key: cord-0899935-di6qz2h3
authors: Kraft, M.; Renaudin, J.M.; Ensina, L.F.; Kleinheinz, A.; Bilò, M.B.; Scherer Hofmeier, K.; Dölle‐Bierke, S.; Worm, M.
title: Anaphylaxis to vaccination and polyethylene glycol: a perspective from the European Anaphylaxis Registry
date: 2021-06-01
journal: J Eur Acad Dermatol Venereol
DOI: 10.1111/jdv.17327
sha: cc78bd4699e939933ae6b12cb2ef3a3fd9d16898
doc_id: 899935
cord_uid: di6qz2h3

The Covid-19 pandemic is currently one of the most important health challenges, and the recently approved vaccines can save millions of lives. However, the fact that anaphylaxis might occur after vaccination has raised much concern. Currently, Centers for Disease Control and Prevention (CDC) reported the rate of 2.5 - 4.7 cases/million mRNA vaccine doses administered.

To the Editor, The COVID-19 pandemic is currently one of the most important health challenges, and the recently approved vaccines can save millions of lives. However, the fact that anaphylaxis might occur after vaccination has raised much concern. Currently, Centers for Disease Control and Prevention (CDC) reported the rate of 2.5-4.7 cases/million mRNA vaccine doses administered. 1 The allergen(s) causing these reactions remain unknown. Polyethylene glycol (PEG) has surfaced as a possible elicitor, considering that this ingredient has previously been identified as an allergen. 2, 3 The European Anaphylaxis Registry is a database of anaphylaxis cases collected from more than a hundred tertiary allergy centres from twelve European countries and Brazil. 4 Herein, the data from 13 354 cases, reported between 2007 and 2020 was screened to identify reactions caused by vaccination or PEG. Table 1 presents anaphylaxis cases caused by vaccination; 14 of such reactions were reported (14/2350; 0.6% of all reactions caused by drugs). The majority of them were observed in children (10/14). Four patients had an atopic background. Reactions to all major types of vaccines were reported. More than half of the reactions (8/13) occurred within 10 min after immunization; however, four reactions had a delayed onset (>1 h). Six reactions were classified as moderate and eight reactions as severe. 5 Table 2 presents data on reactions to PEG. Six reactions to PEG and one to polysorbate (a possibly cross-reactive allergen) were identified (7/2350; 0.3% of all drug-induced anaphylaxis cases). All patients were adults. An atopic background was reported in three cases. The basal tryptase was within normal range in all patients with available data (4/4). The time between exposure and onset of the symptoms was within half an hour (6/ 6). All reactions manifested with skin and cardiovascular symptoms, two of them were classified as severe and five as moderate. 5 The Anaphylaxis Registry is not a population-based database, and it is not suitable to estimate incidence. However, a very low number of reactions reported to vaccinations (14/13 354) or PEG (6/13 354) suggests that these reactions are very rare, confirming previously published data (incidence of anaphylaxis to vaccination in the USA was recently estimated as 1.3/ 1 000 000 6 ). The reactions to PEG in the registry might be underreported (and reported as idiopathic anaphylaxis or misdiagnosed, for example as anaphylaxis to corticosteroids, paclitaxel or local anaesthetics), as PEG is a commonly used additive, which might have been 'overlooked' in some cases.

The rate of patients with an atopic background in our study [29% (4/14) for vaccine and 43% (3/7) for PEG anaphylaxis] was very similar to the one reported by CDC (29%; 6/21) 7 and in the currently published case series of 10 Danish patients allergic to PEG (30%; 3/10). 2 This rather low rate of patients with an atopic background, might suggest that these reactions have distinct/additional pathomechanisms 8,9 than, for example common food anaphylaxis. Our study does not suggest that mastocytosis is an underlying disease in these reactions.

Vaccines are an extremely effective method to prevent illnesses and death, and they are safe from an allergist's point of view with only very rare instances of severe reactions. Nevertheless, partially due to misleading information, many patients with allergies feel anxious in terms of getting the SARS-CoV-2 vaccination. 10 This might lead to lower immunization rate and hence higher mortality and morbidity due to this now preventable disease. Therefore, identifying whether PEG is the antigen responsible and determining the mechanisms of these reactions are of great importance. Here, more data on the cases (including data on comprehensive allergological work-up) should be urgently made available to help the scientific community to identify the patients who are truly at risk and thus raise the acceptance of the vaccine.

the submitted work. KSH reports personal fees (advisory board or speaker fee) from Sanofi-Aventis, Novartis, Shire, Menarini and Allergopharma; outside the submitted work. The rest of the authors declare that they have no relevant conflicts of interest.

The Anaphylaxis Registry is supported by The Network for Online Registration of Anaphylaxis NORA e.v. MW and SDB are supported by the German Research Foundation (KFO 339). 

Reports of Anaphylaxis after receipt of mRNA COVID-19 vaccines in the US

Clinical manifestations and impact on daily life of allergy to polyethylene glycol (PEG) in ten patients

Anaphylaxis to the first COVID-19 vaccine: is polyethylene glycol (PEG) the culprit?

Risk Factors and characteristics of biphasic anaphylaxis

Clinical features and severity grading of anaphylaxis

Risk of anaphylaxis after vaccination in children and adults

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

Anti-PEG antibodies: Properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals

Immediate-type hypersensitivity to polyethylene glycols: a review

Risk of severe allergic reactions to COVID-19 vaccines among patients with allergic skin diseases -practical recommendations. A position statement of ETFAD with external experts

We thank all patients, parents and their children for their support in providing data. We thank all centres for patient counselling and data entry into the European Anaphylaxis Registry. The participating centres are listed on www.anaphylaxis.net. 

MK performed data analysis and wrote the manuscript. JMR, LFE, AK, MBB, KSH and SDB collected the data, contributed to the interpretation of data and revised the manuscript critically for important intellectual content. MW managed data acquisition, contributed to the interpretation of data and revised the manuscript critically for important intellectual content. All authors approved the final version of the manuscript for publication.