COVID-19 vaccines: anaphylaxis and anxiety

A total of 47 patients came to the Allergy Unit of the Department of Dermatology and Venereology at the Medical University Hospital Graz, Austria, reporting immediate anaphylactoid symptoms after administration of COVID-19 vaccines (Table 1). Of the patients 85.1% were female, which is in line with previous reports [2]. In addition, 29 patients with a history of drug-induced anaphylaxis wanted to be tested for sensitization against COVID-19 vaccines or vaccine excipients (PEG 2000, PS80) before their first vaccination.

Skin prick tests and intradermal tests were performed in all 76 patients using 10% PEG 2000 (ROTIPURAN Ph. Eur.; Carl Roth GmbH + Co. KG; Karlsruhe, Germany) (n = 63) and/or 0.5% PS80 (Polysorbitanum 80 Oleinatum; Gatt-Koller GmbH, Absam, Austria) (n = 27) sterile solutions, provided inhouse by the local hospital pharmacy. Furthermore, COVID-19 vaccines from BioNTech/Pfizer (n = 33; Mainz, Germany/New York, NY, USA), Astra Zeneca (n = 1; Cambridge, England), or Moderna (n = 10; Cambridge, MA, USA) were used for skin prick tests depending on availability and the vaccine brand, which was suspected to have triggered the anaphylactoid reaction. Skin prick tests with PEG 2000 solution, PS80 solution, and COVID-19 vaccines were performed undiluted. Intradermal tests with PEG and PS80 solutions were performed at 1:10 and 1:100 dilutions. In all but one patient the test results were negative, which was in line with previous studies [1, 10, 11]. The female individual with the positive intradermal test result was tested for PEG 2000 and PS80 (skin prick test and intradermal test). She responded with a positive local reaction at all four sites of the intradermal test. In addition, she was tested by skin prick test with the COVID-19 vaccine from BioNTech/Pfizer (skin prick test undiluted) and responded with a 1 mm wheal. In 2008, this patient was also tested with intradermal tests for the contrast agents Hexabrix, Ultravist, Iomeron, Xenetix and Visipaque and responded positively to Hexabrix and Ultravist.

Patients with a negative test result were given the recommendation for (repeated) COVID-19 vaccination and to take an antihistamine approximately 1h before the next COVID-19 vaccination.

An overview of this study is depicted in Fig. 1a. We developed a questionnaire for this patient cohort (sent out in September 2022) to gather follow-up information. Inclusion criteria were ≥ 18 years of age and at least one anaphylactic or anaphylactoid reaction to medication and/or a COVID-19 vaccine (anamnestically diagnosed and graded according to Ring and Messmer grades 1–4) [12]. Exclusion criteria were inability to personally consent and a bad general state of health. The original German and translated questionnaire can be found in the supplement. In short, the questionnaire addressed reactions to COVID-19 vaccines, potential premedication, and sensitization, additional triggers of anaphylaxis, as well as the willingness and motives concerning future vaccinations. From the 76 patients, 52 (68%) were contacted and asked to fill in the questionnaire because they had a doctor’s rated anaphylaxis grade II or higher to a COVID-19 vaccine or to medication and 50 patients agreed to fill in the questionnaire. Of the patients 38 (74%) returned the filled-in questionnaires along with their written informed consent, 4 questionnaires were excluded from the analysis: 2 questionnaires contained conflicting statements, as the indicated answers did not align with the doctor’s notes. A third participant stated having actually experienced the symptoms 5 days after vaccination instead of an immediate response. The fourth participant was in the 13th week of gestation at the time of vaccination, and experienced nausea, headache, vertigo, paresthesia in lips and tongue, and tremor. Hence, we could not exclude that the symptoms might have been due to the pregnancy. This study was approved by the local ethical committee (ethical approval number: 34-467 ex 21/22) and all procedures were performed after written informed consent of the study participants in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1946, as revised in 2008 [13].

Out of 34 (91%) study participants 31 were female (Fig. 1b). The age ranged between 24 and 68 years (Fig. 1c). Of the 29 patients with drug-induced anaphylaxis who had come to the clinic to predict a sensitization to COVID-19 vaccine ingredients, 5 filled in the questionnaire and 3 did not receive a COVID-19 vaccination (Fig. 2a). One out of them was the patient, who had a positive intradermal test result. All study participants, who did receive at least one COVID-19 vaccination (31 patients), reported an anaphylactoid response shortly after at least one of their received COVID-19 vaccinations (Fig. 2a). In the questionnaire, we asked for the vaccine brand and at which vaccination time point antihistamines were taken as premedication and how strong the anaphylactic response was. A symptom table with grades according to Ring and Messmer was included in the questionnaire, to facilitate self-grading of the perceived anaphylactic reaction [12]. While only one patient already took antihistamines as premedication for their COVID-19 vaccination before the doctor’s appointment, most (68%) took antihistamines according to the doctor’s advice at their subsequent COVID-19 vaccination (Fig. 2a). Still, half of the patients who had at least one more shot of COVID-19 vaccine after the doctor’s consultation reported a (repeated) anaphylactoid response to it (Fig. 2a). To validate the patient’s grading, we compared the responses, which happened before the consultation with the doctor’s grading based on the anamnesis (Fig. 2b). The study participants tended to grade their anaphylactoid responses more severe than the medical doctor (Fig. 2b); however, when comparing their responses with or without antihistamine pretreatment, an overall significant reduction in severity was reported for COVID-19 vaccinations, when antihistamines were taken (Fig. 2c). This pattern recurred in different COVID-19 vaccine brands, where more than three vaccinations were reported (Fig. 2d). Of note, all but two vaccinations were carried out before September 2022. In September 2022, variant-adapted modifications of the vaccines became available in Austria. We can therefore exclude that the milder responses with antihistamine pretreatment are due to differences in the administered vaccines of the same brand.

We wanted to know whether a possible PEG exposure from other medications, such as laxatives and ultrasound contrast agents, could have been associated with the reported anaphylactic response to COVID-19. Some but not all study participants likely had contact with ingredients such as high molecular weight PEG or PS80 prior to their COVID-19 vaccination (Fig. 3a). This might have led to a sensitization, although only 11 (32.3%) reported anaphylaxis to macrogol and/or contrast agents (Fig. 3a). Interestingly, 23 of the 31 (74%) COVID-19 vaccinated study participants reported to have experienced anaphylactoid reactions to triggers other than the COVID-19 vaccine (Fig. 3a), which has also previously been reported [14]. Of the patients 14 mentioned drug-induced anaphylaxis and some participants stated reactions to multiple triggers (Fig. 3b, c).

We wanted to know whether the experienced response to the COVID-19 vaccine triggered anxiety and whether this led to trigger avoidance. The study participants reported whether they had been anxious of an anaphylactic response to COVID-19 vaccines or other medication already before their reaction to the COVID-19 vaccine and/or since their reaction. We further asked if this fear was strong (Fig. 4a). As expected, more study participants have been anxious since their reaction to the COVID-19 vaccine (24 of 31; 77%), than before it (29%). Of those who were anxious since their reaction, 62.5% reported a strong feeling of anxiety for a future anaphylactic reaction upon COVID-19 vaccination (Fig. 4a). This seems mirrored in the high rate of 58% of refusal to be vaccinated against COVID-19 in the future. Indeed, when correlating these two parameters, most participants, who did not want another shot of COVID-19 vaccine in the future, reported anxiety of an anaphylactic reaction to it (Fig. 4b). The reasons given against another COVID-19 vaccination in the future partially indicated the same trend (Table 2): “to protect myself. The vaccine is not good for my body” and “due to my risk-benefit analysis” strongly indicate a comparable argumentation, as “I don’t want to experience an anaphylactic reaction again”. A total of 6 participants (19.3%) also reported to “still suffer from health problems due to that vaccine”; however, the eight participants, who were willing to have another COVID-19 vaccination in the future, had the completely opposite view as they saw the benefits of disease protection by the vaccination outweighing the risks of an anaphylactic reaction to the vaccine.