Type 3 hypersensitivity in COVID-19 vasculitis

Abstract

Coronavirus Disease 2019 (COVID-19) is an ongoing public health emergency and new knowledge about its immunopathogenic mechanisms is deemed necessary in the attempt to reduce the death burden, globally. For the first time in worldwide literature, we provide scientific evidence that in COVID-19 vasculitis a life-threatening escalation from type 2 T-helper immune response (humoral immunity) to type 3 hypersensitivity (immune complex disease) takes place. The subsequent deposition of immune complexes inside the vascular walls is supposed to induce a severe inflammatory state and a cytokine release syndrome, whose interleukin-6 is the key myokine, from the smooth muscle cells of blood vessels.

Keywords: Coronavirus disease 2019 (COVID-19); Immune complex disease; Interleukin-6 (IL-6); Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2); Type III hypersensitivity; Vasculitis.

Fig. 1

Ileal and splenic infarctions in a 72-year-old Italian male patient affected by COVID-19 and submitted to rescue surgery after 18 days from SARS-CoV-2 molecular detection through nasopharyngeal swab [IL-6 sequential dosages by serum immune assays: from 154.03 ρg/ml - day 1 to 2656.46 ρg/ml - day 18]: on sagittal abdomen computed tomography (CT) scan with contrast medium, an aortic thrombus (A, red arrow) and one at the celiac tripod (A, yellow arrow) are clearly visible, while on axial abdomen CT scans a large ischemic intestinal loop shows pneumatosis intestinalis (A, green arrow) and only a central portion of healthy spleen (A, blue arrow) remains vascularized by the splenic artery; grossly, the transition zone between the upper residual spleen parenchyma and the lower discolored infarcted area is captured (B); on histopathology, the splenic artery appears thrombosed and involved by vasculitis (C, hematoxylin & eosin, 2.5× objective); at higher magnification (D, hematoxylin & eosin, 10× objective), the inflammation is arranged around (periarteritis) and inside (panarteritis) the vascular wall; in the cytological details, neutrophils and karyorrhexis are well noticeable, a classical histological picture for LCV (E, hematoxylin & eosin, 60× objective), while Toluidine blue stain highlights the purple granules of a mast cell in the degranulation phase close to polymorphonuclear neutrophils (F, 100× objective); phosphotungstic acid hematoxylin reveals blue spots of fibrinoid necrosis in the full thickness of the splenic artery wall (G, 40× objective), more concentrated just below the internal elastic membrane in the innermost part of tunica media (H, 100× objective); immunofluorescence confirms the presence of green-brightened immune complexes, mainly consisting of IgG (I, anti-human polyclonal IgG/FITC, 100× objective), but also of IgM (J, anti-human polyclonal IgM/FITC, 100× objective) and IgA (K, anti-human polyclonal IgA/FITC, 100× objective), together with C3 complement deposits (L, anti-human polyclonal C3 complement/FITC, 100× objective). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).