A Rare Cutaneous Manifestation: Leukocytoclastic Vasculitis after Pfizer-BioNTech COVID-19 Vaccination

There is growing evidence that vaccines against SARS-CoV-2 can cause various skin reactions, many of which have autoimmune origins. These specific vaccine-induced autoimmune conditions with cutaneous manifestations include lupus erythematosus, bullous pemphigoid, vitiligo, alopecia areata, and leukocytoclastic vasculitis (LCV). In particular, LCV, which is also called hypersensitivity vasculitis, is an inflammation of small blood vessels. We present a case of an 81-year-old male evaluated in the emergency department for a bilateral purpuric non-blanching rash that appeared ten days after receiving the Pfizer-BioNTech booster vaccine against SARS-CoV-2. Results of a skin biopsy indicated LCV, and the rash completely resolved three weeks after clinical presentation.


Introduction
Vasculitis refers to infammation of blood vessels leading to tissue destruction with or without organ damage. Vasculitis is classifed as small, medium, or large vessel vasculitis and may be either idiopathic or associated with an underlying disease [1]. Leukocytoclastic vasculitis (LCV) is a smallvessel vasculitis characterized histopathologically by immune complex-mediated vasculitis of the dermal capillaries and venules [1,2]. Tis condition can be idiopathic or associated with infections, neoplasms, autoimmune disorders, certain drugs, and the administration of vaccines, including those for infuenza, hepatitis B virus (HBV), Bacille Calmette-Guérin (BCG), and human papillomavirus (HPV) [3]. LCV has been also identifed as a rare extraintestinal skin manifestation of ulcerative colitis and more commonly occurs after the UC diagnosis in 59% of cases, and 68% of patients have active intestinal disease at the time of LCV diagnosis [4]. Clinical features of LCV include palpable purpura, small vessel infammation, and extracutaneous involvement in approximately 30 percent of afected individuals [3]. In this report, we present a case of LCV after the patient received the Pfzer-BioNTech COVID-19 vaccine.

Case Presentation
An 81-year-old male with a past medical history of atrial fbrillation, hypertension, and hypothyroidism presented to the emergency department for evaluation of a bilateral lower extremity purpuric non-blanching rash that appeared two days prior. He had received the Pfzer-BioNTech booster vaccine against SARS-CoV-2 ten days before developing the rash. He reported having a similar rash after the second dose of the Pfzer-BioNTech COVID-19 vaccine six months before evaluation that was self-limited and resolved without further intervention. Physical examination was remarkable for purpuric 1 to 3 mm macules, some barely palpable and located in the shin and anterior and medial thighs of the lower extremities (Figures 1(a) and 1(b)). Tere was sparing of the abdomen, back, chest, upper extremities, and neck. Initial laboratory tests showed WBC 9.35 × 10 9 /L, Hgb 13.3 g/dL, HCT 41.9%, Na 137 mEq/L, K 3.9 mmol/L, Cr 1.09 mg/dL, AST 18 U/L, ALT 16 U/L, CRP 9 mg/L, ESR 16 mm/hr, C3 120 mg/dL, and C4 20 mg/dL. Urinalysis was normal and without evidence of proteinuria or microhematuria. Additional laboratory tests were negative and included cANCA, pANCA, ANA, Hep C, and B serologies, syphilis screen, and Lyme antibodies. Ultrasound of the lower extremities was also performed and showed no evidence of venous thrombosis. Patient home medications included aspirin, fnasteride, levothyroxine, and metoprolol tartrate. He denied the use of any new medications and any additional symptoms, including abdominal pain, vomiting, nausea, melena, hematochezia, hematuria, myalgia, arthralgia, fatigue, headache, fever, and chills.
Te patient was admitted to the medicine foor for further investigation of the bilateral lower extremities' purpuric rash. During hospitalization, the dermatology and rheumatology specialists evaluated the patient and recommended performing a skin biopsy. A skin biopsy was performed and showed extravasation of erythrocytes, perivascular infltrate of neutrophils, nuclear dust, and eosinophils, consistent with LCV and negative direct immunofuorescence (Figures 2(a) and 2(b)). Te consensus decision was to treat conservatively without the use of systemic corticosteroids or any additional treatment and the patient was discharged home. In the outpatient follow-up, the patient reported complete resolution of the rash three weeks after the symptoms frst appeared, and there was no need for any further testing or treatment.

Discussion
LCV is the histopathologic descriptor of a common form of small-vessel vasculitis involving arterioles, capillaries, and postcapillary venules [5]. Te disease can be confned to the skin or afect many organs, including the kidneys, central nervous system, heart, gastrointestinal tract, and lungs [6]. Te incidence of cutaneous LCV ranges from 15 to 38 cases per million annually in the United States and appears to afect both sexes and all ages equally, although some studies have noted a slightly higher incidence in males and older individuals [5]. LCV presents as erythematous macules with palpable purpura that involve primarily the lower extremities, but dependent areas, such as the back and buttocks, may also be afected [3,5]. Patients may be completely asymptomatic or complain of burning, itching, or pain in the involved skin. Systemic symptoms can appear in approximately 30% of patients and may include low-grade fever, malaise, weight loss, myalgias, arthralgias, blood in the urine or stool, abdominal pain, vomiting, cough, numbness, and weakness [7]. Te cutaneous manifestations of LCV usually appear approximately 1 to 3 weeks after the triggering event and usually resolve over 2 to 3 weeks [3,5].
Although history and physical examination are sometimes sufcient to establish a working diagnosis, systematic laboratory tests are usually warranted to perform the differential diagnosis [5]. Tests should include analysis for infectious diseases (e.g., HBV, HCV, and human immunodefciency virus), serum protein electrophoresis, immunoglobulins (IgG, IgA, and IgM), an antinuclear antibody panel, rheumatoid factor, serum C3, and C4 complement levels, ANCAs, and cryoglobulins [5,6]. Te cornerstone of LCV diagnosis is a skin biopsy with direct immunofuorescence, which should be performed whenever possible for confrmation [3]. After diagnosis, the recommended treatment depends on two major factors: the etiology and the extent of the disease. If LCV is limited to the skin, the management strategy should primarily focus on symptomatic relief since most acute episodes of cutaneous small-vessel vasculitis are self-limited and do not recur, even without treatment [3,5]. When the cause of LCV is obvious, such as infection or drugs, eliminating or treating the trigger, whenever possible is crucial and often sufcient. In contrast, treatment should generally include systemic corticosteroids when symptoms are severe, intractable, or recurrent [5].

Case Reports in Dermatological Medicine
Half of all cases of LCV are idiopathic but secondary causes such as infections and medications have been proposed as the most common triggers [7]. Te medications commonly known to cause LCV are beta-lactams, erythromycin, clindamycin, quinolones, vancomycin, sulfonamide, furosemide, allopurinol, NSAIDs, amiodarone, betablockers, TNF-alpha inhibitors, SSRIs, metformin, and warfarin [2,8]. In addition, several vaccines, including those against infuenza, HBV, BCG, and HPV, have been implicated in the development of LCV [7,9]. Including the case detailed here, there have been a few case reports of the development of LCV after administration of the Moderna and Pfzer-BioNTech COVID-19 vaccines [7]. Te mechanism by which the SARS-CoV-2 vaccine induces this type of vasculitis is not completely clear, but could potentially be driven by of-target immune activation after vaccination [7,9]. Te SARS-CoV-2 vaccines are DNA/RNA-based vaccines that contain recombinant adenoviral vectors encoding the spike protein of SARS-CoV-2, stabilizers, and immune adjuvants [10]. It is possible that molecular mimicry might develop between the peptides that are expressed in the viral spike protein and host endothelial cells [10,11]. It has been suggested that the SARS-CoV-2 spike protein can activate the alternative complement pathway, thereby leading to the infammation of the cutaneous microvasculature.
Recent studies show evidence that the administration of the Moderna and Pfzer-BioNTech COVID-19 vaccines can lead to the development of cutaneous manifestations. Tese cutaneous manifestations ranged in a wide spectrum, including chilblain-like, urticarial eruptions, vesicular, morbilliform eruptions, livedoid, delayed large reactions, local injection site reactions, and vasculitis lesions [12,13]. Delayed large local reactions are mostly found, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions [12,13]. Additionally, fewer common reactions include pernio, cosmetic fller reactions, zoster, herpes simplex fares, and pityriasis rosea-like reactions [13]. Recent data shows that approximately 20% of patients receiving the Pfzer-BioNTech COVID-19 vaccine reported skin reactions after the frst dose only, 74% after the second dose only, and 6.0% after both doses, but there is insufcient evidence after the booster dose. Te case presented here shows some new evidence of cutaneous manifestation after the booster vaccination. Te patient in this case didn't have any systematic symptoms such as fever, abdominal pain, fever, arthralgia, or renal failure at the time of presentation, ruling out other forms of systemic vasculitis including IGA vasculitis, and suggesting more a cutaneous limited form of vasculitis like LCV. Although vasculitis development after SARS-CoV-2 vaccine administration could be worrisome, data suggest that cutaneous reactions to SARS-CoV-2 vaccination are generally minor and selflimited and should not discourage vaccination [13].

Conclusions
Vaccines against COVID-19 represent a pivotal and efective countermeasure to control the COVID-19 pandemic. Tis case reveals a potential association between the administration of a COVID-19 vaccine and the development of vasculitis. Tis could be secondary to complement activation or autoimmunity provoked by the vaccine's SARS-CoV-2 spike protein, leading to infammation of the cutaneous microvasculature and resulting in vasculitis [3]. Although vasculitis may not be considered a contraindication of vaccination, further investigation is necessary to clarify the characteristics of vasculitis following COVID-19 vaccination.

Data Availability
All the data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Ethical Approval
Ethical approval is not required for this study in accordance with local or national guidelines.

Consent
Te patient gave written informed consent for the publication of the case and accompanying images. Te patient understood that his name and initial will not be published and due eforts will be made to conceal his identity.

Conflicts of Interest
Te authors declare that they have no conficts of interest.

Authors' Contributions
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for the manuscript, take responsibility for the integrity of the work, and have given fnal approval to the version to be published. Yaritza Serrano Gomez conceptualized the study, performed acquisition, interpreted the study, designed, and prepared the manuscript. Brittney Grella performed acquisition, edited and reviewed the article. Hongbei Wang performed histopathological imaging analysis and interpretation.