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

To the Editor:

With great interest we have read the article “Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: a case series” by Picard et al. In 3 of the 6 polyethylene glycol (PEG)-allergic patients, the diagnosis was confirmed by the positive oral provocation test (OPT) to PEG 3350 after ingestion of 2 to 7 g of PEG 3350, respectively, and 4 of them tolerated messenger RNA (mRNA) vaccines with PEG. There are also other reports in the literature, including ours, showing that patients may tolerate COVID-19 mRNA vaccination despite PEG allergy. , We would like to extend these observations with 5 patients with PEG allergy, presenting systemic symptoms either at skin prick tests (SPT), intradermal tests (IDT), and/or OPT, and discuss possible consequences of different eliciting thresholds for the tolerance of COVID-19 mRNA vaccines.

From February 2021 to September 2021, we encountered systemic reactions to PEG allergy testing in 5 patients confirming PEG allergy (2 male, 3 female; age: 27-73 years): SPT with PEG led to systemic reactions in 1, IDT in 3, and OPT in 1 patient. All had a history positive for immediate-type allergic reactions to PEG and positive skin test or positive OPT (Table I ) and have had anaphylaxis after ingestion of PEG 2 months to 20 years before testing at our center. Patients developed either generalized urticaria (n = 2), erythema and dizziness (n = 2), or skin symptoms and gastrointestinal cramps (n = 1). Notably, elicitation thresholds varied strongly from reacting already to SPT with a 10% solution of PEG in aqua destillata to tolerating 13 g of PEG 4000 in OPT. Vaccination was tolerated in 3 of 5 patients with DNA vaccines; at that time, we did not offer mRNA vaccination.

Table I

Clinical details on 5 patients with PEG allergy and systemic reactions to allergy tests

Patient	Elicitor	Reaction	SPT results	IDT results	BAT results	OPT	SARS CoV2 vaccination
28, female	(1) Cold medication syrup (PEG 6000) (2) Local anesthetic injection (mepivacaine, contains PEG) (3) Colon cleansing solution (Movicol, is PEG 3350) (4) Iodide solution (contains PEG)	(1) Few minutes after intake throat swelling, dyspnea, generalized pruritus (2) Few minutes after injection urticaria, dyspnea, drop in blood pressure, runny nose (3) 5 min after intake urticaria, dyspnea, drop in blood pressure (4) One hour after application (on foot) urticaria	2013: SPT: positive to PEG 40002021: SPT: negative to PEG 2000, 4000, 6000, PS 80, Comirnaty2013: After SPT generalized urticaria	2021: IDT: positive to ComirnatyNegative to PEG 2000, 4000, 6000, PS 80, VaxzevriaGeneralized urticaria 1 h after IDT	BAT: negative to PEG 2000, 4000, 6000, PS 80, VaxzevriaPositive to Comirnaty, Spikevax	No OPT performed because of systemic reaction after skin test	Tolerated first shot of fractionated Vaxzevria (0.1 mL; 0.4 mL) under inpatient emergency preparedness, without premedication
73, male	Colon cleansing solution (=PEG 3350)	30 min after third or fourth cup of PEG preparation palmar erythema, generalized itch, dizziness	SPT: positive to PEG 3350, 4000Negative to PEG 2000, PEG 6000, PS 80	IDT: positive to PEG 3350, 4000, 6000Negative to PEG 2000 and PS 80After IDT generalized itch and palmar erythema	BAT: positive to PEG 4000,6000, Comirnaty, SpikevaxNegative to PEG 2000, 3350, PS 80, Vaxzevria	No OPT performed because of systemic reaction after skin test	Tolerated first shot of fractionated Vaxzevria (0.1 mL; 0.4 mL) under inpatient emergency preparedness, without premedication
59, female	(1) Colon cleansing solution (Movicol Orange) (=PEG 3350) (2) Corticosteroid + local anesthetic injection (lidocaine/triamcinolone + PEG)	(1) 1 h after intake of Moviprep Orange swelling of hands, generalized urticaria, nausea, vomiting, diarrhea (2) Few minutes after injection of lidocaine/triamcinolone preparation generalized urticaria, dyspnea, dizziness	SPT: positive to PEG 4000, 6000Negative to PEG 2000, PS 80, Moviprep Orange.After SPT nausea and dizziness	No IDT performed after systemic symptoms at SPT	BAT: positive to SpikevaxNegative to PEG 2000, 3350, 4000, 6000, PS 80, Comirnaty, Vaxzevria	No OPT performed because of systemic reaction after skin testSubcutaneous challenge to triamcinolone articaine (without PEG), negative	Tolerated Vaccine Janssen unfractionated under emergency preparedness
27, male	Erythromycin syrup (Infekto mycin, contains PEG 6000)	Generalized urticaria, angioedema of the eyelids, dizziness, pruritus in the throat, dyspnea after 30 min	2006: SPT: positive to PEG 4000After SPT systemic reaction with itching at the palate and dizziness2021: negative to PEG 2000, 4000, 6000, Vaxzevria, Comirnaty, Spikevax	2021: IDT: Systemic reaction with generalized urticaria 20 min after start of IDT	BAT: NTX	Labial and OPT tolerated until the maximal dose of 30 mg of PEG 4000, discontinued because of systemic reaction in SPT	No vaccination
60, female	(1) Docetaxel (PS 80) (2) Paclitaxel (macrogolglycerol ricinoleate) (3) TriamHEXAL (PEG 4000, PS 80) and MepiHEXAL (4) Colon cleansing solution (PLENVU) (=PEG 3350) (5) Contrast media	(1) Generalized itching (2) Nausea, clouding of consciousness, rash (3) 10 min after injection generalized itch, rise in blood pressure, sensation of heat (4) Generalized urticaria (5) After 20 min generalized urticaria, sensation of heat	SPT: negative to PEG 2000, 4000, 6000, 3350, PS 80, Comirnaty, Spikevax, Vaxzevria, Vaccine Janssen, TriamHEXAL, Gadotersäure (Dotagraf), Gadoxetsäure (Primovist), Gadobutrol (Gadovist)	IDT: positive to ComirnatyNegative to PEG 2000, 4000, 6000, 3350, PS 80, Spikevax Vaxzevria, Vaccine Janssen, TriamHEXAL, Gadotersäure (Dotagraf), Gadoxetsäure (Primovist), Gadobutrol (Gadovist)	BAT: positive to DMG-PEG (Bühlmann), Comirnaty, SpikevaxBorderline positive to PEG 2000 (Bühlmann), PEG 2000, 4000, 6000, 3350, PS 80 Vaxzevria, Vaccine JanssenNegative to PEG 200	Tolerated OPT with PEG 4000 up to 900 mg. Systemic reaction at OPT with PEG 3350 at 38 g (tolerated up to 13 g of PEG 3350): urticaria, tingling of fingertips, shivering, nausea, stomach/abdominal cramps	No vaccination

BAT, Basophil activation test; IDT, intradermal test (wheal ≥5 mm); OPT, oral provocation test; NTX, not tested, PEG, polyethylene glycol; PS, polysorbate; SPT, skin prick test (wheal ≥3 mm).

Our data demonstrate that in some patients only minute amounts applied by skin testing may suffice to elicit systemic reactions, whereas in others, eliciting thresholds are multifold higher. Variables for tolerance are the dose, application mode, type of PEG, and time interval since the last positive reaction. The amount of PEG of 1 full dose of the Moderna vaccine is 0.05 mg, whereas the quantity of PEG in our IDT was much lower (0.0005 mg) and the one of the SPT cannot be estimated. PEG applied parenterally is more likely to trigger anaphylaxis as compared with oral application. SPT allergenicity of PEG increases with molecular weight and may be low for PEG 2000, and it may also be altered when presented within micelles. Nevertheless, patients already reacting with systemic symptoms at SPT or IDT likely have a higher risk of systemic reactions at COVID-19 mRNA vaccination than others tolerating ≥1 g of PEG 3350.

Whether or not our patients tolerate PEG-containing mRNA vaccines remains speculative. It appears likely for patient 5 tolerating 13 g of PEG 4000 at OPT, but for the others tolerance is more difficult to predict. There is a need to generate more data on comparing PEG threshold levels in patients with PEG allergy and tolerance of PEG-containing mRNA vaccines before drawing final conclusions. We aim for vaccinating PEG-allergic patients with mRNA vaccines, beginning with those with low level of sensitization.