Incidence of Cutaneous Reactions After Messenger RNA COVID-19 Vaccines

Letters

matous inflammation that expressed CD163, consonant with consultancy from AbbVie, Alnylam Pharmaceuticals, Array BioPharma, Bayer, an M2 macrophage phenotype. Although the dynamic spec- Bristol Myers Squibb, Checkmate, CStone Pharmaceuticals, Eisai, EMD Serono, 3 KSQ Therapeutics, Janssen, Inzen Therapeutics, MacroGenics, Merck, Mersana, trum of TAMs has not been clearly delineated, this shifting Nektar, Novartis, Pfizer, Regeneron, Ribon Therapeutics, Rubius Therapeutics, macrophage profile across clinically distinct lesions in 2 pa- Silicon Therapeutics, Synlogic Therapeutics, TRex, Werewolf Therapeutics, Xilio tients underscores the fundamental role and plasticity of mac- Therapeutics, and Xencor; research support from AbbVie, Agios, Array, Astellas, rophages in the evolution of this eruption. We suspect that the Bristol Myers Squibb, Corvus Pharmaceuticals, EMD Serono, Immatics, Incyte, Kadmon, MacroGenics, Merck, Moderna, Nektar, Numab, Replimune, Rubius critical role of macrophages and their associated cytokines in Therapeutics, Spring Bank, Synlogic, Takeda, Trishula Therapeutics, Tizona wound healing and scar formation4 as well as the production Therapeutics, and Xencor outside the submitted work; and having patents of interleukin 34, one of 2 distinct ligands for colony- (provisional) for Serial No. 15/612,657 (Cancer Immunotherapy) and PCT/US18/ 36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: stimulating factor 1 receptor, by keratinocytes and hair fol- Diagnostic, Prognostic and Therapeutic Uses Thereof). Dr Chmura reported 5 licles may contribute to this pathogenesis. receiving grants from Bristol Myers Squibb, Merck, AstraZeneca, Takeda, and The striking near-complete normalization of lesions on ces- EMD Serono; serving on a scientific advisory board (no stock) for AstraZeneca; sation of therapy in 3 patients suggests a compensatory im- receiving compensation for consultancy from RefleXion Medical; and having a spouse receiving salary from Astellas Pharma outside the submitted work. No munologic response that facilitated repair. Recapitulation of other disclosures were reported. this phenomenon in other disease states (eg, connective tis- Additional Contributions: We thank the patient for granting permission to sue disease) has wide-reaching implications. publish this information. Limitations of this study include its observational nature 1. Hume DA, MacDonald KP. Therapeutic applications of macrophage and small sample size. A previous report describes 2 patients colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) receiving treatment with nivolumab and cabiralizumab who signaling. Blood. 2012;119(8):1810-1820. doi:10.1182/blood-2011-09-379214

developed atrophic lesions characterized histologically by der- 2. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by mal elastolysis,6 which likely represents the same phenom- tumour-associated macrophages inhibits phagocytosis and tumour immunity. enon seen in the present cohort. We suspect that additional Nature. 2017;545(7655):495-499. doi:10.1038/nature22396 cases of punctate anetoderma will emerge with increasing use 3. Jaguin M, Houlbert N, Fardel O, Lecureur V. Polarization profiles of human of these combination therapies. M-CSF-generated macrophages and comparison of M1-markers in classically activated macrophages from GM-CSF and M-CSF origin. Cell Immunol. 2013;281 (1):51-61. doi:10.1016/j.cellimm.2013.01.010

4. Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate Julia Dai, MD scar formation and chronic wound healing. Int J Mol Sci. 2017;18(7):1545. Yuanyuan Zha, PhD doi:10.3390/ijms18071545 Corey C. Foster, MD, MS 5. Wang Y, Szretter KJ, Vermi W, et al. IL-34 is a tissue-restricted ligand of CSF1R Jason J. Luke, MD required for the development of Langerhans cells and microglia. Nat Immunol. Steven J. Chmura, MD, PhD 2012;13(8):753-760. doi:10.1038/ni.2360 Mark D. Hoffman, MD 6. Dickinson KE, Price L, Wanat KA, Swick BL. Dermal elastolysis in the setting of combination immunotherapy. J Cutan Pathol. 2019;46(9):684-687. doi:10. Author Affiliations: Section of Dermatology, Department of Medicine, 1111/cup.13492 University of Chicago Medical Center, Chicago, Illinois (Dai, Hoffman); Department of Pathology, University of Chicago Medical Center, Chicago, Illinois (Zha); Department of Radiation Oncology, Vanderbilt University Medical Center, Incidence of Cutaneous Reactions Nashville, Tennessee (Foster); Section of Hematology/Oncology, University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, Pennsylvania After Messenger RNA COVID-19 Vaccines (Luke); Department of Radiation and Cellular Oncology, University of Chicago Mucocutaneous reactions, such as pruritus, urticaria, and an- Medical Center, Chicago, Illinois (Chmura). gioedema, may occur after COVID-19 messenger RNA (mRNA) Accepted for Publication: April 27, 2021. vaccination. To our knowledge, the incidence of these reac- Published Online: June 30, 2021. doi:10.1001/jamadermatol.2021.2049 tions and recurrence with subsequent vaccination has not been Corresponding Author: Mark D. Hoffman, MD, Section of Dermatology, described. Cutaneous reactions may contribute to unneces- Department of Medicine, University of Chicago Medical Center, sary avoidance of future vaccination doses. 5841 S Maryland Ave, MC 5067, Chicago, IL 60637 (mdhoffman@ uchicago.edu). Author Contributions: Drs Dai and Hoffman had full access to all the data in the Methods | We prospectively studied Mass General Brigham em- study and take responsibility for the integrity of the data and the accuracy of ployees who received an mRNA COVID-19 vaccine (first dose: De- the data analysis. Concept and design: Dai, Luke, Chmura, Hoffman. cember 16, 2020, to January 20, 2021; follow-up through Feb- Acquisition, analysis, or interpretation of data: All authors. ruary 26, 2021; eMethods in the Supplement). Institutional Drafting of the manuscript: Dai, Luke, Hoffman. review board approval was Critical revision of the manuscript for important intellectual content: provided by the Mass General All authors. Supplemental content Obtained funding: Chmura. Brigham human research Administrative, technical, or material support: Dai, Zha, Luke, Hoffman. committee with a waiver of Supervision: Chmura, Hoffman. informed consent. For 3 days after vaccination, employees com- Conflict of Interest Disclosures: Dr Luke reported receiving personal fees for pleted daily symptom surveys through a multipronged scientific advisory boards (no stock) from 7 Hills and Spring Bank; receiving approach, including email, text message, phone, and personal fees for scientific advisory boards (stock) from Actym Therapeutics, Alphamab Oncology, Arch Oncology, Kanaph Therapeutics, Mavupharma, smartphone application links. Cutaneous reactions included Onc.AI, Pyxis, and Tempest Therapeutics; receiving compensation for rash or itching (other than the injection site), hives, and/or

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Table. Self-reported Cutaneous Reactions After mRNA COVID-19 Vaccination

No. (%) [95% CI] Reaction Both mRNA vaccines Pfizer Moderna Dose 1 reaction No. 40 640 10 445 30 195 Cutaneous reactiona 776 (1.9) [1.78-2.05] 150 (1.4) [1.22-1.68] 626 (2.1) [1.92-2.24] Itching or rashb 599 (1.5) [1.36-1.60] 128 (1.2) [1.02-1.46] 471 (1.6) [1.42-1.71] Hives/urticaria 162 (0.4) [0.34-0.46] 25 (0.2) [0.15-0.35] 137 (0.5) [0.38-0.54] Swelling/angioedema 120 (0.3) [0.24-0.35] 16 (0.2) [0.09-0.25] 104 (0.3) [0.28-0.42] Recurrent dose 2 reaction No. 609 124 485 Cutaneous reactiona 101 (17) [13.7-19.8] 20 (16) [10.14-23.81] 81 (17) [13.49-20.32] Itching or rashb 81 (13) [10.7-16.3] 17 (14) [8.19-21.04] 64 (13) [10.31-16.54] Hives/urticaria 20 (3.3) [2.02-5.03] 3 (2.4) [0.50-6.91] 17 (3.5) [2.05-5.55] Swelling/angioedema 16 (2.6) [1.51-4.23] 3 (2.4) [0.50-6.91] 13 (2.7) [1.43-4.54] New dose 2 reaction

No. 33 939 9055 24 884 Abbreviation: mRNA, messenger Cutaneous reactiona 765 (2.3) [2.10-2.42] 128 (1.4) [1.18-1.68] 637 (2.6) [2.37-2.76] RNA. Itching or rashb 546 (1.6) [1.48-1.75] 100 (1.1) [0.90-1.34] 446 (1.8) [1.63-1.96] a Numbers do not sum to the total, as individual employees can report Hives/urticaria 194 (0.6) [0.49-0.66] 27 (0.3) [0.20-0.43] 167 (0.7) [0.57-0.78] multiple cutaneous reactions. Swelling/angioedema 125 (0.4) [0.31-0.44] 15 (0.2) [0.09-0.27] 110 (0.4) [0.36-0.53] b Other than at injection site.

Figure. Self-reported Cutaneous Reactions After Messenger RNA COVID-19 Vaccination

49 197 Received dose 1

40 640 Survey respondents (83%)

39 864 No cutaneous 776 Cutaneous symptoms (98%) symptoms (1.9%)

39 488 Received dose 2a 741 Received dose 2b (99%) (95%)

33 939 Survey respondents 609 Survey respondents (86%) (82%) a A total of 117 employees scheduled for dose 2 and 259 not scheduled/unknown. 33 174 No cutaneous 765 Cutaneous 508 No cutaneous 101 Cutaneous b A total of 5 employees scheduled symptoms (98%) symptoms (2.3%) symptoms (83%) symptoms (17%) for dose 2 and 30 not scheduled/unknown.

swelling of the lips, tongue, eyes, or face (eAppendix in the Cutaneous reactions were reported by 776 respondents Supplement). after dose 1 (1.9%; 95% CI, 1.8%-2.1%; Table and Figure). We calculated the number and frequency of self- Rash and itching (other than at the injection site) was the reported cutaneous reactions with 95% confidence intervals most common cutaneous reaction, which was reported by using symptom survey respondents by dose as the denomi- 559 (1%; 95% CI, 1.8%-2.1%). The mean (SD) age of those nator. We compared frequencies using χ2 tests. Statistical reporting cutaneous reactions was 41 (14) years. Cutaneous analyses were conducted using SAS, version 9.4 (SAS Insti- reactions were more common in women (656 [85%]) than tute), and statistical significance was set at P< .05. men (120 [15%]; P < .001) and differed by race (62% White individuals, 7% Black individuals, and 12% Asian individu- Results | Of 49 197 employees who received the first dose of a als; P < .001]). More than one-third of employees who COVID-19 vaccine, 12 464 (25%) received the Pfizer- reported cutaneous reactions were physicians or nurses BioNtech vaccine and 36 733 (75%) received the Moderna (285 [37%]). vaccine. At least 1 symptom survey was completed by Of those with self-reported cutaneous reaction to the 40 640 (83%) after the first dose of the vaccine. first dose, 741 (95%) received their second dose. Among the

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609 who completed a symptom survey after the second Author Contributions: Drs Robinson and Blumenthal had full access to all of dose, 508 (83%) reported no recurrent cutaneous reactions. the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Among those with no cutaneous reaction to the first Concept and design: Robinson, Blumenthal. dose, 765 (2.3%) reported cutaneous reactions after the sec- Acquisition, analysis, or interpretation of data: Robinson, Hashimoto, Wickner, ond dose. Rash and itching (other than the injection site) Shenoy, Landman, Blumenthal. was the most common (546 [1.6%]; 95% CI, 1.5%-1.8%). Drafting of the manuscript: Robinson, Blumenthal. Critical revision of the manuscript for important intellectual content: Robinson, Hashimoto, Wickner, Shenoy, Landman, Blumenthal. Discussion | In this prospective cohort of almost 50 000 health Obtained funding: Blumenthal. care employees, 1.9% self-reported cutaneous reactions after Administrative, technical, or material support: Hashimoto, Wickner, Shenoy, Landman, Blumenthal. receiving the first dose of an mRNA COVID-19 vaccine. With Supervision: Blumenthal. more than 600 employees with first-dose cutaneous reac- Conflict of Interest Disclosures: Dr Blumenthal reports grants from the tions included, 83% did not have recurrent cutaneous reac- American Academy of Allergy Asthma and Immunology Foundation, CRICO, and tions. An additional 2.3% reported cutaneous reactions only Massachusetts General Hospital outside the submitted work. Dr Landman after the second dose of the vaccine. reports personal fees from Abbott Medical Device Cybersecurity Council outside the submitted work. Dr Wickner reports employment with CVS Health Cutaneous reactions were more commonly reported outside the submitted work. No other disclosures were reported. among women, which was similar to reported local Funding/Support: This work was supported by National Institutes of Health injection site reactions and anaphylaxis after mRNA COVID (NIH) grant K01 AI125631 and the Massachusetts General Hospital (MGH) DOM vaccinations.1,2 To our knowledge, the underlying cause for Transformative Scholar Program. this difference is not yet known, although drug allergies are Role of the Funder/Sponsor: The funding organizations had no role in the more common in women.3 design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; The limitations of this study include the use of self- and decision to submit the manuscript for publication. reported data. However, many employees were clinicians; thus, Additional Contributions: We thank many colleagues in the Mass General the data may be more reliable. Self-reported reactions may con- Brigham health system for the design and implementation of the COVID-19 tribute to vaccine hesitancy. This study captures cutaneous revaccination program, including Paul D. Biddinger, MD, Thomas D. Sequist, MD, actions that occurred within 3 days after vaccination and thus MPH, Upeka Samarakoon, MS, PhD, MPH, Rajesh Patel, MD, MPH, Leeann 2 Ouimet, MBA, Allen Judd, AB, Aleena Banerji, MD, Anna R. Wolfson, MD, cannot assess for delayed cutaneous reactions. Rebecca Saff, MD, PhD, Aidan A. Long, MD, Lily Li, MD, Tanya M. Laidlaw, MD, Cutaneous reactions, including itching, rash, hives and David I. Hong, MD, Anna M. Feldweg, MD, Katrin Stinson, MPH, Amanda J. swelling, occurred in more than 4% of those who received Centi, PhD, Lynn Simpson, MPH, Nahal Beik, PharmD, BCPS, Christian M. Mancini, BS, Amelia S. Cogan, MPH, and Aubree E. McMahon, BA. No the 2-dose mRNA COVID-19 vaccines. The spectrum of compensation was received. reported cutaneous reactions after mRNA vaccination Disclaimer: The content is solely the responsibility of the authors and does not include large local reactions, urticaria, and morbilliform necessarily represent the official views of the NIH, Mass General Brigham, reactions.2,4 Unlike anaphylaxis, cutaneous reactions alone nor MGH. are not a contraindication to revaccination.5 In this cohort, 1. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA most individuals received the second dose without recur- COVID-19 vaccines in the US—December 14, 2020-January 18, 2021. JAMA. 2021;325(11):1101-1102. doi:10.1001/jama.2021.1967 rent reactions. Referral to an allergist or dermatologist is not necessary for most reactions but should be considered for 2. Blumenthal KG, Freeman EE, Saff RR, et al. Delayed large local reactions to mRNA-1273 vaccine against SARS-CoV-2. N Engl J Med. 2021;384(13):1273-1277. 6 patients who experience immediate or severe reactions. doi:10.1056/NEJMc2102131 These data are reassuring for the millions of Americans who 3. Blumenthal KG, Li Y, Acker WW, et al. Multiple drug intolerance syndrome may develop cutaneous reactions after vaccination in the and multiple drug allergy syndrome: Epidemiology and associations with coming year. anxiety and depression. Allergy. 2018;73(10):2012-2023. doi:10.1111/all.13440 4. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases. J Am Acad Dermatol.S0190-9622(21)00658-7. In Press. Lacey B. Robinson, MD, MPH 5. Kelso JM, Greenhawt MJ, Li JT, et al. Adverse reactions to vaccines practice Xiaoqing Fu, MS parameter 2012 update. J Allergy Clin Immunol. 2012;130(1):25-43. doi:10.1016/j. Dean Hashimoto, MD jaci.2012.04.003 Paige Wickner, MD, MPH 6. US Centers for Disease Control and Prevention. What to do if you have an Erica S. Shenoy, MD, PhD allergic reaction after getting a COVID-19 vaccine. Accessed March 5, 2021. https://www.cdc.gov/coronavirus/2019ncov/vaccines/safety/ Adam B. Landman, MD allergic-reaction.html. Kimberly G. Blumenthal, MD, MSc

Author Affiliations: Massachusetts General Hospital, Boston (Robinson, Fu, OBSERVATION Shenoy, Blumenthal); Mass General Brigham, Sommerville, Massachusetts (Hashimoto); Brigham and Women’s Hospital, Boston, Massachusetts (Wickner, Landman). Treatment of Posttraumatic Reactive Accepted for Publication: May3,2021. Angioendotheliomatosis Published Online: June 23, 2021. doi:10.1001/jamadermatol.2021.2114 With Topical Timolol Maleate Reactive angioendotheliomatosis (RAE) is a rare benign vas- Corresponding Author: Lacey B. Robinson, MD, MPH, Massachusetts General Hospital, 55 Fruit St, Cox 201, Boston, MA 02114 (lbrobinson@ cular proliferation that is usually seen in the setting of sys- mgh.harvard.edu). temic disorders. To our knowledge, there is no standard

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