Retinal Vasculitis Following COVID-19 Infection: A Systematic Review

Purpose: We conducted a systematic review of literature to identify cases of vasculitis following corona-virus disease (COVID-19) infection and analyse their specific systemic and ocular features. Methods: We used the key-words “retina” AND “vasculitis” AND vessels” AND COVID-19 to identify potential papers. We analysed case series, and case reports. Results: 10 papers that describing 12 patients contained enough data to permit analysis and these were included in the study. There were seven female (58.3%) and five male patients (41.6%) with ages ranging from 11 to 66 (mean 42.6 years). Time from onset of the vasculitis following COVID-19 infection varied from three to 150 days (mean 41.0 days). Clinical findings were described in 15 of the 24 eyes of these 12 patients (62.5%) and included anterior uveitis; optic neuropathies; retinal infiltrates and clinical and unilateral or bilateral retinal vasculitis. Conclusions: Patients with retinal vasculitis appear to constitute a distinct subset and may require different treatment protocols.

COVID-19 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has had significant systemic and ocular implications globally.COVID-19 infection has been associated with both a prothrombotic state and a hyperinflammatory state and the systemic implications include the vascular system of the eye.Numerous retinal and retinal vascular lesions have been reported including hemorrhages, cotton wool spots, arterial and venous occlusions, and vasculitis.We suggest that patients with vasculitis may constitute a distinct subset of patients as compared to patients with vascular occlusion such retinal arterial or venous occlusion.We conducted a systematic review of literature to identify cases of vasculitis following COVID-19 infection and analyse their specific systemic and ocular features.

Methods
We conducted a systematic review to identify and analyze cases of retinal vasculitis following COVID-19 infection using the Pubmed database (www.pubmed.gov)for English language articles.This search was performed on 14/5/2023.We used the key-words "retina" AND "vasculitis" AND Vessels" AND COVID-19 to identify potential papers.We analysed case series, and case reports but excluded reviews, editorials, and non-relevant papers.Demographic findings, systemic features, and ocular lesions detected were entered into a Microsoft Excel sheet.
Virtually all patients (12 patients) underwent fundus photography, OCT and FFA which led to the primary diagnosis.
The salient findings of these patients are summarized in Table 1.IgA and are thought to occur following an upper respiratory tract infection of SARS-CoV-2and the subsequent upregulation of IL-6.The cytokine storm frequently associated with SARS-COV-2 infection may have a causative role as well.Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis characterized by immune complex-mediated inflammation of skin capillaries usually linked to a rise in IL6 levels [11] .
Increasingly many studies and case reports have described the retinal vascular lesions associated with COVID-19.D' Alessandro conducted a systematic review of vascular retinal manifestations and described the cumulative findings of 21 studies.The review described a range of findings that ranged from cotton wool spots, hemorrhages to retinal artery and vein occlusions [12] .
With an emphasis on retinal vascular occlusions, Yeo and co-workers conducted a systematic review and analysed the prevalence and clinical findings in such patients.They were able to identify 13 cases of retinal artery occlusion (RAO) and 14 cases of retinal vein occlusion (RVO) from COVID -19 recovered with 50% of both groups lacking any other potentially contributory systemic illness.The authors note that COVID-19 per se is associated with thrombosis possibly via endothelial injury and vessel wall inflammatory reactions.Additional factors include hypercoagulability and platelet activation.They noted that most cases of arterial occlusion present with abnormal coagulation markers likely due to the overwhelming systemic inflammation whereas patients with retinal vascular occlusion may, in addition, also possess local pathogenic factors such arteriovenous crossing pathology or localised vasospasm.The authors did not describe signs of intraocular inflammation in any of these patients [13] .
Similar findings have also been reported following COVID-19 vaccination.Li et al, in their case series, have described the occurrence of intraocular inflammation following vaccination.1 case of frosted branch angiitis was observed in this series.
They have postulated that molecular mimicry due to an antigenic similarity between vaccine derived proteins and uveal peptides may play a causative role [14] .Bolletta et al described the lesions of 34 patients and reported the presence of two cases of retinal vasculitis.They suggest that an increase in IFN-I secretion may potentially cause or exacerbate autoimmune phenomenon [15] .
We describe the findings of 12 patients with retinal vasculitis following COVID-19 infection.This group of patients appears to be distinct from the group that presents with retinal vascular occlusion such as RAO/RVO as suggested by the frequent association with other signs of intraocular inflammation such as anterior uveitis or vitritis and a good response to steroids with almost all patients maintaining vision or recovering vision.Potential causative mechanisms include the presence of a prothrombotic state due to endothelial injury or inflammation.The naturally occurring antithrombotic activity of the endothelium may be lost due to direct viral infection or the resultant inflammation [16] .Immune system dysregulation with a subsequent cytokine storm with the production of TNF-alpha and IL-6 may also contribute to the vessel wall inflammation and thrombosis.We suggest that while multiple pathogenic mechanisms appear to cause retinal vascular pathology and may exist simultaneously, this may cause a clinical spectrum of disease.Patients with a predominantly inflammatory reaction may present with a vasculitic picture whereas those with a predominantly prothrombotic reaction may present as a vascular occlusion with minimal signs of intraocular inflammation.This group of patients may benefit from primary steroid treatment as opposed to anticoagulant treatment as described for vascular occlusions.

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The authors report no conflict of interest.
Endothelial cell inflammation is common and occurs in association with arterioles, veins and capillaries thus leading to tissue hypoperfusion and consequent injury.COVID-19 infection may thus be associated with several different types of systemic vasculitis.Wong and co-authors, in a systematic review, were able to identify leucocytoclastic vasculitis (LCV), IgA vasculitis, and Kawasaki disease like vasculitis in patients with COVID-19 infection.They described the endothelial inflammation, apoptosis, and dysfunction that commonly occurs as potential causative mechanisms.Kawasaki disease (KD), a medium vessel vasculitis, is an acute inflammation that largely affects the coronary arteries of children younger than 5 years of age.SARS-CoV-2 infection may potentially cause inflammation within the endothelium triggering the development of KD.IgA Vasculitis is a small-vessel vasculitis that is caused by immune-complexes deposits containing Qeios, CC-BY 4.0 • Article, December 11, 2023 Qeios ID: TWA4JO • https://doi.org/10.32388/TWA4JO5/8 Discussion COVID-19 is an infection caused by SARS-CoV 2 that can involve a wide range of organs especially the vascular system.