Acta Clinica Belgica International Journal of Clinical and Laboratory Medicine

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Allergic reactions to COVID-19 vaccines: statement of the Belgian Society for Allergy and Clinical Immunology (BelSACI)

Sebastiaan Tuyls, Xavier Van Der Brempt, Margaretha Faber, Romy Gadisseur, Bita Dezfoulian, Rik Schrijvers & Antoine Froidureon behalf of the BelSACI

To cite this article: Sebastiaan Tuyls, Xavier Van Der Brempt, Margaretha Faber, Romy Gadisseur, Bita Dezfoulian, Rik Schrijvers & Antoine Froidureon behalf of the BelSACI (2021): Allergic reactions to COVID-19 vaccines: statement of the Belgian Society for Allergy and Clinical Immunology (BelSACI), Acta Clinica Belgica, DOI: 10.1080/17843286.2021.1909447 To link to this article: https://doi.org/10.1080/17843286.2021.1909447

Published online: 01 Apr 2021.

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Allergic reactions to COVID-19 vaccines: statement of the Belgian Society for Allergy and Clinical Immunology (BelSACI) Sebastiaan Tuylsa*, Xavier Van Der Bremptb*, Margaretha Faber c, Romy Gadisseurd, Bita Dezfouliane, Rik Schrijversf and Antoine Froidure g,h on behalf of the BelSACI aPulmonology Department, Sint Augustinus Ziekenhuis GZA, Antwerpen and UZ Leuven, Leuven, Belgium; bPulmonology Department and Allergopôle, Clinique Saint-Luc, Bouge, Belgium; cAllergology and Immunology Department, World Allergy Organization (WAO) Center of Excellence, Universitaire Ziekenhuizen Antwerpen and Universiteit Antwerpen, Antwerpen, Belgium; dClinical Biology Department, CHU Liège and Université de Liège, Liège, Belgium; eDermatology Department, CHU Liège and Université de Liège, Liège, Belgium; fKU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium; gPulmonology Department, WAO Center of Excellence, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium; hInstitut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Bruxelles, Belgium

ABSTRACT KEYWORDS Vaccination against COVID-19 constitutes a huge hope and a major challenge. For the first time COVID-19; vaccine; allergy; in modern history, a global vaccination campaign has started worldwide in a short period of anaphylaxis; adverse events time and with products that were recently developed. Consequently, legitimate concerns regarding the safety and tolerability of COVID-19 vaccines arise. In line with international allergy societies, the Belgian Society for Allergy and Clinical Immunology (BelSACI) provides this statement to guide health care providers (general practi­ tioners, specialists including allergists) and stakeholders. In this statement, we first review current evidence on allergic reactions to vaccines and the potential risk factors that have been identified. Second, we provide a risk stratification method that may be used as a worksheet during the vaccination campaign. Finally, we discuss the management of suspected or confirmed allergic reactions following vaccination.

Introduction coding mRNA for the Spike (S) protein of the corona­ The SARS-Cov-2-related disease 2019 (COVID-19) pan­ virus is injected, resulting in the production of demic currently affects most countries since S protein by the patient’s cells and subsequent immu­ March 2020 and results in an unprecedented burden nization. Of note, this technology has already been on health care systems [1] and death excess [2,3]. used in animal vaccines, but this is the first time in Overall mortality is substantially higher than that human vaccines. Two other vaccines are now available from other respiratory viruses like Influenza [4]. In (https://www.cbip.be), developed by AstraZeneca Belgium, the first and second waves peaked in April (AZT1222 vaccine) [9] and the Gamaleya Institute for and November 2020, respectively, with, for both Epidemiology and Microbiology (Gam-COVID-Vac, aka waves, close to 6,000 hospitalized patients including Sputnik V vaccine). These two are based on the recom­ almost 1,500 patients in intensive care units (ICU), binant adenovirus (rAd) technology, which consists in often requiring mechanical ventilation (www.scien the injection of coding DNA (cDNA) for the coronavirus sano.be). Beside the human losses, this pandemic has S protein, a non-replicative chimpanzee-originating already resulted in a very high cost from a socio- adenovirus being used as the vector [10]. This relatively economic perspective [5]. recent technique also results in the generation of spe­ To date, there is no effective treatment to cure cific antibodies toward the S protein. All four vaccines COVID-19, and current therapeutic measures only aim have been evaluated in phase III randomized trials, at dampening disease severity and mortality, with with efficacy rates ranging from 70% to more than sometimes conflicting results from different clinical 95% and a favourable safety profile, paving the way trials [6]. Fortunately, vaccines have been developed for their use in large populations across the globe. and are currently available: the first two vaccines hav­ Thus, the development of vaccines against COVID- ing shown efficiency are mRNA-based vaccines, devel­ 19 represents both a huge hope and a major challenge: oped by Pfizer-BioNTech and Moderna [7,8]. In brief, this is the first time in history that a worldwide

CONTACT Antoine Froidure [email protected] Pulmonology Department, Cliniques Universitaires Saint-Luc and WAO Center of Excellence, Université Catholique de Louvain, Avenue Hippocrate 10, Bruxelles 1200, Belgium *These authors contributed equally to this work. © Belgian Society of Internal Medicine and Royal Belgian Society of Laboratory Medicine (2021) 2 S. TUYLS ET AL. vaccination campaign is undertaken in such a short administered, and only eight fatal events between period and in pandemic circumstances. This, along 1990 and 2016 [17]. with the relatively short period of time from develop­ In the two main studies that evaluated the effect of ment to availability of vaccines against COVID-19, has RNA vaccines against COVID-19 [7,8], the same number raised concerns regarding possible adverse events, of possible allergic reactions was observed in the trea­ especially allergic reactions [11]. Although precautions ted groups and the placebo groups: the events related are needed, unjustified mistrust toward vaccines [12] to hypersensitivity concerned 0.63% and 1.5% of the could slowdown the vaccination campaign, which patients who received Pfizer-BioNTech and Moderna would preclude to reach a sufficient vaccination cover­ vaccines, respectively, compared to 0.51% and 1.1% of age, and result in many unjustified resources to advice the patients in placebo groups in the same studies. from health care providers. Therefore, in line with the Additionally, the Food and Drug Administration (FDA) European Academy of Allergy and Clinical Immunology identified a weak signal suggesting more cases of (EAACI) and the Center for Disease Control (CDC), the hypersensitivity reactions in the vaccine group, but Belgian Society for Allergy and Clinical Immunology none of these reactions were severe or required the (BelSACI) wishes to provide the necessary indications administration of adrenaline. Note that patients with to caregivers and patients regarding the risk of allergic documented allergies to one of the vaccine compo­ reaction in case of administration of the vaccine nents were excluded from the studies. In addition, against COVID-19. patients with severe reactions associated with any vac­ cine were excluded from the Pfizer-BioNTech vaccine, those with a history of urticaria or anaphylaxis from the Current evidence on vaccine-related Moderna vaccine and those with a history of anaphy­ hypersensitivity laxis or angioedema from the AstraZeneca vaccine. The Vaccine-associated hypersensitivity reactions are rate of adverse allergic reactions was very low in both uncommon. Most adverse reactions to vaccines are phase III studies evaluating the efficacy of rAd vaccines, mild, including local swelling, pain, and localized with only one reported case of anaphylaxis for 12,021 rash. Those reactions are usually not reproducible patients having received the AZT1222 vaccine [9] and when the subject is re-exposed to the vaccine [13]. zero cases of anaphylaxis in the study on Sputnik III. Of note, local nodules are described in up to 20% of As the vaccination program for COVID-10 is under­ the patients receiving vaccines with an aluminium- way globally, real-life immunization data suggest that based adjuvant. Immunoglobulin (Ig)G-mediated anaphylaxis to these vaccines is rare. Recently, the delayed hypersensitivity (Arthus reaction) is rare Center for Disease Control (CDC) (https://www.cdc. and provokes a large and severe local reaction, gov) published two more detailed reports (Morbidity occurring within 72 hours, in sensitized individuals and Mortality Weekly Report, MMWR) on the docu­ [14]. Immediate hypersensitivity reactions are rare mented anaphylaxis cases at that time. For the Pfizer- to very rare but are important to identify, given BioNTech vaccine (MMWR 15 January 2021; 70:46–51 the large number of people vaccinated every year. https://www.cdc.gov/mmwr/volumes/70/wr/ IgE-mediated allergy may lead to a variety of symp­ mm7002e1.htm) from December 11 to 23, almost toms, usually occurring within 30 minutes following 2 million doses were administered in the United the injection (and rarely after 4 hours). Symptoms States, with 175 cases of possible allergic reaction range from urticaria (wheals accompanied with itch­ reported. However, only 21 anaphylaxis cases have ing and burning) to angioedema (swelling of deeper been documented according to the Brighton subcutaneous tissues of the face and throat) and Collaboration case definition criteria. Of these 21 anaphylaxis, the latter two being potentially fatal cases, 17 occurred in people with a prior documented [15]. Proper recognition of immediate hypersensitiv­ history of allergic reactions, of which 7 had previously ity reactions allows adequate management [16] (see experienced anaphylactic reactions in other circum­ the “Management of suspected anaphylactic reac­ stances. The median time between injection and reac­ tion” section) and may lead to the identification of tion was 13 minutes and the majority (86%) of the culprit allergen, along with extra precautions for reactions occurred within 30 minutes. The 20 patients subsequent injections and/or the implication of for whom information is available have all fully recov­ desensitization protocols. Delayed reactions, occur­ ered. Regarding the reactions considered as non- ring in hours or days following the injection, are anaphylactic, 86 were probable allergic non- mostly rashes and are not always immune- anaphylactic reactions and 61 were non-allergic side mediated. effects (extensive local reaction, malaise, etc.). For the Although all vaccines have the potential to trigger Moderna vaccine, a similar report (https://www.cdc. anaphylactic reactions, anaphylaxis to vaccine is extre­ gov/mmwr/volumes/70/wr/mm7004e1.htm) was mely rare: recent data suggest a prevalence of severe published with only 10 anaphylaxis cases from allergic reactions of 1.3 per 1 million doses December 21 until January 10. Nine of these patients ACTA CLINICA BELGICA 3 had a history of allergy including to drugs (n = 6), patients with a previous history of hypersensitivity contrast media (n = 2), and foods (n = 1). The median (food, drug-related, or respiratory) and 80% of cases time between injection and reaction was 7.5 minutes occurred within 4 hours following the injection. and no fatalities occurred. The latest update of the Most of documented cases of vaccine-related ana­ Vaccine Adverse Event Reporting System (VAERS, phylaxis are IgE-mediated and linked to an allergen accessible via https://wonder.cdc.gov/VAERS.html) in contained in the vaccine. In such case, the binding of the United States on 18 January 2021 reported 50 the allergen to a specific IgE triggers mast cell and anaphylaxis cases out of 9.943.247 Pfizer-BioNTech basophil degranulation, resulting in a systemic reaction. vaccine doses administered (5.0 per 1 million doses) However, recent experimental data suggest that some and 21 anaphylaxis cases out of 7.581.429 Moderna drug-anaphylactic reactions may be non-allergic and vaccine doses administered (2.8 per 1 million) [18]. It involve, among other mediators, the activation of the should be noted that at this stage we do not have complement cascade [22,23]. Altogether, anaphylaxis such complete data for the rAd vaccines. induced by vaccination is a rare event that may occur in the absence of a previous history of hypersensitivity. Risk factors for vaccine-related anaphylaxis According to the Brighton Working Group [19], ana­ Risk stratification for COVID-19 vaccination phylaxis is defined as a clinical syndrome of sudden (Table 1) onset and rapid progression of symptoms involving at Standard of care least two organs, usually dermatological, mucosal, and cardio-respiratory system. Most common symptoms To the extent that the vaccination campaign against include generalized urticaria, laryngospasm, angioe­ COVID-19 constitutes an unprecedented administration dema, hypotension, and respiratory distress. Gastro- of recently developed drugs to millions of people, stan­ intestinal tract may be involved, resulting in nausea, dard procedure should include the administration of the vomiting, and diarrhoea. The most common causes of vaccine by experimented professionals (nurses, doctors), anaphylaxis are food allergens, venom, and drugs [20]. with medical supervision and availability of drugs and In a report published in 2017 on hospital admission for material to face eventual adverse reactions. As in other anaphylaxis in the United States by Motosue et al. [20], scientific societies [24,25], we recommend a routine 15- anaphylactic reactions resulted in hospitalization in minute on-site surveillance following the injection. 11.5% of cases, admission in ICU in 5.3%, mechanical We would like to stress that mild allergic and ventilation in 1.5%, and 0.45% of cases were described immune diseases, including controlled asthma, chronic as ‘near-fatal.’ The main identified risk factor for severe anaphylaxis (requiring hospitalization) was age ≥65 (odd ratio (OR) 3.15). Cardiac and lung diseases were asso­ Table 1. Risk stratification and recommendations for COVID-19 vaccines. ciated with a mild increase in risk (OR 1.56 and 1.23, Ensure that appropriate medical treatment and supervision are readily respectively). Although sometimes listed as a risk factor available to manage anaphylaxis (e.g. adrenalin, intubation material, for anaphylaxis, asthma was not associated with a higher fluids, oxygen) risk in this study. This latter finding was in line with Standard precautions High precautions Contraindication a previous study on almost 12,000 patients admitted in Proceed with Proceed with Do not administer the vaccination vaccination vaccine emergency departments for anaphylaxis [21]: 22% had 15-minute 30-minute Allergy workup severe anaphylaxis requiring hospitalization. Here also, surveillance surveillance recommended in case of an uncertain the main risk factor was older age, while previous con­ diagnosis$ sultation with an allergist was associated with ● General population ● History of ● Documented ● All allergic or anaphylaxis hypersensitivity to a significantly lower risk of severe reaction and better immune diseases ● Severe uncon­ PEG or polysorbate outcome. not included in the trolled asthma ● Documented ● Vaccine-triggered anaphylaxis may exceptionally ‘high precaution’ or Immediate hypersensitivity to ‘contraindication’ hypersensitivity any excipient of the result in death (eight cases identified in the VAERS groups to vaccines# COVID-19 vaccine between 1990 and 2016 [17]). Hypersensitivity reac­ ● Clonal mast cell Rem: consider disorders* desensitization pro­ tions to vaccines are usually caused by an inactive ● Idiopathic ana­ tocols in selected ingredient or excipient [13,15]. To date, culprit phylaxis (no patients clear cause) * allergens contained in vaccines include compounds # provide allergy used as adjuvants or additives, namely gelatine, egg workup *preferably in proteins (ovalbumin), milk protein, and adjuvants. The hospital setting viral (or bacterial) protein is rarely the culprit for ana­ $ Increased awareness or referral for an allergy workup can be advised for phylactic reactions. Of the 823 available records of patients with unevaluated anaphylaxis after parenteral administration of drugs containing PEG (for instance, Depo- severe anaphylactic reaction reported in the VAERS Medrol® and Diprophos®) or oral exposure to large amounts of PEG between 1190 and 2016, only 487 (59%) concerned (for instance, prior to colonoscopy). 4 S. TUYLS ET AL. spontaneous urticaria, and allergic rhinitis, are not at desensitization protocols could be considered in specia­ higher risk for vaccine-induced anaphylaxis. The same lized allergy clinics, although this would be unprece­ applies to patients with a history of immediate allergic dented. In this rare subgroup, prior assessment of reactions (excluding anaphylaxis) to drug, food, latex, COVID-19 serology could identify those with pre- or venom. existing immunity. However, to date, vaccination is also recommended in patients who have recovered from COVID-19. Patients requiring high precautions Anaphylactic reactions triggered by vaccination are extremely rare. However, available data today suggest Management of suspected anaphylactic that patients with a previous history of anaphylaxis to reaction any allergen are more at risk. In the same line, people Anaphylaxis is a systemic reaction usually occurring suffering from idiopathic anaphylaxis, clonal mast cell a few minutes after the administration of the drug: disorders, and uncontrolled asthma should be kept most reported reactions occurred within 30 minutes. under special surveillance. For asthmatics, reaching Local reactions (swelling, redness) and symptoms of proper control of the disease could be an objective slight fatigue, stiffness, or fever are possible after prior to administration. Of note, a recent report any vaccination and should under no circumstances demonstrated a good tolerability of the vaccine in be considered allergic reactions. two patients with a clonal mast cell disorder [26], As stated earlier, a person presenting a severe reac­ receiving vaccination after premedication with H1 tion (generalized hives, malaise, abdominal pain, and H2 antihistamines and montelukast in a hospital respiratory distress, cardio-respiratory arrest) during setting. Finally, patients having presented or just after the injection of the firstdose of the vaccine a documented hypersensitivity reaction to a vaccine should be evaluated by a specialist before possible should also be monitored closely. For all these administration of the second dose. Testing for serum patients, we recommend vaccination to be provided tryptase 1–4 hours after the reaction should help to in a hospital setting, with a 30-minute surveillance. determine if this is indeed anaphylaxis [16]. One must also pay attention to other allergens present during Patients requiring extreme precautions the procedure (disinfectants such as chlorhexidine and latex gloves). The vaccines from Pfizer-BioNTech and Moderna do not Adequate treatment of anaphylaxis consists in contain any food or drug or latex allergen, or any immediate administration of epinephrine (0.3–0.5 mg component that may interact with hymenoptera intramuscular (IM) for an adult, half the dose in chil­ venoms, but both contain polyethylene glycol (PEG), dren (for instance, Jext® or Epipen® 300 µg IM in adults a potential allergen [27]. To date, PEG is suspected to and 150 µg in children)). Adrenalin injection should be be the culprit in some anaphylactic reactions occurring repeated every 5–10 minutes if necessary. Very severe after vaccination with mRNA vaccines, although this reactions require life support measures including fluids remains to be proven. The AstraZeneca vaccine does and oxygen administration. Antihistamines and corti­ not contain PEG but does contain polysorbate 80, costeroids are second-line therapy without any effect which may cross-react with PEG. Allergies to PEG or on the acute phase of the reaction. Administration of polysorbate-80 are extremely rare [28] but currently glucagon may be considered in case of severe refrac­ constitute a formal contra-indication for the adminis­ tory hypotension [29]. tration of the Pfizer-BioNTech, Moderna, and AstraZeneca vaccines. Similarly, patients who have suf­ All materials and medicines, including adrenalin, fered from an allergic reaction after administration of should be readily available in every vaccination the first dose of a COVID-19 vaccine should not be centre, and healthcare providers in charge of vac­ administered the second dose without a complete cination should be trained on the management of allergic workup. Given the restricted window of admin­ potentially severe hypersensitivity reactions. In istering the booster within 3–4 weeks, ruling-out aller­ such settings, the fatality rate is close to zero, as gies and a possible new reaction might be very demonstrated by recent real-life data from the difficult, with a formal contra-indication for a second CDC: all patients who presented an anaphylactic dose ensuing this uncertainty. If necessary, the com­ reaction to the COVID vaccine recovered and plete list of excipients contained in the vaccines is were discharged. available on manufacturers’ notices. Patients who recover after a single dose of adrenalin We would like to point out that in case a vaccination is may be discharged after 4–8 hours. For more severe required in a priority patient with suspected or docu­ reactions, in-hospital surveillance is warranted for at mented PEG or polysorbate allergy (i.e. a health care least 24 hours. In all cases of anaphylaxis, a complete provider in close contact with COVID-19 patients), workup in a specialized allergy clinic is advised. ACTA CLINICA BELGICA 5

Conclusion [6] Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and treat­ Vaccination against COVID-19 constitutes both a major ment of coronavirus disease 2019 (COVID-19): a hope and a huge challenge. The rapid development of review. JAMA. 2020;324(8):782–793. PubMed PMID: vaccines and the lack of knowledge of existing data 32648899. may lead to an over perception of the risk and fear [7] Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. from patients, which might infer with the proper con­ N Engl J Med. 2020;383(27):2603–2615. PubMed duct of the vaccination campaign. All available data PMID: 33301246; PubMed Central PMCID: demonstrate that anaphylaxis to vaccines is rare. For PMCPMC7745181. COVID-19 mRNA vaccines, the highest rate is 11 cases/ [8] Baden LR, El Sahly HM, Essink B, et al. Efficacy and million doses with the Pfizer-BioNTech vaccine, con­ Safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl sidering that the extreme mediatization and excitation J Med. 2020. PubMed PMID: 33378609; PubMed Central PMCID: PMCPMC7787219. DOI:10.1056/ surrounding the arrival of this vaccine may have led to NEJMoa2035389. an initial overreporting of adverse reactions. [9] Voysey M, Clemens SAC, Madhi SA, et al. Safety and In the present article, we provide guidance to health efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) care providers, including allergists, and stakeholders to against SARS-CoV-2: an interim analysis of four rando­ guarantee that a maximum of patients will benefit mised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021;397(10269):99–111. PubMed PMID: from the vaccine in the safest possible conditions. 33306989; PubMed Central PMCID: PMCPMC7723445. Finally, we wish to stress that the benefitof an effective [10] Logunov DY, Dolzhikova IV, Shcheblyakov DV, et al. vaccine against COVID-19 far outweighs the risk of Safety and efficacy of an rAd26 and rAd5 vector-based a severe allergic reaction. The risk of anaphylaxis exists heterologous prime-boost COVID-19 vaccine: an with all medicines, including vaccines, but is low interim analysis of a randomised controlled phase 3 enough in view of the expected benefits. trial in Russia. Lancet. 2021;397:671–681. PubMed PMID: 33545094; PubMed Central PMCID: PMCPMC7852454. [11] Krause PR, Gruber MF. Emergency use authorization of Disclosure statement COVID vaccines - safety and efficacy follow-up considerations. N Engl J Med. 2020;383(19):e107. The authors declare that they have no conflict of interest to PubMed PMID: 33064383. disclose in relation to this article. [12] Karafillakis E, Larson HJ, consortium A. The benefit of the doubt or doubts over benefits? A systematic litera­ ture review of perceived risks of vaccines in European ORCID populations. Vaccine. 2017;35(37):4840–4850. PubMed PMID: 28760616. Margaretha Faber http://orcid.org/0000-0002-1277-5052 [13] Caubet JC, Ponvert C. Vaccine allergy. Immunol Allergy Antoine Froidure http://orcid.org/0000-0001-7133-1788 Clin North Am. 2014;34(3):597–613, ix. PubMed PMID: 25017679. [14] Peng B, Wei M, Zhu FC, et al. The vaccines-associated References Arthus reaction. Hum Vaccin Immunother. 2019;15 (11):2769–2777. PubMed PMID: 30945978; PubMed [1] Tyrrell CSB, Mytton OT, Gentry SV, et al. Managing Central PMCID: PMCPMC6930064. intensive care admissions when there are not enough [15] McNeil MM, DeStefano F. Vaccine-associated beds during the COVID-19 pandemic: a systematic hypersensitivity. J Allergy Clin Immunol. 2018;141 review. Thorax. 2020;76:302–312. PubMed PMID: (2):463–472. PubMed PMID: 29413255; PubMed 33334908. Central PMCID: PMCPMC6602527. [2] Kontis V, Bennett JE, Rashid T, et al. Magnitude, demo­ [16] Castells M. Diagnosis and management of anaphylaxis graphics and dynamics of the effectof the firstwave of in precision medicine. J Allergy Clin Immunol. the COVID-19 pandemic on all-cause mortality in 21 2017;140(2):321–333. PubMed PMID: 28780940. industrialized countries. Nat Med. 2020;26 [17] Su JR, Moro PL, Ng CS, et al. Anaphylaxis after vaccina­ (12):1919–1928. PubMed PMID: 33057181. tion reported to the vaccine adverse event reporting [3] Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. system, 1990-2016. J Allergy Clin Immunol. 2019;143 N Engl J Med. 2020;383(25):2451–2460. PubMed (4):1465–1473. PubMed PMID: 30654049; PubMed PMID: 32412710. Central PMCID: PMCPMC6580415. [4] Piroth L, Cottenet J, Mariet AS, et al. Comparison of the [18] Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis characteristics, morbidity, and mortality of COVID-19 after receipt of mRNA COVID-19 vaccines in the and seasonal influenza: a nationwide, US-December 14, 2020-January 18, 2021. JAMA. population-based retrospective cohort study. Lancet 2021;325:1101. PubMed PMID: 33576785. Respir Med. 2020;9:251–259. PubMed PMID: 33341155. [19] Ruggeberg JU, Gold MS, Bayas JM, et al. Anaphylaxis: [5] Nurchis MC, Pascucci D, Sapienza M, et al. Impact of case definition and guidelines for data collection, ana­ the burden of COVID-19 in Italy: results of lysis, and presentation of immunization safety data. disability-adjusted life years (DALYs) and productivity Vaccine. 2007;25(31):5675–5684. PubMed PMID: loss. Int J Environ Res Public Health. 2020;17(12):4233. 17448577. PubMed PMID: 32545827; PubMed Central PMCID: [20] Motosue MS, Bellolio MF, Van Houten HK, et al. Risk PMCPMC7345321. factors for severe anaphylaxis in the United States. Ann 6 S. TUYLS ET AL.

Allergy Asthma Immunol. 2017;119(4):356–61e2. of severe allergic reactions to COVID-19 vaccines. PubMed PMID: 28958375. Allergy. 2021. PubMed PMID: 33452689. DOI:10.1111/ [21] Clark S, Wei W, Rudders SA, et al. Risk factors for severe all.14739. anaphylaxis in patients receiving anaphylaxis treat­ [26] Rama TA, Moreira A, Castells M. mRNA COVID-19 vac­ ment in US emergency departments and hospitals. cine is well tolerated in patients with cutaneous and J Allergy Clin Immunol. 2014;134(5):1125–1130. systemic mastocytosis with mast cell activation symp­ PubMed PMID: 24985399. toms and anaphylaxis. J Allergy Clin Immunol. [22] Castells MC, Phillips EJ. Maintaining safety with 2021;147:877–878. PubMed PMID: 33485650; PubMed SARS-CoV-2 vaccines. N Engl J Med. 2020;384:643–649. Central PMCID: PMCPMC7816615. PubMed PMID: 33378605; PubMed Central PMCID: [27] Garvey LH, Nasser S. Anaphylaxis to the first COVID-19 PMCPMC7787218. vaccine: is polyethylene glycol (PEG) the culprit? Br [23] Kozma GT, Meszaros T, Vashegyi I, et al. Pseudo- J Anaesth. 2020. PubMed PMID: 33386124; PubMed anaphylaxis to polyethylene glycol (PEG)-coated lipo­ Central PMCID: PMCPMC7834677. DOI:10.1016/j. somes: roles of anti-PEG IgM and complement activation bja.2020.12.020 in a porcine model of human infusion reactions. ACS [28] Wenande E, Garvey LH. Immediate-type hypersensitiv­ Nano. 2019;13(8):9315–9324. PubMed PMID: 31348638. ity to polyethylene glycols: a review. Clinical and [24] Klimek L, Jutel M, Akdis CA, et al. ARIA-EAACI state­ Experimental Allergy: Journal of the British Society ment on severe allergic reactions to COVID-19 vac­ for Allergy and Clinical Immunology. 2016;46 cines - an EAACI-ARIA position paper. Allergy. 2020. (7):907–922. PubMed PMID: 27196817. PubMed PMID: 33378789. DOI:10.1111/all.14726. [29] Dhami S, Panesar SS, Roberts G, et al. Management of [25] Sokolowska M, Eiwegger T, Ollert M, et al. EAACI state­ anaphylaxis: a systematic review. Allergy. 2014;69 ment on the diagnosis, management and prevention (2):168–175. PubMed PMID: 24251536.