Safety of COVID-19 vaccination in patients with polyethylene glycol allergy: A case series.

Allergists may offer supervised mRNA coronavirus disease 2019 (COVID-19) vaccination to polyethylene glycol–allergic patients.

Polyethylene glycol (PEG) allergy is generally considered a contraindication to mRNA coronavirus disease 2019 (COVID-19) vaccines because they are formulated in lipid nanoparticles containing a PEGylated lipid. However, given the high benefits of COVID-19 vaccination and the uncertain risk of allergy to mRNA vaccines in PEG-allergic patients, a shared decision making between patient and allergist is recommended by an international expert panel.

To date, there are only 2 cases of patients who had a systemic allergic–like reaction to the first dose of the Pfizer-BioNTech vaccine that were subsequently diagnosed with PEG allergy. , To our knowledge, there is no report of mRNA COVID-19 vaccination in patients with a documented PEG allergy prior to vaccination.

COVID-19 vaccination was initiated on December 14, 2020, in the Province of Quebec, Canada. Three COVID-19 vaccines are currently available: Pfizer-BioNTech, Moderna, and AstraZeneca. Since May 13, 2021, the Astra Zeneca vaccine is no longer offered to unvaccinated patients given safety concerns regarding rare cases of vaccine-induced thrombotic thrombocytopenia. Patients who had received AstraZeneca as a first dose can opt to receive a mRNA vaccine for their second dose. Whereas the AstraZeneca vaccine does not contain PEG, it contains polysorbate 80, which may be cross-reactive with PEG in some patients.

A group of allergists has been designated by the Association of Allergists and Immunologists of Quebec to evaluate and vaccinate patients with allergic-like reactions to COVID-19 vaccines or with a history of PEG allergy. Since the beginning of the vaccination campaign in Quebec, 9 allergists in 6 different hospitals evaluated 12 cases of confirmed or very likely PEG allergy. Patients were offered vaccination with either an mRNA or the AstraZeneca COVID-19 vaccine after discussion of the risks and benefits. Ten patients were vaccinated with an mRNA vaccine and 2 with the AstraZeneca vaccine. In this case series, we present the characteristics and vaccination outcomes of those 12 patients. All patients gave consent to be included in this case series and the study was institutional review board–approved.

All but 1 patient had a history of systemic reaction after oral ingestion of several grams of laxatives made of PEG 3350. Several patients also reported immediate reactions after injection of either methylprednisolone or medroxyprogesterone, which contain PEG 3350. One patient only reported reactions after using skin care products containing PEG.

Six patients had a confirmed allergy to PEG 3350 through either a positive skin prick test (SPT) or a positive drug provocation test (DPT) to PEG 3350 (Table I and Appendix E1; available in this article’s Online Repository at www.jaci-inpractice.org). Two of those patients also showed a positive intradermal test (IDT) to the Pfizer-BioNTech vaccine diluted 1:100, which is nonirritant. The other 4 patients were not skin-tested to the vaccine. Four patients with a confirmed PEG 3350 allergy tolerated an mRNA vaccine: 3 received the Pfizer-BioNTech and 1 the Moderna. Patient 2 received both doses of the Pfizer-BioNTech vaccine in 4 steps. Patient 1, who seemed to have the lowest reaction threshold to PEG in our cohort, tolerated the Pfizer-BioNTech vaccine in a single step despite a positive IDT to the vaccine. Two patients received the AstraZeneca vaccine: patient 5 was vaccinated with 2 doses before allergy evaluation, and patient 6 opted to receive the AstraZeneca vaccine based on positive SPT and DPT results to PEG 3350 and before the AstraZeneca vaccine was no longer recommended for unvaccinated individuals.

Table I

Patients with confirmed PEG allergy vaccinated against COVID-19

Patient	Age	Sex	PEG product causing reaction	Clinical manifestations of PEG allergy	Diagnostic tests for PEG allergy∗	COVID vaccine administered∗	Method of COVID vaccine administration	Clinical manifestations after vaccination	Follow-up
1	57	M	PEG 3350 and electrolyte solution (PegLyte) for bowel cleansing before colonoscopy	Skin pruritus starting after 15 g. Diffuse skin flushing and hypotension (83/56 mm Hg) after 60 gTreated with epinephrine2 y before vaccination	Tested 1 wk before vaccination:SPT + to PEG 3350 (0.7 mg/mL) (size: 10/25)	Pfizer-BioNTechSkin tests 1 wk before vaccination:SPT – to vaccine (undiluted)IDT + to vaccine (diluted 1:100) (size: 5/15)	Single dose (0.3 mL) in allergy clinic1 h observation	No reaction	Second dose administered in allergy clinic as a single dose without any reaction
2	37	F	PEG 3350 (Lax-A-Day) for constipation	Diffuse skin pruritus with hives and swelling of the face and hands starting 30 min after single dose (17 g)Treated with epinephrine2.5 y before vaccination	Tested 1.5 y before vaccination:SPT + to PEG 3350 (70 mg/mL) (size: 8)	Pfizer-BioNTechSkin tests on day of vaccination:SPT – to vaccine (undiluted)IDT + to vaccine (diluted 1:100) (size: 8/25)	Divided doses every 15 min in allergy clinic:1:10 dilution:1. 0.05 mLFull-strength:2. 0.05 mL3. 0.1 mL4. 0.15 mL1 h observation	No reaction	Second dose administered in 4 steps (as first dose) because of patient preference without any reaction
3	35	F	PEG 3350 (Lax-A-Day) for constipation	Diffuse urticaria within minutes of a single dose (17 g)2 y before vaccination	Tested 2 mo before vaccination:SPT – to PEG 3350 (70 mg/mL)DPT + to PEG 3350 (Lax-A-Day): diffuse urticaria 20 min after ingesting 2 gTreated with cetirizine	Pfizer-BioNTech	Single dose (0.3 mL) in allergy clinic1 h observation	No reaction	Second dose administered in a vaccination center without any reaction
4	46	F	PEG 3350 (Emolax) for constipation	Diffuse urticaria and malaise within 2 min of a single dose (17 g)5 mo before vaccination.	Tested 2 wk before vaccination:SPT – to PEG 3350 (concentration not recorded in file)DPT + to PEG 3350 (Emolax): diffuse urticaria and malaise 10 min after ingesting 2 gTreated with cetirizine and epinephrine.	Moderna	Divided doses every 20 min in allergy clinic:Full-strength:1. 0.05 mL2. 0.45 mL1 h observation	No reaction	Second dose administered in a vaccination center without any reaction
5	57	M	PEG 3350 (Lax-A-Day) for constipation	Face angioedema, throat and chest tightness within minutes of a single dose (17 g) Treated with cetirizine1 y before vaccination	Tested 1 wk after the second dose of vaccine:SPT – to PEG 3000 (50%).SPT + to PEG 3350 (500 mg/mL) (size:10),PEG 20000 (10%) (size: 9), PEG 20000 (1%) (size: 9), PEG 20000 (0.1%) (size: 7), PEG 20000 (0.01%) (size: 9)SPT – to polysorbate 80 (20%) and PEG 35 castor oil† (527 mg/mL).	AstraZeneca	Both doses were administered in a vaccination center	No reaction	If needed, an mRNA vaccine could be administered as a single dose in the allergy clinic
6	69	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 g5 y before vaccination	Tested 1 wk before vaccination:SPT – to PEG 3000 (50%)SPT + to PEG 3350 (500 mg/mL) (size: 7/7), PEG 20000 (10%) (size: 10/30), PEG 20000 (1%) (size: 8/20), PEG 20,000 (0.1%) (size: 8/10), PEG 20000 (0.01%) (size: 6/8)SPT – to polysorbate 80 (20%) and PEG-35 castor oil† (527 mg/mL).DPT + to PEG 3350 (Lax-A-Day): diffuse urticaria and lip angioedema 10 min after ingesting 7 gTreated with cetirizine	AstraZeneca	Both doses were administered in a vaccination center	No reaction	If needed, an mRNA vaccine could be administered as a single dose in the allergy clinic

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.

Also known as Cremophor EL.

A PEG allergy was considered very likely in 6 patients, although their skin test results were negative (Table II ). Owing to time constraints and considering their high pretest probability, DPTs were not performed to confirm PEG allergy in those patients. Two patients also refused a DPT. In our cohort, most patients did not undergo SPT to high molecular weight (MW) PEGs or IDT to methylprednisolone acetate, which could be more sensitive than SPT to PEG 3350, , , possibly explaining the low percentage of skin test–positive patients. It is also possible that their skin test reactivity to PEG waned over time, as previously shown, or that an immunoglobulin E–mediated mechanism was not responsible for their initial reaction to PEG. All 6 patients tolerated an mRNA vaccine in a single step. Patient 11 suffered a second lifetime anaphylaxis to PEG 3350 between the first and the second doses of the Moderna vaccine. Whereas she had tolerated the first dose in 1 step, the second dose was administered without reaction in 5 steps given the positive IDT result to the vaccine diluted 1:100, the recent anaphylaxis to PEG 3350, and patient preference. Patient 12 reported a very mild and limited skin reaction with the second dose of the Pfizer-BioNTech vaccine that was judged unlikely to be allergic. No other patient reported a reaction with the second dose.

Table II

Patients with a high probability of PEG allergy vaccinated against COVID-19

Patient	Age	Sex	PEG product causing reaction	Clinical manifestations of PEG allergy	Diagnostic tests for PEG allergy	COVID vaccine administered∗	Method of COVID vaccine administration	Clinical manifestations after vaccination	Follow-up
7	43	F	PEG 3350 (Lax-A-Day) for constipation.Methylprednisolone (Depo-Medrol) on 2 different occasions (intra-articular) Contains PEG 3350 (28–29 mg/dose)	Acute rhinitis and diffuse pruritus within 5 min of a single dose (17 g)Several years before vaccinationImmediate pruritus, rhinitis, and urticaria3 y before vaccination	Tested on day of vaccination:SPT – to PEG 3350 (170 mg/mL)Tested on day of vaccination:IDT – to Depo-Medrol (0.01 mg/mL)	Pfizer-BioNTech	Single dose (0.3 mL) in allergy clinic1 h observation	No reaction	If needed, can receive a second dose of Pfizer-BioNTech vaccine in a vaccination center without any special precautionsPatient had tolerated AstraZeneca vaccine as a first dose
8	46	F	PEG 3350 (Lax-A-Day) for constipationMethylprednisolone (Depo-Medrol) intra-articular Contains PEG 3350 (28–29 mg/dose).Medroxy-progesterone acetate (Depo-Provera) on 2 separate occasionsContains PEG 3350 (29 mg/dose)	Urticaria and abdominal pain 2 h after a single dose (17 g)More than 10 y before vaccinationUrticaria, angioedema, and dyspnea within minutes of injectionTreated with epinephrineMore than 10 y before vaccinationUrticaria, angioedema, and dyspnea within minutes of injectionTreated with epinephrine	Tested on day of vaccination:SPT – to PEG 3350 (170 mg/mL)Patient refused DPTTested on day of vaccination:IDT – to Depo-Medrol (0.01 mg/mL)Not tested	Pfizer-BioNTech	Single dose (0.3 mL) in allergy clinic1 h observation	No reaction	Received second dose in allergy clinic without any reaction
9	36	F	PEG 3350 (Lax-A-Day) for constipation	Oral followed by hand and feet pruritus, dysphagia, and dyspnea within minutes of ingesting about 2 gTreated with epinephrine by paramedics5 y before vaccination	Tested on day of vaccination:SPT – to PEG 3350 (170 mg/mL)IDT – to Depo-Medrol (0.01 mg/mL)	Pfizer-BioNTech	Single dose (0.3 mL) in allergy clinic1 h observation.	No reaction	Received second dose in allergy clinic without any reaction
10	35	M	Skin care products containing PEG (MW not specified) such as shower gels, sunscreens, and lubricants	Diffuse pruritus and difficulty breathing within 1 h of using such products on multiple occasionsTreated with salbutamol and antihistamine3 y before vaccination	Tested 3 wk before vaccination:SPT – to PEG 3000 (50%), PEG 3350 (500 mg/mL), PEG 20,000 (10%), polysorbate 80 (20%), and PEG-35 castor oil† (527 mg/mL)Patient refused DPT	Pfizer-BioNTech	Single dose (0.3 mL) in a vaccination center	No reaction	Received second dose in vaccination center without any reaction
11	32	F	PEG 3350 (Lax-A-Day) for constipationPEG 3350 and electrolyte solution (PegLyte) for bowel cleansing before colonoscopy.	Diffuse flushing and pruritus, gum swelling, difficulty breathing within minutes of a single dose (17 g)Treated with an antihistamine and prednisone2.5 y before vaccinationEyelid angioedema, difficulty breathing and diffuse pruritus 15 min after first dose (15 g)Treated with epinephrineTwo mo after first vaccine dose and 6 mo before second vaccine dose	Tested 6 mo after most recent reaction to PEG 3350 and on same day of second vaccine doseSPT – to PEG 3350 (70 mg/mL)IDT – to Depo-Medrol (0.4 mg/mL)	ModernaSkin tests 6 mo after most recent reaction to PEG 3350 and on same day of second vaccine dose:SPT – to vaccine (undiluted).IDT + to vaccine (diluted 1:100) (size: 3/7)	First dose administered as a single dose (0.5 mL) in a vaccination center 2 mo before most recent reaction to PEG 3350 and before allergy referral	No reaction	Second dose administered in 5 steps given positive IDT to vaccine, anaphylaxis to PEG 3350 2 mo after the first vaccine dose and patient preferenceDivided doses every 20 min in allergy clinic:1/10 dilution:1. 0.05 mLFull-strength:2. 0.05 mL3. 0.1 mL4. 0.15 mL5. 0.2 mL1.5 h observationNo reaction
12	47	F	PEG 3350 (Emolax) for constipation	Sneezing, nasal congestion, urticarial, and dyspnea within minutes of a single dose (17 g)Treated with an antihistamine8 mo before vaccination	Tested on day of vaccination:SPT – to PEG 3350 (concentration not recorded in file)	Pfizer-BioNTechSkin tests on day of vaccination:SPT – to vaccine (undiluted)IDT – to vaccine (diluted 1:100)	Single dose (0.3 mL) in allergy clinic1 h observation	No reaction	Second dose administered in a vaccination centerPatient reported redness on his chin within minutes after the dose, which resolved without any interventionIf third dose necessary, it will be administered in allergy clinic

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.

Also known as Cremophor EL.

A plausible explanation for the lack of reactivity observed to the mRNA vaccines in this case series is that the MW and the dose of PEG contained in the vaccines were below the reaction threshold of our patients. Although the data are very limited given the rarity of PEG allergy, the amount of PEG, its route of administration, and its MW seem to influence the risk of reaction. Each dose of Pfizer-BioNTech mRNA vaccine contain 0.05 mg of PEG 2000 linked to a lipid. The exact amount of PEG 2000 in the Moderna vaccine is not listed in its fact sheet, although it is likely in the same range. In contrast, all patients in this case series, except 1, reported reactions to at least 28 mg of PEG 3350. However, most patients were not tested to PEGs of MWs below 3350 or to polysorbate 80, which is structurally similar to lower MW PEGs. The only 2 patients tested to PEG 3000 and polysorbate 80 had negative results and were vaccinated with the AstraZeneca vaccine.

PEGylated lipids, such as the one in the PfizerBioNTech vaccine, can trigger basophil activation ex vivo in some PEG-allergic patients. However, in vivo, the bioavailability of the PEGylated lipids to basophils and mast cells upon vaccine inoculation is unknown but could be minimal, thereby contributing to the observed lack of reactivity. This hypothesis could also help explain the lack of reaction in the 2 patients who had a positive IDT to the vaccine, although it could not be determined whether their skin test reactivity to the vaccine was caused by its PEGylated lipid component. It is also possible that vaccine administration in multiples steps favored tolerance in patients 2 and 11. Finally, even though all patients in this case series had a convincing history of PEG allergy, it is possible that some patients were no longer reactive to PEG at the time of COVID-19 vaccination.

This case series is the first to show that mRNA COVID-19 vaccines may be safely administered to some PEG-allergic patients. Importantly, we found that skin test reactivity to the vaccine, at a nonirritating concentration (1:100), does not reliably predict reactivity on vaccine inoculation. The absence of a standardized approach to patients with PEG allergy led to variability in their evaluation in different hospitals. Patients also differed in the time elapsed since their last reaction to PEG. This heterogeneity, the small number of patients evaluated, as well as the observational nature of this report limit the generalizability of our findings. Although, as rarely described, , some PEG-allergic patients may react to mRNA COVID vaccines, supervised administration of mRNA vaccines to PEG-allergic patients could be offered by allergists after discussion of its risks and benefits. More research is needed to establish the safety profile of mRNA COVID vaccines in larger cohorts of PEG-allergic patients.