Background: The most common immediate hypersensitivity to macrogols is associated with PEG 3350, however the epidemiology, mechanisms and cross-reactivity are poorly understood. Thousands of medications contain either PEGs or structurally similar polysorbates. Objective: Our objective was to better understand the mechanism, cross-reactivity and scope of PEG hypersensitivity. Methods: Two cases with a past history of immediate hypersensitivity to PEG-containing medications were used to study potential mechanisms and cross-reactivity of immediate reactions to PEG 3350. Skin testing and oral challenges with PEG and polysorbate-containing agents were employed to determine clinical reactivity and cross-reactivity between the two allergens. Enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescent immunoassay were used to detect anti-PEG specific IgG and IgE respectively, using PEGylated protein or PEG alone as antigens in two cases and six PEG 3350 tolerant controls. We searched FDA adverse event reports for immediate reactions to PEG 3350 to determine the potential scope of this problem in the United States. Results: Skin and provocation testing demonstrated symptomatic reactivity in both cases to PEG 3350 and polysorbate 80. Plasma samples were positive for anti-PEG specific IgE and IgG antibodies only in cases and binding increased directly proportional to the molecular weight of PEG tested. FDA adverse event reports revealed 53 additional cases of possible PEG 3350 anaphylaxis. Conclusions: Immediate hypersensitivity to PEG 3350 with cross-reactive polysorbate 80 hypersensitivity may be under recognized in clinical practice and can be detected with clinical skin testing. Our studies raise the possibility of an IgE mediated Type I hypersensitivity mechanism in some cases.

Allergic reactions after messenger RNA (mRNA) COVID-19 vaccines have been reported to be as high as 2%, with anaphylaxis occurring in up to 2.5 per 10 000 individuals. 1 There is uncertainty as to whether to administer a second dose of mRNA COVID-19 vaccine after a firstdose reaction. 2,3 In this study, we examine the safety of the second dose of Pfizer-BioNTech or Moderna vaccine in those with a history of immediate and potentially allergic reactions to the first dose.Methods | This multicenter, retrospective study conducted by Massachusetts General Hospital (Boston), Brigham and Women's Hospital (Boston, Massachusetts),

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IMPORTANCEVaccination against SARS-CoV-2 is a highly effective strategy to prevent infection and severe COVID-19 outcomes. The best strategy for a second dose of vaccine among persons who had an immediate allergic reaction to their first SARS CoV-2 vaccination is unclear.OBJECTIVE To assess the risk of severe immediate allergic reactions (eg, anaphylaxis) to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose.DATA SOURCES MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021.STUDY SELECTION Included studies addressed immediate allergic reactions of any severity to a second SARS-CoV-2 vaccine dose in persons with a known or suspected immediate allergic reaction (<4 hours after vaccination) after their first SARS-CoV-2 vaccine dose. Studies describing a second vaccine dose among persons reporting delayed reactions (>4 hours after vaccination) were excluded.DATA EXTRACTION AND SYNTHESIS Paired reviewers independently selected studies, extracted data, and assessed risk of bias. Random-effects models were used for meta-analysis. The GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach evaluated certainty of the evidence. MAIN OUTCOMES AND MEASURESRisk of severe immediate allergic reaction and repeated severe immediate allergic reactions with a second vaccine dose. Reaction severity was defined by the reporting investigator, using Brighton Collaboration Criteria, Ring and Messmer criteria, World Allergy Organization criteria, or National Institute of Allergy and Infectious Diseases criteria. RESULTS Among 22 studies of SARS-CoV-2 mRNA vaccines, 1366 individuals (87.8% women; mean age, 46.1 years) had immediate allergic reactions to their first vaccination. Analysis using the pooled random-effects model found that 6 patients developed severe immediate allergic reactions after their second vaccination (absolute risk, 0.16% [95% CI, 0.01%-2.94%]), 232 developed mild symptoms (13.65% [95% CI, 7.76%-22.9%]), and, conversely, 1360 tolerated the dose (99.84% [95% CI, 97.09%-99.99%]). Among 78 persons with severe immediate allergic reactions to their first SARS-CoV-2 mRNA vaccination, 4 people (4.94% [95% CI, 0.93%-22.28%]) had a second severe immediate reaction, and 15 had nonsevere symptoms (9.54% [95% CI, 2.18%-33.34%]). There were no deaths. Graded vaccine dosing, skin testing, and premedication as risk-stratification strategies did not alter the findings. Certainty of evidence was moderate for those with any allergic reaction to the first dose and low for those with severe allergic reactions to the first dose. CONCLUSIONS AND RELEVANCEIn this systematic review and meta-analysis of case studies and case reports, the risk of immediate allergic reactions and severe immediate reactions or anaphylaxis associated with a second dose of an SARS-CoV-2 mRNA vaccine was low among persons who experienced an immediate allergic reaction to their fir...

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