Discussion
Confirmed anaphylaxis towards an ingredient of a vaccine is extremely rare and may reach an estimated rate of 1-2 cases per million vaccinations in Germany [8-10]. After starting the world-wide vaccination program against COVID-19, an increased reaction rate for SARS-CoV-2 vaccines has been observed [3] with hypersensitivity against PEG being suspected to be causal [1]. However, only in exceptional cases evidence for PEG as the culprit could be substantiated [11]. Thus, the association between PEG allergy and anaphylaxis to SARS-CoV-2 vaccines remains uncertain.
So far drug and/or vaccine induced hypersensitivity reactions can be caused either IgE-dependent, via a G-protein signalling pathway (MRG-PX2) or through activation of the complement system [12]. Whether PEGs or other vaccine excipients are capable to induce a hypersensitivity reaction besides the IgE dependent pathway is currently not known.
In this multicenter data assessment, out of 334 individuals with suspected hypersensitivity to SARS-CoV-2 vaccines and presenting for an allergy workup only 45 were diagnosed with immediate hypersensitivity reactions after vaccination, according to Brighton criteria. As reported previously, patients were mostly females [13]. The overall analyses of the symptom profiles of these patients revealed angioedema to be more common in this patient group, even more frequent than urticaria. This finding is interesting as acquired angioedema shows a predominance in female middle-aged patients as well and may indicate a role of sex hormones for the development of the observed hypersensitivity reactions. In addition previous studies have shown that females experience allergic symptoms more often, e. g. in food allergies, although being less frequently sensitized [14].
The allergy workup in our cohort showed very few positive skin test reactions and almost all of them appeared only in IDT. As unspecific positive IDT reactions are not uncommon in testing drugs, particularly vaccines, positive results have to be interpreted with great caution [9]. Nevertheless, negative skin tests in a large proportion of patients applying recommended test concentrations indicate that the test conditions have a high specificity >95% and are suited to impede concerns of doctors and patients against allergy towards SARS-CoV-2 vaccines.
The basophil activation test appears to be non-irritant in the concentrations tested, but only provided additional information in exceptional patients and needs further validation. In the vast majority of patients, after allergy testing, an allergic reaction to PEG, PS80, DSCP and trometamol was ruled out and further vaccination recommended. Even in those few patients with positive reactions in the IDT, unspecific and irritant reactions cannot be finally ruled out, as patients were advised to receive a vaccine not containing the ingredient leading to a positive skin test reaction.
Tolerability of the second vaccine dose shown by us and by other groups [15] suggest that re-vaccination is safe in the vast majority of these patients. As some symptoms concerning the respiratory tract, circulatory or gastrointestinal system are subjective, these might be an expression of anxiety rather than an allergic or other adverse organ reaction or may be triggered via vasovagal activation.
Thus, we propose that patients reporting systemic reactions after SARS-CoV-2 vaccination should be carefully evaluated for differential diagnosis, e.g., vasovagal, or stress-triggered reactions. If possible, patients should be evaluated for an increased serum tryptase 2-4 hours after the reaction to gather further evidence for an allergic reaction, and a thorough allergy workup should follow. Here, we propose a SPT and – if negative – in selected cases IDT with both the SARS-CoV-2 vaccines and hypersensitivity eliciting ingredients. Recent data from the literature indicate that a SPT with 50% PEG 20,000 may be useful as a screening test for PEG allergy when lower MW PEGs test are negative, whereas IDT with PEG requires confirmation regarding safety and validity [16].
Overall, IgE-mediated hypersensitivity towards SARS-CoV-2 vaccines is extremely low and not increased in comparison to the reported hypersensitivity rates for other vaccines. However, the tremendous amount of patients seeking allergological advice regarding the tolerability of COVID-19 vaccination points to the need of appropriate information campaigns in the general population in order to facilitate high vaccination rates.
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