Reply to "Variability of eliciting thresholds in PEG allergy limits prediction of tolerance to PEG-containing mRNA COVID vaccines".

To the Editor:

We thank Mathes et al for their correspondence regarding our article “Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: a case series.” The authors raise the interesting issue that some polyethylene glycol (PEG)-allergic patients with low reaction thresholds and systemic reactions to PEG skin testing could be at risk of reacting to messenger RNA (mRNA) COVID-19 vaccines, which contain very small amounts of PEG 2000 linked to a lipid. Although this hypothesis is plausible, we would like to point out that the only mean of ascertaining this risk is to vaccinate these patients with an mRNA vaccine.

In our case series, we identified 3 patients with a positive skin test to an mRNA vaccine who then tolerated the vaccine (one of them—patient 1—in a single dose on 2 occasions). This patient also had a low reaction threshold as he was positive on skin prick testing (SPT) to PEG 3350 at a concentration of 0.7 mg/mL.

Since the publication of the case series, we evaluated 2 other patients with a positive SPT to PEG 3350 (Table I ). One accepted vaccination and tolerated an mRNA vaccine in a single dose. In addition, 1 patient (patient 6) from the original case series with a positive SPT to PEG 3350 tolerated an mRNA vaccine in a single dose, which she received as a booster after receiving the AstraZeneca vaccine for her initial immunization (Table I). Hennighausen et al recently published a case report showing tolerance to an mRNA vaccine (in divided doses and with antihistamine premedication) in a patient with a positive basophil activation test to the vaccine and to the PEG 2000 lipid component. Taken together, these findings argue that skin testing and/or a basophil activation test to PEG of any molecular weight or to the vaccine itself does not reliably predict reactivity on vaccine inoculation.

Table I

Patients with confirmed PEG allergy evaluated for COVID-19 vaccination since publication of the case series

Patient∗	Age	Sex	PEG product causing reaction	Clinical manifestations of PEG allergy	Diagnostic tests for PEG allergy	COVID-19 vaccination
6	70	F	PEG 3350 and electrolyte solution (PegLyte) for bowel cleansing before colonoscopy	Lip and tongue angioedema and diffuse urticaria within minutes after ingesting between 3 and 6 gFive years before vaccination	Tested 1 wk before the first dose of AstraZeneca vaccine:PEG 3350 (Lax-A-Day):SPT + (500 mg/mL) (size: 7/7)	Tolerated Pfizer-BioNTech vaccine in a single dose (0.3 mL)Had previously received 2 doses of AstraZeneca vaccine without any reaction
13	39	F	Skin care products containing PEG (MW not specified)	Localized skin pruritus and erythema in contact with product. Dyspnea sometimes associated with skin symptomsSeveral years before allergy evaluation	At the time of allergy evaluation:PEG 3350 (Lax-A-Day):SPT + (70 mg/mL) (size: 10/30)Pfizer-BioNTech:SPT + (undiluted) (6/15)IDT + (1:100) (15/30)	Refused vaccination to mRNA and AstraZeneca vaccines in a single or divided doses
14	39	F	PEG 3350 and electrolyte solution (PegLyte) for bowel cleansing before colonoscopy	Oral pruritus, diffuse skin pruritus with hives, and mild dyspneaThree years before vaccination	Tested on day of vaccination:PEG 3350 (Lax-A-Day):SPT + (500 mg/mL) (7/25)Pfizer-BioNTech:Not tested	Tolerated Pfizer-BioNTech vaccine in a single dose (0.3 mL). Had previously received 2 doses of AstraZeneca vaccine without any reaction
			Methylprednisolone acetate (Depo-Medrol) intralesional	Diffuse urticaria within minutes of injectionEight years before vaccination	Tested 1 mo after vaccination:Methylprednisolone acetate (Depo-Medrol):SPT + (40 mg/mL) (6/17)Methylprednisolone succinate (Solu-Medrol):SPT- (40 mg/mL) and IDT- (4 mg/mL)Triamcinolone:SPT- (40 mg/mL) and IDT- (4 mg/mL)

Patients 13 to 14 were evaluated after the publication of the case series.

Size of skin test: first number refers to wheal and second number to flare (mm); when only 1 number is shown, it refers to wheal, and flare was not recorded.

IDT, Intradermal test; MW; molecular weight; PEG, polyethylene glycol; SPT: skin prick test.

Patient numbering refers to the published case series: Picard et al.

As pointed out by Kelso in a recent review article, important lessons can be learned from the egg allergy and influenza vaccine story: before an allergy to a vaccine constituent is considered a contraindication to this vaccine, allergists need to thoroughly evaluate this risk, which entails provocation testing.

In conclusion, given the high benefits of COVID-19 vaccination, especially with mRNA vaccines, and the reassuring data on their safety, , even in patients with a documented PEG allergy, , , we would encourage allergists to offer supervised administration of mRNA vaccines to PEG-allergic patients either in a single or divided doses.