Review: COVID-19 Vasculitis or Novel Vasculitis Mimic?

As the coronavirus disease 2019 (COVID-19) pandemic unfolded, it quickly became evident that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can have significant and serious effects on organ systems through direct or indirect mechanisms.¹

In a recent paper published in Lancet Rheumatology, McGonagle et al have described various forms of vasculitis and potential vasculitis mimics that have been reported with multiorgan manifestations in patients with COVID-19.²

Researchers have observed cutaneous vasculitis, often affecting the dorsal surfaces of the toes, in children and younger, otherwise healthy, patients with COVID-19. These skin lesions with features of vasculitis have typically been found in the absence of COVID-19 pneumonia and generally have a good prognosis. However, in older patients with severe COVID-19 pneumonia, cutaneous manifestations are markedly different and may be associated with a poorer prognosis.²

Skin biopsies of critically ill patients described in a case study³ showed pauci-immune vascular thrombosis “that was disproportionally severe compared with the magnitude of inflammation, suggesting that complement activation was secondary to thrombosis or embolism,” which points to the likelihood of a vasculitis mimic, McGonagle and colleagues noted.²

The differences between cases of severe COVID-19 pneumonia and COVID-19-associated cutaneous vasculitis in otherwise healthy patients appear to result from the lack of a type I interferon (IFN) response that has been reported in critically ill patients; however, research findings have been mixed.²

Younger patients have also exhibited a Kawasaki-like disease in the context of multisystem inflammatory syndrome, without the coronary artery aneurysms typically seen in Kawasaki disease. This condition most commonly occurs in the absence of COVID-19 pneumonia or active infection and frequently presents with myocarditis.²

Thus far, the available evidence does not support the presence of primary vasculitis in organs other than the skin and heart.

Systemic Arterial and Venous Thromboembolism

Along with the generalized thrombotic states that may affect critically ill patients with COVID-19, those with COVID-19 pneumonia commonly exhibit systemic arterial and venous thromboses, including deep vein thrombosis and extensive pulmonary thromboembolism.²

“Collectively, arterial tree thrombosis could serve as a source of systemic arterial tree embolism, which [embolizes] distally and then mimics vasculitis; however, overall, this might represent a relatively uncommon vasculitis mimic,” McGonagle and colleagues explained.² 

Pulmonary Venular Thrombosis

Regarding ischemic lesions that have been observed in the brain, skin, and peripheral organs of patients with COVID-19 with severe pneumonia, McGonagle et al proposed that the vasculitis mimic may stem from pulmonary immunothrombosis, termed “pulmonary intravascular coagulopathy,” as distinct from disseminated intravascular coagulation. This can lead to systemic embolization to the central nervous system, skin, and other organs.² 

Reports have indicated small- and medium-sized pulmonary arteriole and venule thromboses with no apparent endothelial infection in patients with COVID-19.⁴ In addition, a substantial number of patients with severe COVID-19 pneumonia have demonstrated dilated distal vessels in the subpleural lung on computer tomography (CT) pulmonary angiography.⁵

Involvement of Brain and Other Organs

Mc Gonagle and colleagues also explored whether involvement of the brain in COVID-19 stemmed from a vasculitis mimic or viral infection. Severe small arteriolar and venular thromboses have been found in the kidneys, liver, and spleen of patients with severe COVID-19, and it remains unclear whether these are mediated by a vasculitis mimic.²

Overall, McGonagle et al presented a “novel potential mechanism for vasculitis mimics in the context of SARS-CoV-2 infection involving immunothrombosis in the pulmonary venule circulation and secondary systemic embolization….” However, additional investigation is needed to elucidate this process.²

To get further insight on COVID-19 vasculitis and its manifestations, we interviewed Richard C. Becker, MD, FAHA, professor of medicine and director of the Heart, Lung and Vascular Institute at the University of Cincinnati College of Medicine. Dr Becker is also the author of a review paper on COVID-19 vasculitis and vasculopathy published in Journal of Thrombosis and Thrombolysis.¹

What do recent observations suggest about vasculitis and the novel vasculitis mimics related to COVID-19?

Richard C. Becker, MD: Vascular inflammation and accompanying endothelial cell dysfunction are common themes in COVID-19 and can involve small, medium, and large caliber arteries. The density of inflamed blood vessels is greatest within the lungs but can involve any organ system including the heart, central nervous system, peripheral nervous system, gastrointestinal and hepato-biliary systems, kidneys, and skin.

What are some of the proposed mechanisms driving these manifestations?

Dr Becker: The mechanisms are under active investigation. However, several leading thoughts [on mechanisms] include viral binding, membrane fusion and invasion, nuclear damage with release of viral remnants, nucleosomes (histones and chromatin), and DNA complex formation with neutrophils, referred to as neutrophil extracellular traps (NETs), unregulated immune response, and autoantibody formation to multiple antigens or conformationally exposed cellular epitopes.

What are the clinical implications in terms of screening, long-term symptom monitoring, and treatment?

Dr Becker: Vasculitis, with accompanying endothelial cell injury, dysfunction, and exposure of subendothelial cell constituents, has acute, subacute, and potentially long-term implications that range from thrombosis and tissue injury to impaired autonomic regulation, accelerated atherosclerosis, aneurysm formation, and systemic autoimmune syndromes.

Clinicians must have a high index of suspicion when symptoms of COVID-19 persist, recur, or evolve to include new or systemic features. The prevention of SARS-CoV-2 infection and early treatment designed to mitigate inflammation, attenuate excess immune responses, and preserve endothelial cell and vascular integrity are vital steps.

Ongoing clinical trials to include an assessment of vascular structure and function as well as autonomic performance will provide much-needed information. COVID-19 registries and networks designed for long-term follow-up will assist with understanding the wide spectrum of COVID-19 phenotypes and their natural history. Funding from federal sources, national organizations, and philanthropic foundations are also needed.

References

1. Becker RC. COVID-19-associated vasculitis and vasculopathy. J Thromb Thrombolysis. 2020;50(3):499-511. doi:10.1007/s11239-020-02230-4
2. McGonagle D, Bridgewood C, Ramanan AV, Meaney JFM, Watad A. COVID-19 vasculitis and novel vasculitis mimics. Lancet Rheumatol. Published online January 7, 2021. doi:10.1016/S2665-9913(20)30420-3
3. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl Res. 2020;220:1-13. doi:10.1016/j.trsl.2020.04.007
4. Schaefer IM, Padera RF, Solomon IH, et al. In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19. Mod Pathol. 2020;33(11):2104-2114. doi:10.1038/s41379-020-0595-z
5. Lang M, Som A, Carey D, et al. Pulmonary vascular manifestations of COVID-19 pneumonia. Radiol Cardiothorac Imaging. 2020;2(3):e200277. doi:10.1148/ryct.2020200277