This is a case study from a small patient cohort in a single allergy center; however, despite the limited number of study participants and the intrinsically subjective answers of our questionnaire, we are confident to state that with this study, we gathered some interesting and important outcomes. First, we could confirm that a higher number of women were affected, and that intradermal tests with PEG 2000 and PS80 might not be suitable to predict an anaphylactic reaction to COVID-19 vaccines [1, 2, 7, 10, 11] as previously described in other studies. Negative skin test results do not rule out future anaphylaxis in a patient. By this, we are in accordance with previous reports that a pseudo-allergic response to COVID-19 vaccines or their excipients, as it can occur in drug-induced anaphylaxis, is conjectural [10, 15, 16].

Second, we could show that antihistamine premedication significantly decreased the severity of anaphylactoid reactions to COVID-19 vaccination in our study cohort. Only one study participant had a severe (grade 3) reaction despite premedication with antihistamines. In this case, it was indicated that the medication was taken 30 min before COVID-19 vaccination, which might have been too soon before the vaccination. All other anaphylactoid symptoms after COVID-19 vaccination with antihistamine premedication were either non-existing or at least not life-threatening. The reasoning of participants who wanted another COVID-19 vaccination in the future, was actually well in agreement with this observed ameliorating effect, as vaccinations with antihistamine premedication showed no or milder (grade ≤ 2) anaphylactic responses in our cohort. Antihistamine premedication should thus be recommended for patients with previous anaphylaxis. Another approach to avoid anaphylaxis or anaphylactoid reactions suggested by a medical center in Venice, was to divide vaccine injection into two parts with a waiting period of 20 min between them. This approach did not trigger anaphylactic reactions even in patients with diagnosed PEG sensitization [17].

Third, most patients who reported immediate anaphylactoid reactions after COVID-19 vaccinations also reported experienced anaphylactic or anaphylactoid reactions to other triggers, such as drugs, Hymenoptera venom and/or food. This indicates that patients reacting with anaphylactoid symptoms to COVID-19 vaccines might have a tendency to react more easily to external triggers in general; however, this does not mean that patients with anaphylaxis triggered by food or Hymenoptera venom will necessarily react to a COVID-19 vaccine, because in that case the reported frequency of anaphylactoid reactions to COVID-19 vaccines would be much higher.

Hesitancy to vaccinate against COVID-19 is quite common in the general population. According to a survey of the general population in the United Kingdom, 16.6% were unsure whether they wanted to be vaccinated against COVID-19 and 11.7% were strongly hesitant; however, the main motivation for vaccination refusal was mistrust and not fear of an anaphylactic event [18]. An anaphylactic reaction can trigger panic and fear for life. This can lead to a subsequent posttraumatic stress disorder [19]. It is thus not surprising that we found anxiety for anaphylaxis reoccurrence at the next COVID-19 vaccination and refusal for future COVID-19 vaccinations in most participants of our study. In general, it seems difficult to diagnose anaphylaxis to COVID-19 vaccines as not all mentioned symptoms (Table 1) are typical for anaphylactic or anaphylactoid reactions in our cohort. We also do not have information about serum tryptase levels during the anaphylactic episode of our patients, which could serve as a diagnostic marker. A differential diagnose of a panic reaction could thus be possible; however, we do not want to ascribe this to our patients, especially, as most participants reported no anxiety for anaphylaxis before they had their first anaphylactoid reaction to a COVID-19 vaccine.

Although skin testing to vaccine and vaccine excipients (in the case of COVID-vaccines) seems to lack precision, as the mechanism of adverse reactions in most cases is less likely to be IgE-mediated or the quantity of PEG/PS80 in the vaccines is very low and therefore subthreshold to provoke a reaction, the other side of the coin is a reported sensitivity of 95.8% regarding skin tests in patients with suspected PEG allergy in a large review [6, 20, 21]. Therefore, testing vaccine excipients may be useful for detecting those who, with a personal history highly compatible with PEG/PS allergy, have developed a specific IgE reactivity, to address the consequent decision-making and estimate the risks of other possible PEG/PS exposures [20].

In conclusion, our results demonstrate the urgent need for studies focusing on the underlying immunological mechanisms of these reactions to learn how they can be diagnosed, predicted, and avoided. A clear diagnosis and appropriate measures of avoidance could reduce anxiety in those affected and might increase their willingness to be vaccinated (with antihistamine premedication) in the future. In addition, it might be useful to establish an interdisciplinary collaboration with psychologists to assist drug-induced anaphylaxis patients dealing with their anxiety.