Clinical Review & Education JAMA Insights | CLINICAL UPDATE Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine Tom Shimabukuro, MD, MPH, MBA; Narayan Nair, MD On December 11, 2020, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the Pfizer- BioNTech coronavirus disease 2019 (COVID-19) vaccine, adminis- tered as 2 doses separated by 21 days.1 Shortly after, the Advi- sory Committee on Immuniza- tion Practices (ACIP) issued an interim recommendation for its use.2 Multimedia Following implementation of vaccination, reports of anaphylaxis af- ter the first dose of the Pfizer-BioNTech COVID-19 vaccine emerged.3 Anaphylaxis is a life-threatening allergic reaction that occurs rarely after vaccination, with onset typically within minutes to hours.4 Notifications and reports of suspected severe allergic reac- tions and anaphylaxis following vaccination were captured in the Vaccine Adverse Event Reporting System (VAERS), the national Table. Characteristics of Cases of Anaphylaxis (N = 21) Following Receipt of Pfizer-BioNTech COVID-19 Vaccine Reported to the Vaccine Adverse Events Reporting System (VAERS), December 14-23, 2020a Age, y Sex Anaphylaxis Signs and symptoms Reaction onset, min Diffuse erythematous rash, sensation of throat closure Diffuse erythematous rash, swollen tongue Treatment setting Epinephrine received Brighton levelc 2 Outcome or dispositiond Recovered at time of report Discharged home Yes, rabies vaccine Generalized urticaria, wheezing Inpatient Yes Discharged home Yes, sulfa drugs Wheezing, stridor, nausea Inpatient Generalized urticaria, wheezing Inpatient Inpatient Yes Past history Allergies or allergic reactionsb Tropical fruit Rabies vaccine Sulfa drugs Bee sting No No Shellfish, eggs Metoprolol, clarithromycin Iodinated contrast media No Wasp sting Eggs, milk, sulfa drugs, jellyfish sting Yes, jellyfish sting Prochlorperazine Yes, prochlorperazine Penicillin, azithromycin M No Hydrocodone, nuts Cats, dogs Influenza A(H1N1) vaccine Sulfa drugs Steroids Yes, influenza A(H1N1) vaccine No No No No No No No No No No No No No No 27 35 55 52 30 32 60 29 52 49 36 40 33 41 57 45 46 30 44 29 29 F M F F F F F F F F F F F F F F F F F F 2 5 5 7 8 10 10 10 10 13 13 14 15 15 23 25 30 34 54 ED ED ED ED ED ED ED ED ED ED ED ED ED ED ED Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes Yes 1 1 1 1 2 2 1 1 1 2 2 1 2 2 2 2 2 1 2 1 Diffuse erythematous rash, difficulty breathing Diffuse erythematous rash, hoarseness Generalized urticaria, swollen lips and tongue Generalized urticaria, stridor, wheezing Generalized urticaria, swollen throat Generalized urticaria, nausea Diffuse erythematous rash, swollen lip Diffuse erythematous rash, persistent dry cough Generalized urticaria, swollen airway Diffuse erythematous rash, difficulty swallowing Generalized pruritus, wheezing Generalized urticaria, swollen lips Sulfa drugs, walnuts Yes, walnuts Generalized urticaria, nausea Yes, unspecified 15 Diffuse pruritic rash, hoarseness ED Discharged home Recovered at time of report Discharged home Recovered at time of report Discharged home Recovered at time of report Recovered at time of report Not specified Discharged home Recovered at time of report Discharged home Recovered at time of report Discharged home Discharged home Discharged home Discharged home Generalized urticaria, persistent cough 150 Diffuse pruritic rash, swollen lip ED Recovered at time of report Discharged home Abbreviations: COVID-19, coronavirus disease 2019; ED, emergency department. a Table is reproduced from the MMWR report.3 b As documented in the VAERS report or medical records, or through confirmation with the treating clinician or the patients themselves. c The Brighton Collaboration case definition uses combinations of symptoms to define levels of diagnostic certainty. Brighton level 1 represents the highest level of diagnostic certainty that a reported case is indeed a case of anaphylaxis; levels 2 and 3 are successively lower levels of diagnostic certainty. Level 4 is a case reported as anaphylaxis but that does not meet the Brighton Collaboration case definition. Level 5 is a case that was neither reported as anaphylaxis nor meets the case definition.6 d As documented in the description of the adverse event in the VAERS report. 780 JAMA February 23, 2021 Volume 325, Number 8 (Reprinted) jama.com © 2021 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/05/2022 JAMA Insights Clinical Review & Education passive surveillance (spontaneous reporting) system for adverse events after immunization.5 Physicians at the US Centers for Dis- ease Control and Prevention (CDC) evaluated these reports and applied Brighton Collaboration case definition criteria6 to classify case reports as anaphylaxis or not anaphylaxis. Nonallergic adverse events, mostly vasovagal or anxiety-related, were excluded from the analysis. Anaphylaxis and nonanaphylaxis allergic reaction cases with symptom onset occurring later than the day after vacci- nation were also excluded because of the difficulty in clearly attrib- uting allergic reactions with delayed onset after vaccination. Because the Moderna COVID-19 vaccine was only available begin- ning December 21, 2020, this article focuses on the Pfizer- BioNTech COVID-19 vaccine. During December 14 to 23, 2020, after administration of a re- ported 1 893 360 first doses of Pfizer-BioNTech COVID-19 vaccine (1 177 527 in women, 648 327 in men, and 67 506 with sex of recipi- ent not reported),3 CDC identified 21 case reports submitted to VAERS that met Brighton Collaboration case definition criteria for anaphylaxis (Table), corresponding to an estimated rate of 11.1 cases per million doses administered. Four patients (19%) were hospital- ized (including 3 in intensive care), and 17 (81%) were treated in an emergency department; 20 (95%) are known to have been dis- charged home or had recovered at the time of the report to VAERS. No deaths from anaphylaxis were reported. Median interval from vaccine receipt to symptom onset was 13 minutes (range, 2-150 minutes); 15 patients (71%) had onset within 15 minutes; 18 (86%) had onset within 30 minutes.3 The most com- mon symptoms and signs were urticaria, angioedema, rash, and a sense of throat closure. Seventeen (81%) of 21 patients with anaphy- laxis had a documented history of allergies or allergic reactions, in- cluding to drugs or medical products, foods, and insect stings; 7 (33%) had experienced an episode of anaphylaxis in the past, including one after receipt of rabies vaccine and another after receipt of influenza A(H1N1) vaccine (Table). During the same period, VAERS identified 83 cases of nonanaphylaxis allergic reactions after Pfizer-BioNTech COVID-19 vaccination.3 Commonly reported symptoms in nonana- phylaxis allergic reactions included pruritus, rash, itchy and scratchy sensations in the throat, and mild respiratory symptoms. Mortality from COVID-19 in populations at high risk is substantial,7 and treatment options are limited. Widespread vaccination against COVID-19 with highly effective vaccines represents an important tool in efforts to control the pandemic. CDC guidance on use of mRNA COVID-19 vaccines8 and management of anaphylaxis is available.9 Specifically, vaccination locations should (1) ensure that necessary sup- plies are available to manage anaphylaxis, especially sufficient quan- tities of epinephrine in prefilled syringes or autoinjectors; (2) screen potential vaccine recipients to identify persons with contraindica- tions and precautions; (3) implement recommended postvaccina- tion observation periods, either 15 or 30 minutes depending on each patient’s previous history of allergic reactions; (4) ensure that physi- cians and other health care professionals can recognize signs and symptoms of anaphylaxis early; and (5) immediately treat suspected anaphylaxis with intramuscular epinephrine (because of the acute, life- threatening nature of anaphylaxis, there are no contraindications to epinephrine administration). Patients experiencing anaphylaxis should be transported to fa- cilities to receive appropriate medical care. All patients should be in- structed to seek immediate medical care if they develop signs or symptoms of an allergic reaction after their observation period ends and they have left the vaccination location. Clinicians have an im- portant role in vaccine safety monitoring by being vigilant in recog- nizing and reporting adverse events to VAERS.10 ARTICLE INFORMATION REFERENCES Author Affiliations: Immunization Safety Office, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia (Shimabukuro); Division of Epidemiology, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland (Nair). Corresponding Author: Tom Shimabukuro, MD, MPH, MBA, Immunization Safety Office, Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, GA 30329 (ayv6@cdc.gov). Published Online: January 21, 2021. doi:10.1001/jama.2021.0600 Conflict of Interest Disclosures: None reported. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of CDC or FDA. Mention of a product or company name is for identification purposes only and does not constitute endorsement by CDC or FDA. Additional Contributions: We thank investigators from the CDC COVID-19 Response Team; the FDA Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research; and the Clinical Immunization Safety Assessment Project. 1. FDA. Fact sheet for healthcare providers administering vaccine (vaccination providers): Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). Revised January 2021. Accessed January 17, 2021. https:// www.fda.gov/media/144413/download 2. Oliver SE, Gargano JW, Marin M, et al. The Advisory Committee on Immunization Practices’ interim recommendation for use of Pfizer-BioNTech COVID-19 Vaccine—United States, December 2020. MMWR Morb Mortal Wkly Rep. 2020;69(50):1922- 1924. doi:10.15585/mmwr.mm6950e2 3. Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine—United States, December 14–23, 2020. MMWR Morb Mortal Wkly Rep. Published January 6, 2021. doi:10.15585/mmwr.mm7002e1 4. McNeil MM, DeStefano F. Vaccine-associated hypersensitivity. J Allergy Clin Immunol. 2018;141 (2):463-472. doi:10.1016/j.jaci.2017.12.971 5. Shimabukuro TT, Nguyen M, Martin D, DeStefano F. Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS). Vaccine. 2015;33(36):4398-4405. 6. Rüggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data. Vaccine. 2007;25(31): 5675-5684. doi:10.1016/j.vaccine.2007.02.064 7. Rossen LM, Branum AM, Ahmad FB, et al. Excess deaths associated with COVID-19, by age and race and ethnicity—United States, January 26–October 3, 2020. MMWR Morb Mortal Wkly Rep. 2020;69 (42):1522-1527. doi:10.15585/mmwr.mm6942e2 8. CDC. Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States. Updated January 6, 2021. Accessed January 17, 2021. https://www.cdc.gov/ vaccines/covid-19/info-by-product/clinical- considerations.html 9. CDC. Interim considerations: preparing for the potential management of anaphylaxis after COVID-19 vaccination. Updated December 31, 2020. Accessed January 18, 2021. https://www.cdc. gov/vaccines/covid-19/info-by-product/pfizer/ anaphylaxis-management.html 10. Vaccine Adverse Event Reporting System: report an adverse event to VAERS. Accessed January 18, 2021. https://vaers.hhs.gov/ reportevent.html jama.com (Reprinted) JAMA February 23, 2021 Volume 325, Number 8 781 © 2021 American Medical Association. 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