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\title{Bullous hemorrhagic Sweet syndrome induced by SARS-CoV-2 Oxford
AstraZeneca vaccine}



\author[1]{T. Zagar}%
\author[1]{N. Hlaca}%
\author[1]{I. Brajac}%
\author[1]{L. Prpic-Massari}%
\author[1]{S. Peternel}%
\author[1]{M. Kastelan}%
\affil[1]{Klinicki bolnicki centar Rijeka}%


\vspace{-1em}



  
  \date{June 14, 2024}


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Bullous hemorrhagic Sweet syndrome induced by SARS-CoV-2 Oxford
AstraZeneca vaccine

T. Zagar\textsuperscript{1}, N. Hlaca\textsuperscript{1,2}, I.
Brajac\textsuperscript{1,2}, L. Prpic-Massari\textsuperscript{1,2} , S.
Peternel\textsuperscript{1,2}, M. Kastelan\textsuperscript{1,2}

\textsuperscript{1}Department of Dermatovenerology, Clinical Hospital
Centre Rijeka, Rijeka, Croatia; and \textsuperscript{2}Faculty of
Medicine, University of Rijeka, Rijeka, Croatia

Corresponding author:

Nika Hla\selectlanguage{polish}č\selectlanguage{english}a, MD

Department of dermatovenerology, Clinical Hospital Centre Rijeka

Faculty of Medicine, University of Rijeka, Rijeka, Croatia

e-mail: nika.hlaca@uniri.hr

tel: +38551658283

mobile: +385915607690

Word count: 596

Figures: 2

Competing interests

The authors declare that they have no competing interests.

Acknowledgement

All authors read and agreed to the final version of this manuscript. TZ,
NH, SP and MK conceived the original idea and wrote the final version of
manuscript. IB and LPM have been involved in drafting the manuscript and
revising it critically for important intellectual content.

Informed consent was obtained from the patient for publication of this
report.

To the editor,

Concurrent to the increasing use of COVID-19 vaccines, the number of
vaccine-related adverse reactions has also increased\textsuperscript{1}.
We report a case of a 49-year-old male patient who presented with a
10-day-history of generalized painful cutaneous eruption. He denied any
preceding respiratory or gastrointestinal symptoms or introduction of
any medications, however, ten days before the rash onset, he received
the first dose of the SARS-CoV-2 Oxford-AstraZeneca vaccine. Upon
physical examination, we observed symmetrically distributed erythematous
to violaceous vesicular papules and targetoid plaques on the lower part
of the trunk and extremities, along with multiple grouped hemorrhagic
blisters on both hands and feet (Figure 1A). Fingers of the right hand
were edematous with large tense hemorrhagic bullae, while the left hand
was less affected (Figure 1B). The patient was subfebrile and reported
mild arthralgia, no other extracutaneous symptoms were present. Initial
laboratory tests showed leukocytosis with neutrophilia, while C-reactive
protein, liver and renal function tests, urine analysis, ANA, ANCA,
cryoglobulins, rheumatoid factor were all within the reference range.
The SARS-CoV-2 RT-PCR test was negative, while IgG SARS-CoV-2 antibodies
were positive (895.3 AU/ml). Serology tests for viral and bacterial
agents were all negative. Chest X-ray and abdominal ultrasound were
unremarkable. Histopathological analysis revealed dense perivascular and
periadnexal to diffuse neutrophilic infiltrate with marked
leukocytoclasia involving the upper and mid-dermal layers. There was
massive edema of papillary dermis resulting in subepidermal blister
along with extravasated erythrocytes (Figure 2A-B). These findings were
consistent with Sweet syndrome (SS). Thus, intravenous
methylprednisolone (0.8 mg/kg/d) was initiated and most of the existing
lesions started to recede in the next few days. Due to suspected
secondary ischemia of the right-hand fingers, the vascular surgeon
recommended antithrombotic prophylaxis with low-molecular-weight heparin
and acetylsalicylic acid in addition to hyperbaric oxygen therapy. After
two weeks of ongoing treatment, there was remarkable improvement in
clinical status. The patient was discharged from the hospital with
methylprednisolone 32 mg daily therapy and slow tapering over the
following eight weeks.

Up to date, the most commonly reported cutaneous adverse events of
SARS-CoV-2 vaccines are mild to moderate injection-site reactions
occurring as a result of nonspecific stimulation of
inflammation\textsuperscript{1}. To our knowledge, there are only ten
cases of SS induced by any vaccine reported in the literature, three
with seasonal influenza, two with pneumococcal, two with tuberculosis,
two with smallpox, one with influenza A\textsuperscript{2}.
Additionally, three cases of acute febrile neutrophilic dermatosis
induced by SARS-CoV-2 Pfizer-BioNTech mRNA vaccines have been reported
so far. In the reported cases, the time from vaccination to the onset of
the skin lesions ranged from 12 hours to 15 days\textsuperscript{1,3,4}.
Our patient developed SS 10 days after the first dose of the
Oxford-AstraZeneca vaccine. Generally, local and systemic reactions to
the Oxford-AstraZeneca vaccine were mild and reported more often after
the first dose and more frequently in adults aged
18-65\textsuperscript{1}. Vaccination with Oxford-AstraZeneca is linked
to thromboembolic events and very rarely to prothrombotic immune
thrombocytopenia with cutaneous lesions similar to drug-induced
cutaneous vasculitis\textsuperscript{1}.

The bullous variant of SS, seen in our case, is a rare form of the
disease. Drugs, tumors or infectious agents may start a network of
cytokines involved in the onset of SS\textsuperscript{5}. SARS-CoV-2
infection may also trigger SS as reported recently\textsuperscript{6}.
To our best knowledge, this is the first case of SS induced by the
Oxford-AstraZeneca vaccine. Balancing the possible link between
vaccination and SS, we decided to contraindicate the second dose of
vaccine for our patient. Because of the ongoing pandemic and
introduction of new vaccines, it is of great importance that all
potential side effects are reported and considered.

References

\begin{enumerate}
\tightlist
\item
  Castells MC, Phillips EJ. Maintaining Safety with SARS-CoV-2 Vaccines.
  N Engl J Med 2021;384: 643-649.
\item
  Pedrosa AF, Morais P, Nogueira A, Pardal J, Azevedo F. Sweet's
  syndrome triggered by pneumococcal vaccination. Cutan Ocul Toxicol
  2013;32:260-261.
\item
  Darrigade AS, Th\selectlanguage{ngerman}éophile H, P, Sanchez-Pena P, Milpied B, Colbert M,
  Pedeboscq S, Pistone T, Jullié ML, Seneschal J. Sweet syndrome induced
  by SARS-CoV-2 Pfizer-BioNTech mRNA vaccine. Authorea March 12 2021.
  doi: 10.22541/au.161553544.40263874/v1.
\item
  Banerji A, Wickner PG, Saff R, Stone CA Jr, Robinson LB, Long AA,
  Wolfson AR, Williams P, Khan DA, Phillips E, Blumenthal KG. mRNA
  Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions:
  Current Evidence and Suggested Approach. J Allergy Clin Immunol Pract
  2021;9:1423-1437.
\item
  Heath MS, Ortega-Loayza AG. Insights Into the Pathogenesis of Sweet's
  Syndrome. Front Immunol 2019;10:414.
\item
  Ta\selectlanguage{polish}ş\selectlanguage{english}k\selectlanguage{polish}ı\selectlanguage{english}n B, Vural S, Altu\selectlanguage{polish}ğ \selectlanguage{english}E, Demirkesen C, Kocat\selectlanguage{ngerman}ürk E, Çelebi \selectlanguage{polish}İ,
  \selectlanguage{english}Ferhano\selectlanguage{polish}ğ\selectlanguage{english}lu B, Alper S. Coronavirus 19 presenting with atypical Sweet's
  syndrome. J Eur Acad Dermatol Venereol 2020;34:e534-e535.
\end{enumerate}

Figure 1. Clinical presentation of Sweet syndrome; a) edematous
red-violet papules and targetoid plaques on the trunk and lower
extremities, b) violaceous, edematous plaques and hemorrhagic blisters
on hands.

Figure 2. Skin biopsy from the lower trunk showing (a) subepidermal
blister and diffuse dermal inflammatory infiltrate (H\&E, 100x)
consisting of (b) predominantly neutrophils with pronounced
leukocytoclasia (b, 400x).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1-SS/Figure-1-SS}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-SS/Figure-2-SS}

\end{center}
\end{figure}

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