key: cord-0936135-3i4704js
authors: Hourihane, Jonathan O’B.; Byrne, Aideen M.; Blümchen, Katharina; Turner, Paul J.; Greenhawt, Matthew
title: Ascertainment Bias in Anaphylaxis Safety Data of COVID-19 Vaccines
date: 2021-05-04
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.04.025
sha: a3fca3dc689f8f1699c1c71dc61169ef22327f4a
doc_id: 936135
cord_uid: 3i4704js

nan

Vaccination against coronavirus disease 2019 (COVID-19) began in the United Kingdom and the United States in December 2020. In the United Kingdom, 3 initial reports of anaphylaxis resulted in a temporary embargo on the vaccination of those with a history of anaphylaxis. 1 Initial US surveillance data reported an anaphylaxis rate of 11.1 cases per million doses for the Pfizer-BioNTech COVID-19 vaccine 2 and 2.5 cases per million doses for the Moderna vaccine, 3 highlighting an apparently much higher occurrence of anaphylaxis reported into Centers for Disease Control and Prevention (CDC) passive vaccine surveillance systems, compared with historical data from existing vaccines, typically around 1.3 per million doses. 4 The phenomenon of an initial "spike" in adverse event reporting that subsequently "settles" with time is common with safety reporting systems designed to be very sensitive to event detection. As the denominator (number of vaccines given) increases and additional information becomes available, case definitions are revised and reporting fatigue occurs. 5 As COVID-19 vaccine roll out accelerates, regulatory agencies must constantly review safety decisions on the basis of information generated from relatively small case numbers from the earliest stages, potentially biased by the reporting spike phenomenon. It is imperative to hold the analysis and interpretation of adverse event reporting to the highest standards.

It is not uncommon for any adverse reaction occurring in association with a vaccination to be considered "allergic," for example, nausea or subjective oropharyngeal symptoms that are often psychogenic and difficult to refute on physical examination, in particular by nonallergy specialists who may lack robust experience in making such determinations. Hoarseness can represent laryngeal edema from an allergic reaction, but also vocal cord dysfunction, which can be anxiety-related. 6 Evidence from placebo-controlled allergen challenges shows that even urticaria can be stress-related.

Anaphylaxis treatment guidelines advocate the early use of intramuscular epinephrine to treat possible or likely anaphylaxis, but such epinephrine doses may be also administered "early" for only skin symptoms that might have resolved without progression to anaphylaxis. Usage of epinephrine also varies between physicians. Thus, epinephrine use (and resolution of symptoms) cannot be considered a surrogate in a post hoc diagnosis of anaphylaxis, 7 and we are reassured that none of the currently used scoring schemes does so, though we recognize that, outside the allergy community, use of epinephrine still may be interpreted mistakenly as such.

In the context of new vaccines developed and licensed at an unprecedented pace in response to the COVID-19 pandemic, there is additional pressure to properly distinguish symptoms that are a direct result of mast cell degranulation from other mechanisms of action, to discern true immune-mediated allergic reactions within the larger umbrella of adverse reactions.

The Brighton Collaboration case definition criteria were developed for the remote, post hoc evaluation of vaccine-related adverse events. 8 without remuneration, to Ireland's Health Products Regulatory Authority and National Immunisation Advisory Council. K. Blümchen has provided lectures and expert testimony for Novartis and Bencard Allergie; has provided lectures for HAL Allergy, ThermoFisher, Allergopharma, ALK, and Nutricia; has provided lectures and expert testimony and received institutional grants from DBV Technologies (France) and Aimmune Therapeutics (USA); and has provided expert testimony for Nestle. P. J. Turner has provided expertise to the UK MHRA without remuneration; and has an honorary contract with Public Health England.

M. Greenhawt has served as a consultant for the Canadian Transportation Agency, ThermoFisher, Intrommune, and Aimmune Therapeutics; is a member of physician/medical advisory boards for Aimmune Therapeutics, DBV Technologies, Sanofi/Genzyme, Genentech, Nutricia, Kaleo Pharmaceutical, Nestle, Acquestive, Allergy Therapeutics, Pfizer, US World Meds, Allergenis, Aravax, and Monsanto; is a member of the Scientific Advisory Council for the National Peanut Board; has received honorarium for lectures from ThermoFisher, Aimmune, DBV, Before Brands, multiple state allergy societies, the American College of Allergy, Asthma & Immunology, and the European Academy of Allergy and Clinical Immunology; is an associate editor for the Annals of Allergy, Asthma, and Immunology; and is a member of the Joint Taskforce on Allergy Practice Parameters. The views expressed in this publication are those of the authors and not necessarily those of any National Health Service, government department or agency, or arms' length bodies. For all levels of diagnostic certainty Anaphylaxis is a clinical syndrome characterized by sudden onset AND rapid progression of signs and symptoms AND involving multiple (2) organ systems, as follows Level 1 of diagnostic certainty 1 major dermatological AND 1 major cardiovascular AND/OR 1 major respiratory criterion Level 2 of diagnostic certainty 1 major cardiovascular AND 1 major respiratory criterion OR 1 major cardiovascular OR respiratory criterion AND 1 minor criterion involving 1 different system (other than cardiovascular or respiratory systems) OR (1 major dermatologic) AND (1 minor cardiovascular AND/OR minor respiratory criterion) J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBERcertainty" (Table I) . We have reviewed the recently published data from the CDC COVID-19 Vaccine Task Force, 2,3 and conclude that, when using the Brighton case definition, a large proportion of the apparent anaphylaxis reactions reported to date do not actually meet the Brighton criteria, despite classification as such (Table II) . Furthermore, on application of the more widely used clinical criteria for anaphylaxis (NIAID/WAO), many (up to 71%) of the Brighton-defined anaphylactic reports for both the Pfizer-BioNTech and Moderna vaccines would not be classified as anaphylaxis (Table II) .

If these more stringent criteria are also applied to the report by McNeil et al 4 summarizing reactions to non-COVID vaccinations reported to the US Vaccine Adverse Event Reporting System between 2009 and 2011, far fewer cases (defined according to the Brighton criteria) have to be excluded. This is evidence that the Brighton criteria are open to overinterpretation and thus to ascertainment bias. Recent publication of a case series from a large medical center in the United States supports this conclusion, with a similar pattern of reclassification when the Brigton and NIAID criteria were both used. 11 Overestimation of the anaphylaxis rate after COVID-19 vaccination may delay or deter vaccination through increased hesitancy. Public health bodies and health care professionals must apply the most accurate criteria on the basis of sufficient clinical information to assign a diagnosis of anaphylaxis in the context of vaccine adverse event surveillance. This may imply that perhaps the Brighton Collaboration Criteria no longer are the best choice for vaccine-related anaphylaxis. The Pfizer-BioNTech vaccine currently appears to be associated with a 3to 5-fold higher rate of anaphylaxis compared with the rate of anaphylaxis after non-COVID vaccines, but this rate is still very low and in contrast to other allergens used in immunotherapy, no anaphylaxis fatalities have been reported to date. This rate may even fall further with more data points.

The medical community has a duty to ensure transparency and availability of reliable data to inform the public and policy, and to not risk contributing to vaccine hesitancy. Covid-19 vaccine hesitancy is a worldwide threat to timely achievement of COVID-19 herd immunity. A US survey 12 recently showed that more than a fifth of its participants reported vaccine hesitancy, most commonly among 35-to 45-year-old women, a similar cohort to that represented in the CDC COVID-19 vaccine anaphylaxis reports. 2, 3 Vaccine safety concern is an important determinant of both vaccine hesitancy and resistance. Thus, early reporting of overestimated anaphylaxis rates to COVID-19 vaccines is a likely contributor to reduced vaccine uptake, to undue referral for evaluation by immunologists or allergists, and to diversion of both human and other resources to hospital-supervised vaccination.

The variable national responses to COVID-19 showed that rapid activation of public health measures was the most effective public health strategy before vaccines became available. Now that vaccination is underway using new vaccines, the allergy community must reassure governments, public health bodies, and vaccination programs to proceed with vaccination at the fastest possible pace.

We propose that the criteria for defining anaphylaxis in the context of vaccine adverse event surveillance should be those used with current clinical and research-based consensus. Anaphylaxis, defined using the most rigorous and clinically relevant criteria, is not much more common with the COVID-19 vaccines than with other vaccines that have been used safely for more than 70 years and are widely accepted by the public. 

Available from: www.gov.uk/government/news/ confirmation-of-guidance-to-vaccination-centres-on-managing-allergic-reactionsfollowing-covid-19-vaccination-with-the-pfizer-biontech-vaccine

Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine

Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine-United States

Risk of anaphylaxis after vaccination in children and adults

Allergic symptoms after pandemic influenza vaccination rarely mediated by vaccine-specific IgE

Vocal cord dysfunction: analysis of 27 cases and updated review of pathophysiology & management

The emperor has no symptoms: the risks of a blanket approach to using epinephrine autoinjectors for all allergic reactions

Anaphylaxis: case definition and guidelines for data collection, analysis, and presentation of immunization safety data

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

World Allergy Organization anaphylaxis guidance 2020

Acute allergic reactions to mRNA COVID-19 vaccines

COVID-19 vaccination hesitancy in the United States: a rapid national assessment