COVID-19 associated pediatric vasculitis: A systematic review and detailed analysis of the pathogenesis

Abstract

Objectives: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, has opened a new era in the practice of pediatric rheumatology since it has been associated with inflammatory complications such as vasculitis and arthritis. In this review, we aimed to present a detailed analysis of COVID-19 associated pediatric vasculitis.

Methods: A systematic review of the English literature was performed through Pubmed/MEDLINE and Scopus up to January 1st, 2022. Articles including data about the patients with 1) onset of vasculitis <18 years of age, 2) evidence of SARS-CoV-2 exposure, 3) evidence of vasculitis diagnosis (imaging, histopathologic evidences or fulfilling the specific diagnostic/classification criteria) were included in the final analysis. Patients with Kawasaki disease-like vasculitis associated with multisystem inflammatory syndrome in children (MIS-C) were excluded.

Results: A total of 25 articles describing 36 patients with COVID-19 associated pediatric vasculitis (median age 13 years; M/F: 2.3) were included. The most frequent phenotype was IgA vasculitis (n=9) followed by chilblains (n=7) and ANCA associated vasculitis (AAV) (n=5). Skin (58.3%) and renal (30.5%) involvements were the most common manifestations of vasculitis. The majority of patients received corticosteroids (40%), while rituximab (14.2%) and cyclophosphamide (11.4%) were the most frequently used immunosuppressive drugs. Remission was achieved in 23 of 28 patients. Five patients (4 with central nervous system vasculitis; 1 with AAV) died.

Conclusion: Although COVID-19 associated pediatric vasculitis is very rare, awareness of this rare entity is important to secure earlier diagnosis and treatment. The clinical features of COVID-19 associated pediatric vasculitis subtypes look similar to those in pediatric vasculitis not associated with COVID-19. Whether COVID-19 is the reason of the vasculitis or only the trigger remains unknown.

Keywords: COVID-19; Pathogenesis; Pediatric vasculitis; SARS-CoV-2.

Fig. 1

The PRISMA flow diagram of literature screening for patients with COVID-19 associated pediatric vasculitis.

Fig. 2

Possible mechanisms of COVID-19 associated vasculitis: Normally, ACE2 converts ATII to AT1-7 which induces endothelial cells to produce NO. When ACE2 was downregulated by SARS-CoV-2 binding, ATII increases and NO decreases. Type I IFN response against SARS-CoV-2 may further decrease NO by inhibiting NO synthetase. NO is important for vasodilation and control of inflammation since it sets macrophages to M2 (anti-inflammatory) status. Thus, an increase in ATII and decrease in NO lead to vasoconstriction and inflammation. Inflammation and direct damage introduced by viral replication cause endothelitis and loss of endothelial barrier. This exposes collagen and TF in the basement membrane and platelets interact with these. As a result of platelet-TF/collagen/virus interactions, platelet activation occurs which lead to a microenvironment prone to coagulation. Furthermore, activated platelets, M1 macrophages, and activated lymphocytes (as a result of immune response against virus) release proinflammatory cytokines contributing to the vessel wall inflammation. ACE2, angiotensin converting enzyme; AT, angiotensin; collgn, collagen; IFN, interferon; MQ, macrophage; NO; nitric oxide; NOS, nitric oxide synthetase; plt, platelet; PMNL, polymorphonuclear lymphocyte; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TF, tissue factor.