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Table 1 Summary of the characteristics of the included studies with evidence on anaphylactic reactions and SARS-CoV-2 vaccines (n = 12), 2020–2021

From: Anaphylactic and nonanaphylactic reactions to SARS-CoV-2 vaccines: a systematic review and meta-analysis

Author, year, study location Study design, setting Age (years) Male, n (%) Past history of allergies or allergic reactions Past history of anaphylaxis Vaccine brand and dose Reaction onset after vaccination [min] Signs and symptoms Anaphylaxis level of severity Tryptase level was measured; AND if elevated§ Treatment setting: therapy given for reaction Epinephrine received, n (%) Outcome Skin test performed? [Time from reaction to the skin test]; and result Assessment of study risk of bias (tool used; finding) Key findings
Blumenthal et al. 2021 [22], United States Prospective cohort, multicenter
Self-reporting by HCWs after their first dose of an mRNA COVID-19 vaccine through a multipronged approach
Mean (SD), 41 (14) 1 (14.3) Three (43%) persons had prior allergies or allergic reactions, including to drugs or medical products, foods, and shellfish One (14.3%) person had a prior episode of anaphylaxis from prior exposures; including to contrast media, sulfa antibiotics, morphine, ciprofloxacin, penicillin, cat dander, peanuts, tree nuts, and shellfish Pfizer-BioNTech, dose 1 Mean [range], 14 [10–30] Pruritus, urticaria, and/or angioedema, sensation of throat closure, cough, wheeze, and/or dyspnea, hypotension and/or tachycardia, nausea, vomiting, and/or diarrhea All cases were classified as Brighton Level 2 (7 [100%]) a
Cases met NIAID/FAAN criteria Grade I (3 [43%]) or Grade II (4 [57%]) c
Not measured One patient was hospitalized in ICU, and four were treated in an ED 6 (86) All patients had recovered or been discharged home. No deaths from anaphylaxis were reported (NOS; 8) Allergists and immunologists reviewed the EHRs of HCWs to identify anaphylaxis
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [7]/doses administered [25,929] = 270
Blumenthal et al. 2021 [22], United States Prospective cohort, multicenter
Self-reporting by HCWs after their first dose of an mRNA COVID-19 vaccine through a multipronged approach
Mean (SD), 41 (13) 0 (0) Seven (78%) persons had prior allergies or allergic reactions, including to drugs or medical products, foods, and shellfish Four (44%) persons had a prior episode of anaphylaxis from prior exposures; including to contrast media, sulfa antibiotics, morphine, ciprofloxacin, penicillin, cat dander, peanuts, tree nuts, and shellfish Moderna, dose 1 Mean [range], 19 [1–120] Pruritus, urticaria, and/or angioedema, sensation of throat closure, cough, wheeze, and/or dyspnea, hypotension and/or tachycardia, nausea, vomiting, and/or diarrhea All cases were classified as Brighton Level 1 (1 [11%]) or Level 2 (6 [67%]) or Level 3 (2 [22%])a
Cases met NIAID/FAAN criteria Grade I (4 [44%]) or Grade II (5 [56%])c
Yes; AND was elevated in 1 patient (11) Five patients were treated in an ED 3 (33) All patients had recovered or been discharged home. No deaths from anaphylaxis were reported (NOS; 8) Allergists and immunologists reviewed the EHRs of HCWs to identify anaphylaxis
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [9]/doses administered [38,971] = 231
Frank et al. 2021 [25], United States Case report 55-year-old female HCW 0 (0) A history of significant allergies, including to fresh fish, iodine solution, and the rabies vaccine A history of anaphylactic reactions Pfizer-BioNTech, dose 1 10 min Despite premedication with I.V. diphenhydramine and dexamethasone 30 min prior to vaccine, patient experienced hives on chest, sensation of throat closure, dyspnea, and wheezing Case was classified as Brighton Level 1 a Not measured Patient was treated at the ED with I.M. epinephrine and I.V. fluids 1 (100) Patient was discharged from the hospital with a prescription for a steroid taper and EpiPen, instructions to not receive the second dose of the COVID-19 vaccine (NOS; 6) Patient’s allergic reaction demonstrated by edema of tongue was refractory requiring an epinephrine infusion for nearly 3 days
Case was thought to be secondary to the PEG component of the vaccine
Kadali et al. 2021 [27], United States A randomized, cross‐sectional study using an independent online survey questionnaire was conducted to collect responses from HCWs Average age of all participants who completed the survey (n = 432) was 43.76 years About 10.65% of participants were males Not reported Not reported Moderna, unknown dose Not reported Not reported Not measured Not reported Not reported Patient recovered with complete resolution of the suspected adverse drug reaction. No death from anaphylaxis was reported RoB 2; low risk of bias Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [5]/doses administered [432] = 231
Mathioudakis et al. 2021 [29], United Kingdom Self-reporting by participants via an online survey conducted to compare the safety of available COVID-19 vaccines Age groups [40–49; n = 3]; [50–59, n = 2] AND [60–69; n = 2] 4 (57) Not reported Not reported Pfizer-BioNTech, dose 1 (n = 1,673), AND dose 2 (n = 509) Not reported Not reported All episodes of anaphylaxis reported were described as mild or moderate Not measured None required hospital admission (only treatment or advice from a HCW outside the hospital), suggesting that they most likely represented anaphylactoid reactions Not reported Patients recovered with complete resolution of the suspected adverse drug reaction. No deaths from anaphylaxis were reported (NOS; 6) Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [7]/doses administered [2182] = 3208
Pfizer-BioNTech vaccine recipients reported a considerably lower incidence of anaphylaxis: [RR (95% CI): 0.19 (0.04–0.94); multivariate logistic regression coefficient = -1.890, p = 0.024]
Mathioudakis et al. 2021 [29], United Kingdom Self-reporting by participants via an online survey conducted to compare the safety of available COVID-19 vaccines Age groups [30–39; n = 1] AND [40–49; n = 1] 0 (0) Not reported Not reported Moderna, dose 1 (n = 282), AND dose 2 (n = 1) Not reported Not reported All episodes of anaphylaxis reported were described as mild or moderate Not measured None required hospital admission (only treatment or advice from a HCW outside the hospital), suggesting that they most likely represented anaphylactoid reactions Not reported Patients recovered with complete resolution of the suspected adverse drug reaction. No deaths from anaphylaxis were reported (NOS; 6) Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases (5)/doses administered [283] = 7067
Ontario Public Health Agency 2021 [33], Canada Ontario’s vaccine safety surveillance system Age group [18–64] AND 65 +  Most were females About 4 (28.6%) reported either a history of allergies (e.g., food, drugs, other vaccines, other common allergens, etc.) Five (35.7%) persons had a prior episode of anaphylaxis from prior exposures; including to 1st dose of COVID-19 and non-COVID-19 vaccines, drugs, food, and household products Pfizer-BioNTech, unknown dose Median [range], 10.5 [9–19.7] Cases were classified as Brighton Level 1 (9 [64%]) or Level 2 (5 [36%]) a Not measured Twelve patients (85.7%) were hospitalized and treated in an ED 13 (92.8) All patients had recovered or been discharged home. No deaths from anaphylaxis were reported (NOS; 6) Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [14]/doses administered [737,728] = 19
Ontario Public Health Agency 2021 [33], Canada Ontario’s vaccine safety surveillance system Age group [18–64] - Patient had a prior allergic reaction to non-COVID-19 vaccine Patient reported a prior history of anaphylaxis to a non-COVID-19 vaccine Moderna, unknown dose 11 min Case was classified as Brighton Level 1 (1 [100%]) a Not measured Patient was treated in an ED 1 (100) Patient had recovered or been discharged home. No death from anaphylaxis was reported (NOS; 6) Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases (5)/doses administered [152,876] = 6.5
Park et al. 2021 [34], United States Case report 34-year-old female HCW 0 (0) A history of childhood asthma and eczema; and a large hive at the site of injection after receiving influenza vaccine. Patient described a greater than 10-year history of inducible episodes of pruritus, swelling, and hives that were most notable at times of sweating. Patient noted an inability to take warm showers as well as limitations with exercise due to pruritus and hives in what was suspicious for cholinergic urticaria Patient reported no prior history of anaphylaxis Pfizer-BioNTech, dose 1 3 min Patient developed flushing, urticaria on her extremities and face, generalized pruritus, tongue swelling, nausea, light-headedness, racing pulse, and SOB Yes; AND level was not elevated Patient was treated at the ED with I.M. epinephrine and diphenhydramine 1 (100) Patient recovered with complete resolution of the suspected adverse drug reaction. No death from anaphylaxis was reported Yes. [Not reported]; and patient showed no reactions to intradermal PEG, polysorbate 80 and Pfizer-BioNTech vaccine (NOS; 6) Serum tryptase level was within reference range (4.7 μg/L and 5.4 μg/L)
Cholinergic urticaria was confirmed via exercise provocation challenge guided by a standardized protocol (53)
Patient tolerated a second dose of Pfizer-BioNTech vaccine, without premedication, exhibiting only transient, mild nausea and a sense of warmth
Pitlick et al. 2021 [35], United States Retrospective case reports, multicenter 22-year-old female 0 (0) Allergic rhinitis Patient reported no prior history of anaphylaxis Moderna, dose 1 20 min Angioedema, wheezing, and throat pruritus Case was classified as Brighton Level 1a Not measured Patient was treated in the ED and given antihistamines and steroids 0 (0) Patient recovered with complete resolution of the suspected adverse drug reaction. No death from anaphylaxis was reported Yes. [Three weeks after the resolution of clinical symptoms]; and patient showed no reactions to intradermal PEG, polysorbate 80, and polysorbate 20 (NOS; 7) Second vaccine dose was successfully given to patient [51 days after the 1st dose] with a 30-min observation period. Patient experienced minor lip or tongue tingling only
Restivo et al. 2021 [36], Italy Case report 30-year-old female HCW 0 (0) A polyallergic subject with a prior reported urticaria-angioedema episode and multiple other immediate cutaneous reaction elicited by chocolate, honey, some cosmetics, and detergents. The first reaction arose a few hours after the ingestion of a meal containing shrimps. Patient had a suspected sensitization to products containing LTP and PEG. Patient was not allergic to vaccines containing polysorbate Patient reported no prior history of anaphylaxis Pfizer-BioNTech, dose 1 5 h after the administration of the vaccine Patient developed erythematous spots on the face and neck and the feeling of a slurred mouth and hoarseness Yes; AND level was not elevated Patient was treated in the ED and given 8 mg I.V. dexamethasone, one vial I.V. chlorphenamine maleate, 250 mL I.V. 0.9% NaCl, and conventional oxygen therapy (2 L/min) 0 (0) Patient recovered with complete resolution of the suspected adverse drug reaction. No death from anaphylaxis was reported Yes. [Two weeks after the resolution of clinical symptoms]; and SPT in patient showed an old dosage of specific IgE with positivity to house dust mites, peach, and other fruits (NOS; 6) Patient reported self-administering prednisone (25 mg, one tablet) 14 h before, one tablet 7 h before and one tablet with an I.M. vial (10 mg) of chlorphenamine maleate 1 h before the administration of the vaccine
Tryptase value detected in relation to the patient’s medical history did not suggest a mast cell disease
The BAT in the patient’s reported history identified the reactivity towards PEG
Sellaturay et al. 2021 [38], United Kingdom Case report 52-year-old female 0 (0) Patient had prior allergies or allergic reactions, including to azithromycin containing PEG 6000; shampoos, conditioners, shower gels containing PEG; and toothpastes and mouthwash containing PEG Patient had prior history of anaphylaxis to drugs Pfizer-BioNTech, dose 1 1 min Patient developed throat constriction, cough and then loss of consciousness. She had a respiratory rate of 30/min, tachycardia of 150/min and oxygen saturation of 85% Yes; AND level was not elevated Patient was treated at the ED with I.M. epinephrine 0.5 mg, I.V. hydrocortisone 200 mg, chlorphenamine 10 mg, and fluids and oxygen 15 L/min 1 (100) Patient recovered with complete resolution of the suspected adverse drug reaction. No death from anaphylaxis was reported Yes. [Not reported]; and SPT in patient showed no reactions to Pfizer-BioNTech vaccine, its other excipients, polysorbate 80 and the AstraZeneca COVID-19 vaccine. However, testing was positive to PEG 4000 at 1% of concentration (NOS; 5) PEG allergy was diagnosed as the cause of patient Pfizer-BioNTech vaccine anaphylaxis
Tryptase levels measured immediately, 1 h and 3 h after this episode were 5.5, 5.5 and 4 ng/ml (normal range 2–14 ng/ml), respectively
Shimabukuro et al. 2021 [39], United States National passive surveillance (spontaneous reporting) after immunization captured in the VAERS Median (IQR), 40 (30–50) 2 (9.5) Seventeen (81%) of 21 patients with anaphylaxis had a documented history of allergies or allergic reactions, including to drugs or medical products, foods, and insect stings Seven (33%) had experienced an episode of anaphylaxis in the past, including one after receipt of rabies vaccine and another after receipt of influenza A (H1N1) vaccine Pfizer-BioNTech, dose 1 Median [range], 13 [2–150] The most common
symptoms and signs were urticaria, angioedema, rash, and a
sense of throat closure
All cases were classified as Brighton Level 1 (10 [47.6%]) or Level 2 (11 [52.4%]) a Not measured Four patients (19%) were hospitalized (including 3 in ICU), and 17 (81%) were treated in an ED 19 (90.5) Twenty (95%) were discharged home or had recovered. No deaths from anaphylaxis were reported (NOS; 8) CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylaxis or not anaphylaxis
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [21]/doses administered [1,893,360] = 11.1
Shimabukuro et al. 2021 [40], United States National passive surveillance (spontaneous reporting) after immunization captured in the VAERS Median (IQR), 39 (27–63) 3 (6.4) Thirty-six (77%) noted a prior allergies or allergic reactions, including to drugs or medical products, foods, and jellyfish stings and unspecified exposures Sixteen (34%) noted a prior episode of anaphylaxis from prior exposures; included vaccines (rabies, influenza A [H1N1], seasonal influenza, unspecified), contrast media (gadolinium-based, iodine-based, unspecified I.V.), unspecified infusions, sulfa drugs, penicillin, prochlorperazine, latex, walnuts, unspecified tree nuts, and jellyfish stings Pfizer-BioNTech, dose 1 (n = 37), dose 2 (n = 4) AND unknown dose (n = 6) Median [range], 10 [< 1–1140] b Common symptoms and signs were generalized urticaria, diffuse erythematous rash, angioedema, respiratory and airway obstruction symptoms, and nausea Cases were classified as Brighton Level 1 (21 [45%]) or Level 2 (23 [49%]) or Level 3 (3 [6%]) a Not measured All patients were treated in health care settings; some were treated in an ED and some were hospitalized (including some in ICU, few of whom required ETI) Most of the anaphylaxis cases (≈92%) received epinephrine as part of emergency treatment Most of the cases (≈92%) were discharged home or had recovered. No deaths from anaphylaxis were reported (NOS; 8) CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylaxis or not anaphylaxis
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [47]/doses administered [9,943,247] = 4.7
Shimabukuro et al. 2021 [40], United States National passive surveillance (spontaneous reporting) after immunization captured in the VAERS Median (IQR), 41 (24–63) 0 (0) Sixteen (84%) noted a prior allergies or allergic reactions; including to drugs or medical products, foods, and jellyfish stings and unspecified exposures Five (26%) noted a prior episode of anaphylaxis from prior exposures; including to drugs or medical products, foods, and jellyfish stings and unspecified exposures Moderna, dose 1 (n = 17), dose 2 (n = 1) AND unknown dose (n = 1) Median [range], 10 [1–45] Common symptoms and signs were generalized urticaria, diffuse erythematous rash, angioedema, respiratory and airway obstruction symptoms, and nausea Cases were classified as Brighton Level 1 (10 [52%]) or Level 2 (8 [43%]) or Level 3 (1 [5%]) a Not measured All patients were treated in health care settings; some were treated in an ED and some were hospitalized (including some in ICU, few of whom required ETI) Most of the anaphylaxis cases (≈92%) received epinephrine as part of emergency treatment Most of the cases (≈92%) were discharged home or had recovered. No deaths from anaphylaxis were reported (NOS; 8) CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylaxis or not anaphylaxis
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [19]/doses administered [7,581,429] = 2.5
Shimabukuro et al. 2021 [39], United States National passive surveillance (spontaneous reporting) after immunization captured in the VAERS Median (IQR), 47 (31–63) 0 (0) Nine (90%) persons had a documented history of allergies or allergic reactions; including to drugs (n = 6), contrast media (n = 2), and foods (n = 1) Five (50%) persons had a previous history of anaphylaxis; none of which was associated with receipt of a vaccine Moderna, dose 1 Median [range], 7.5 [1–45] Vomiting, nausea, respiratory failure, periorbital edema, hypotension, wheezing, erythematous rash, and tongue swelling Cases were classified as Brighton Level 1 (6 [60%]) or Level 2 (3 [30%]) or Level 3 (1 [10%]) a Not measured Six patients were hospitalized (including five in ICU, four of whom required ETI), and four were treated in an ED 10 (100) All patients had recovered or been discharged home. No deaths from anaphylaxis were reported (NOS; 6) CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylactic or nonanaphylactic
Incidence of vaccine-triggered anaphylaxis per 106 doses = number of anaphylaxis cases [10]/doses administered [4,041,396] = 2.5
  1. BAT Basophil Activation Test, CDC Centres for Disease Control and Prevention, CI confidence interval, COVID-19 coronavirus disease 2019, ED emergency department, EHRs electronic health records, ETI endotracheal intubation, h hour, HCWs healthcare workers; ICU, intensive care unit, IDT intradermal test, I.M. intramuscular, I.V. intravenous, LTP lipid transfer protein, NIAID/FAAN National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria, NOS Newcastle Ottawa Scale, PEG polyethylene glycol, RoB 2 Version 2 of the Cochrane risk-of-bias tool for randomized trials, RR risk ratio, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, SOB shortness of breath, SPT skin prick test, VAERS Vaccine Adverse Event Reporting System
  2. aThe Brighton Collaboration case definition uses combinations of symptoms to define levels of diagnostic certainty. Brighton level 1 represents the highest level of diagnostic certainty that a reported case is indeed a case of anaphylaxis; levels 2 and 3 are successively lower levels of diagnostic certainty. Level 4 is a case reported as anaphylaxis but that does not meet the Brighton Collaboration case definition. Level 5 is a case that was neither reported as anaphylaxis nor meets the case definition [42]
  3. bTime to symptom onset missing in 2 Pfizer-BioNTech reports
  4. cNIAID/FAAN clinical criteria for the diagnosis of anaphylaxis must meet 1 of the following criteria: (1) acute onset with involvement of skin and/or mucosal tissue and either (a) respiratory compromise or (b) reduced blood pressure or associated symptoms of end organ dysfunction; (2) 2 or more of the following occur after exposure to a likely allergen for that patient: (a) involvement of skin or mucosal tissue, (b) respiratory compromise, (c) reduced blood pressure or associated symptoms, or (d) persistent gastrointestinal symptoms; and (3) reduced blood pressure after exposure to a known allergen for that patient [43]
  5. §An elevated tryptase level was defined as either above the upper limit of normal or > (2 + 1.2 × baseline tryptase level)