Cutaneous leukocytoclastic vasculitis following COVID-19 vaccination 
with Ad26.COV2.S vaccine: a case report and literature review
Laura Đorđević Betetto1, Boštjan Luzar2,3, Živa Pipan Tkalec2, Svjetlana Ponorac1,3 ✉
1Department of Dermatovenereology, University Medical Centre Ljubljana, Ljubljana, Slovenia. 2Institute of Pathology, Faculty of Medicine, University 
of Ljubljana, Ljubljana, Slovenia. 3Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
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2022;31:83-87
doi: 10.15570/actaapa.2022.12
Introduction
The COVID-19 pandemic is one of the greatest challenges not only 
in modern medicine but even in modern history. The need to stop 
the high transmission rate and mortality led to the rapid develop-
ment of various types of vaccines and their authorization for use. 
Because the number of immunized persons worldwide is increas-
ing, reports of post-vaccination cutaneous adverse events have 
also begun to emerge. The incidence of cutaneous adverse events 
after COVID-19 vaccines is low, with local injection site reactions, 
delayed large local reactions, urticaria, and morbilliform erup-
tions most frequently reported (1, 2). Severe cutaneous adverse 
events are even more rare, with only a few cases reporting cutane-
ous vasculitis (1, 3–15).
We present a case of cutaneous leukocytoclastic vasculitis 
(CLV) occurring 17 days after inoculation with adenoviral vector 
vaccine (Ad26.COV2.S).
Case report
A 30-year-old previously healthy male patient presented to our 
dermatology department in October 2021 with a 10-day history of 
painful hemorrhagic papules and vesicles on his soles, shins, and 
elbows. He denied abdominal pain, hematuria, or gastrointesti-
nal, musculoskeletal, or respiratory symptoms. Apart from receiv-
ing the first dose of COVID-19 adenoviral vector vaccine (Ad26.
COV2.S) 17 days prior to the occurrence of the lesions, his medi-
cal history was unremarkable. He denied any signs of infection or 
taking new medications or dietary supplements. He also denied 
any previous drug- or vaccine-associated adverse events.
On clinical examination, purpuric and hemorrhagic non-
blanching papules and vesicles, some with central erosions, were 
present on both soles and spreading onto the dorsum of the feet 
and distal part of the legs. Some hemorrhagic vesicles were also 
present on the elbows. The lesions on the soles were painful and 
more nodular on palpation (Fig. 1). There was no mucosal involve-
ment or lymphadenopathy, and the rest of the clinical examina-
tion was normal.
Laboratory blood examinations (complete blood count, com-
prehensive metabolic panel, international normalized ratio, C-
reactive protein, erythrocyte sedimentation rate, liver function 
panel, blood urea nitrogen, creatinine, and glomerular filtration 
rate) revealed mild leukocytosis (10.3; reference range 4.00–10.00 
10^9/l), neutrophilia (8.24 and 80%; reference range 1.50–7.40 
10^9/l and 40.0–80.0%), and a slightly elevated erythrocyte 
sedimentation rate (18; reference range 0–15 mm/h). Urinalysis 
showed moderate proteinuria (2), and the urine sediment exami-
nation showed borderline erythrocyturia (3; reference range up 
to 3). Further etiopathological laboratory workup (anti-neutrophil 
cytoplasmic antibodies, cryoglobulins, anti-nuclear antibodies, 
extractable nuclear antigen antibodies, anti-double stranded 
DNA antibodies, antiphospholipid antibodies, and rheumatoid 
factor) was negative.
A punch biopsy from the left foot was performed and showed 
erosion of the epidermis and papillary dermis with surrounding 
reactive changes and only discrete vasculitis changes, suggestive 
of secondary vasculitis. For direct immunofluorescence (DIF) mi-
croscopy, a skin sample was frozen in liquid nitrogen and cryostat 
sections were stained with FITC-labeled antisera to human im-
munoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin 
M (IgM), complement component 3 (C3), complement component 
1q (C1q), and fibrin/fibrinogen (DakoCytomation, Denmark). The 
results were positive for granular deposits of IgM, C3, and fibrin/
fibrinogen in the walls of the small vessels in the dermis, poten-
tially compatible with vasculitis, although this could also be un-
specific or secondary (Fig. 2).
Abstract
Cutaneous vasculitis is a recognized and potentially serious adverse event of immunization with several vaccines, and COVID-19 
vaccines are no exception. We present a case of cutaneous leukocytoclastic vasculitis occurring 17 days after inoculation with ad-
enoviral vector vaccine (Ad26.COV2.S) in a previously healthy 30-year-old patient with no history of prior adverse events following 
vaccination. Transient laboratory abnormalities (mild proteinuria, cryoglobulinemia, and slightly diminished C3 complement level) 
were also noted, but they resolved with the resolution of skin changes after treatment with topical steroids. Although the frequen-
cy of cutaneous vasculitis after COVID-19 vaccines is extremely low, it presents an important challenge for the clinician when faced 
with an uncertain and delicate decision whether these patients can safely receive booster doses of COVID-19 vaccine. Because 
vaccination certificates are necessary for day-to-day activities and have a limited validity date, this may be an uncomfortable issue.
Keywords: cutaneous small vessel vasculitis, leukocytoclastic vasculitis, COVID-19 vaccine, Ad26.COV2.S, adverse events, cryo-
globulinemia
Acta Dermatovenerologica 
Alpina, Pannonica et Adriatica
Acta Dermatovenerol APA
Received: 1 April 2022 | Returned for modification: 4 May 2022 | Accepted: 31 May 2022
✉ Corresponding author: svjetlana.ponorac@kclj.si
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Acta Dermatovenerol APA | 2022;31:83-87L. Đorđević Betetto et al.
The patient was instructed to rest and was prescribed a potent 
topical corticosteroid cream. At a checkup 10 days later, we ob-
served some new lesions on the feet and regression of the lesions 
on the elbows. A punch biopsy from a lesion on the foot was re-
peated, and the histopathology changes were now more evident 
and consistent with leukocytoclastic vasculitis (Fig. 3). The results 
of DIF were similar to the previous examination and showed gran-
ular deposits of IgM, C3, and fibrin/fibrinogen in the walls of the 
small vessels in the dermis (Fig. 2). A diagnosis of cutaneous small 
vessel vasculitis (SVV) was established; the patient was admitted, 
and further diagnostic evaluation proceeded.
Chest X-ray and abdominal ultrasound were normal. Routine 
laboratory tests and additional specific blood tests (serum protein 
electrophoresis, fibrinogen, D-dimer, lactate dehydrogenase, lu-
pus anticoagulants, cold agglutinins, complement activation as-
say, and levels of C3 and C4 complement) revealed a slightly lower 
level of complement C3 (0.55; reference range 0.60–1.30 g/l) and 
C4 level at the lower limit (0.10; reference range 0.10–0.30 g/l), 
but these were otherwise within normal limits. Cryoglobulins were 
incidentally re-ordered and were surprisingly positive (the titer 
was not determined). Serologies for Epstein–Barr virus, human 
immunodeficiency virus (HIV), syphilis, hepatitis B virus (HBV), 
and hepatitis C virus (HCV) were negative, as well as SARS-CoV-2 
RT-PCR of the nasopharynx. Repeated fecal occult blood test and 
urinalysis were normal. Due to previously detected proteinuria, a 
nephrologist was consulted, who excluded renal involvement.
Because a steady regression of skin lesions was noted, we 
continued treatment with local corticosteroids, which resulted in 
somewhat slow but complete regression of skin lesions after a few 
weeks. At a checkup, a laboratory test for cryoglobulins was re-
peated and was negative. With regard to no other instigating event, 
negative diagnostic evaluation of commonly recognized causes of 
vasculitis, and a clear temporal association, our patient’s cutane-
ous vasculitis was linked to the Ad26.COV2.S vaccine. The patient 
was referred to an allergologist for evaluation regarding whether 
he can receive other COVID-19 vaccines in the future. A report of an 
adverse event was also submitted to the national drug and vaccine 
adverse event reporting system.
Discussion
CLV is a SVV (16) in which a predominant neutrophil inflamma-
tion and leukocytoclasia surrounding cutaneous vessels can be 
seen on histopathology (17, 18). Leukocytoclasia is a process in 
which neutrophils undergo death and break down, releasing nu-
clear debris, also called nuclear dust (17). The terms cutaneous 
SVV and CLV are often used interchangeably because most cases 
of cutaneous SVV show leukocytoclasia on histopathology (19, 
Figure 1 | Clinical presentation, patient at the time of presentation: palpable purpuric non-blanching deeply set tender papules and vesicles, some with central 
erosions on the A) ankle, B) sole, and C) elbows; patient at last control examination: D) complete regression of skin changes with only a few discrete hyperpig-
mented macules on the soles.
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Acta Dermatovenerol APA | 2022;31:83-87 Cutaneous adverse event of COVID-19 vaccine
Figure 2 | Direct immunofluorescence revealed A) IgM, B) C3, and C) fibrinogen deposits in the dermal vessel walls (magnification: 400× in A and B, 200× in C). IgM 
= immunoglobulin M, C3 = complement component 3.
Figure 3 | Histopathologic changes characteristic of leukocytoclastic vasculitis: A) low-power magnification showing acral skin with dense superficial and deep 
perivascular and interstitial inflammatory cell infiltrate accompanied by extravasation of erythrocytes; B) intermediate-power magnification revealing perivascular 
and interstitial inflammatory cell infiltrate with extravasation of erythrocytes; C) high-power magnification; endothelial cells of the superficial vascular plexus are 
swollen. Note also extravasation of erythrocytes, perivascular and interstitial mixed inflammatory cell infiltrate, and nuclear debris.
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Acta Dermatovenerol APA | 2022;31:83-87L. Đorđević Betetto et al.
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vigilant attentiveness after new vaccine implementation remains 
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with self-antigens (28). Because some of the vaccine proteins are 
analogous to viral antigens, the pathogenetic mechanism may 
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In our case, CLV was also accompanied by transient laboratory 
abnormalities, such as mild proteinuria, low complement levels, 
and cryoglobulinemia. This constellation of laboratory changes 
and CLV has been reported in two other patients after COVID-19 
vaccination (11, 15) and also after pneumococcal (29) and influen-
za (30) vaccinations. In our patient, cryoglobulins were negative 
at the time of first presentation, and cryoglobulinemia occurred 
more than a month after initial cutaneous symptoms. This peculi-
arity points toward a clinically insignificant transient cryoglobu-
linemia, unlike two other cases, in which true cryoglobulinemic 
vasculitis developed (15, 29). Detectable cryoglobulins, without 
clinical manifestations of vasculitis, can be found even in healthy 
individuals, but they are particularly common in patients with 
connective tissue disorders, such as systemic lupus erythemato-
sus (31), and chronic infections such as HIV and HCV, and espe-
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these laboratory changes combined with the onset of vasculitis 
in a previously healthy individual only heightens the probability 
of an immune-mediated etiopathological link with the COVID-19 
vaccine. Although we cannot exclude the coincidental onset of 
vasculitis, the temporal association with COVID-19 immunization 
and no other instigating event support their causal relationship.
Finally, because the COVID-19 certificate of our patient is about 
to expire, we are faced with another delicate decision: can pa-
tients that have experienced cutaneous vasculitis or other poten-
tially serious cutaneous adverse events after COVID-19 immuniza-
tion receive a booster dose and, if so, which type of vaccine is safe 
for them to receive? A study on cutaneous adverse events follow-
ing mRNA COVID-19 vaccines reported that cutaneous reactions 
to mRNA COVID-19 vaccines are generally mild and transient. 
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the second dose. It was therefore concluded that cutaneous ad-
verse events are not a contraindication for further doses (1). How-
ever, in cases of cutaneous vasculitis or other potentially serious 
adverse events, the answer is more complex and uncertain.
Nevertheless, the substantial repercussions of the COVID-19 
pandemic on physical and psychological health, as well as on so-
cioeconomic aspects of life, underscore the need for increasing 
the global immunization rate and getting the virus under control.
Conclusions
Cutaneous vasculitis is a recognized and potentially serious ad-
verse event of immunization with several vaccines, and COVID-19 
vaccines are no exception. Its frequency seems to be extremely 
rare, although that might increase with immunization coverage 
rates. Because vaccination certificates are becoming necessary 
for day-to-day activities but have a limited validity date, doctors 
may be faced with the delicate decision of determining whether 
booster doses of COVID-19 vaccines are safe for such patients.
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