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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