Alberto Corrà1†
Alice Verdelli2†
Elena Biancamaria Mariotti1
Valentina Ruffo di Calabria1
Lavinia Quintarelli2
Cristina Aimo1
Cord H. Sunderkötter3
Marzia Caproni2*- 1Section of Dermatology, Department of Health Sciences, University of Florence, Florence, Italy
- 2Immunopathology and Rare Skin Diseases Unit, Department of Health Sciences, Azienda USL Toscana Centro (ERN-SKIN), University of Florence, Florence, Italy
- 3Department of Dermatology and Venereology, University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
Cutaneous vasculitis (CV) is an inflammatory skin-limited vascular disease affecting the dermal and/or hypodermal vessel wall. From the pathogenetic point of view, idiopathic forms are described as well as the induction from various triggers, such as drugs, infections, and vaccines. Following SARS-CoV-2 pandemic outbreak, cases of CV induced by both COVID-19 and COVID-19 vaccinations have been reported in literature. The aim of our work was to collect multiple cases available in the literature and analyze the frequency of the different forms of induced vasculitis, as well as their histological and immunopathological features. Although rare, CV induced by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and vaccines may provide interesting insights into the pathogenesis of these inflammatory processes that may in the future be useful to understand the mechanisms underlying cutaneous and systemic vasculitis.
Introduction
The term vasculitis encompasses a wide and heterogeneous group of disorders with shared histopathological findings. It is a pathological process characterized by an inflammatory process affecting the vessel wall, both arterial and venous, of different sizes and of any body area (1). Inside the vessel wall, there is an infiltrate, which can create discontinuity of the wall itself with red blood cells leaking. One of the most successful attempts at proper classification of such condition has been proposed by the 2012 Chapel Hill consensus cVonference nomenclature of vasculitides (CHCC 2012) (2), which divides them according to the diameter of the affected vessel: Large Vessel Vasculitis and Medium Vessel Vasculitis, which in the skin can cause necrosis and ulceration and livaedo reticularis; Small Vessel Vasculitis, manifesting with purpura and vesiculo-bullous lesions.
Since the skin is one of the most affected organs in vasculitides, in 2018, a Dermatological Addendum has been suggested to further help the clinician in dealing with such conditions, improving the definition of some forms of cutaneous vasculitis (CV) and adding other dermatological relevance (3). Accordingly, CV may be a cutaneous manifestation of systemic vasculitis or a skin-limited or skin-dominant variant of systemic vasculitis, but when affecting only the skin in the absence of any other systemic involvement, the term single-organ vasculitis (SOV) should be used.
CV is mainly a small-vessel vasculitis affecting dermal and/or hypodermal capillaries and venules, which usually show histopathologic findings consistent with leukocytoclastic vasculitis, characterized by fibrinoid necrosis of vessel wall, erythrocyte extravasation, and neutrophilic infiltrate with degeneration known as leukocytoclasis with nuclear dust (karyorrhexis) (4). The immune infiltration may be mainly lymphocytic in lesions that appeared more than 48 h before. Direct immunofluorescence (DIF) of lesional skin is helpful in the diagnosis of CV, with maximum efficacy for the diagnosis of IgA vasculitis and lupus vasculitis. It can aid in the accurate diagnosis even when the histological changes are minimal (5–7). However, DIF positivity is strongly influenced by the timing of the biopsy (8).
Even though in more than half cases of CV it is impossible to assess the disease-inducing or promoting factor, it is well-known that the most common triggering factors are related to immunopathogenic mechanisms secondary to infections or drug intake (9, 10). Therefore, it is not surprising that since the beginning of the COVID-19 pandemic and after the introduction and administration of COVID-19 vaccines on a global scale, cases of COVID-19-associated and vaccine-associated CV have been reported (11–13).
When involving the skin, clinical manifestations of the COVID-19 infection show a great range of signs and symptoms (14). Five major classes of cutaneous manifestations in the setting of COVID-19 infection have been proposed by Tan et al. (15), e.g., pseudo-chilblains lesions, urticarial rash, vesicular (varicella-like) eruption, maculo-papular rash, and vaso-occlusive lesions. Several cases of both new onset and flares of CV have also been linked to COVID-19 and SARS-CoV-2 vaccination. However, they are not included in the aforementioned classification due to their low frequency (12, 16, 17).
Similarly, many heterogeneous cutaneous reactions to COVID-19 vaccination have been reported and classified by Shakoei et al. into the following major categories: local site reactions, type 1 (immediate) hypersensitivity reactions, type 4 (delayed) hypersensitivity reactions, autoimmune-mediated reactions, functional angiopathies, and reactivation of other viral conditions (18). In this classification, CV are classified among the auto immune-mediated reactions. Most of the cases reported occurred after the administration of messenger ribonucleic acid (mRNA)-based vaccines (19). In the literature, vaccine-associated CVs have been more frequently reported than CVs secondary to the COVID-19 infection. The number of persons that received at least one dose of the vaccine worldwide is larger when compared to that of the persons who contracted the infection. However, it is known that the vaccine reproduces only a small degree of adverse effects provoked by the natural infection of the immune system. Therefore, more vaccine-associated CVs are diagnosed and reported due to the greater attention that has been given by patients to all the side effects related to the COVID-19 vaccine.
In this review, we analyze and compare the current and most recent literature on clinical and immunohistopathologic features of CV induced by systemic SARS-CoV-2 infection and CV secondary to the SARS-CoV-2 vaccine, focusing on the possible underlying pathogenetic mechanisms.
SARS-CoV-2 infection and cutaneous vasculitis
We collected clinicopathological features of a series of CV that occurred in association with the SARS-CoV-2 infection available in the literature (Table 1). Our search was restricted to cases with histological confirmation of leukocytoclastic vasculitis. Totally, 19 cases were included, mostly males (13/19) with variable age distribution ranging from 13 to 93 years with an average of 48.4 years. In three cases, the diagnosis was COVID-19-associated IgA vasculitis, while in five cases the patients had been diagnosed with COVID-19-associated urticarial vasculitis; finally, the other cases may be considered as cutaneous leukocytoclastic vasculitis associated with COVID-19, being not further classified according to the Dermatologic Addendum to the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (3). Regarding the clinical presentation, a comparison between the frequency of different types of lesions did not reveal feasible given the heterogeneity of their description. However, it is reasonable to consider palpable purpura as the main clinical manifestation, sometimes with necrotic features and hemorrhagic blistering. The most common sites affected were the lower limbs and trunk, as for the idiopathic forms of CV. The cases diagnosed with urticarial vasculitis showed slight clinical differences, since skin lesions were characterized by wheals or urticarial manifestations, associated with purpuric aspects. The edematous component of cutaneous lesions in COVID-19-associated urticarial vasculitis was appreciable at histological evaluation in 2 out of 5 cases, whose report mentioned dermal or endothelial swelling. The latency time between skin rash occurrence with SARS-CoV-2 infection is highly variable, ranging from concomitant signs appearing at the time of onset to more than 30 days after the first positive nasopharyngeal swab. The totality (3/3) of COVID-19-associated IgA vasculitis cases presented kidney involvement, but it is of interest that in two out of three cases, the direct immunofluorescence (DIF) performed on lesional skin resulted negative while positivity was seen in all three cases when performed on kidney biopsy. Although based on a few cases, our results are in accordance with Jedlowski et al., which published a case series of 10 subjects with COVID-19-associated systemic IgA vasculitis; in fact, authors found positive skin DIF in less than half of the series (40%) while kidney biopsies showed IgA deposition in all the cases. Moreover, it is of note that COVID-19-associated IgA vasculitis more commonly affects adults when compared to the classical form of IgA vasculitis in which 90% of cases occur in the pediatric population. In our series, one DIF resulted non-specifically positive for C3, while in nine cases, it was negative for all the reactants. No cases of cutaneous IgG/IgM vasculitis were diagnosed and in eight subjects DIF was not performed. Interestingly, three cases assessed the colocalization of SARS-CoV-2 in the vessel wall, finding positivity in 2/3 cases by the PCR technique. This may support the direct role of SARS-CoV-2 in the pathogenesis of cutaneous vasculitis and its tropism for a broad variety of human tissues.
Table 1. Clinical, histological, and immunological findings in patients with COVID-19-associated CV.
SARS-CoV-2 vaccination and cutaneous vasculitis
In the mini-series presented (Table 2), only patients with histological confirmation of leukocytoclastic vasculitis were included. Totally, 39 patients developed CV after the COVID-19 vaccine. Women were found to be more involved than men, counting 24 females vs. 15 males developing CV. The weighted average of the patients reported was of 53.2 years (range 22–94).
Table 2. Clinical, histological, and immunological findings in patients with COVID-19-vaccine associated CV.
Clinically, purpuric papules or maculae in the lower extremities were the most commonly reported skin manifestation (Figure 1). DIF was not reported in 21 cases (53.8%) and in 5 cases (12.8%) it was negative. Features were heterogeneous in the remaining 13 cases, with 5 cases (12.8%) of IgA vasculitis and 3 cases (7.7%) of vasculitis with C3 deposition, and some isolated cases of IgM vasculitis with fibrinogen deposit.
Figure 1. (A,B) Purpuric maculae and papules in the lower extremities in a patient with a recent anamnesis of COVID-19 vaccination. (C,D) Direct immunofluorescence performed on lesional skin, with evidence of perivascular deposition of C3. (c: 10% magnification, d: 20% magnification).
Most of the reported cases (n = 19, 48.7%) were associated with mRNA vaccines; particularly, 13 patients underwent BNT162b2 [BioNTech/Pfizer] vaccines and five patients underwent mRNA-1273 [Moderna] vaccines. In one case, the commercial name of the vaccine was not reported. Eleven cases (28.2%) of CV were associated with adenoviral vector-based vaccines, of whom 10 were with ChAdOx1 nCoV-19 [Oxford-AstraZeneca] and one was with Ad26.Cov2.S [Johnson & Johnson].
Among the nine cases (23.1%) associated with inactivated vaccines, only one was not named, three cases were found after the administration of both Covaxin and Sinovac, and two cases after Sinopharm administration.
Nineteen patients (48.7%) developed CV after the first dose of the vaccine, while 16 (41%) after the second dose; only 3 (7.7%) cases were reported to occur after the third dose of the vaccine injection. In one case (2.6%), the dose number was non-specified.
Discussion
Our review reported the main aspects of both CVs induced by COVID-19 infection and vaccines. Only leukocytoclastic vasculitis was included, and DIF pattern was also analyzed. Unfortunately, in many of the reported cases, DIF was not conducted, while some cases were negative. Its evaluation is extremely important in defining the type of CV and DIF positivity may raise the suspicion of systemic disease, providing useful prognostic information where histology alone cannot. Therefore, DIF should be always performed especially on early lesions because immune deposits may disappear in lesions that occurred more than 48 h before.
To date, the exact pathogenetic mechanisms underlying COVID-19-associated CV have not been fully understood. Since its outbreak in 2019, COVID-19 had spread all over the world causing a global pandemic affecting more than 500 million people and at least 6 million deaths (20). The enveloped RNA virus called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiologic agent, which primarily affects the respiratory tract leading to general symptoms like fever, fatigue, anosmia, and dysgeusia, while respiratory symptoms are variable in severity ranging from cough and rhinorrhea to dyspnea, pneumonia, or acute respiratory distress syndrome. However, evidence about the involvement of other organs and systems is increasing; in fact, knowledge about the neurological, gastrointestinal, and ocular manifestations of SARS-CoV-2 infection is deepening (21, 22). Similarly, cutaneous signs of COVID-19 are continuously reported and attempts at classifications are already available in the literature, together with the first prevalence estimations in which dermatologic manifestations would place between 1.8 and 20.4% of the COVID-19 patients (23, 24). In particular, several works identified clusters of skin manifestations that are suggestive of skin vascular damage, namely chilblain-like lesions, acral ischemia, acral vasculitis, livedo reticularis, livedo racemosa, purpuric “vasculitic” rash, or petechial eruptions (25–27). While a definitive nomenclature is justifiably actually lacking, considering the novelty of these entities, it is well known that SARS-CoV-2 features a markable tropism for endothelial cells. The first hypothesis of vascular damage provoked by the novel coronavirus was provided from autoptic studies showing platelet-fibrin thrombi in lung blood vessels in patients who died of severe COVID-19 (28), advancing the evidence of coagulopathy as a main pathogenetic mechanism of single- or multiorgan damage induced by SARS-CoV-2. Indeed, the term “immunothrombosis” is now used to refer to the typical pattern of lung damage resulting from massive viral-induced inflammation, which leads to the activation of the endothelium and triggers intravascular coagulation. Similar mechanisms may be responsible for skin manifestations reflecting vascular dysfunction or true vasculitis, since it was demonstrated that ACE2 is expressed in the skin basal cell layer, dermal vessels endothelium, eccrine glands, and subcutaneous fat tissue and act as a receptor for SARS-CoV-2 Spike protein binding (29). Viral uptake precludes the ACE2-dependent protective action of angiotensin 1–7 and results in oxidative stress, inflammatory cytokine production, and vasoconstriction (30, 31). Endotheliitis following virus internalization enhances endothelial injury, thrombogenesis, and immune recruitment, while the cytokine storm typical of severe cases may additionally boost the same mechanism in multiple anatomical districts (32). Moreover, sustained activation of the complement system causes microvascular injury and a procoagulant state triggered by the deposition of complement component C4d and colocalization of SARS-CoV-2 Spike protein in dermal vessels (33). All these mechanisms contribute to the inflammatory dermal microenvironment, which may be the subject of the innate and adaptive immune cell recruitment leading to the extension of inflammatory process toward the vessel wall, causing vasculitis. Another proposed pathogenetic mechanism may involve an autoimmune response targeting vessel wall components following a break of tolerance or molecular mimicry with SARS-CoV-2 proteins (34). Furthermore, CV was described in the context of Kawasaki-like syndrome, a generalized inflammatory disease affecting mainly infants for which the term “multisystem inflammatory syndrome in children (MIS-C) has been coined. However, the specificity of skin vasculitis in the setting of MIS-C still remains unclear, also due to the less frequency of skin biopsies performed in children.
All vaccines authorized for use by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA) have been thoroughly studied and found to be safe and effective in preventing severe COVID-19 cases (35). However, as globally millions of people have now been vaccinated, with increasing frequency, vaccination-related diseases have been observed (36), including CV.
Almost all the available COVID-19 vaccines have been associated with CV, e.g., mRNA vaccines (Pfizer BioNTech), mRNA-1273 (Moderna), adenoviral vector-based vaccines (ChAdOx1 nCoV-19; Oxford-AstraZeneca), and inactivated vaccines (Covaxin, Sinovac). Correlations between vaccination and the subsequent appearance of several types of vasculitis have been also described in the literature with vaccines against influenza, hepatitis B, serogroup B meningococcus, hepatitis A, Human Papilloma Virus (HPV) and with Bacillus of Calmette-Guérin (BCG) (37).
An important criterion guiding the assessment of causality is the temporal relationship between immunization and the side event: for drug- and vaccine-induced vasculitis it is considered to be in the range of 1–6 weeks (38). Most of the cases were self-limiting skin forms without systemic involvement, solved spontaneously or after systemic treatment.
The link between vasculitis and vaccination from a pathogenetic point of view is not clear but may involve an immune complex and antibodies deposition in the blood vessel walls (39). Recently, cytoplasmatic granular positivity for SARS-CoV-2 Spike protein was found in some skin specimens of infection-related CV (40). The vaccine proteins are structurally analogous to the wild viral antigens and could induce a pro-inflammatory cascade similar to that caused by the viral protein. Thus, vaccine antigens may activate B/T cells and cause antibody formation with subsequent immune complex deposition in small-caliber vessels. Along with this, Baiu et al. demonstrated the role of Th1 response and suggested that interferon-gamma is critically required for the initiation of vascular inflammation (41). Then, the whole-virion inactivated SARS-CoV-2 vaccine induces primarily a Th1-biased response, which could lead to the induction of an inflammatory response in the vessel wall (42). An open issue for patients who developed such adverse events following COVID-19 vaccination is whether the booster dose should be administered or not. In fact, repeating the administration could potentially cause more severe immunologic reactions (43). However, cutaneous small-vessel vasculitis secondary to infections, drugs, and vaccines is reported to have a less protracted course when compared to primary vasculitis. Therefore, this should not be a deterrent to the use of the COVID-19 vaccine, which is the most effective weapon to curb the pandemic (44).
Conclusion
Although rarely, CV has been reported in both SARS-CoV-2 -infected and SARS-CoV-2-vaccinated patients. In many cases, these were self-limiting skin forms without systemic involvement, solved spontaneously or after systemic treatment. Studies on this topic are however important to better understand the pathogenetic mechanisms underlying their origin.
With the evolution of the infection and with the finding of less aggressive SARS-CoV-2 variants, it will be necessary to follow the patients who will develop a CV, to better define their characteristics, and possibly understand which variants are more associated with the development of CV. Moreover, the epidemiological trend of COVID-19 infection and the need to protect especially the fragile population made it necessary to start a vaccination campaign with a fourth additional dose. Therefore, careful monitoring of these patients is essential to identify the presence of CV and to make a correct diagnosis, based not only on histological examination but also on DIF, essential to better define the characteristics of SARS-CoV-2 and vaccine-related CV.
Author contributions
AV, CHS, and MC contributed to conception and design of the study. EM organized the database of cases collected. AC, EM, VR, and AV wrote the first draft of the manuscript. LQ and CA wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
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Keywords: vasculitis, cutaneous vasculitis, COVID-19, leukocytoclastic vasculitis, IgA vasculitis, urticarial vasculitis, COVID-19 vaccines, vaccine-induced vasculitis
Citation: Corrà A, Verdelli A, Mariotti EB, Ruffo di Calabria V, Quintarelli L, Aimo C, Sunderkötter CH and Caproni M (2022) Cutaneous vasculitis: Lessons from COVID-19 and COVID-19 vaccination. Front. Med. 9:1013846. doi: 10.3389/fmed.2022.1013846
Received: 07 August 2022; Accepted: 28 October 2022;
Published: 09 December 2022.
Edited by:
Giusto Trevisan, University of Trieste, ItalyReviewed by:
Sebastiano Recalcati, Alessandro Manzoni Hospital, ItalyCopyright © 2022 Corrà, Verdelli, Mariotti, Ruffo di Calabria, Quintarelli, Aimo, Sunderkötter and Caproni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Marzia Caproni, bWFyemlhLmNhcHJvbmkmI3gwMDA0MDt1bmlmaS5pdA==; YWxiZXJ0by5jb3JyYSYjeDAwMDQwO3VuaWZpLml0
†These authors have contributed equally to this work and share first authorship