Polyethylene glycol and polysorbate testing in 12 patients before or after coronavirus disease 2019 vaccine administration.

Immediate allergic reactions compatible with anaphylaxis have been reported severalfold higher with the coronavirus 19 disease (COVID-19) vaccine than other vaccines. It is hypothesized that immunoglobulin E (IgE)-mediated reactions to polyethylene glycol (PEG) 2000, an excipient in the messenger RNA vaccines (such as Pfizer and Moderna) used to stabilize the lipid nanoparticle, are responsible for reported COVID-19 vaccine reactions. COVID-19 vaccine-induced anaphylaxis has only been linked to PEG allergy in few patients to date, , with many more patients having allergic reactions, making other mechanisms more likely. Activation of the contact system by the nucleic acid, complement recognition of vaccine-activating allergic effector cells, or direct mast cell activation may lead to similar clinical presentations.

The adenovirus vaccine by Johnson & Johnson does not contain PEG but contains polysorbate (PS), which is structurally similar and has clinical cross-reactivity. Polyethylene glycol has not been previously used in a vaccine, but PS is common in vaccines and can cause allergic vaccine reactions.

In addition to being the active ingredient in a typically used osmotic laxative, PEG is an ingredient in countless products as thickener, solvent, softener, and moisture carrier. Although PEG was long considered safe and biologically inert, a growing number of PEG-associated anaphylaxis case reports suggest otherwise. Most reported adverse events occur on first exposure to a parenteral PEG-containing product, indicating previous sensitization, likely cutaneous.

This study was a retrospective chart review approved by our institution's institutional review board. We describe the clinical histories and skin testing results of 12 cases (Table 1 ) using previously published recommendations for skin testing indications and procedures. Two patients who developed systemic allergic reactions after the first COVID-19 vaccine dosage were referred to the allergy and immunology clinic for evaluation and underwent PEG and PS skin testing. Many other patients were referred for isolated cutaneous reactions or reactions not believed to be IgE-mediated and did not undergo testing. We also evaluated 10 patients with clinical histories concerning reaction to PEG or PS before COVID-19 vaccination. Specific details regarding patients 1 to 4 will be described herein.

Table 1

Clinical Details of Patients

Patient number	Age (y)Sex	Allergic history	COVID-19 vaccine history	Allergy skin testing
#1	63 Female	Anaphylaxis (grade 3) to oral penicillin as a teenager. Tolerated PS-containing vaccines and oral PEG 3350.	Evaluated postvaccination. Anaphylaxis (grade 3) to the Pfizer COVID-19 vaccine first dosage. Second Pfizer dosage not administered. Received J & J vaccine without complications.	Negative PEGNegative PS
#2	60 Female	Tolerated PS-containing vaccines.	Evaluated postvaccination. Anaphylaxis (grade 1) to the Pfizer COVID-19 vaccine first dosage. Received second Pfizer dosage without complications.	Negative PEGNegative PS
#3	18 Female	Anaphylaxis (grade 4) to high-dosage combined oral contraceptives containing PEG 8000. History of dermatitis to cosmetics. Tolerated PS-containing vaccines.	Evaluated prevaccination. Recommended patient receive PS-containing vaccine. The family chose not to administer the vaccine.	Positive PEG 3350 skin prick (1 mg/mL 10/10 mm, 10 mg/mL 10/15 mm, 100 mg/mL 12/17 mm).Negative PS
#4	27 Female	Anaphylaxis to oral PEG 3350 (grade 4) and cough syrup containing PEG (grade 4). Tolerated PS-containing vaccines.	Evaluated prevaccination. The patient received the J & J vaccine without complications.	Positive PEG 3350 skin prick (1.7 mg/mL 5/10 mm, 17 mg/mL 14/20 mm, 40 mg/mL 11/19 mm, 170 mg/mL 12/20 mm).Negative PS 80 skin prick (40 mg/mL) and positive intradermal (4 mg/mL).
#5	54 Female	History of recurrent idiopathic anaphylaxis. Tolerated PS-containing vaccines.	Evaluated prevaccination. Received Moderna vaccine in both doses with the only adverse effect being vertigo for 48 h after the second dosage.	Negative PEGNegative PS
#6	52 Female	Urticaria or angioedema to multiple oral or injectable medications and contrast. Tolerated PS-containing vaccines and oral PEG 3350.	Evaluated prevaccination. Received Pfizer vaccine in both doses without complications.	Negative PEG
#7	35 Female	Urticaria to multiple oral medications and urticaria after influenza vaccination (unknown if PS-containing).	Evaluated prevaccination. Received Pfizer vaccine in both doses without complications.	Negative PEG
#8	60 Female	History of anaphylaxis or urticaria/angioedema to multiple oral and injectable medications. Tolerated PS-containing vaccines.	Evaluated prevaccination. Received Pfizer vaccine in both doses without complications.	Negative PEGNegative PS
#9	77 Male	History of urticaria to pegylated interferon alfa tolerates nonpegylated interferon alfa. Tolerated PS-containing vaccines and oral PEG 3350.	Evaluated prevaccination. Received Pfizer vaccine in both doses without complications.	Negative PEGNegative PS
#10	68 Female	History of anaphylaxis (unknown grade) to Taxotere, which contains PS. Tolerated PS-containing vaccines.	Evaluated prevaccination. Received Pfizer vaccine in both doses without complications.	Negative PEGNegative PS
#11	65 Male	History of allergic reactions to multiple oral and injectable medications.	Evaluated prevaccination. Received Moderna vaccine in both doses without complications.	Negative PEGNegative PS
#12	65 Female	History of angioedema of mouth to chlorhexidine mouthwash, which contains PEG, anaphylaxis (unknown grade) to the swine flu vaccine in 1976 (ingredients unclear).	Evaluated prevaccination. Received Pfizer vaccine first dosage without complications, scheduled to receive the second dosage.	Negative PEGNegative PS

Abbreviations: COVID 19, coronavirus disease 2019; J & J, Johnson & Johnson; PEG, polyethylene glycol; PS, polysorbate.

NOTE. Nonsterile MiraLAX used for PEG prick testing. Sterile methylprednisolone was used for PEG intradermal testing and some PS testing. Sterile Refresh eye drops are used for most PS testing. PEG 3350 skin prick testing performed with 1 mg/mL, 10 mg/mL, 40 mg/mL, 100 mg/mL concentrations. Intradermal skin testing performed with 0.4 mg/mL and 4 mg/mL concentrations. Skin prick testing for PS 80 was performed with 40 mg/mL concentration and intradermal skin testing was performed with 4 mg/mL concentration.

Patient 1 developed symptoms 35 minutes after the first Pfizer COVID-19 vaccination. She had pruritic urticaria throughout her chest and neck with dizziness, palpitations, diaphoresis, sense of impending doom, near-syncope, hypertension, and tachycardia. She received antihistamines and corticosteroids in the emergency department with symptom resolution within an hour. Epinephrine was not administered. Nine hours postvaccination, she developed abdominal cramping and diarrhea. Skin testing to PEG and PS was negative (Table 1). Because of the severity of her reaction to a PEG-containing vaccine, we recommended she complete her series with a PS-containing vaccine, which she did without complications.

Patient 2 developed symptoms 40 minutes after the first Pfizer COVID-19 vaccination. She had pruritic urticaria on her cheeks, mild lip angioedema, dizziness, and a globus sensation in her throat. She took antihistamines without seeking medical care and symptoms mostly resolved within an hour. Skin testing to PEG and PS was negative (Table 1). Of note, the patient has a history of similar globus sensation previously. Because of her mild symptoms, we recommended that she receive her second Pfizer COVID-19 vaccine, which she did without complications.

Patient 3 was evaluated before COVID-19 vaccination because of a history of anaphylaxis to high-dosage PEG-containing oral combined contraceptives for dysfunctional uterine bleeding. After taking the medication for 4 days, within a few minutes of taking the pill, she developed conjunctival injection, diffuse pruritic urticaria, wheezing, and laryngeal edema with difficulty swallowing. The emergency department administered antihistamines, corticosteroids, and epinephrine, and her symptoms resolved. She tolerated an in-office challenge to an oral contraceptive with similar hormones without PEG. Skin testing to PEG was positive and PS was negative (Table 1). Owing to her confirmed PEG allergy, we advised her to receive a PS-containing COVID-19 vaccine, which the family elected not to receive. We suspect that her delayed reaction after 4 days was because of PEG's previously described dose-dependent allergic potential.

Patient 4 was evaluated before COVID-19 vaccination because of a history of diffuse pruritic urticaria, wheezing, and throat pruritis 1 hour after taking oral PEG 3350 for the first time for constipation. The emergency department administered antihistamines and corticosteroids. Symptoms resolved quickly. Years later, she had a PEG-containing cough syrup with similar symptoms, including a biphasic reaction. Skin testing to PEG and PS was positive, but the patient tolerated PS-containing vaccines previously. She received a PS-containing COVID-19 vaccine without complications.

In our cohort, 2 patients with systemic allergic reactions to oral PEG had positive skin testing results, confirming the correlation between positive skin testing and IgE-mediated reaction to PEG. However, 2 patients with systemic reactions to a PEG-containing vaccine had negative skin testing, suggesting their reactions were not IgE-mediated reactions to PEG. The remaining 8 patients evaluated because of clinical histories compatible with a PEG or PS allergy, though less likely than patients 3 and 4, all had negative skin testing to PEG and PS, confirming a low false-positive rate with PEG skin testing because of irritant reaction. Thus, in our experience, screening prevaccination did not yield any positive skin testing results, and vaccination was generally well tolerated. All vaccines are administered in a single dosage. Patient 4 had a positive PS skin test result but tolerated PS, likely because of cross-reactivity not reflecting true allergy. Our results suggest that skin testing for PEG and PS after a suspected allergic reaction to a COVID-19 vaccine has limited use and there are likely other explanations for some reactions that are not PEG IgE-mediated reactions. There has likely been more than a diagnosis and misdiagnosis of systemic allergic reactions to messenger RNA COVID-19 vaccines. Patient 2 has exhibited that some patients with mild anaphylaxis can safely receive the second vaccine, which confirms a recent multisite study in the United States.

A major limitation of this study is the limited sample size and inability to perform skin testing with the vaccine itself. It would also have been useful to have had tryptase values for patients 1 and 2 after vaccination (baseline tryptases were normal). However, our results reaffirm similar studies , and can guide allergists and immunologists in their evaluation of patients before and after COVID-19 vaccine administration.