key: cord-0862477-z0dndiia
authors: Pienkowski, Marek M.; Pienkowski, Stefan M.
title: Evaluation of Anaphylaxis Risk by Skin Testing with Covid-19 mRNA Vaccines on Anaphylactic Patients
date: 2021-09-30
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2021.09.021
sha: a70c42a1c497bdc610774cf04aa505c5a742ae8b
doc_id: 862477
cord_uid: z0dndiia

nan

Vaccination to SARS-CoV-2 has been shown to be effective in reducing the risks of infection of SARS-CoV-2 and severe COVID-19 outcomes. In the United States, Pfizer-BioNTech, Moderna COVID-19 vaccines (aka the mRNA vaccines) have been used safely for these purposes. 1, 2 First post-market reports on the use of these vaccines describe 4.7 cases of anaphylaxis per million doses of Pfizer vaccine and 2.5 cases per million Moderna doses given. 3 These early reports also describe 43.8 cases of non-anaphylactic allergic reactions per million Pfizer doses given. 4 Among individuals who experienced anaphylaxis to the Pfizer vaccine, 81% had a documented history of allergies triggered by drugs, vaccines, medical products, foods, and/or insect stings, and 33% of these individuals experienced anaphylaxis in the past. Similarly, 90% of individuals with a history of anaphylaxis to the Moderna vaccine had a documented history of allergic reactions, and 50% of these individuals experienced anaphylaxis in the past.

The presumed causes of allergic reactions are the different polyethylene glycols (PEGs) in the mRNA vaccines. While PEG allergy is rare, PEG has been shown to cause anaphylaxis. 5 Moreover, skin testing of PEGs of differing molecular weights has been shown to be effective in confirming anaphylaxis to PEGs in patients with a documented history of anaphylaxis to PEG. 6 However, in a cohort of 8 individuals with allergic reactions to the first dose of an mRNA vaccine, PEG skin testing was shown to be negative. 7 The 2012 Vaccine Practice Parameters published by the American Academy of Allergy, Asthma, and Immunology recommends that individuals with suspected anaphylaxis to a particular vaccine receive skin testing with that vaccine to assess their risk of anaphylaxis. 8 Since the mRNA vaccines contain components other than PEG that may cause allergic reactions, the AAAAI recommendations for assessing risk of anaphylaxis to vaccines are appropriate for the mRNA vaccines as well. In fact, Greenhawt et. al recently suggested using the 2012 parameters for patients with an a prior documented allergy to one of the mRNA vaccines. 9 Many of our patients who have experienced anaphylaxis express hesitancy towards receiving vaccines due to fears of anaphylaxis and continue to delay their COVID-19 vaccination. To meet this demand, we offered skin testing with mRNA vaccines for our patients who requested evaluation of their risk of anaphylaxis.

In this communication, we will describe our first 30 patients (female n=27, male n=3) skin tested with the mRNA vaccines. Patients were either self-referred or referred to us by other physicians. All patients had a self-reported history of anaphylaxis to a variety of substances including foods, venoms, drugs, environmental, flu vaccine, unknown sources, and/or the 1 st dose of a COVID-19 mRNA vaccine. The risks and benefits of skin testing were discussed with patients, and consent forms were signed by patients. Patients were probed for self-reported reactions to PEG containing products (i.e. toothpaste and colonoscopy prep). Patients' ages ranged from 27 to 80 years old. Two patients had a history of Covid-19 confirmed by PCR.

Skin testing occurred from January 22 nd 2021 to March 25 th 2021. Remnants of the mRNA vaccines were collected the morning of testing from the Johnson City Medical Center in coordination with the Tennessee Department of Health and used for skin testing within 6 hours of the vials' opening. Patients were advised to refrain from using antihistamines and oral glucocorticoids starting 3 days before testing. Skin testing was performed on patients' ventral forearms using the protocol recommended by the AAAI with modifications to increase safety.

Testing began with standard histamine and normal saline applied by prick technique and by intradermal injection of 0.05 ml of each as positive and negative controls, respectively. Next, a 1:10 dilution with normal saline of the Pfizer or Moderna vaccine was applied by prick technique. After twenty minutes, wheal sizes were measured and recorded. When negative, every twenty minutes a dose of 0.05 ml of diluted vaccine was applied intradermally, starting with a 1:1000 dilution, then a 1:100 dilution, and finally a 1:10 dilution. After recording the final wheal size, pictures of the skin tests were taken, patients were observed for an additional 30 minutes, and patients were requested to submit pictures of their skin test at 4 to 6 hours after testing to assess late phase reactions and at 24 hours after testing to assess delayed reactions. Later, patients were evaluated via direct interviews for their reaction to subsequent vaccination.

Results are presented in Table 1 . Five patients had positive immediate skin reactions at doses ranging from 1:100 to 1:10 dilution of an mRNA vaccine. One of these patients had an anaphylactic reaction during skin testing of 1:100 dilution of the Moderna vaccine. These five patients also had positive late phase reactions. Six patients had late phase reactions without immediate reactions. Unfortunately, most patients did not comply with our request to submit delayed reaction pictures. Patients with positive immediate reactions were recommended to receive the Janssen Covid-19 vaccine. Patients with negative immediate reactions (n=25) were recommended to receive their choice of Covid-19 vaccine. None of the patients with negative skin test to an mRNA vaccine who were subsequently vaccinated to Covid-19 (n=19, confirmed through records in the Tennessee Immunization Information System) have had any allergic reaction to vaccination. After our risk assessment, 66% of patients went on to receive full Covid-19 immunization.

Based on these observations, skin testing with the mRNA vaccines appears safe, and patients with negative immediate reactions to skin testing tolerated the corresponding mRNA vaccine (n=19). Additionally, 3 patients with only positive late phase reactions to skin testing did not experience reactions to vaccination. Consequently, skin testing should be considered as an adjunct procedure to evaluate risk for patients with a history of anaphylaxis, especially when the patients are delaying vaccination. These data are limited due to our reliance on self-reporting and small sample size. Furthermore, patients with positive immediate reactions to skin testing were advised to receive the Janssen vaccine, therefore the positive predictive value of skin testing cannot be determined. Importantly, testing with the vaccine carries risk of causing anaphylaxis (as documented by 1 patient in our cohort), which is similar to the reporting of skin testing with PEG. 6 Consequently, skin testing with the mRNA vaccines needs to be performed according to AAAAI guidelines. 

Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine

Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine

Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US

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

Immediate-type hypersensitivity to polyethylene glycols: a review

Polyethylene glycol-induced systemic allergic reactions (anaphylaxis)

Polyethylene glycol and polysorbate skin testing in the evaluation of coronavirus disease 2019 vaccine reactions

Adverse reactions to vaccines practice parameter 2012 update

The COVID-19 pandemic in 2021: avoiding overdiagnosis of anaphylaxis risk while safely vaccinating the world

Acknowledgments: Dr. David Lang for his kind review of the manuscript and suggestions. Dr. David Reagan and Dr. David Reagan from the Tennessee Health Department for facilitating receiving vaccine remnants. Blake Huggins for logistical assistance.