key: cord-0707637-pbx7sg0d
authors: Greenhawt, Matthew; Abrams, Elissa M.; Oppenheimer, John; Vander Leek, Timothy K.; Mack, Douglas P.; Singer, Alexander G.; Shaker, Marcus
title: The COVID-19 Pandemic in 2021: Avoiding Overdiagnosis of Anaphylaxis Risk While Safely Vaccinating the World
date: 2021-01-30
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.01.022
sha: 463987a921c0dd3bbe17a3375f0b92f60ac319af
doc_id: 707637
cord_uid: pbx7sg0d

nan

MG has served as a consultant for the Canadian Transportation Agency, Thermo Fisher, 50

Intrommune, and Aimmune Therapeutics; is a member of physician/medical advisory boards for 51

Aimmune Therapeutics, DBV Technologies, Sanofi/Genzyme, Genentech, Nutricia, Kaleo 52

Pharmaceutical, Nestle, Acquestive, Allergy Therapeutics, Pfizer, US World Meds, Allergenis, 53

Aravax, and Monsanto; is a member of the scientific advisory council for the National Peanut 54

Board; has received honorarium for lectures from Thermo Fisher, Aimmune, DBV, Before 55

Brands, multiple state allergy societies, the American College of Allergy Asthma and 56

Immunology, the Eurpoean Academy of Allergy and Clinical Immunology; is an associate editor 57

for the Annals of Allergy, Asthma, and Immunology; and is a member of the Joint Taskforce on 58

Allergy Practice Parameters. EA is on the Steering Committee of Food Allergy Canada's 59

National Food Allergy Action Plan; is a collaborator with the Institute for Health metrics and 60

Evaluation; and has received moderator/speaker fees from AstraZeneca, GSK and Sanofi. EA is 61 a collaborator with the Institute for Health Metrics and Evaluation, is on the National Advisory 62

Board for Food Allergy Canada and is on the National Food Allergy Action Plan Action Steering 63

Team for Food Allergy Canada. JO Merck, Covis and Pediapharm and has been part of an advisory board for Pfizer and Bausch 75

Health. AS has no conflicts to disclose.MS is a member of the Joint Taskforce on Allergy 76

Practice Parameters; has a family member who is CEO of Altrix Medical; serves on the Editorial 77

Board of the Journal of Food Allergy and the Annals of Allergy, Asthma, and Immunology. It is important to realize that as current knowledge evolves guidance will likely be conditional -89 and may change as our understanding of the pandemic and COVID-19 vaccines develops. 90

Particularly in light of present uncertainties and a somewhat volatile future, a judicious approach 91 involves decision making grounded in understanding lessons learned from prior experience with 92 vaccine anaphylaxis. Such lessons can be applied to approaches to vaccine skin testing, 93 management of known excipient allergy, vaccine graded challenge, and vaccine deferral during 94 the COVID-19 pandemic. As Banerji and colleagues discuss, any approach must balance risks 95 and benefits -both of preventing COVID-19 on patient and population levels, as well as 96 mitigating risk for anaphylaxis. Navigating these somewhat competing priorities remains a 97 challenge. As allergists, we must remain focused on risk assessment, cost-effectiveness, broad 98 public health implementation, and consideration of the potential unintended consequences of 99 screening and vaccine avoidance. In this regard, there are several important points to highlight 100 when approaching patients who are concerned about allergy risk and COVID-19 vaccination. consequences of any strategy aimed at pre-emptive screening to prevent vaccine anaphylaxis (5). 118

We need better understanding of adverse reactions to COVID-19 vaccines, and we as allergists 119 need to be discerning in our investigation of these events, rather than simply accepting self-120

reported encounters or media coverage as bona fide evidence of an allergic reaction. We would 121 urge restraint in concluding that vaccine anaphylaxis to this agent is anything more than a 122 statistically rare event. Moreover, even assuming these reported events were indeed immune-123 mediated, the broader population perspective must be considered. Specifically, if we are to 124 presume every case considered to be anaphylaxis in a recent MMWR report is correctly 125 classified, 21 events out nearly 2 million doses remains an exceedingly low absolute risk (7). In 126 this setting, the contrast between relative and absolute risk becomes important. While the 127 increase from 1.3 to 11.1 cases per million is a large relative risk, the absolute risk increase is 128 quite low (7). In fact, this remains still much lower than the disclosed hypersensitivity rate of 129 0.1% stated in the EUA (1000 cases per 1 million vaccinations) for all-comer hypersensitivity. unnecessary. It is also worthwhile to consider past experience with vaccine excipients 138 constituting a risk of an allergic reaction. Indeed, there is a mixed and somewhat inglorious 139 recent history with respect to well-intentioned risk assessment of key vaccine excipients in 140 excipient allergic individuals, which has led to unnecessary exclusion and declaration of risk. 141

For example, modern influenza vaccine contains egg. For years, guidance recommended caution 142 and restricting influenza vaccination in egg allergic individuals, only to discover that this risk 143 was unfounded for modern influenza vaccines, with no risk over baseline to the egg sensitized 144 recipient, resulting in unnecessary avoidance of the vaccine. Furthermore, egg is a far more 145 ubiquitous allergen than PEG, and it is worthwhile to recall this experience with egg and 146 influenza vaccine (as well as with measles, mumps, and rubella (MMR) vaccine, which was 147 handled similarly). (5, 6) However, particularly in the context of the MMR vaccine, it is also 148 important not to completely disregard any potential role of excipients in triggering allergic 149 reactions to vaccines, and gelatin content in MMR vaccine is a notable example that can be 150 mitigated and managed by allergists to successfully achieve subsequent vaccination.(6) 151 J o u r n a l P r e -p r o o f Importantly, perception of risk becomes anchored with earliest available information, and is very 152 difficult to retroactively change, in particular when professional organizations declare an 153 excipient a culprit without firm evidence of causality, and recommend altered management for 154 particular vaccine recipients. This is the current case with some COVID-19 vaccine 155 recommendations, which is concerning, given the lack of clear evidence to inform practice. We 156 can ill afford additional communication missteps during the current pandemic. The bottom line is 157 that even in excipient-allergic persons, it is rare that the excipient concentration is of sufficient 158 threshold to provoke an allergic reaction deeming vaccine deferral necessary, and we may very 159 well cause more harm through preventing their vaccination than we do by preventing an allergic 160 reaction to the vaccine (if efforts at risk-stratification even have the ability to mitigate 161 anaphylaxis). From a risk communication perspective, it is important to anchor guidance in 162 robust and accurate information. We must be cautious to avoid slipping backwards into 163 "presuming danger until proven safe" as this has the possible unintended consequence of 164 contributing to vaccine hesitancy, or in the worst case, chasing the wrong risk factor (e.g., egg 165 and MMR/ modern influenza vaccines). We should learn from the mistakes of the past in this 166 regard as the stakes are too high with SARS-CoV-2 to repeat the same course. 167 168 Third, even assuming PEG is the allergen, there is historical difficulty in consistently and 169 accurately assessing anti-PEG IgE through skin testing. Again, the literature on PEG allergy is 170 small, albeit growing, but the one commonality in all the small case reports has been that skin 171 testing does not always produce wheal and flare in recipients with true PEG allergy. (11) (12) (13) (14) 172

That inconsistency speaks to poor reliability of the substance as a skin testing allergen when 173 absence of any positive predictive value for a non-standardized allergen testing agent without a 195 discernable population prevalence. In such an instance, the only thing that could be established 196 would be a positive or negative likelihood ratio, but even that is lacking for PEG skin testing. The only contraindication to COVID-19 vaccination, as currently stated in both the United States 219 and Canada, is an allergy to the actual vaccine or excipient ingredient. Importantly, any 220 population screening approach for sensitization to excipients is not justified, has no validity, is 221 not necessary prior to COVID-19 vaccination, is likely poorly feasible and sustainable on a 222 broad scale, and has the potential to reduce vaccine acceptance and rollout. As allergists, we 223 must guard against a tendency of 'screening creep' to populations without severe allergic 224 reactions to parenteral PEG containing agents who can simply receive vaccination. Immunology (16, 17) . This approach is consistent with 231 decades of experience in managing vaccine allergy; however, as for most vaccines, the safety 232 and efficacy of this approach specifically as it relates to newly released COVID-19 vaccines is 233 unknown or not informed by high certainty evidence.(6) It is also important for allergists to note 234 that confidence is generally quite low in the ability of premedication with antihistamines and/or 235 glucocorticoids to prevent anaphylaxis, and such an approach has not been recommended 236 previously in evaluation and management of vaccine hypersensitivity.(6,18) Again, we would 237 urge restraint in presuming that prior history of a reaction to an injectable medication is a risk for 238 COVID-19 vaccine anaphylaxis, and strongly caution against deferring, delaying, or requiring 239 additional supervision for vaccinating such individuals. While Banerji and colleagues highlight 240 the fact that 17/21 cases of anaphylaxis reported by the CDC on January 6, 2021 had an 241 imprecise history of pre-existing "allergy" (including "bee stings", "sulfa drugs", "cats and 242 dogs", "iodinated contrast media", and "hydrocodone, nut"), we do not know the number of the honest and open about that. The pandemic is the much larger and more pressing public health 253 risk. Patients are seen in allergy clinics every day with an array of conditions that place them at 254 risk for allergic reactions, anaphylaxis, and even death. However, it must be remembered that 255 many of these conditions carry a risk of fatality much lower than risks patients take in everyday 256 living -risks that even include driving to the doctor's office for that very appointment, or even 257 being struck by lightning. One example of comparative anaphylaxis risk resonates with all 258

allergists. Every day, in nearly every allergy practice in the US, we inject persons with known 259 allergic sensitivity to a mixture of allergens in the form of immunotherapy, bearing a known risk phenomenon. However, the point is that allergists are trained and experienced to provide needed 264 medications and therapies to patients at risk for anaphylaxis -and it is very, very rare that we are 265 unable to provide a critical medication (or vaccine) to a patient at risk. And whether it be through 266 J o u r n a l P r e -p r o o f immunotherapy, drug desensitization, or graded challenge, allergists have the tools to provide 267 therapies in spite of (and sometimes because of) demonstrable allergen sensitization. Even 268 assuming an at-risk population can be identified, that PEG is a culprit for reactions, and that PEG 269 skin testing is reliable and predictive, providing an mRNA vaccine containing PEG to someone 270 with a positive skin test to PEG may not be a larger risk than we manage routinely in our clinics. (which is a present issue given rationed supply in the early phase roll-out of the vaccination 284 campaign), a graded challenge may be a very reasonable approach for a patient with documented 285 history of prior mRNA vaccine anaphylaxis, to ensure both safety and ability to receive the 286 vaccine (6, 16, 17). Even presuming patients can wait for an alternative vaccine (also a decision 287

where we could be instilling our values onto the patient), such as an adenovirus vector vaccine, 288 there is no guarantee at the moment that or that it will be safer or as effective as other vaccines. 289 J o u r n a l P r e -p r o o f anaphylaxis occur, effective treatment is rapidly available. We are unable to say this with the 291 same certainly if an unvaccinated individual was to contract COVID-19. 292

We must be vigilant to avoid adding complexity through over-diagnosing anaphylaxis risk to a 294 global vaccine effort which is already facing unprecedented challenges of distrust and 295 disinformation campaigns. As allergists, we must provide a clear, evidence based, and balanced 296 perspective on anaphylaxis risk. The world is looking to our expertise, as we rise to meet this 297 moment. This is a virus that has killed millions worldwide, whereas only a very small number of 298 patients have suffered from reactions following vaccination, none of which have led to a fatality. 299

The medical community has begun to evaluate these reactions and respond. The guidance 300 provided by Banerji and colleagues is an example for a starting approach, and we wish to 301 supplement how the allergist-immunologist can approach this through discussing some 302 additional contextualized issues to consider in weighing options for how to proceed. While we 303 wait for evolving science to further inform our practice, we applaud the incorporation of shared 304 decision-making into COVID-19 vaccination, to make sure the patient's values and preferences 305 are at the forefront of critical efforts to immunize the world and turn the tide on a devastating 306 pandemic. 307

mRNA 311 Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current 312 Evidence and Approach

Maintaining safety with SARS-CoV-2 Vaccines

Epub ahead of print

Interim clinical considerations for use of mRNA COVID-19 vaccines currently 318 authorized in the United States -Appendix B

Available at: 320

Confirmation of guidance to vaccination centres on managing allergic reactions 323 following COVID-19 vaccination with the Pfizer/BioNTech vaccine

Administration of influenza vaccines to egg allergic 328 recipients: A practice parameter update 2017

Adverse reactions to vaccines practice parameter 2012 update

Allergic reactions 334 including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 335 vaccine -United States

Vaccine-associated hypersensitivity

COVID-19 vaccine (BNT162, PF-07302048) [FDA Briefing

Silver Spring, MD: United States Food and Drug Administration, Vaccines 342 and Related Biological Products Advisory Committee

CSACI Statement on Pfizer/BioNTech Vaccine Anaphylaxis

Anti-PEG IgE 348 in anaphylaxis associated with polyethylene glycol

Polyethylene Glycol-Induced Systemic Allergic 352 Reactions (Anaphylaxis)

Immediate-type hypersensitivity to polyethylene glycols: a 354 review

Immediate 356 Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We 357 Have Recognized

Weber 361 R; American Academy of Allergy

Allergy diagnostic testing: an updated practice 363 parameter

ARIA-EAACI statement on severe allergic reactions to 366 COVID-19 vaccines -an EAACI-ARIA position paper

COVID-19 vaccine testing and 369 administration guidance for allergists/immunologists from the CSACI

Anaphylaxis-a 2020 practice parameter 373 update, systematic review, and Grading of Recommendations, Assessment, Development 374 and Evaluation (GRADE) analysis

Johns Hopkins Coronavirus Resource Center

Allergen 380 immunotherapy: a practice parameter third update