Evaluation of anaphylaxis risk by skin testing with Covid-19 messenger RNA vaccines on patients with anaphylaxis

Anapylaxis Risk Analysis via Skin Testing with Covid-19 Vaccines

    Vaccination has been found to be effective in reducing the risks of infection of severe acute respiratory syndrome coronavirus and severe coronavirus disease 2019 (COVID-19) outcomes. In the United States, Pfizer-BioNTech and Moderna COVID-19 vaccines (aka the messenger RNA [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 vaccine3 and 2.5 cases per million Moderna doses given.4 These early reports also describe 43.8 cases of non-anaphylactic allergic reactions per million Pfizer doses given. Among individuals who experienced anaphylaxis to the Pfizer vaccine, 81% had a documented history of allergies triggered by drugs, vaccines, medical products, foods 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. Although PEG allergy is rare, PEG has been found to cause anaphylaxis.5 Moreover, skin testing of PEGs of differing molecular weights has been found to be effective in confirming anaphylaxis to PEGs in patients with a documented history of anaphylaxis to PEG.6 Nevertheless, in a cohort of 8 individuals with allergic reactions to the first dosage of an mRNA vaccine, PEG skin testing result was found to be negative.7


    The 2012 vaccine practice parameters published by the American Academy of Allergy, Asthma, and Immunology (AAAAI), recommend that individuals with suspected anaphylaxis to a particular vaccine receive skin testing with that vaccine to evaluate their risk of anaphylaxis.8 Because the mRNA vaccines contain components other than PEG that may cause allergic reactions, the AAAAI recommendations for evaluating risk of anaphylaxis to vaccines are appropriate for the mRNA vaccines as well. In fact, Greenhawt et. al.9 recently suggested using the 2012 parameters for patients with a previously documented allergy to one of the mRNA vaccines.9 

 Many of our patients who have experienced anaphylaxis express hesitancy toward receiving vaccines, owing 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) who had skin testing with the mRNA vaccines. The 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 or the first dosage of a COVID-19 mRNA vaccine.

    The risks and benefits of skin testing were discussed with the patients, and consent forms were accordingly signed. The patients were probed for self-reported reactions to PEG-containing products (ie, toothpaste and colonoscopy preparation). Ages of the patients ranged from 27 to 80 years. Of the patients, 2 had a history of COVID-19 confirmed by polymerase chain reaction testing.

Disclosures: The authors have no conflicts of interest to report. Funding: The authors have no funding sources to report.



    Skin testing occurred from January 22, 2021, to March 25, 2021. Remnants of the mRNA vaccines were collected on 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 from opening of the vials. The patients were advised to refrain from using antihistamines and oral glucocorticoids starting 3 days before the testing.

    Skin testing was performed on the ventral forearms of the patients using the protocol recommended by the AAAI with modifications to increase safety. Testing began with stan- dard histamine and normal saline applied by prick technique and by intradermal injection of 0.05 mL of each as positive and negative con- trols, respectively. Next, a 1:10 dilution with normal saline of the Pfizer or Moderna vaccine was applied by prick technique. After 20 minutes, wheal sizes were measured and recorded. Whenever the result was negative, every 20 minutes a dosage 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, the patients were observed for an additional 30 minutes, and they were requested to submit pictures of their skin test at 4 to 6 hours after testing to evaluate late-phase reactions and at 24 hours after testing to evaluate delayed reactions. Afterward, the patients were evaluated by direct interviews for their reaction to subsequent vaccination.


    The results are presented in Table 1. There were 5 patients who had positive immediate skin reactions at doses ranging from 1:100 to 1:10 dilution of an mRNA vaccine. Of these patients, 1 had an anaphylactic reaction during skin testing of 1:100 dilution of the Moderna vaccine. These 5 patients also had positive late-phase reactions. There were 6 patients who had late-phase reactions without immediate reactions. Unfortunately, most patients did not comply with our request to submit pictures from delayed reaction.

    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 vac- cine. None of the patients with negative skin test result to an mRNA vaccine who were subsequently vaccinated to COVID-19 (n = 19, con- firmed through records in the Tennessee Immunization Information System) have had any allergic reaction to vaccination. After our risk assessment, 66% of the patients went on to receive full COVID-19 immunization.

Click the image to enlarge.

Click the image to enlarge.


    On the basis of these observations, skin testing with the mRNA vaccines seems safe, and patients with negative immediate reactions to skin testing tolerated the corresponding mRNA vaccine (n = 19). Furthermore, 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 owing 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 docu- mented 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 the AAAAI guidelines.


We acknowledge Dr. David Lang for his kind review of the manuscript and suggestions. We also acknowledge Dr David Reagan from the Tennessee Health Department for facilitating in receiving the vaccine remnants. We thank Mr. Blake Huggins for logistical assistance.

Marek M. Pienkowski, MD, PhD Stefan M. Pienkowski, MA

East Tennessee State University College of Medicine Johnson City, Tennessee pienkowski@etsu.edu

Anapylaxis Risk Analysis via Skin Testing with Covid-19 Vaccines