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Polyethylene glycol and polysorbate skin testing in the evaluation of coronavirus disease 2019 vaccine reactions

2021; Elsevier BV; Volume: 126; Issue: 6 Linguagem: Inglês

10.1016/j.anai.2021.03.012

1534-4436

Mitchell M. Pitlick, Andrea Sitek, Susan A. Kinate, Avni Y. Joshi, Miguel A. Park,

Contact Dermatitis and Allergies

In December 2020, the US Food and Drug Administration (FDA) issued emergency use authorizations for coronavirus disease 2019 (COVID-19) vaccines from Pfizer-BioNTech and Moderna, and widespread vaccination is ongoing. Contraindications to vaccination include a history of immediate allergic reaction to a component or previous dose of an messenger RNA (mRNA) COVID-19 vaccine.1Centers for Disease Control and Prevention. Interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States—appendix B. Available at: https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html#Appendix-B. Accessed December 24, 2020.Google Scholar As of January 18, 2021, anaphylaxis to the Pfizer-BioNTech (Pfizer Inc, New York, New York, BioNTech SE, Mainz, Germany) and Moderna (Moderna, Inc, Cambridge, Massachusetts) vaccines have occurred at rates of 4.7 and 2.5 cases per million doses, respectively.2Shimabukuro T Cole M Su JR Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18-2021.JAMA. 2021; 325: 780-781Crossref PubMed Scopus (226) Google Scholar The mechanism of allergic reaction is unknown, although inactive vaccine components such as polyethylene glycol (PEG) have been proposed as possible culprit antigens. PEG is a primary ingredient in osmotic laxatives and a widely used excipient in many medications. It has not been previously used in vaccines, and the molecular weight and structure of the PEG 2000 used in the mRNA COVID-19 vaccines are distinct compared with laxative preparations.3Institute for Vaccine Safety, Johns Hopkins Bloomberg School of Public Health. Excipients in vaccines per 0.5-mL dose. Available at: https://vaccinesafety.edu/components-excipients.htm. Accessed January 26, 2021.Google Scholar Allergy to PEG has been described, particularly with higher molecular weight concentrations.4Sellaturay P Nasser S Ewan P Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).J Allergy Clin Immunol Pract. 2021; 9: 670-675Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 5Stone Jr, CA Liu Y Relling MV et al.Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized.J Allergy Clin Immunol Pract. 2019; 7 (1533-1540.e8)Abstract Full Text Full Text PDF Scopus (259) Google Scholar, 6Wenande E Garvey LH Immediate-type hypersensitivity to polyethylene glycols: a review.Clin Exp Allergy. 2016; 46: 907-922Crossref PubMed Scopus (268) Google Scholar A review of FDA adverse event reports from 2005 to 2017 revealed an average of 4 cases of anaphylaxis to PEG per year.5Stone Jr, CA Liu Y Relling MV et al.Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized.J Allergy Clin Immunol Pract. 2019; 7 (1533-1540.e8)Abstract Full Text Full Text PDF Scopus (259) Google Scholar Skin testing has been successfully used to confirm suspected allergy to PEG-containing laxatives and medications, and guidelines for skin testing with nonirritating concentrations of PEG 3350 and polysorbate are available.5Stone Jr, CA Liu Y Relling MV et al.Immediate hypersensitivity to polyethylene glycols and polysorbates: more common than we have recognized.J Allergy Clin Immunol Pract. 2019; 7 (1533-1540.e8)Abstract Full Text Full Text PDF Scopus (259) Google Scholar,7Broyles AD Banerji A Barmettler S et al.Practical guidance for the evaluation and management of drug hypersensitivity: specific drugs.J Allergy Clin Immunol Pract. 2020; 8: S16-S116Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar Recent expert opinion has also provided an algorithm that includes skin testing as part of COVID-19 vaccine reaction evaluation, but the predictive values of PEG and polysorbate skin testing in relation to the risk of hypersensitivity reaction to COVID-19 vaccines are still unknown.8Banerji A, Wichner PG, Saf R, et al. mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach [e-pub ahead of print]. J Allergy Clin Immunol Pract. doi:10.1016/j.jaip.2020.12.047, Accessed February 1, 2021.Google Scholar We report the first 15 cases of PEG and polysorbate skin testing completed in patients who had allergic symptoms after their first dose of the mRNA COVID-19 vaccines or reported a PEG or polysorbate allergy before their first vaccine dose. Skin testing was performed in patients referred to the allergy divisions of the Mayo Clinics based in Rochester, Minnesota, and Scottsdale, Arizona. The clinical need for skin testing and test selection was provider-determined at the time of evaluation. PEG 3350 (MiraLAX) testing was performed using sequential skin pricks at 1.7 mg/mL, 17 mg/mL, and 170 mg/mL. Methylprednisolone acetate (PEG-containing), methylprednisolone sodium (control), and triamcinolone acetonide (polysorbate 80–containing) testing were performed starting with a skin prick at 40 mg/mL, with subsequent 1:100 and 1:10 intradermal with an additional 1:1 intradermal administration for triamcinolone. Polysorbate 20 testing was performed and given as a 1:1 skin prick followed by 1:100 and 1:10 intradermally with a 0.5 mg/mL concentration with a sterile water diluent. This study was an institutional review board–approved retrospective chart review. Between January 15, 2021, and February 1, 2021, 15 patients underwent skin testing; 8 had testing because of a reaction to the first dose of COVID-19 vaccine, and 7 had tested before vaccination because of reported PEG or polysorbate allergies (the characteristics and skin testing results of which are presented in Table 1). All 8 patients with first vaccine dose reactions had negative PEG 3350 testing, whereas 4 patients had methylprednisolone acetate testing, 3 had triamcinolone acetonide testing, and 2 had polysorbate 20 testing—all of which were negative. One patient had a positive polysorbate 20 reaction (given at 1:10 dilution intradermally), but a sterile water given intradermally resulted in an identical wheal and flare in the patient and one of the authors; thus, this test was interpreted as false-positive owing to irritation. A total of 7 patients successfully received their second COVID-19 vaccine dose without premedication or split-dosing, with the final patient delaying the second dose until vaccine skin testing or split-dosing capabilities are available. In the 7 patients with previous PEG or polysorbate allergy, 1 patient had positive testing to PEG 3350 and methylprednisolone acetate with negative testing to methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20. The 6 other patients all tested negative for PEG. The 3 patients with expanded skin testing also tested negative for polysorbate 20, methylprednisolone acetate, and triamcinolone acetonide. All 6 patients who tested negative received the first dose of the vaccine without any reaction. The patient who tested positive is not yet eligible to receive the vaccine.Table 1Characteristics and Skin Test Results of Patients With Reaction to First COVID-19 Vaccine Dose and Previous PEG/Polysorbate AllergyaPatients 1 to 8: reaction to first COVID vaccine dose; patients 9 to 15: no previous vaccine dose, reported previous PEG or polysorbate allergy.PatientAge/sexPrevious allergic diseaseCulprit agentsSymptomsAnaphylaxisbDetermined by using the Brighton criteria.9Time to onsetTreatmentEDTime to resolutionSkin test performedTime from reaction to the skin testSkin test resultTime between vaccine dosesVaccine outcomecRefers to second vaccine dose in patients 1 to 8 or first vaccine dose in patients 9 to 15. All doses were given with a 30-minute observation period.124FNonePfizer-BioNTech vaccineUrticariaNo3 hAntihistaminesNo4 dPEG12 dNegative23 dNo reaction254FDrug allergyPfizer-BioNTech vaccineTachycardia, rhinorrheaNo10 minNoneNo10 minPEG, MP acetate7 dNegative18 dNo reaction336FNonePfizer-BioNTech vaccineFacial flushingNo5 minAntihistaminesNo1 hPEG, MP acetate, TC acetonide20 dNegative21 dNo reaction452MVenom anaphylaxisPfizer-BioNTech vaccineOral pruritus, throat fullnessNoImmediateNoneNo5 minPEG10 dNegative21 dNo reaction545FFood allergyPfizer-BioNTech vaccineUrticaria, throat tightnessNo8 hNoneNoUnknownPEG20 dNegative29 dNo reaction633FAsthma, venom anaphylaxisPfizer-BioNTech vaccineUrticaria, tachycardiaNo15 minAntihistaminesNo12-24 hPEG20 dNegative23 dNo reaction720MVaccine allergy (flu)Moderna vaccineAngioedemaNo3 hSteroids, antihistaminesYes24 hExpandeddExpanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.20 dNegativeN/ANot given822FAllergic rhinitisModerna vaccineAngioedema, wheezing, throat pruritusLevel 120 minAntihistamines, steroidsYes6 hExpandeddExpanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.21 dNegative51 dMinor lip/tongue tingling969MDrug allergyMoviprep (PEG)Rash, flushingNoDuring prepAntihistaminesNo1 hPEG2 yNegativeN/ANo reaction (Pfizer)1073FAsthma, drug allergyMoviprep (PEG)Headache, nauseaNoUnknownUnknownNoUnknownPEG5 yNegativeN/ANo reaction (Moderna)1146FVaccine allergy (flu)Methylprednisolone acetate (PEG)Urticaria, dizzy, flushingNo15 minEpinephrine, steroids, antihistaminesNo12 hExpandeddExpanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.3 moPositive (PEG and MP acetate)ePEG 1:1 skin prick: 5 × 5 wheal, 10 × 10 flare; methylprednisolone acetate 0.1 mg/mL intradermal: 6 × 6 wheal, 8 × 8 flare (all measurements in mm).N/ANot given1274MDrug allergyTriamcinolone acetonide (polysorbate 80)Urticaria, wheezingLevel 11 hSteroids, antihistaminesYesUnknownPEG, MP acetate, TC acetonide3 yNegativeN/ANo reaction (Pfizer)1355FAnaphylaxisInfluenza vaccinesfH1N1 vaccines FluBlok and Fluxrix. (polysorbate 20/80)Flushing, wheezing, cough, throat tightnessLevel 120 minEpinephrine, steroids, antihistaminesYesUnknownPEG, Polysorbate 207 yNegativeN/ANo reaction (Pfizer)1467FFood allergy, anaphylaxisMiraLAX (PEG)Oral urticariaNo2 hUnknownNoUnknownExpandeddExpanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.UnknownNegativeN/ANo reaction (Moderna)1560MVaccine allergy (Shingrix)Shingrix (polysorbate 80)Flushing, urticariaNo2 hAntihistamines, steroidsYes2 dExpandeddExpanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.3 moNegativeN/ANo reaction (Moderna)Abbreviations: COVID-19, coronavirus disease 2019; ED, emergency department; F, female; M, male; MP, methylprednisolone; PEG, polyethylene glycol; TC, triamcinolone.a Patients 1 to 8: reaction to first COVID vaccine dose; patients 9 to 15: no previous vaccine dose, reported previous PEG or polysorbate allergy.b Determined by using the Brighton criteria.9Gold MS Gidudu J Ewrlewyn-Lajeunesse M Law B Brighton Collaboration Working Group on AnaphylaxisCan the Brighton Collaboration case definitions be used to improve the quality of Adverse Event Following Immunization (AEFI) reporting? Anaphylaxis as a case study.Vaccine. 2010; 28: 4487-4498Crossref PubMed Scopus (36) Google Scholarc Refers to second vaccine dose in patients 1 to 8 or first vaccine dose in patients 9 to 15. All doses were given with a 30-minute observation period.d Expanded skin testing included PEG, methylprednisolone acetate, methylprednisolone sodium, triamcinolone acetonide, and polysorbate 20.e PEG 1:1 skin prick: 5 × 5 wheal, 10 × 10 flare; methylprednisolone acetate 0.1 mg/mL intradermal: 6 × 6 wheal, 8 × 8 flare (all measurements in mm).f H1N1 vaccines FluBlok and Fluxrix. Open table in a new tab Abbreviations: COVID-19, coronavirus disease 2019; ED, emergency department; F, female; M, male; MP, methylprednisolone; PEG, polyethylene glycol; TC, triamcinolone. This is one of the earliest reports on the use of skin testing to evaluate both possible COVID-19 vaccine reactions and previous PEG or polysorbate allergies before vaccination. In our cohort, only 1 patient had positive testing. No patients with reactions to their first vaccine dose had positive testing. It may be hypothesized in these cases that PEG is not the culprit antigen or that non–immunoglobulin E-mediated mechanisms such as complement activation–related pseudoallergy are involved. In addition, the short interval between reaction and skin testing may increase the risk of false negatives. A preliminary success has been seen with the safe administration of the second vaccine dose after negative skin testing after a possible first dose reaction. One area of uncertainty is the ability of skin testing to predict COVID-19 vaccine reactions in patients who report previous PEG or polysorbate allergies. Systemic reactions to PEG are dependent on a combination of the molecular weight and absolute amount of PEG in the culprit medication, which can differ substantially between injectable and oral forms of PEG.4Sellaturay P Nasser S Ewan P Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).J Allergy Clin Immunol Pract. 2021; 9: 670-675Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar Furthermore, the threshold needed to induce a systemic reaction likely differs among individuals.4Sellaturay P Nasser S Ewan P Polyethylene glycol-induced systemic allergic reactions (anaphylaxis).J Allergy Clin Immunol Pract. 2021; 9: 670-675Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar These facts make interpretation of skin tests difficult in patients who have yet to receive a COVID-19 vaccine. An additional area of interest has been the recognition of the innumerable medications and vaccines that contain PEG or polysorbate.8Banerji A, Wichner PG, Saf R, et al. mRNA vaccines to prevent COVID-19 disease and reported allergic reactions: current evidence and suggested approach [e-pub ahead of print]. J Allergy Clin Immunol Pract. doi:10.1016/j.jaip.2020.12.047, Accessed February 1, 2021.Google Scholar One of our patients with a COVID-19 vaccine reaction also reported a possible reaction to a polysorbate 80–containing influenza vaccine. The magnitude of risk these previous reactions confer on individuals yet to receive a COVID-19 vaccine and the ability of skin testing to quantify that risk remains unclear. Although our cohort size precludes any inferences regarding the predictive value of this skin testing, it is clear that allergists will play an essential role in the COVID-19 vaccination effort. As vaccination numbers increase, the absolute number of adverse reactions will also increase, which will provide opportunities to both refine the testing strategy (with no or limited testing potentially being the best strategy) and address vaccination hesitation, with the ultimate goal being accurate risk stratification and safe vaccine administration to the population as a whole. The authors thank Dr Matthew A. Rank, Dr Gerald W. Volcheck, Dr Alexei Gonzalez-Estrada, and Dr James T. Li for their contributions to this manuscript, including intellectual conception and critical review.