To the Editor:
The American Academy of Dermatology/International League of Dermatological Societies COVID-19 Dermatology registry has collected 733 cases of skin reactions reported after coronavirus disease 2019 (COVID-19) vaccination between December 24 and April 25, 2021.1 Here we report the first 12 cases of new-onset subepidermal blistering eruptions (Table I ). A total of 7 females and 5 males (median age 82.5-years; range 42-97 years), without a history of bullous pemphigoid (BP) or autoimmunity, developed inflammatory vesicles and bullae a median of 7 days (range 12 hours-21 days) after receiving the first or second dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. All were evaluated by dermatologists, who recorded cutaneous bullae distant from the injection site and skin biopsies demonstrating subepidermal separation and dermal infiltrates with eosinophils. An additional 13th patient with a history of BP had worsened disease but did not undergo further testing.
Table I.
Diagnosis, treatment, and disease outcomes of patients with BP arising after COVID-19 vaccination
| Age (y)/Sex/Vaccine | History∗ | Latency to blisters† | H&E staining‡ | DIF at DEJ | BP180/230§ | Treatment | Outcome |
|---|---|---|---|---|---|---|---|
| 97/F/Pfizer | Psoriasis | (Dose 2) on d 2 | + | IgG/C3/IgA SSS, roof |
130/81 | TCS, DCN, NAM | Improving at wk 2 |
| 75/M/Pfizer | Eczematous dermatitis | (Dose 2) on d 10; (dose 1 worsened dermatitis) | + | C3 | 169/nd | OCS, TCS, DCN, NAM | Improving at wk 3, no longer taking an OCS |
| 64/M/Pfizer | None | (Dose 2) on d 14 | + | C3; SSS, floor | 26/82 | TCS | Improving at wk 4 |
| 82/M/Pfizer | Dermatitis | (Dose 2) on d 1; (dose 1 worsened dermatitis) | + | IgG/C3/weak IgA SSS, roof |
Neg/Neg | TCS | Resolved at wk 2 |
| 95/F/Pfizer | Nonmelanoma skin cancer | (Dose 1) on d 5; (dose 2 no flare) | + | IgG/C3/weak IgA SSS, roof | Neg/Neg | TCS, DCN, NAM | Resolved at wk 8, no longer taking DCN, NAM |
| 87/M/Moderna | Stasis dermatitis, Alzheimer disease | (Dose 2) on d 21; (dose 1 worsened dermatitis) | + | C3 | +/+ | OCS, DCN, NAM | Ongoing at d 105 |
| 42/F/Moderna | Hand eczema | (Dose 2) on d 3 | + | IgG/C3/weak granular IgM | >200/59 | IMCS, TCS, IVCS | Ongoing at d 23, improving with CS |
| 85/M/Pfizer | Dementia | (Dose 1) on d 5; (dose 2 withheld) | + | IgG/C3 | nd | OCS | Ongoing at d 59¶ |
| 83/F/Moderna | Raynaud syndrome, major depression | (Dose 1) on d 8; (dose 2 withheld) | + | Neg; IIF result Neg | Neg/Neg | OCS, TCS | Ongoing at mo 2 |
| 66/F/Pfizer | Atopic dermatitis | (Dose 1) on d 7; (dose 2) mild flare‖ | + | Neg; IIF result Neg | Neg/Neg | OCS, TCS | Resolved at wk 3 |
| 70/F/Moderna | Herpes simplex | (Dose 1) on d 9; (dose 2) no reported flare | + | Neg | nd | OCS | Resolved at 1d 5 d |
| 83/F/Pfizer | Dementia | (Dose 2) on d 7 | + | nd | nd | OCS, TCS, DCN, NAM | Ongoing at wk 6 |
| 83/M/Pfizer | BP¶ | (Dose 1) on d 7; (dose 2 withheld) | nd | nd | nd | OCS, TCS | Ongoing at d 45 |
DCN, Doxycycline; DEJ, dermal epidermal junction; DIF, direct immunofluorescence histology; H&E, hematoxylin and eosin; F, female; IIF, indirect immunofluorescence; IMCS, intramuscular corticosteroid; IVCS, intravenous corticosteroid; M, male; Moderna, Moderna COVID-19 mRNA vaccine; NAM, nicotinamide; Neg, negative; OCS, oral corticosteroid; nd, no data; Pfizer, Pfizer COVID-19 mRNA vaccine; SSS, salt split skin immunofluorescence histology; TCS, topical corticosteroid; Vac, vaccine.
Dermatology history, medical conditions associated with BP.
Blisters were distant from the immunization site in all and widespread unless otherwise noted (by the symbol ‖).
Consistent with BP (subepidermal split, infiltrate with eosinophils).
Serum IgG level according to ELISA, U/mL. Test results were considered negative if BP180 was less than 14 U/mL and BP230 was less than 9 U/mL.
Blisters on arms, hands, and lips only after dose 1. A few new blisters on the hands after dose 2.
BP was diagnosed in October 2020 (before vaccination). The BP was under control without oral medication before vaccination and flared 5 days after vaccination, requiring systemic treatment. A repeat diagnostic biopsy was not performed.
The diagnosis of BP was confirmed in 8 patients with direct immunofluorescence with or without salt split skin analysis and/or serum BP180-IgG ELISA. Four patients did not meet the full criteria for diagnosis because immunologic testing was either not performed (n = 1) or yielded a negative result (n = 3).
Of the 5 patients who developed blisters after the first vaccine, 3 tolerated the second dose (1 with mild flaring), and 2 of the 5 had a second dose withheld. Three patients diagnosed with dermatitis before vaccination reported worsening dermatitis after the first vaccination and bullae after the second. Blistering resolved or improved in 7 of the 12 patients in a median of 3 weeks (range 2-8 weeks) with combinations of topical corticosteroids, doxycycline, nicotinamide, and systemic corticosteroids. Disease was ongoing in 5 of the 12 patients at the time of writing of this letter. These outcomes may reflect different pathophysiologies: conventional BP coincident to vaccination with ongoing disease requiring stronger treatment in some versus a vaccine-triggered, benign BP-like condition in others.
These observations raise the question of whether SARS-CoV-2 vaccines might play a role in BP initiation. Certainly, the association could be coincident: the annual incidence of BP worldwide is estimated at between 2.4 and 21.7 new cases per million,2 so as large populations are vaccinated, some individuals will also develop BP. BP-like disease has been observed after immunization with numerous vaccines, including the measles, varicella zoster, influenza, hepatitis B, and human papilloma virus vaccines.3 , 4 It is possible that some individuals who developed BP after SARS-CoV-2 immunization harbored subclinical BP or undiagnosed eczematous-variant BP that was unmasked by vaccination. It is conceivable that in those with more rapid development of bullae (eg, after the first dose), transient bystander immune activation invigorated an existing subclinical autoreactivity. In those with more delayed kinetics, a new cutaneous response may have been primed. However, this is the first use of mRNA vaccines in humans,5 and a more complete understanding of any potential off-target immunostimulatory properties will require additional investigation.
Dermatologists and other clinicians should be aware that BP-like disease may develop after COVID-19 mRNA vaccination, particularly in older patients. Symptoms may improve rapidly with conservative treatment, as observed in 7 of the 12 patients reported here. Given the risks of SARS-CoV-2 infection, the rarity of these events, and the uncertainty of causality, clinicians should encourage full vaccination, including completion in those with blisters after the first dose. Our experience suggests that the natural history of SARS-CoV-2 mRNA vaccine–associated BP-like disease may differ from that of conventional BP in some individuals, but further studies are required to confirm this hypothesis.
Acknowledgments
We would like to thank Drs Rachel Abuav, Lisa Aquino, Sara Brooks, Stephen Mason, and Angela Wyatt for their contributions to this work.
Footnotes
The American Academy of Dermatology/International League of Dermatological Societies COVID-19 Dermatology Registry is supported by a grant from the International League of Dermatologic Societies to Massachusetts General Hospital and by in-kind support from the American Academy of Dermatology. Dr Damsky is supported by a Career Development Award from the Dermatology Foundation.
Disclosure of potential conflict of interest: E. E. Freeman and L. P. Fox are part of the American Academy of Dermatology Ad Hoc Task Force on COVID-19 (unpaid). E. E. Freeman is the principal investigator of the COVID-19 Dermatology Registry, and she is a coauthor for UpToDate on COVID-19 Dermatology. The rest of the authors declare that they have no relevant conflicts of interest.
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