Table 2.
Summary of the characteristics of the included studies with evidence on nonanaphylactic reactions and SARS-CoV-2 vaccines (n = 17), 2020–2021
| 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 | 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ackerman et al. 2021 [18], France | Case report | 55-year-old male HCW | 1 (100) | No past medical history and no drug allergy | Patient reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 | 180 min | Patient experienced injection-site soreness in the deltoid region with localized pruritic erythematous eruption which later spread on the face, trunk, upper extremities and thighs | Patient was hospitalized and treated with dermocorticoids | Not reported | A gradual improvement over the days with treatment in parallel with the improvement of liver enzymes | Not reported | (NOS; 6) | A persistent maculopapular eruption (1 month) with liver damage [slight hepatic cytolysis (ASAT and GGT 2 N) and biopsy shown haematoxylin and eosin-stained sections showed slight lymphocytic perivascular infiltrate] which led not to give the second dose of Pfizer-BioNTech vaccine |
| Baden et al. 2021 [19], United States | A phase 3 randomized, observer-blinded, placebo-controlled trial, multicenter | Mean (range), 51.4 (18–95) | 7,923 (52.2) | Not reported | Not reported | Moderna, dose 1 and dose 2 | Unsolicited delayed adverse events of hypersensitivity (defined in that trial as those with an onset on or after day 8) | Allergic and atopic dermatitis (n = 8), contact dermatitis (n = 21), hypersensitivity (n = 5), injection site rash (n = 37), injection site urticaria (n = 15), rash (n = 45), allergic rhinitis (n = 10), and urticaria (n = 27) | – | – | The reactions typically resolved over the following 4–5 days | – | RoB 2; low risk of bias |
Incidence of hypersensitivity reactions per 106 doses = number of nonanaphylactic cases [233]/doses administered [15,185] = 15,344 Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group |
| Bae et al. 2021 [20], South Korea | A self-administered online questionnaire to HCWs after vaccination | About 190 (68.6%) of the HCWs were in the age group of 20–39 | 92 (33.2) | Not reported | Not reported | Pfizer-BioNTech, dose 1 | Not reported | The most common nonanaphylactic reactions were foreign sensation in the throat (n = 27), throat swelling and tightness (n = 16), nasal obstruction (n = 16), angioedema (n = 12), tongue edema (n = 10), hoarseness (n = 6), skin rash (n = 5), and urticaria (n = 2) | Antipyretics use was less common in the Pfizer-BioNTech vaccine group compared to the AstraZeneca vaccine group regardless of the day of reporting [34.3% vs 82.3%] | – | – | – | (NOS; 5) |
Incidence of allergy-like reactions per 106 doses = number of nonanaphylactic cases [94]/doses administered [277] = 339,350 Allergy-like reactions (e.g., foreign body sensation in the throat, swelling in the throat) were significantly less commonly reported in the Pfizer-BioNTech vaccine group compared to the AstraZeneca vaccine group (all p < 0.001) |
| Bianchi et al. 2021 [21], Italy | Case series | Median [range], 37.5 [27–55] | 1 (16.7) | Allergic rhinitis (n = 6), asthma (n = 1), atopic dermatitis (n = 1) and contact allergy to nickel sulphate and fragrances (n = 1) | Patients reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 | Median (range), 15 (5–1,440 [24 h]) | Generalized acute urticaria, angioedema (tongue, gums, and lips), flushing of the face | One case was treated with I.V. betamethasone sodium phosphate | – | – | Yes. [ Not reported]; SPT resulted always negative, but IDT induced, 12 h after, an erythematosus, edematous and infiltrated asymptomatic reaction in all patients | (NOS; 6) |
Incidence of mucous-cutaneous adverse reactions per 106 doses = number of nonanaphylactic cases [6]/doses administered [5574] = 1076 All patients then received the second dose of vaccine without relapses |
| Blumenthal et al. 2021 [22], United States | Case series | Median (IQR), 44 (37.2–48.5) | 2 (16.7) | About 8 (66.7%) of the cases had prior contrast allergy (hives), penicillin, sulfasalazine and influenza vaccine allergy (hives and fever), urticaria, wasp allergy (hives), almond allergy (hives), angioedema, rhinitis, and rash. However, four (33.3%) cases had no allergy history | Patients reported no prior history of anaphylaxis | Moderna, dose 1 | Delayed adverse events of hypersensitivity (defined as those with an onset on or after day 8); and a range of 4–11 days | Pruritus, burning, pain, warmth, erythema, induration, swelling and hyperpigmentation. Five of the reactions were Grade 3 plaques (≥ 10 cm in diameter) | Most patients received treatment for their symptoms (e.g., with ice and antihistamines). Some patients received glucocorticoids, and 1 patient received antibiotic therapy for presumptive cellulitis | – | The symptoms resolved a median of 6 days after onset (range, 2 to 11) | – | (NOS; 7) |
All 12 patients completed Moderna vaccination. Although half the patients did not have a recurrence of large local reactions, 3 patients had recurrent reactions that were similar to those after the initial dose, and 3 patients had recurrent reactions that were of a lower grade than those after the initial dose. The median onset of cutaneous symptoms after the 2nd dose (day 2; range, 1–3) was earlier than that after the 1st dose Second vaccine dose was administered with premedication [including cetirizine, diphenhydramine, fexofenadine and loratadine] in 8/12 [66.7%] of the cases Authors also reported a 27-year-old Caucasian male who developed an erythematous plaque at the site of Moderna vaccine inoculation, 7 days after injection of Dose 1. A skin punch biopsy was taken and was found to represent a T-cell–mediated hypersensitivity reaction |
| CDC COVID-19 Response Team 2021 [24], United States | National passive surveillance (spontaneous reporting) after immunization captured in the VAERS | Median [range], 43 [18–65] | 8 (9.6) | For 56/83 (67%) case reports, a past history of allergies or allergic reactions, mostly to foods and drugs, was documented | Patients reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 | 12 (< 1–1,200 [20 h]) | Commonly symptoms included pruritus, rash, itchy and scratchy sensations in the throat, and mild respiratory symptoms | Not reported | Not reported | All patients had recovered or been discharged home. No deaths from anaphylaxis were reported | – | (NOS; 7) |
Incidence of nonanaphylactic reactions per 106 doses = number of nonanaphylactic cases [83]/doses administered [1,893,360] ≈ 4 CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylaxis or not anaphylaxis About 72/83 (87%) of the nonanaphylactic allergic reactions were classified as nonserious |
| Corbeddu et al. 2021 [23], Italy | Case series | Median [range], 56 [36–61] | 4 (36.4) | Majority of patients (72.7%, n = 8) had a previous history of allergy or allergic diathesis | Patients reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 AND dose 2 | Median (range), 48 h (1 h–72 h) | Cutaneous symptoms [such as erythematoedematous reaction at injection site, diffuse morbilliform rash, mild erythema and positive dermographism] | The patient who manifested a relapse of atopic dermatitis underwent a short oral steroids course prescribed by his GP | – | All manifestations resolved spontaneously within 2–3 days without treatment, except in the patients with extracutaneous symptoms | – | (NOS; 6) |
Incidence of cutaneous symptoms per 106 doses = number of nonanaphylactic cases (5)/doses administered [3170] = 3470 Authors concluded cutaneous reactions observed in their series were very mild and do not constitute a contraindication to a 2nd dose of vaccine |
| Johnston et al. 2021 [26], United States | Case series | Median [range], 38 [25–89] | 3 (18.7) | About 1/16 (6.2%) reported a prior localized vaccine reaction (mild reaction to an influenza vaccine) | Patients reported no prior history of anaphylaxis | Moderna, dose 1 AND dose 2 | Median [range], 7 days [2–12 days] | HCWs experienced delayed localized cutaneous reactions that occurred at or near the injection site and were described as pruritic, painful, and edematous pink plaques | Treatments included topical steroids, oral antihistamines, and cool compresses; 1 patient had received cephalexin for presumed cellulitis | – | – | – | (NOS; 8) |
Reactions to the first vaccine dose had a median (range) duration of 5 (1–21) days Skin biopsy specimen demonstrated a mild predominantly perivascular mixed infiltrate with lymphocytes and eosinophils, consistent with a dermal hypersensitivity reaction Of participants who had a reaction to first vaccine dose (15 of 16 patients), most (11 patients) developed a similar localized injection-site reaction to the second vaccine dose; most (10 patients) also developed the second reaction sooner as compared with the first-dose reaction |
| 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, dose 1 AND dose 2 | Not reported | Among the 432 vaccine recipients, (n = 58) reported rash*, (n = 35) reported palpitations, (n = 15) reported cough, (n = 10) reported SOB, (n = 8) reported chest pain, (n = 7) reported hives, (n = 4) reported syncope, and (n = 2) reported swelling in the mouth/throat | Only 17/432 (3.94%) required seeking help from an outpatient provider, 1/432 (0.23%) required seeking help from ED providers, and none of the participants required hospitalization | – | Patients recovered with complete resolution of the suspected adverse drug reactions. No deaths were reported | – | RoB 2; low risk of bias |
Incidence of nonanaphylactic reactions per 106 doses = number of nonanaphylactic cases [139]/doses administered [432] = 321,759 Most of the symptoms reported were nonlife threatening. Despite the wide array of self-reported symptoms, there appears to be a higher acceptance for this vaccine |
| Kelso et al. 2021 [28], United States | Case reports | Median (IQR), 45 (42.2–53.7) | 0 (0) | Not reported | Not reported | Pfizer-BioNTech (n = 3) AND Moderna (n = 1); both brands after dose 1 | Median [range], 3.5 [1.2–12.5] | Sensation of throat swelling, SOB, hot and sweaty, headache, disoriented, pruritus, itching, flushing, puffy eyelids, and hives | One patient (25%) was hospitalized and needed ICU healthcare and other 3 patients (75%) were treated at the ED; and the 4 cases patients were treated with prednisone, cetirizine, epinephrine, famotidine, methylprednisolone, diphenhydramine, dexamethasone, hydroxyzine, epinephrine and diazepam | 2 [50] | Patients recovered with complete resolution of the suspected adverse drug reactions. No deaths were reported | Yes. [ Not reported]; and SPTs and IDTs in all patients showed no reactions to the individual COVID-19 vaccine taken previously as a 1st dose | (NOS; 6) |
Subsequent vaccine skin testing suggested that the reactions were not IgE-mediated [anaphylactic], and 3 of 4 have received their second doses either without symptoms or with only mild transient symptoms Despite negative skin testing results, 1 patient declined her second dose. The skin test results and subsequent vaccination outcomes in these patients indicate that their initial reactions were not allergic |
| McMahon et al. 2021 [30], United States | An international registry of COVID-19 vaccine cutaneous reactions by HCWs only | Median (IQR), 45 (36–60) | 29 (8.4) | Among the 343 cases, (n = 12) reported atopic dermatitis, (n = 10) reported contact dermatitis, (n = 6) reported psoriasis, (n = 5) reported urticaria and (n = 4) reported acne vulgaris | Not reported | Moderna, dose 1 AND dose 2 |
First dose: Median [IQR], 7 days [2–8] Second dose: Median [IQR], 1 days [1, 2] |
Among the 369 administered doses [1st and 2nd], there were nausea (n = 43), urticaria (n = 23), morbilliform (n = 18), diarrhea (n = 13), angioedema (n = 5), and erythema multiforme (n = 3) |
Patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. Antibiotics were not required for resolution but were sometimes given by HCWs concerned that the reaction might be cellulitis | Not reported | No patients with these findings experienced anaphylaxis or another severe adverse event. These reactions resolved after a median of 3–4 days | Not reported | (NOS; 6) |
Incidence of nonanaphylactic reactions per 106 doses = number of nonanaphylactic cases [105]/doses administered [369] ≈ 284,553 For both Moderna and Pfizer-BioNTech vaccines, cutaneous reactions were reported mostly by dermatologists (30%), other physicians (26%), and other HCWs (22%); and almost all the cases came from the United States (98%) About 414 cutaneous reactions to mRNA COVID-19 vaccines were recorded from Moderna (83%) and Pfizer-BioNTech (17%) For both vaccines, about 21% reported reactions after the 1st dose only, 63% reported a reaction after the 2nd dose only, and 16% reported reactions to both doses |
| McMahon et al. 2021 [30], United States | An international registry of COVID-19 vaccine cutaneous reactions by HCWs only | Median (IQR), 42 (36–54) | 11 (15.5) | Among the 71 cases, (n = 5) reported atopic dermatitis, (n = 2) reported contact dermatitis, (n = 3) reported psoriasis, (n = 2) reported urticaria and (n = 2) reported acne vulgaris | Not reported | Pfizer-BioNTech, dose 1 AND dose 2 |
First dose: Median [IQR], 7 days [2–8] Second dose: Median [IQR], 1 days [1, 2] |
Among the 74 administered doses [1st and 2nd], there were urticaria (n = 17), morbilliform (n = 9), nausea (n = 7), angioedema (n = 1), and diarrhea (n = 1) | Patients responded well to topical corticosteroids, oral antihistamines, and/or pain-relieving medications. Antibiotics were not required for resolution but were sometimes given by HCWs concerned that the reaction might be cellulitis | Not reported | No patients with these findings experienced anaphylaxis or another severe adverse event. These reactions resolved after a median of 3–4 days | Not reported | (NOS; 6) |
Incidence of nonanaphylactic reactions per 106 doses = number of nonanaphylactic cases [35]/doses administered [74] ≈ 472,973 Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions Serious adverse events did not develop in any of the patients in the registry after the first or second dose |
| Mustafa et al. 2021 [31], United States | Two case reports |
A 64-year-old female (patient 1) AND a 39-year-old female (patient 2) |
0 (0) | Patient 1 had history of shellfish allergy AND patient 2 had a history of allergic rhinitis | Both patients reported no prior history of anaphylaxis | Moderna, dose 1 | 10 min (patient 1) AND 15 min (patient 2) |
Patient 1 had generalized pruritus, urticaria, and self-reported tachycardia but no angioedema, respiratory or gastrointestinal symptoms, or hypotension Patient 2 developed chest neck urticaria and mild facial angioedema |
Patient 1 was treated at vaccination site and given 50 mg of oral diphenhydramine Patient 2 was given 25 mg of oral diphenhydramine at the vaccination site, then transported by ambulance to the ED, where she received 20 mg of I.V. famotidine and 125 mg of methylprednisolone |
0 (0) | Both patients recovered with complete resolution of the suspected adverse drug reaction | Yes. [Not reported]; and SPTs in both patients showed no reactions to PEG, polysorbate, and Moderna; however, IDTs in the two patients shown positive reaction to Moderna | (NOS; 5) |
Second vaccine dose was administered without premedication through a graded dosing protocol. Patient 1 had no symptoms during the protocol. Patient 2 reported pruritus after doses 2 and 5, but it resolved without medical intervention. Both patients reported no additional symptoms over the following 24 h In addition, 3 to 4 weeks after receiving the second dose, both patients had IgG antibodies directed against the spike protein of COVID-19, suggesting vaccination was efficacious |
| Ocáriz et al. 2021 [32], Spain | Investigational clinical trial, single centre | 43-year-old female | 0 (0) | A history of severe asthma | Patient reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 | 10 min | Patient developed nasal obstruction and rhinolalia and pruriginous erythematous macules on the neck and upper thorax | Patient was treated at the allergy department and given I.M. dexchlorpheniramine | 0 (0) | Patient recovered with complete resolution of the suspected adverse drug reaction | Yes. [Not reported]; and SPT in patient was not allergic to PEG-3350 | RoB 2; some concerns risk of bias | No modification on tryptase levels compared with the baseline was found |
| Pitlick et al. 2021 [35], United States | Retrospective case reports, multicenter | Median (IQR), 36 (24–52) | 2 (28.6) | About 4 (57.1%) of the cases had prior drug (influenza vaccine and antihistamines) and food allergy; and asthma. However, two (28.6%) cases had no allergy history | Two (28.6%) cases had prior insect stinging (venom) anaphylaxis | Pfizer-BioNTech (n = 6) AND Moderna (n = 1); both brands after dose 1 | Median [range], 97 [6–405] | Urticaria, tachycardia, rhinorrhea, facial flushing, oral pruritus, throat fullness and tightness, and angioedema | Patients were treated at the vaccination sites and given antihistamines and steroids | – | Patient recovered with complete resolution of the suspected adverse drug reaction. The symptoms resolved a median of 6 h after onset (range, 0.2 to 24) | Yes. [A median of 16 days after the resolution of clinical symptoms (range, 9 to 20); and patients showed no reactions to PEG, polysorbate 80, and polysorbate 20 | (NOS; 7) | All patients successfully received their 2nd vaccine dose without premedication or split-dosing. Patients experienced no allergic reactions |
| Riad et al. 2021 [37], The Czech Republic | A cross-sectional self-administered online questionnaire | About 50.2% of participant were ≤ 43 years old | 100 (11.4) | About 21.8% and 5.9% of participants reported a history of asthma and allergy, respectively | Patients reported no prior history of anaphylaxis | Pfizer-BioNTech, dose 1 AND dose 2 | Not reported | Rash (n = 28), urticaria (n = 10), tongue tingling (n = 5), and swollen lips (n = 4) | – | – | – | – | (NOS; 6) |
Incidence of nonanaphylactic reactions per 106 doses = number of nonanaphylactic cases [47]/doses administered [877] ≈ 53,592 Rash and urticaria were more common among the ≤ 43 years old group than the older age group |
| Shimabukuro et al. 2021 [39], United States | National passive surveillance (spontaneous reporting) after immunization captured in the VAERS | Median [range], 43 [22–96] | 4 (9.3) | For 26/43 (60%) case reports, a past history of allergies or allergic reactions, mostly to foods and drugs, was documented | Patients reported no prior history of anaphylaxis | Moderna, dose 1 | 15 (< 1–1,440 [24 h]) | Commonly symptoms included pruritus, rash, itchy sensations in the mouth and throat, sensations of throat closure, and respiratory symptoms | – | – | 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 [43]/doses administered [4,041,396] = 10.6 CDC physicians evaluated these reports and applied Brighton Collaboration case definition criteria to classify case reports as anaphylactic or nonanaphylactic About 26/43 (60%) of the nonanaphylactic allergic reactions were classified as nonserious |
| Vieira et al. 2021 [41], Portugal | Prospective cohort, single center | 31 | 0 (0) | Allergic rhinitis | Sixty reported a previous history of drug anaphylaxis | Pfizer-BioNTech, dose 1 | 10 | HCW developed a sudden onset generalized urticaria | – | – | – | A total of 115 HCWs performed SPTs and IDTs with the Pfizer-BioNTech SARS-CoV-2 vaccine (83% women, mean age of 44 ± 12 years) | (NOS; 6) |
SPTs and IDTs were performed for each person with the undiluted vaccine and a 1/10 dilution with saline solution Fifty-five of participants were control subjects, who had tolerated the vaccine Of the 60 participants who reported a history of anaphylaxis, four subjects had positive results to the IDTs. All 4 were then tested with PEG 2000 with SPTs and IDTs. Only one tested positive to the IDTs A HCW developed generalized urticaria was to Pfizer-BioNTech was premedicated with 20 mg of cetirizine |
CDC Centres for Disease Control and Prevention, COVID-19 coronavirus disease 2019, ED emergency department, GP general practitioner, h hour, HCWs healthcare workers, ICU intensive care unit, IDT intradermal test, I.M. intramuscular, I.V. intravenous, NOS Newcastle Ottawa Scale, PEG polyethylene glycol, RoB 2 Version 2 of the Cochrane risk-of-bias tool for randomized trials, SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, SOB shortness of breath, SPT skin prick test, VAERS Vaccine Adverse Event Reporting System
*Rash was reported as both localized side effect and allergic side effect