key: cord-1004120-guuvfyi0
authors: Otani, Iris M.; Tsao, Lulu R.; Tang, Monica
title: COVID-19 Vaccine Administration in Patients with Reported Reactions to Polyethylene Glycol- and Polysorbate-Containing Therapeutics
date: 2022-03-12
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2022.03.006
sha: 519ab605ca99cfa6054195b30bf96e6d7020ffd7
doc_id: 1004120
cord_uid: guuvfyi0

Background: Polyethylene glycol (PEG) and polysorbate reactions were initially implicated as a likely risk factor for reacting to COVID-19 vaccines and remain a source of vaccine hesitancy despite increasing evidence that they do not pose an increased risk for COVID-19 vaccine reactions. Objective: To investigate COVID-19 vaccine safety outcomes in patients with reported reactions to PEG and polysorbate containing medications/vaccines. Methods: COVID-19 vaccine safety was reviewed in patients identified with PEG/polysorbate reactions documented in their electronic medical records at a tertiary academic medical center (cohort 1) and patients referred to allergy/immunology with reported PEG/polysorbate reactions (cohort 2). COVID-19 vaccine safety was also reviewed following reported symptoms (onset ≤12 hours) to 1 st dose PEG-containing mRNA COVID-19 vaccine (cohort 3). Results: Of 252 patients in cohort 1 (n=202) and cohort 2 (n=50), 236 (94%) received mRNA COVID-19 vaccines (106 Pfizer, 130 Moderna); 235 received both doses and only 3 developed mild rash following vaccination. None of the 44 patients in cohort 3 with acute symptoms following 1 st dose mRNA COVID-19 vaccine (27 Pfizer, 17 Moderna) had previously reported PEG/polysorbate reactions. Of these 44, 43 received 2 nd dose and all 3 who developed symptoms following 2 nd dose (one required epinephrine) had negative PEG skin testing. Conclusion: Patients with reported reactions to PEG/polysorbate safely received COVID-19 vaccines. PEG/polysorbate skin testing did not identify patients at risk for 1 st dose or recurrent reactions to COVID-19 vaccines. Screening for PEG/polysorbate allergy may only increase vaccine hesitancy without identifying patients at risk for COVID-19 vaccine reactions.

Anaphylaxis to the mRNA COVID-19 vaccine has been reported to both Pfizer-BioNTech and Moderna mRNA COVID-19 vaccines, primarily after receipt of the 1 st dose. [1] [2] [3] [4] Allergic reactions to PEG and polysorbate were implicated as a risk factor for an allergic reaction to vaccines as PEG is the only known potentially allergenic component in the COVID-19 mRNA vaccines and polysorbate is the only known potentially allergenic component in the COVID -19 Johnson & Johnson (J&J) vaccine. [5] [6] [7] [8] Current CDC guidance highlights allergic reactions to PEG as a contraindication to receiving mRNA COVID-19 vaccine and allergic reactions to polysorbate as a contraindication to receiving J&J COVID-19 vaccine. 9 Published guidance following CDC recommendations for 1 st dose risk stratification has suggested that (1) patients with a possible PEG and polysorbate allergy be referred to an allergist for possible PEG/polysorbate skin testing, (2) patients with a possible PEG allergy receive the J&J COVID-19 vaccine or be referred to an allergist for possible PEG/polysorbate skin testing, and (3) patients with a possible polysorbate allergy receive any COVID-19 vaccine if they have subsequently tolerated a polysorbate-containing vaccine or receive mRNA COVID-19 vaccine if they have not. 4 While this strategy provides a vaccine option for most patients, vaccination sites are still left with the important but arduous task of screening for PEG and polysorbate allergy, as PEG and polysorbate can be found in numerous medications and vaccines. 10 Differentiating between allergic and non-allergic reactions can also pose challenges. Furthermore, a national survey found that vaccine efficacy has the largest influence on people's reported likelihood of receiving a vaccine, and patients cleared to receive J&J COVID-19 vaccine may still prefer allergy evaluation for clearance to receive mRNA COVID-19 vaccines due to reports of higher efficacy with these vaccines. [11] [12] [13] [14] As such, assessing COVID-19 vaccination safety in patients with history of PEG/polysorbate reactions has become a question that allergists face often. A recently published International Consensus document on the risk of allergic reactions to COVID-19 vaccines recommends that patients with past medical history of reaction to a COVID-19 vaccine excipient are referred to allergy for assessment of vaccination safety. 15 To investigate COVID-19 vaccine safety outcomes in patients with reported reactions to PEG and polysorbate containing medications/vaccines, we reviewed vaccine safety outcomes in patients with reported reactions to PEG and polysorbate containing medications and vaccines.

We reviewed demographics, documented allergies, PEG/polysorbate reaction histories, allergy evaluations, and vaccine safety outcomes in 3 patient cohorts with possible PEG/polysorbate reactions. This study was approved by our institution's institutional review board (IRB #21-33623 Patients with a history of PEG, polysorbate, vaccine, or paclitaxel reactions already established in the allergy/immunology clinic or referred for COVID-19 vaccine clearance between 12/1/2020-8/31/2021 were included in this cohort. Patients with a history of reactions to any vaccine were included as it was not always clear which vaccine patients had reacted to. Patients with a history of paclitaxel reactions were included as paclitaxel contains a PEG derivative that is structurally similar to the excipient mRNA COVID-19 vaccines. 17 Available reaction comments/descriptions of anaphylaxis, allergic reaction, erythema/redness, flushing, rash, urticaria/hives, angioedema/swelling, wheezing, shortness of breath, coughing, throat tightness, and difficulty swallowing were categorized as a history possibly consistent with allergy. Reaction comments/descriptions of body/muscle aches, chills, fever, Guillain-Barre Syndrome, hand-foot syndrome, injection site reactions, mania, migraine, nausea, neuropathy, and vasculitis were categorized as a history not consistent with allergy.

Patients referred between 12/1/2020-8/31/2021 to allergy/immunology for PEG/polysorbate testing after experiencing symptoms following 1 st dose COVID-19 vaccine were included in this cohort. Patients with symptom onset <20 hours after vaccine receipt were included as a prior report of anaphylaxis cases from Vaccine Safety Datalink found that symptom onset when documented occurred within 20 hours. 18 Testing PEG 3350 and polysorbate testing were performed closely following guidance outlined in Banerji et al. 9 Triamcinolone IDT 40 mg/ml was not performed due to our prior clinical experience with false positives at that dilution. Testing with Refresh eyedrops was not performed. The highest dilutions used for testing are shown in eTable 1.

There were 202 patients with PEG/polysorbate reactions documented in the EMR prior to receiving COVID-19 vaccines, and all (100%) did not have documented reactions to the COVID-19 vaccine received: 120 (59%) received Moderna, 82 (41%) received Pfizer, 188 (93%) received two doses. No patients were documented as having received J&J. No patients were documented as having received an allergy evaluation prior to receiving the COVID-19 vaccine.

Characteristics are shown in Table 1 .

The PEG/polysorbate reactions documented in the EMR prior to patients receiving COVID-19

vaccines were documented to PEG in 19% and to polysorbate in 85%. The specific PEG-and polysorbate-containing medications/vaccines documented as allergies are shown in Table 1 .

Reactions were documented a median of 1010 days (interquartile range 458-2059) prior to receipt of the 1 st COVID-19 vaccine dose. A polysorbate-containing vaccine had been administered in 72% of patients after their PEG/polysorbate reaction was first documented and prior to receipt of the 1 st COVID-19 vaccine dose. Although details regarding reaction history was not available for over half of the documented reactions, cutaneous symptoms were the most common documented symptom ( Table 1) .

Taken together, these findings suggest that patients with documented reactions PEG/polysorbatecontaining medications/vaccines can receive mRNA COVID-19 vaccines safely.

There were 50 patients referred to allergy/immunology with a history of PEG, polysorbate, vaccine, or paclitaxel reaction. There were 44 patients referred without any prior PEG/polysorbate testing, 3 patients referred for repeat evaluation after positive PEG/polysorbate testing, and 3 patients who had a history of positive in-clinic testing/challenge to polysorbatecontaining vaccines. All were cleared to receive COVID-19 vaccines. Of these patients, 37

received COVID-19 vaccines (24 Pfizer, 10 Moderna, 3 J&J). The only side effects reported were mild delayed rash (n=2; Pfizer 1, Moderna 1), mild immediate rash around the injection site (n=1; Pfizer), and hypertension (n=2; Pfizer 2) as described further below.

Of 44 patients referred without any prior PEG/polysorbate testing, 33 received COVID-19

vaccines. Demographics and vaccines received are shown in Table 2 . There were 26 patients whose PEG/polysorbate reaction history was consistent with allergy and 18 patients who PEG/polysorbate reaction was clearly inconsistent with allergy. Of 26 patients whose Three patients were referred for repeat evaluation after positive PEG/polysorbate testing, as shown in Table 3 . Two had negative testing at our clinic and one declined repeat PEG/polysorbate testing. Only one of these patients subsequently received COVID-19 vaccine.

Three patients who had positive in-clinic testing/challenge to polysorbate-containing vaccines (one had positive challenge to Tdap vaccine, one had positive challenge to influenza vaccine, and one had positive testing and history of urticaria following influenza vaccine) were able to receive both doses of mRNA COVID-19 vaccine (Pfizer). One patient developed an acute localized rash around the injection site after both doses of Pfizer vaccine.

Taken together, these findings suggest that patients with reported reactions to medication/vaccine containing PEG/polysorbate, even those with a history strongly suggestive of allergy to polysorbate-containing vaccines, can receive COVID-19 vaccines safely.

There were 44 patients referred for evaluation of symptoms that occurred within the first 20 hours following 1 st dose of Pfizer (n=27) or Moderna (n=17) COVID-19 vaccination.

Demographics, reaction history, and testing results are shown in Table 4 . All 44 patients reported symptom onset within 12 hours. Although patients with symptom onset <20 hours after vaccine receipt were included per a prior report of anaphylaxis cases from Vaccine Safety Datalink, it is important to note that symptom onset <4 hours is considered immediate per CDC guidance and the 2 cases with symptom onset 5-12 hours after vaccination would be considered delayed. 9, 18 The 2 delayed cases occurred after Moderna (n=1) and Pfizer (n=1) vaccination. Of note, although 57% reported at least one drug allergy at time of evaluation, none had a preexisting documented PEG/polysorbate reaction. All received the 2 nd dose.

Fourteen patients underwent testing for Miralax (n=14), methylprednisolone acetate (n=14), methylprednisolone succinate (n=9), triamcinolone (n=13), and Prevnar-13 (n=12). All testing was negative except for one questionable positive to methylprednisolone succinate (IDT 1:10 dilution) and two questionable positives to Prevnar-13 (IDT 1:100 dilution). One patient had a questionable irritant reaction to Miralax (SPT 17 mg/ml) but repeat negative testing to Miralax at a higher dilution (SPT 170 mg/ml) and negative methylprednisolone acetate testing, highlighting the fallibility of PEG 3350 testing.

Following the 2 nd dose, 4 (9%, 4/44) patients reported symptoms that were visible or required treatment (Pfizer 3, Moderna 1). All occurred after negative PEG/polysorbate skin testing. All 4 patients had reported cutaneous symptoms with first dose and had received treatment with H1 antihistamines ( Table 4) . Additionally, 2 patients had reported lower respiratory and 3 tongue/throat sensation symptoms after 1 st dose, and 2 had received epinephrine ( Table 4) .

Reported symptoms following 2 nd dose were (1) coughing and rashes treated with 2 doses of IM epinephrine, (2) acute throat tickling and difficulty swallowing treated with H1 antihistamines,

(3) facial erythema and shaking for 10 minutes resolving without treatment, and (4) eyelid/facial angioedema, throat sensation, and difficulty swallowing for which 5 doses of intramuscular epinephrine was administered (2 initially and then 3 for ongoing throat tightness) and was admitted to the hospital for observation from the emergency department.

Taken together, these findings demonstrate that none of the patients who experienced symptoms following 1 st dose COVID-19 vaccine had pre-existing PEG/polysorbate reactions and that PEG/polysorbate testing did not predict those who were able to safely receive a 2 nd dose.

Our study found that patients with documented reactions to PEG/polysorbate-containing medications/vaccines can indeed receive COVID-19 vaccines safely. This study adds to the growing body of evidence that screening for PEG/polysorbate allergy prior to administering COVID-19 vaccines only serves to increase vaccine hesitancy without identifying patients at risk for COVID-19 vaccine reactions.

A recently published study found that 8 patients with PEG/polysorbate-containing injectable medications or vaccines safely tolerated vaccine at a large academic hospital employee vaccination program. Seven of these patients were cleared by an allergist for vaccination based on their history of subsequently tolerating PEG/polysorbate. 19 We add to this with our Cohort 1 data by specifically investigating 1 st dose COVID-19 vaccine safety without any allergy evaluation in patients with reactions to multiple different PEG/polysorbate-containing medications/vaccines, 57 of whom had no documentation of tolerating polysorbate-containing vaccines prior to receiving a COVID-19 vaccine.

We found that both patients with PEG/polysorbate reactions documented in the EMR (cohort 1) and reported to patients' providers (cohort 2) received COVID-19 vaccines safely. No specific pattern of atopy was observed in cohort 2. Although EMR documentation and patient reports of vaccine occurring in patients without a history of PEG or polysorbate allergy. 2, 3 Additionally, as observed in prior reports, the results of PEG/polysorbate testing did not correspond with whether patients experienced symptoms with COVID-19 vaccines. 25, 26 Indeed, all of the patients who had a recurrent reaction to the 2 nd dose, including those requiring epinephrine, had negative PEG testing.

A non-IgE-mediated mechanism may explain why most patients with symptoms following 1 st dose COVID-19 vaccine are able to tolerate the 2 nd dose, as observed in our patient cohort 3 as well as in prior reports. [27] [28] [29] There is evidence that PEGylated nanoparticles can activate the complement system depending on the form and structure of PEGylation. 30 Further investigation into the mechanism by which reactions occur to mRNA COVID-19 vaccines is needed.

Non-IgE-mediated anxiety-related adverse events have been reported to COVID-19 vaccines. 31 In cohort 2, an anxiety diagnosis was the 2 nd most commonly observed comorbidity following drug allergy, and in cohort 3, it was the 3 rd most commonly observed after drug allergy and environmental allergy. This highlights the need for avenues to provide adequate patient reassurance prior to COVID-19 vaccine administration. These avenues would ideally extend beyond the allergy/immunology clinic, as general practitioners and vaccine administration sites are often first-line in discussing vaccine safety concerns with patients.

While negative PEG/polysorbate excipient allergy testing could provide reassurance for patients with histories of PEG/polysorbate reactions, it is not routinely recommended. 15 Not only is IgEmediated hypersensitivity to PEG/polysorbate likely not responsible for most mRNA COVID-19 vaccine reactions, but PEG/polysorbate testing is fraught with false positives. A prior report found that Refresh eyedrops are irritating. 25 Skin testing with COVID-19 vaccines has been studied but may carry similar risk for false positives. 32, 33 We additionally found that Prevnar-13 intradermal testing and possibly methylprednisolone succinate testing at 4mg/ml is likely irritating. Positive testing, even if followed by repeat negative testing, understandably increases vaccine hesitancy and we observed this in patients referred to our clinic. Taken together, our findings support the recommendation that PEG/polysorbate skin testing is not routinely performed to evaluate COVID-19 vaccine safety, even in patients with histories of PEG/polysorbate reactions. Larger studies are needed to identify whether there are clinical factors that would more accurately identify patients at risk for developing symptoms COVID-19

vaccines.

There are limitations to our study. Chart review and data extracted from the EMR do not always accurately reflect true reaction history as documentation in the allergy section of the electronic medical record can be incomplete and inaccurate. 34 

First Month of COVID-19 Vaccine Safety Monitoring -United States

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine

Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine -United States

COVID-19 Vaccination in Patients with Reported Allergic Reactions: Updated Evidence and Suggested Approach

Immediate Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have Recognized

Anti-PEG IgE in anaphylaxis associated with polyethylene glycol

Anaphylaxis to PEGylated liposomal echocardiogram contrast in a patient with IgE-mediated macrogol allergy

Allergic reactions to the first COVID-19 vaccine: A potential role of polyethylene glycol? Allergy

COVID-19 Vaccines for People with Allergies

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach

Centers for Disease Control and Prevention. Johnson & Johnson's Janssen COVID-19 Vaccine Overview and Safety

Influence of a COVID-19 vaccine's effectiveness and safety profile on vaccination acceptance

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach

COVID-19 vaccines tolerated in patients with paclitaxel and docetaxel allergy

Risk of anaphylaxis after vaccination in children and adults

An academic hospital experience screening mRNA COVID-19 vaccine risk using patient allergy history

Safety of administration of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase. Pediatr Blood Cancer

Tolerability of polysorbate 80 containing COVID-19 vaccines in confirmed PEG allergic patients

mRNA COVID-19 vaccine safety in patients with previous immediate hypersensitivity to pegaspargase

The safety of SARS-CoV-2 vaccines in persons with a known history of pegaspargase allergy: A single institution experience

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

First-Dose mRNA COVID-19 Vaccine Allergic Reactions: Limited Role for Excipient Skin Testing

Polyethylene glycol and polysorbate testing in twelve patients prior to or after COVID-19 vaccine administration

Safety Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With Immediate Reactions to the First Dose

Allergic symptoms after mRNA COVID-19 vaccination and risk of incomplete vaccination

Anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines: Don't give up on the second dose! Allergy

Overcoming Nanoparticle-Mediated Complement Activation by Surface PEG Pairing

Anxiety-Related Adverse Event Clusters After Janssen COVID-19 Vaccination -Five

Coronavirus disease 2019 vaccine hypersensitivity evaluated with vaccine and excipient allergy skin testing

Evaluation of anaphylaxis risk by skin testing with coronavirus disease 2019 messenger RNA vaccines on patients with anaphylaxis

Drug Allergy Labels Lost in Translation: From Patient to Charts and Backwards

We thank Mark Marino, David Pines, and Stephanie Villanueva for their guidance and ongoing partnership in incorporating rapidly changing clinical practices for COVID-19 vaccine reaction management.