Vasculitis in COVID-19 Endothelial cell inflammation, apoptosis and dysfunction occur in patients with COVID-19 [37]. The interface of endothelial cells and viruses is of longstanding interest. For example, a major viral attachment and entry site for viruses is heparan sulfate. This is found on the endothelial surface and consists of repeating disaccharide unites of glucosamine and uronic acid with interspaced sulfate group attachments (reviewed in Agelidis) [53]. The highly sulfated state results in a negative density and binding capacity for a variety of positively charged ligands. A partial but representative summary of individual sites of vasculitis is provided (Table 1) [54–69]. Table 1 COVID-19 vasculitis Patient (n) Age (Y) Sex Country Organ system Signs and symptoms Diagnostic test Treatment Outcomes References 1 69 M Brazil CNS (VBS) Trochlea Nerve palsy MRI MR IV Methyl-prednisone Resolved De Oliveira 1 NR NR NR CNS Corpus Callosum infarct MRI NR NR Varatharaj 7 11–17 4M 3F Spanish Skin Chilblains “COVID-Toes” Biopsy Observation Resolved 8 weeks Colmenero 17 15–63 11M 6F France Skin Chilblains Toes, heels, fingers Biopsy N NR Kanitakis 19 11–17 14M 5F Italy Skin Chilblains Toes, heels, soles Biopsy NR Resolution >30days El-Hachem 1 65 M France CNS Altered mental status MRA MRI Supportive NR Hanafi 1 50 M Asia Kidney Liver Lung Sepsis Hypoxia Necropsy Biopsy Supportive Deceased Xu 1 NR NR NR GI Tract Diarrhea Biopsy Supportive Recovered Carnevale 10 5–16 7M 3F Italy Coronary Arteries Fever Skin rash Diarrhea Hypotension Clinical Echocardiography IVIG Aspirin Recovered Verdoni 1 > 53 NR Switzerland Lung Dyspnea Fever Necropsy NR Deceased Menter 4 50–76 3M 1F Spain Aorta Acute Limb Ischemia Stroke CTA Thrombectomy Anticoagulation 3 discharged 1 deceased Gomez Arbelaez - 1 67 M Italy Aortic Prosthetic graft Respiratory failure Arterial Duplex Supportive Deceased Giacomelli 2 60, 75 M UK Mesentery Aorta Acute Limb ischemia Abdominal pain CTA CTA Thrombectomy Bowel Resection Discharged Villliany 5 57–71 3M 2F France Aorta Acute limb ischemia CTA Arterial Duplex Surgery Anticoagulation Amputation Kashi 1 NR NR Spain Retinal Artery No symptoms Fundoscopy Observation No symptoms Quintana-Castanedo VBS vertebrobasilar system, NR not reported, IVIG intravenous immunoglobulin, CTA Computed Tomography Angiography, UK United Kingdom Urticarial vasculitis occurred in two patients with COVID-19 [70]. While several skin manifestations of COVID-19 occur, including varicella-like exanthemas, dengue-like petechial rashes and urticaria, urticarial vasculitis is a form of leukocytoclastic vasculitis with deposition of immunocomplexes. Pinot et al. [71] reported a case of central nervous system vasculopathy with antimyelin oligodendrocyte glycoprotein antibodies in a patient with COVID-19. There was rapid clinical improvement following immunomodulating treatment. Autoimmune disorders, such as Giullain–Barre’ syndrome have been reported [72]. A lymphocytic vasculitis presenting with skin lesions on the toes, feet, heals and hands occurs in COVID-19. Most cases have been in children and adolescents, but not solely [56, 73]. Histopathology of biopsy-derived material show dermatitis and vascular degeneration of the basal epidermal layer. Endotheliitis within lymphocytic infiltration of the dermal vesicles and arterioles, and microthrombosis of papillary dermal capillaries are common findings. Immunohistochemistry reveals an inflammatory infiltrate predominately comprised of mature T cells with a predominance of helper t lymphocytes. Cytoplasmic granular positivity for SARS–CoV-2 spike protein is present in endothelial cells of the capillary and post-capillary vesicles and in epithelial cells of eccrine units. Coronavirus-like particles are detectable on electron microscopy. Digital video capillaroscopy of patients with dermal lesions, including erythema nodosum shows pericapillary edema, dilated and abnormal appearing capillaries and microhemorrhages. In children with chilblain lesions, IgA antibodies to SARS–CoV-2 spike protein S1 domain are observed, suggesting that their immune response represents mucosal protection that lessens the likelihood of triggering an IgG response. Acro-ischemia with accompanying skin lesions (bulla, cyanosis) and dry gangrene is likely a combination of arterial vasculitis and coagulopathy compromising perfusion to the fingers, toes and legs. While thrombosis commonly accompanies vasculitis, obliterating arteriolitis can also be a cause for tissue injury [62]. Kawasaki Disease Kawasaki Disease is a systemic vasculitis that predominantly affects small and medium-sized arteries. It si associated with the development of coronary artery aneurysms in up to one-third of untreated patients, and both systemic and cerebral artery aneurysms in 1–2% of patients [74]. The cause of KD has not been determined, but a framework for making the diagnosis is as follows [75]: a genetic predisposition to KD, immunomodulation related to habitual exposures and environmental factors and contact with disease triggers. Kawasaki-like disease Kawasaki Disease (KD) follows an excess innate immune response to viral pathogens. Several investigators have proposed involvement of the stimulator of interferon genes (STING) pathway inhibited upstream by aspirin and intravenous immunoglobulins [76]. The same mechanism may operate in COVID-19 where SARS–COV-2 binding to ACE2 increases STING pathway activation. In most instances, activation occurs during the second phase of illness with immune hyper-responses, decreased lymphocyte counts, increased monocyte populations that secrete cytotoxic cytokines and heightened B and T cell responses as well [77]. Kawasaki-like disease with accompanying toxic shock syndrome or multi-systemic inflammatory disease has been reported in children with COVID-19 [78, 79]-moderate coronary dilations were present in 25% of patients (age range 3–17 years). Myocarditis is also seen [80]. Cardiac MRI showed diffuse myocardial edema on T2-STIR sequences and Native-T1 mapping, with no evidence of late gadolinium enhancement [81]. The pediatric inflammatory multisystem syndrome (PIMS) and KD-like disease described in COVID-19 shares similarities with traditional KD, but there are several differences. PIMS occurs in older children (age 9 years or greater), children of African American, Caribbean, European and Hispanic ancestry rather than Asian ancestry. Gastrointestinal symptoms and a lack of mucocutaneous and lymphatic signs are also differentiating factors. Myocarditis is a distinguishing feature of PIMS as well at times requiring mechanical circulatory support [82]. Adult-onset Kawasaki Disease Shock Syndrome complicated by coronary aneurysms occurred in a 20-year-old man of East Asian ancestry [83]. He received corticosteroids and intravenous immunoglobulin. Securing a diagnosis is critical as early treatment (≤ 4 days) reduces the development of coronary arterial aneurysms and with shock syndrome improves left ventricular performance.