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\begin{document}

\title{Perceived high risk of COVID-19 vaccination: the revealing power of
placebo.}



\author[1]{Beyens Michiel}%
\author[1]{Toscano Alessandro}%
\author[2]{Van Damme Pierre}%
\author[3]{Dogné Jean-Michel}%
\author[1]{Didier Ebo}%
\author[1]{Vito Sabato}%
\affil[1]{Universiteit Antwerpen Faculteit geneeskunde en gezondheidswetenschappen}%
\affil[2]{Universiteit Antwerpen Centrum voor de Evaluatie van Vaccinaties}%
\affil[3]{Universite de Namur}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\emph{Perceived high risk of COVID-19 vaccination: the revealing power
of placebo.}

Beyens Michiel\textsuperscript{1,2}; Toscano
Alessandro\textsuperscript{1,2}; Van Damme Pierre\textsuperscript{3};
Dogn\selectlanguage{ngerman}é Jean-Michel\textsuperscript{4}; Ebo
Didier\textsuperscript{1,2,5*}; Sabato Vito\textsuperscript{1,2,5}

\textsuperscript{1} Department of Immunology, Allergology, Rheumatology
and the Infla-Med Centre of Excellence, Faculty of Medicine and Health
Sciences, University of Antwerp, Antwerp, Belgium

\textsuperscript{2} Immunology, Allergology, Rheumatology, Antwerp
University Hospital, Antwerp, Belgium\textsuperscript{3} Centre for the
Evaluation of Vaccination and Vaccine \& Infectious Disease Institute,
University of Antwerp, Antwerp, Belgium.

\textsuperscript{4} Department of Pharmacy, Namur Research Institute for
LIfe Sciences, University of Namur, Namur, Belgium.

\textsuperscript{5} Immunology and Allergology, AZ Jan Palfijn Gent,
Ghent, Belgium

\textbf{ORCID-ID}

MB: 0000-0002-5571-9501; AT: 0000-0002-6303-8159; PVD:
0000-0002-8642-1249; JMD: 0000-0003-2107-1804; DE: 0000-0003-0672-7529;
VS: 0000-0002-1321-314X

\textbf{Acknowledgement}

DE is a senior clinical researcher of the Research Foundation
Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1800614N). VS is a
senior clinical researcher of the Research Foundation Flanders/Fonds
Wetenschappelijk Onderzoek (FWO: 1804518N).

We would like to thank Mr. T. De Cloet and Mrs. K. Vanbillemont for
their efforts during the COVID-pandemic and their aid in the collection
of this data.

The authors declare no conflict of interest in relation to this work

Informed consent was obtained from the participants of this study

This study was approved by the local Ethics board.

Author contribution: MB: Writing and analyzing of data; AT: critical
review and editing; PVD: critical review and editing; JMD: critical
review and editing; DE: supervision and writing; VS: supervision,
writing and conceptualization

\textbf{Keywords} : COVID-19; vaccine, hypersensitivity, allergy,
placebo

To the Editor

Self-limiting mild adverse events (AEs) after COVID-vaccination are
common and should not contraindicate revaccination\textsuperscript{1}.
Unfortunately, these are too often erroneously labeled as
hypersensitivity reactions (HRs), precluding
revaccination\textsuperscript{2}. A patient with a history compatible
with an immediate HR to the vaccine should be offered allergologic
evaluation with the excipients of these vaccines based on the respective
type\textsuperscript{3,4}. In contrast, in the diagnostic work-up of
patients with subjective symptoms or multiple unverified drug
hypersensitivities a placebo-controlled challenge should be
considered\textsuperscript{5}.

In this study, we assessed the reoccurrence rate (RR) of AEs after
vaccination or unrelated to the vaccine in COVID-19-vaccine naïve
patients. We report data on 69 individuals who attended the outpatients'
clinic of the Antwerp University Hospital from April 1 to July 1, 2022,
for risk stratification concerning COVID-19 vaccination. Patient
characteristics are summarized in table 1.

All patients were administered a placebo, either as primary diagnostic
(n=52) or after negative skin testing (n=17). The main reason for
referral was symptoms after previous COVID-19 vaccination (n=41).
Twenty-eight patients were COVID-19-vaccine naïve and reasons for
referral are shown in table 1. Seventeen of the 69 patients were offered
allergologic evaluation including skin tests (STs) with the concerning
excipients or the COVID vaccine, based on clinical suspicion. In 1
patient a polysorbate allergy was diagnosed. She suffered from a so
called 1-1-1-urticaria\textsuperscript{6} after administration of the
first dose of Vaxzevria®. In all other patients, allergologic evaluation
was negative. All 69 patients were (re)vaccinated in a
placebo-controlled manner. In 11 patients previously vaccinated with
Spikevax® (n=3); Jcovden® (n=3) or Vaxzevria (n=5) a switch was made to
Comirnaty® either due to practical reasons of availability of vaccines
in our center (n=10) or because of confirmed hypersensitivity (n=1).

Out of the 41 patients who reported symptoms after previous dose, 14
reported symptoms after placebo administration and were vaccinated
uneventfully afterwards. Two patients had symptoms after re-exposure to
the vaccine: 1 patient experienced dyspnea with urticaria that was
considered anaphylaxis, 1 patient had urticaria immediately after the
vaccination with Comirnaty®. Both did not meet criteria for mast cell
activation\textsuperscript{7}. Of the 28 COVID-19-vaccine naïve
patients, 5 had symptoms after administration with placebo and were
later vaccinated uneventfully. In total, 19 out of 69 patients (27.54\%)
experienced symptoms after placebo. Overall, 67 of 69 patients were
vaccinated uneventfully without premedication and the RR of AEs was 1 in
20 (4.88\%). Details regarding allergologic evaluation and vaccination
are shown in table 2.

The aim of this study was dual: first, to evaluate the RR of presumed
AEs after vaccination and second, to evaluate the rate of AEs unrelated
to the vaccine in COVID-19-vaccine naïve patients. A recent
meta-analysis stated that 13.65\% of individuals experience reoccurrence
of nonlife-threatening symptoms after a second dose\textsuperscript{8}.
In our cohort, the RR of AEs was 4.88\%. The difference might be
explained by the fact that placebo administration enabled to distinguish
the effective reoccurrence of vaccine-induced symptoms from nocebo
effect\textsuperscript{9,10}. Actually, after exposure to placebo 28\%
of patients experienced symptoms (similar to the symptoms that occurred
upon previous exposure to the vaccine). Placebo-controlled provocation
is an important part of drug provocation tests (DPTs) but has not been
described before in the context of possible vaccination
hypersensitivity. Previous studies on placebo and nocebo effects in DPTs
demonstrate that patients with symptoms after exposure, anxiety and/or
depression are prone to nocebo effects\textsuperscript{11}.

We conclude that the RR of AEs after COVID-19 vaccination is low. A
thorough history and clinical details regarding symptoms and timing are
essential for correct risk stratification. The use of placebo is of
great value and should be considered in drug provocation tests,
especially in patients with a history of symptoms after previous
exposure and in patients with anxiety or depression.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Demographics & Demographics & Demographics & Value\tabularnewline
\midrule
\endhead
& M/F & M/F & 8/61\tabularnewline
& Mean age (range) & Mean age (range) & 52 (18-86)\tabularnewline
Relevant clinical history & Relevant clinical history & Relevant
clinical history & Relevant clinical history\tabularnewline
& Asthma & Asthma & 7/69\tabularnewline
& Chronic urticaria & Chronic urticaria & 3/69\tabularnewline
& Aeroallergy & Aeroallergy & 4/69\tabularnewline
& Hypothyroidism & Hypothyroidism & 4/69\tabularnewline
& Celiac disease & Celiac disease & 1/69\tabularnewline
& Chronic pain & Chronic pain & 1/69\tabularnewline
& Diabetes mellitus type II & Diabetes mellitus type II &
1/69\tabularnewline
& Breast carcinoma & Breast carcinoma & 1/69\tabularnewline
Reason for referral & Reason for referral & Reason for referral & Reason
for referral\tabularnewline
& Anxiety & Anxiety & 23/69\tabularnewline
& Multiple anaphylaxis & Multiple anaphylaxis & 1/69\tabularnewline
& Refused by vaccination center & Refused by vaccination center &
4/69\tabularnewline
& & Suspected hypersensitivity to unrelated drugs & 1/4\tabularnewline
& & Suspected hypersensitivity to macrogol & 1/4\tabularnewline
& & Anaphylaxis to diclofenac (which contains tromethamine) in clinical
history & 1/4\tabularnewline
& & Possibly angio-edema after unknown vaccine, more than 10 years ago &
1/4\tabularnewline
& Symptoms after 1\textsuperscript{st} or 2\textsuperscript{nd} dose (+)
& Symptoms after 1\textsuperscript{st} or 2\textsuperscript{nd} dose (+)
& 41/69\tabularnewline
& & (Pre)syncope, hypotension, palpitations immediate after vaccination
& 14/41\tabularnewline
& & Dyspnea immediate after vaccination & 8/41\tabularnewline
& & Dysphagia immediate after vaccination & 2/41\tabularnewline
& & Hoarseness immediate after vaccination & 1/41\tabularnewline
& & Nausea immediate after vaccination & 2/41\tabularnewline
& & Headache immediate after vaccination & 2/41\tabularnewline
& & Pruritus immediate after vaccination & 7/41\tabularnewline
& & Flushing immediate after vaccination & 1/41\tabularnewline
& & Urticaria immediate after vaccination & 4/41\tabularnewline
& & Urticaria \textgreater{} 1 day after vaccination &
2/41\tabularnewline
& & Unspecified skin rash & 4/41\tabularnewline
& & Angio-edema / sensation of swelling immediate after vaccination &
12/41\tabularnewline
& & Angio-edema / sensation of swelling \textgreater{}1 day after
vaccination & 2/41\tabularnewline
& & Measurement of acute serum tryptase & 0/41\tabularnewline
\bottomrule
\end{longtable}

Table 1: Patient characteristics

(+) 17 patients showed signs and symptoms compatible with an immediate
HR after administration of the vaccine.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
Skin testing (limited to patients with diagnosis of anaphylaxis) & Skin
testing (limited to patients with diagnosis of anaphylaxis) & Skin
testing (limited to patients with diagnosis of anaphylaxis) &
17/69\tabularnewline
\midrule
\endhead
& Polysorbate positive & Polysorbate positive & 1/7\tabularnewline
& Polysorbate negative & Polysorbate negative & 6/7\tabularnewline
& Macrogol negative & Macrogol negative & 12/12\tabularnewline
& Tromethamine negative & Tromethamine negative & 1/1\tabularnewline
Administered vaccine & Administered vaccine & Administered vaccine &
Administered vaccine\tabularnewline
& Comirnaty\selectlanguage{ngerman}® & Comirnaty\selectlanguage{ngerman}® & 57/69\tabularnewline
& Jcovden\selectlanguage{ngerman}® & Jcovden\selectlanguage{ngerman}® & 9/69\tabularnewline
& Vaxzevria\selectlanguage{ngerman}® & Vaxzevria\selectlanguage{ngerman}® & 3/69\tabularnewline
Symptoms immediately after vaccination & Symptoms immediately after
vaccination & Symptoms immediately after vaccination &
2/69\tabularnewline
& & Anaphylaxis (dyspnea, urticaria) & 1/2\tabularnewline
& & Urticaria & 1/2\tabularnewline
Symptoms after administration of placebo & Symptoms after administration
of placebo & Symptoms after administration of placebo &
19/69\tabularnewline
& & Subjective feeling of pharyngeal swelling & 4/19\tabularnewline
& & Generalized malaise & 4/19\tabularnewline
& & Headache & 3/19\tabularnewline
& & Pruritus & 3/19\tabularnewline
& & Thoracal pain & 3/19\tabularnewline
& & Nausea & 4/19\tabularnewline
& & Syncope & 1/19\tabularnewline
& & Palpitations & 4/19\tabularnewline
Symptoms after placebo per referral group & Symptoms after placebo per
referral group & Symptoms after placebo per referral group & Symptoms
after placebo per referral group\tabularnewline
& & Anxiety & 4/23\tabularnewline
& & Symptoms after 1\textsuperscript{st} or 2\textsuperscript{nd} dose &
14/41\tabularnewline
& & Multiple anaphylaxis & 0/1\tabularnewline
& & Refused by vaccination center & 1/4\tabularnewline
\bottomrule
\end{longtable}

Table 2: Details regarding allergologic evaluation and vaccination.

\emph{References}

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2. Chiang V, Wong JCY, Chan TS, Lau CS, Li PH. Under-awareness and
over-diagnosis of COVID-19 vaccine 'allergy'. \emph{Contact Dermatitis}
. Jul 25 2022;doi:10.1111/cod.14193

3. Banerji A, Norton AE, Blumenthal KG, Stone CA, Jr., Phillips E. Rapid
progress in our understanding of COVID-19 vaccine allergy: A cause for
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2022;150(1):12-16. doi:10.1016/j.jaci.2022.03.023

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6. Sabato V, Gaeta F, Valluzzi RL, Van Gasse A, Ebo DG, Romano A.
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7. Vitte J, Gonzalez C, Klingebiel C, Michel M. Tryptase and
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8. Chu DK, Abrams EM, Golden DBK, et al. Risk of Second Allergic
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doi:10.1001/jamainternmed.2021.8515

9. Bavbek S, Ayd\selectlanguage{polish}ı\selectlanguage{english}n \selectlanguage{ngerman}Ö, Sözener Z, Yüksel S. Determinants of nocebo effect
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10. Colloca L, Barsky AJ. Placebo and Nocebo Effects. \emph{N Engl J
Med} . Feb 6 2020;382(6):554-561. doi:10.1056/NEJMra1907805

11. Losappio LM, Cappai A, Arcolaci A, et al. Anxiety and Depression
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Pract} . Sep-Oct 2018;6(5):1637-1641. doi:10.1016/j.jaip.2017.12.005

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