      ,

      Fernandez-Nieto D, Hammerle J, Fernandez-Escribano M, et al. Skin manifestations of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers. ‘COVID-arm’: a clinical and histological characterization. J Eur Academy of Dermatology and Venereology. 2021;35(7):425-7.

      ,
      Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA vaccines.
      ,
      • Ramos C.L.
      • Kelso J.M.
      "COVID Arm": very delayed large injection site reactions to mRNA COVID-19 vaccines.
      However, some patients received unnecessary antibiotics owing to concern for cellulitis or other infections, highlighting the need for more providers to recognize that these delayed large local reactions are benign and not a contraindication to the second dose.

      Morbilliform Rashes

      Morbilliform and maculopapular exanthems have been described in 43 participants across 3 observational studies (see Table 3). Of these 43 individuals, 21 (49%) received the BNT162b2 vaccine and 22 (51%) received the mRNA-1273 vaccine (see Table 3). Of these cases, 11 (4 associated with mRNA-1273; 7 associated with BNT162b2) had been submitted to the Vaccine Adverse Event Reporting System (VAERS) and labeled by the Centers for Disease Control and Prevention (CDC) as part of an anaphylaxis reaction.
      CDC COVID-19 Response Team, FDA. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine — United States, December 14–23, 2020.
      Among the cases not characterized as anaphylaxis, most rashes occurred within 2 to 3 days after injection and resolved within 1 week. One recipient of the BNT162b2 vaccine developed a pruritic, maculopapular exanthem that persisted for more than 1 month. This patient, who had no significant past medical history or drug allergy, erupted in an erythematous rash over 30% of his body, including the face, trunk, upper extremities, and thighs, but sparing the oral and genital mucosa.

      Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash after the first dose of Pfizer-BioNTech COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(7):423-5.

      Histologic examination revealed lymphocytic perivascular infiltrates, consistent with maculopapular toxidermia.

      Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash after the first dose of Pfizer-BioNTech COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(7):423-5.

      Despite a lack of other systemic manifestations, the patient developed concomitant liver injury with slightly elevated aspartate transaminase and gamma-glutamyl transferase enzymes.

      Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash after the first dose of Pfizer-BioNTech COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(7):423-5.

      Given the persistence of this exanthem, the patient was advised to avoid the second dose, and gradually the rash and elevated liver enzymes improved with corticosteroids.

      Ackerman M, Henry D, Finon A, et al. Persistent maculopapular rash after the first dose of Pfizer-BioNTech COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(7):423-5.

      Another BNT162b2 vaccine recipient developed a pruritic morbilliform rash across his lower back 48 hours after injection; the rash self-resolved within 24 hours.
      • Jedlowski P.M.
      • Jedlowski M.F.
      Morbilliform rash after administration of Pfizer-BioNTech COVID-19 mRNA vaccine.
      Upon receiving the second dose, he developed a recurrent and more robust morbilliform eruption involving not only the lower back, but also the flanks, proximal extremities, and upper back.
      • Jedlowski P.M.
      • Jedlowski M.F.
      Morbilliform rash after administration of Pfizer-BioNTech COVID-19 mRNA vaccine.
      This rash also resolved within 24 hours without intervention.
      Notably, morbilliform rashes have been reported in several cases of COVID-19 infection in both pediatric and adult populations.
      • Almutairi M.
      • Azizalrahman A.
      Febrile morbilliform rash as a clinical presentation of COVID-19 in a pediatric patient.
      • Avellana Moreno R.
      • Estela Villa L.M.
      • Avellana Moreno V.
      • et al.
      Cutaneous manifestation of COVID-19 in images: a case report.
      • Kulkarni R.B.
      • Lederman Y.
      • Afiari A.
      • et al.
      Morbilliform rash: an uncommon herald of SARS-CoV-2.
      • Najarian D.J.
      Morbilliform exanthem associated with COVID-19.
      Histologic examinations of such cases have revealed spongiosis and mild dermal perivascular lymphocytic infiltrates, suggesting an immune-mediated etiology rather than a direct viral effect.
      • Fattori A.
      • Cribier B.
      • Chenard M.-P.
      • et al.
      Cutaneous manifestations in patients with coronavirus disease 2019: clinical and histological findings.
      Therefore, although the exact mechanism of COVID-19 vaccine-induced morbilliform rashes remains unknown, it is plausible that these cutaneous manifestations are also the result of an immune activation.

      Urticaria

      Urticaria is defined as wheals (hives) that typically resolve within 24 hours.
      • McNeil M.M.
      • DeStefano F.
      Vaccine-associated hypersensitivity.
      It can either present as part of immediate hypersensitivity reactions, defined by the CDC as an onset within 4 hours after injection, or occur as similar reactions 4 hours after injection.
      Centers for Disease C
      Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States.
      This delineation is important to recognize because the former are potential contraindications to the second dose.
      There are 55 cases of urticaria among the 6 observational reports in nontrial literature (see Table 3). Of these 55 individuals, 30 (55%) received the BNT162b2 vaccine and 25 (45%) received the mRNA-1273 vaccine (see Table 3). Of these cases, 11 (1 associated with mRNA-1273 and 10 associated with BNT162b2) had been submitted to the Vaccine Adverse Event Reporting System (VAERS) and labeled by the CDC as part of an anaphylaxis reaction.
      CDC COVID-19 Response Team, FDA. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine — United States, December 14–23, 2020.
      In contrast, in an analysis of 414 COVID-19 dermatology registry cases, none of the 40 urticaria reactions (17 associated with BNT162b2, 23 associated with mRNA-1273) were classified as an immediate hypersensitivity rash.
      • 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.
      One female patient in the report from Park and colleagues
      • Park H.J.
      • Montgomery J.R.
      • Boggs N.A.
      Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria.
      developed pruritic urticaria on her extremities and face within 3 minutes after administration of the BNT162b2 vaccine. However, history and test results demonstrated a baseline proclivity to allergic reactions and revealed a previously undiagnosed, underlying cholinergic urticaria.
      • Park H.J.
      • Montgomery J.R.
      • Boggs N.A.
      Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria.
      Given that she felt overheated while waiting in line for the dose, the anaphylaxis likely arose from heat-induced rather than vaccine-induced cholinergic urticaria. As such, she received the second dose in a cool, temperature-controlled room without incident.
      • Park H.J.
      • Montgomery J.R.
      • Boggs N.A.
      Anaphylaxis after the Covid-19 vaccine in a patient with cholinergic urticaria.
      This case illustrates that categorically denying patients a second dose based solely on an anaphylactic reaction may erroneously prevent patients from reaping the benefits of immunization, because not all cases of anaphylaxis are directly vaccine related.

      Delayed Inflammatory Reactions to Dermal Hyaluronic Acid Fillers

      Hyaluronic acid fillers are increasingly resistant to biodegradation, resulting in longevity and more delayed inflammatory reactions (DIRs) to these implants. Among the known triggers of DIRs to fillers include viral illness, low-quality products, dental procedures, influenza vaccines, and, most recently, COVID-19 vaccines.
      • 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.
      ,
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      To date, 15 cases have been reported across 3 observational studies. Of these reports, 11 (73%) are associated with the mRNA-1273 vaccine and 4 (27%) are associated with the BNT162b2 vaccine (see Table 3).
      In many cases, DIRs occurred to fillers that had been injected more than 1 to 2 years before the COVID-19 vaccination.
      • Munavalli G.G.
      • Knutsen-Larson S.
      • Lupo M.P.
      • et al.
      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.
      These reactions developed rapidly, often within 24 to 48 hours, and presented as swelling and inflammation focused around areas previously treated with fillers.
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      Most cases were recalcitrant to antihistamines, hyaluronidase, and acetaminophen.
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      However, a novel mechanism for these reactions has been proposed, generating a potential pathogenesis-based treatment. Previous research revealed high expression of angiotensin-converting enzyme (ACE) 2 receptors in adipose tissue, where most fillers are injected.
      • Munavalli G.G.
      • Knutsen-Larson S.
      • Lupo M.P.
      • et al.
      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.
      These receptors are targeted by the SARS-CoV-2 spike protein, and the resulting interaction in the skin releases a proinflammatory cascade, which may explain the DIRs to hyaluronic acid fillers seen in COVID-infection.
      • Rowland-Warmann M.
      Hypersensitivity reaction to hyaluronic acid dermal filler following novel coronavirus infection – a case report.
      By blocking the production of angiotensin II and thus reducing the substrate for ACE2, ACE inhibitors (ACE-I) in effect promote an anti-inflammatory response.
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      Indeed, upon initiation with oral lisinopril, all DIRs resolved completely within 24 to 72 hours.
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      Despite the success of ACE-Is in treating DIRs, further research on the proposed mechanism of action is warranted.
      Important factors to consider when treating these reactions with ACE-Is include laboratory tests to assess for metabolic disturbances, especially if a patient is on medications that could interact with ACE-Is.
      • Munavalli G.G.
      • Guthridge R.
      • Knutsen-Larson S.
      • et al.
      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.
      • et al.
      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.
      Given that treatment of DIRs to hyaluronic acid fillers do not require a long course of ACE-Is, a brief discontinuation of concurrent drugs may suffice.

      Pernio and Chilblains

      Pernio-like lesions have been observed in COVID-19 infected individuals since the beginning of the pandemic.
      • Freeman E.E.
      • McMahon D.E.
      • Lipoff J.B.
      • et al.
      Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries.
      ,
      • Freeman E.E.
      • McMahon D.E.
      • Fox L.P.
      Emerging evidence of the direct association between COVID-19 and chilblains.
      Only recently have they also been associated with COVID-19 vaccines. Of the 10 cases described across 3 observation studies, 6 (60%) were associated with the BNT162b2 vaccine, and the rest were associated with the mRNA-1273 vaccine.
      Pernio-like lesions tend to present as painless, erythematous, and violaceous papules and macules on the hands and feet, with some cases exacerbated by cold exposure.

      Lopez S, Vakharia P, Vandergriff T, et al. Pernio after COVID-19 Vaccination. Br J Dermatol 2021.

      ,
      • Kha C.
      • Itkin A.
      New-onset chilblains in close temporal association to mRNA-1273 (Moderna) vaccination.
      Histopathologic examinations of these vaccine-associated lesions reveal dense, perivascular lymphocytic infiltrates in the superficial to deep dermis, confirming the pernio diagnosis.

      Lopez S, Vakharia P, Vandergriff T, et al. Pernio after COVID-19 Vaccination. Br J Dermatol 2021.

      ,
      • Kha C.
      • Itkin A.
      New-onset chilblains in close temporal association to mRNA-1273 (Moderna) vaccination.
      With topical corticosteroids, these lesions can resolve in 1 week to 1 month.

      Lopez S, Vakharia P, Vandergriff T, et al. Pernio after COVID-19 Vaccination. Br J Dermatol 2021.

      ,
      • Kha C.
      • Itkin A.
      New-onset chilblains in close temporal association to mRNA-1273 (Moderna) vaccination.
      The appearance of pernio lesions not just during COVID-19 infection, but also after vaccination suggests that the vaccines and SARS-CoV-2 activate a similar immune pathway. Although the mechanism remains unclear, these findings suggest that the pernio lesions seen in COVID-19 infection and after vaccination may be less directly related to viral effects.

      Other Reactions

      Reports of other cutaneous reactions include early-onset local injection site reactions, erythromelalgia, erythema multiforme, lichen planus, varicella zoster and herpes simplex reactivation, pityriasis rosea-like reactions, petechial rash, and purpuric rash (see Table 3). Local injection site reactions occurring within 3 days of vaccination were the second most common skin manifestations observed in the analysis of 414 COVID-19 dermatology registry cases.
      • 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.
      Of the 202 cases of local injection site reactions, 186 (92%) were attributed to the mRNA-1273 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.
      These findings were also widely reported in clinical trial data, but less frequently discussed in the nontrial literature, likely because this pattern of reactogenicity is commonly observed in other vaccines.
      • Hervé C.
      • Laupèze B.
      • Del Giudice G.
      • et al.
      The how's and what's of vaccine reactogenicity.
      Some reactions, such as erythromelalgia, erythema multiforme, and pityriasis rosea, mimic known cutaneous manifestations of COVID-19 infection. Of the 14 reports of erythromelalgia, 11 (79%) were associated with the mRNA-1273 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.
      Of the 4 cases of erythema multiforme, 3 (75%) were associated with the mRNA-1273 vaccine, and among the 6 reports of pityriasis rosea, 5 (83%) were associated with the BNT162b2 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.
      ,
      • Munavalli G.G.
      • Knutsen-Larson S.
      • Lupo M.P.
      • et al.
      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.
      ,

      Busto-Leis J, Servera-Negre G, Mayor-Ibarguren A, et al. “Pityriasis rosea, COVID-19 and vaccination: new keys to understand an old acquaintance”. Journal of the European Academy of Dermatology and Venereology. n/a.

      Similarly, varicella zoster and herpes simplex reactivations have also been reported with COVID-19 infection cases and after COVID-19 vaccinations (see Table 3). Rarer reactions include a flare of previously well-controlled lichen planus, as well as petechial and purpuric rash, the latter of which has been associated with thrombocytopenia after the mRNA-1273 vaccine.
      • Malayala S.V.
      • Mohan G.
      • Vasireddy D.
      • et al.
      Purpuric rash and thrombocytopenia after the mRNA-1273 (Moderna) COVID-19 vaccine.

      Summary

      As of April 2021, more than 1 billion COVID-19 vaccine doses have been administered worldwide.
      • Hannah Ritchie E.O.-O.
      • Beltekian D.
      • Mathieu E.
      • et al.
      Coronavirus (COVID-19) vaccinations. Online: our World in data.
      Although these vaccines are instrumental against the pandemic, important knowledge gaps remain, such as our understanding of the mechanistic relationship between these vaccines and their associated cutaneous side effects.
      Currently, no reactive dermatoses have been recorded outside of trial data for vaccines other than BNT162b2 and mRNA-1273. However, the COVID-19 vaccine frontier is evolving rapidly. We have summarized the latest clinical trial data for authorized COVID-19 vaccines as of April 15, 2021, and described the associated cutaneous manifestations reported in nontrial literature. Recognition of these common and emerging reactions has key implications for vaccine strategy because concerns about reactogenicity can significantly influence an individual’s willingness to return for a second dose. Because the benefits of immunization far outweigh the risks, it is crucial for health care providers, particularly dermatologists, to recognize our role in encouraging vaccine completion, educating our patients, and allaying their fears.

      Clinics care points

      • The most common cutaneous manifestations of COVID-19 vaccination in clinical trials were local injection site reactions, of which there is a higher incidence in individuals younger than 60 years.
      • The most common cutaneous manifestation of COVID-19 vaccination in real-world settings is delayed large local reactions, of which two-thirds were associated with the mRNA-1273 vaccine and one-third was associated with the BNT162b2 vaccine.
      • Other reactive dermatoses to COVID-19 vaccines in real-world settings include morbiliform rashes, urticaria, erythema multiforme, delayed inflammatory reactions to dermal fillers, erythromelalgia, lichen planus, varicella zoster, herpes simplex, pityriasis rosea, petechiae, purpura. Most are self-limiting and resolve with topical steroids or oral medications.

      ACKNOWLEDGEMENTS

      The International League of Dermatologic Societies (ILDS) provides grant support to Massachusetts General Hospital for the AAD/ILDS COVID-19 Dermatology Registry. AAD provides in-kind support.

      Disclosure

      Dr. Freeman is the Principal Investigator of the AAD/ILDS COVID-19 Dermatology Registry. The authors have nothing to disclose.

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