Acute Allergic Reactions to mRNA COVID-19 Vaccines | Allergy and Clinical Immunology | JAMA | JAMA Network
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Table 1.  Acute Allergic Reactions Self-reported Through Voluntary Reporting and Multipronged Prospective System Surveillance After mRNA COVID-19 Vaccination
Acute Allergic Reactions Self-reported Through Voluntary Reporting and Multipronged Prospective System Surveillance After mRNA COVID-19 Vaccination
Table 2.  Anaphylaxis Cases After mRNA COVID-19 Vaccination (n = 16)
Anaphylaxis Cases After mRNA COVID-19 Vaccination (n = 16)
1.
Shimabukuro  TT, Cole  M, Su  JR.  Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021.   JAMA. Published online February 12, 2021. doi:10.1001/jama.2021.1967PubMedGoogle Scholar
2.
Rüggeberg  JU, Gold  MS, Bayas  JM,  et al; Brighton Collaboration Anaphylaxis Working Group.  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.2007.02.064PubMedGoogle ScholarCrossref
3.
Sampson  HA, Muñoz-Furlong  A, Campbell  RL,  et al.  Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium.   J Allergy Clin Immunol. 2006;117(2):391-397. doi:10.1016/j.jaci.2005.12.1303PubMedGoogle ScholarCrossref
4.
Kim  MH, Lee  SY, Lee  SE,  et al.  Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock.   PLoS One. 2014;9(6):e100154. doi:10.1371/journal.pone.0100154PubMedGoogle Scholar
5.
Gupta  RS, Warren  CM, Smith  BM,  et al.  Prevalence and severity of food allergies among US adults.   JAMA Netw Open. 2019;2(1):e185630. doi:10.1001/jamanetworkopen.2018.5630PubMedGoogle Scholar
6.
Dhopeshwarkar  N, Sheikh  A, Doan  R,  et al.  Drug-induced anaphylaxis documented in electronic health records.   J Allergy Clin Immunol Pract. 2019;7(1):103-111. doi:10.1016/j.jaip.2018.06.010PubMedGoogle ScholarCrossref
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    5 Comments for this article
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    Overlapping 95% CIs
    Jean-Francois Grenier, MD | Private
    With overlapping 95% CIs, I'm a little surprised to read that "Acute allergic reactions were reported by 1365 employees overall (2.10% [95% CI, 1.99%-2.22%]), more frequently with the Moderna vaccine compared with Pfizer-BioNTech (2.20% [95% CI, 2.06%-2.35%] vs 1.95% [95% CI, 1.79%-2.13%]", regardless of the p value level of 0.03.
    CONFLICT OF INTEREST: None Reported
    Did They Get A Second Dose?
    Judy Malmgren, PhD Epidemiology | University of Washington, Department of Epidemiology
    Did the persons that reported non-anaphylactic allergic reactions get their second dose and if so did they have the same reaction? If they got the second dose did they pre-load with antihistamine? Very important information for 2% of the US population which is 6,620,000 people.
    CONFLICT OF INTEREST: None Reported
    Overlapping 95% CIs - Noteable
    Nicholas Kottenstette, PhD | Private
    There is a weak indication of increased relative risk, 1.13 (1.01, 1.26) 95%CI with a p = 0.028 for recipients of the Moderna vaccine as the authors correctly noted. Interestingly, there are 191 reports of anaphylaxis for Pfizer-BioNTech as compared to 101 for Moderna on VAERS as of 03/05/2021 (1). Does anyone know how many vaccinations have been administered for each brand?

    Reference

    1. https://covid.cdc.gov/covid-data-tracker/#vaccination-trends
    CONFLICT OF INTEREST: None Reported
    Cause of Acute Allergic Reactions to mRNA COVID-19 Vaccines
    Robert Boyle, MB ChB | Imperial College London
    The allergen which triggers anaphylaxis to the Pfizer-BioNTech mRNA COVID-19 vaccine was recently identified as polyethylene glycol for at least one case of severe anaphylaxis (1). Polyethylene glycol is also present in the Moderna vaccine.

    This case of mRNA COVID-19 vaccine anaphylaxis triggered by polyethylene glycol also occurred in a female patient with a previous history of anaphylaxis. Although we cannot be certain about the cause of anaphylaxis in most reported cases, polyethylene glycol allergy seems to trigger at least some such reactions, and can potentially be identified using screening questions about previous allergic reactions to medications or
    personal care products.

    Reference

    1. Polyethylene glycol (PEG) is a cause of anaphylaxis to the Pfizer/BioNTech mRNA COVID‐19 vaccinePriya Sellaturay  Shuaib Nasser  Sabita Islam  Padmalal Gurugama  Pamela W. EwanFirst published: 06 April 2021 https://doi.org/10.1111/cea.13874 (https://onlinelibrary.wiley.com/doi/10.1111/cea.13874)
    CONFLICT OF INTEREST: I am joint Coordinating Editor of the journal Clinical and Experimental Allergy
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    History of Allergies and Anaphylaxis in the Whole Group
    Stephan Heberger, General Practitioner | Loosely associated with Technical University Munich, Germany
    The article states "Individuals with anaphylaxis [16; 0,025 %] were a mean age of 41 [ .....] 10 (63%) had an allergy history and 5 (31%) had an anaphylaxis history."

    Do you have any (rough) knowledge what the rate of allergic history and the rate of anaphylaxis history was in the whole group, with and without an allergic or anaphylaxis reaction?

    Allergy prevalence for the whole population lies between 10% to 40 % (Source: AllergyUK), in Germany 20 % (Source: RKI).

    Lifetime prevalence for anaphylaxis lies between 0,5% an 2 to 3%
    (Source: The Epidemiology of Anaphylaxis;
    Joyce E Yu).

    Two questions arise for me as a GP who administers these vaccinations:

    Is an allergy history a good predictor of a higher risk for an allergic reaction to mRNA-vaccines?
    Is an anaphylaxis history a good reason not to recommend the vaccine?

    If the allergy history rate in the whole group was 10% (6490 people) then the 1365 acute allergic reactions make 21% (1 in 5 with an allergic history will get an acute allergic reaction to the mRNA vaccine).

    If the anaphylaxis history rate in the whole group was 0,5 % (324 people, neglecting the lower age of the group) then the 16 anaphylaxis reactions make 5% (1 in 20 with an anaphylaxis history will get an anaphylaxis reaction to the mRNA vaccine).

    Assuming, on top, that the mean age for employees lies well below 60 years, anaphylaxis prevalence is probably lower than 0,5 % and the risk even higher than 5% (1 in 20)!

    So allergy and anaphylaxis history together with gender and mean age of the whole group would be helpful.

    Thanks a lot for your publication and your work.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Research Letter
    March 8, 2021

    Acute Allergic Reactions to mRNA COVID-19 Vaccines

    Author Affiliations
    • 1Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston
    • 2Department of Emergency Medicine, Massachusetts General Hospital, Boston
    • 3Division of Infectious Diseases, Massachusetts General Hospital, Boston
    • 4Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
    • 5Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, Massachusetts
    JAMA. 2021;325(15):1562-1565. doi:10.1001/jama.2021.3976

    Anaphylaxis to the mRNA COVID-19 vaccines is currently estimated to occur in 2.5 to 11.1 cases per 1 million doses, largely in individuals with a history of allergy.1 Allergic concerns contribute to vaccine hesitancy; we investigated acute allergic reaction incidence after more than 60 000 mRNA COVID-19 vaccine administrations.

    Methods

    We prospectively studied Mass General Brigham (MGB) employees who received their first dose of an mRNA COVID-19 vaccine (12/16/2020-2/12/2021, with follow-up through 2/18/2021) (eMethods in the Supplement). For 3 days after vaccination, employees completed symptom surveys through a multipronged approach including email, text message, phone, and smartphone application links. Acute allergic reaction symptoms solicited included itching, rash, hives, swelling, and/or respiratory symptoms (eAppendix in the Supplement).

    To identify anaphylaxis, allergists/immunologists reviewed the electronic health records of employees (1) reporting 2 or more allergy symptoms, (2) described as having an allergic reaction in MGB safety reports, (3) logged by the on-call MGB allergy/immunology team supporting employee vaccination, and (4) referred to MGB allergy/immunology. Episodes were scored using the Brighton Criteria2 and the National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network (NIAID/FAAN) criteria.3 Confirmed anaphylaxis required meeting at least 1 of these 2 sets of criteria.

    We described characteristics and outcomes of anaphylaxis cases. We calculated incidence rates and 95% CIs of self-reported acute allergic reactions and confirmed anaphylaxis, using vaccine administrations as the denominator. We compared frequencies using χ2 tests, considering a 2-sided P value of .05 statistically significant. Analyses were conducted in SAS version 9.4. This study was approved by the MGB Human Research Committee with a waiver of informed consent.

    Results

    Of 64 900 employees who received their first dose of a COVID-19 vaccine, 25 929 (40%) received the Pfizer-BioNTech vaccine and 38 971 (60%) received the Moderna vaccine. At least 1 symptom survey was completed by 52 805 (81%).

    Acute allergic reactions were reported by 1365 employees overall (2.10% [95% CI, 1.99%-2.22%]), more frequently with the Moderna vaccine compared with Pfizer-BioNTech (2.20% [95% CI, 2.06%-2.35%] vs 1.95% [95% CI, 1.79%-2.13%]; P = .03) (Table 1). Anaphylaxis was confirmed in 16 employees (0.025% [95% CI, 0.014%-0.040%]): 7 cases from the Pfizer-BioNTech vaccine (0.027% [95% CI, 0.011%-0.056%]) and 9 cases from the Moderna vaccine (0.023% [95% CI, 0.011%-0.044%]) (P = .76).

    Individuals with anaphylaxis were a mean age of 41 (SD, 13) years, and 15 (94%) were female (Table 2); 10 (63%) had an allergy history and 5 (31%) had an anaphylaxis history. Mean time to anaphylaxis onset was 17 (SD, 28; range, 1-120) minutes. One patient was admitted to intensive care, 9 (56%) received intramuscular epinephrine, and all recovered. Three employees, with prior anaphylaxis history, did not seek care.

    Discussion

    In this prospective cohort of health care employees, 98% did not have any symptoms of an allergic reaction after receiving an mRNA COVID-19 vaccine. The remaining 2% reported some allergic symptoms; however, severe reactions consistent with anaphylaxis occurred at a rate of 2.47 per 10 000 vaccinations. All individuals with anaphylaxis recovered without shock or endotracheal intubation.

    The incidence rate of confirmed anaphylaxis in this study is larger than that reported by the Centers for Disease Control and Prevention based on passive spontaneous reporting methods (0.025-0.11 per 10 000 vaccinations).1 However, the overall risk of anaphylaxis to an mRNA COVID-19 vaccine remains extremely low and largely comparable to other common health care exposures.4 Although cases were clinically compatible with anaphylaxis, the mechanism of these reactions is unknown.

    Most of the vaccine recipients with anaphylaxis had allergy histories, with 31% having prior anaphylaxis. However, given that approximately 5% of adults have severe food allergy histories5 and 1% of adults have severe drug allergy histories,6 this MGB employee cohort likely included almost 4000 individuals with severe food or medication allergy histories who were safely vaccinated.

    Limitations of this study include the use of self-reported data. However, cohort participants were largely health care workers, and therefore self-reported data reliability may be high. The use of vaccine administrations as the denominator for allergic reaction incidence may have resulted in some inaccuracy. Although study methods might have missed cases of potential anaphylaxis, comprehensive prospective surveillance methods were used, and symptom survey alone captured 81% of all vaccinated employees. A northeastern US cohort may not be generalizable.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Kimberly G. Blumenthal, MD, MSc, The Mongan Institute, Massachusetts General Hospital, 100 Cambridge St, 16th Floor, Boston, MA 02114 (kblumenthal@mgh.harvard.edu).

    Accepted for Publication: March 2, 2021.

    Published Online: March 8, 2021. doi:10.1001/jama.2021.3976

    Author Contributions: Dr Blumenthal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Landman and Wickner are co–senior authors.

    Concept and design: Blumenthal, Robinson, Camargo, Banerji, Landman, Wickner.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Blumenthal.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Blumenthal.

    Obtained funding: Blumenthal.

    Administrative, technical, or material support: Blumenthal, Banerji, Landman, Wickner.

    Supervision: Blumenthal, Shenoy, Landman, Wickner.

    Conflict of Interest Disclosures: Dr Blumenthal reported receiving grants from the American Academy of Allergy Asthma and Immunology (AAAAI) Foundation, CRICO, and Massachusetts General Hospital outside the submitted work. Dr Camargo reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Landman reported receiving personal fees from Abbott Medical Device Cybersecurity Council outside the submitted work. Dr Wickner reported receiving grants from CRICO outside the submitted work. No other disclosures were reported.

    Funding/Support: This work was supported by NIH grant K01 AI125631 and the Massachusetts General Hospital Department of Medicine Transformative Scholar Program. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Massachusetts General Hospital.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank many colleagues in the Mass General Brigham health system for the design and implementation of the COVID-19 vaccination program, including Dean M. Hashimoto, MD, Paul D. Biddinger, MD, Thomas D. Sequist, MD, MPH, Upeka Samarakoon, MS, PhD, MPH, Rajesh Patel, MD, MPH, Leeann Ouimet, MBA, Allen Judd, AB, Anna R. Wolfson, MD, Rebecca Saff, MD, PhD, Aidan A. Long, MD, Lily Li, MD, Tanya M. Laidlaw, MD, David I. Hong, MD, Anna M. Feldweg, MD, Katrin Stinson, MPH, Amanda J. Centi, PhD, Lynn Simpson, MPH, Nahal Beik, PharmD, BCPS, Christian M. Mancini, BS, Amelia S. Cogan, MPH, and Aubree E. McMahon, BA. We thank Xiaoqing Fu, MS, for assistance with data analysis. No compensation was received by any of these individuals.

    References
    1.
    Shimabukuro  TT, Cole  M, Su  JR.  Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021.   JAMA. Published online February 12, 2021. doi:10.1001/jama.2021.1967PubMedGoogle Scholar
    2.
    Rüggeberg  JU, Gold  MS, Bayas  JM,  et al; Brighton Collaboration Anaphylaxis Working Group.  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.2007.02.064PubMedGoogle ScholarCrossref
    3.
    Sampson  HA, Muñoz-Furlong  A, Campbell  RL,  et al.  Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium.   J Allergy Clin Immunol. 2006;117(2):391-397. doi:10.1016/j.jaci.2005.12.1303PubMedGoogle ScholarCrossref
    4.
    Kim  MH, Lee  SY, Lee  SE,  et al.  Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock.   PLoS One. 2014;9(6):e100154. doi:10.1371/journal.pone.0100154PubMedGoogle Scholar
    5.
    Gupta  RS, Warren  CM, Smith  BM,  et al.  Prevalence and severity of food allergies among US adults.   JAMA Netw Open. 2019;2(1):e185630. doi:10.1001/jamanetworkopen.2018.5630PubMedGoogle Scholar
    6.
    Dhopeshwarkar  N, Sheikh  A, Doan  R,  et al.  Drug-induced anaphylaxis documented in electronic health records.   J Allergy Clin Immunol Pract. 2019;7(1):103-111. doi:10.1016/j.jaip.2018.06.010PubMedGoogle ScholarCrossref
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