SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases

Abstract

Background: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established.

Objectives: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue.

Methods: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one.

Results: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy.

Conclusions: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.

Figure 1

(a, b) Case 2 and (c, d) case 6. Clinical spectrum of perniotic acral ischaemic lesions.

Figure 2

Case 6, skin biopsy. (a) Acral skin showing superficial and deep perivascular inflammation extending into the subcutis and papillary dermal oedema [haematoxylin and eosin (H&E), original magnification × 20]. (b) Mild exocytosis and vacuolar degeneration (H&E, × 200). (c–f) Lymphocytic infiltration of vessel walls. Note the lifting of endothelium with underlying lymphocytes in (e) (arrow) and transmural inflammation of a large subcutaneous vessel in (f). H&E, original magnification (c, e) × 400; (d, f) × 200.

Figure 3

Case 2, skin biopsy. (a) Acral skin showing superficial and deep perivascular inflammation extending into the subcutis [haematoxylin and eosin (H&E), original magnification × 20]. (b) Mild papillary dermal oedema, vacuolar degeneration of the basal layer and lymphocytic exocytosis together with prominent red cell extravasation (H&E, × 100). (c) Thrombi in superficial dermis vessels (H&E, × 200). (d–f) Lymphocytic vasculitis with thrombosis and fibrin deposition in vessel walls. H&E, original magnification (d) × 200, (e, f) × 400.

Figure 4

(a–c) Cases 4–6. Cytoplasmic granular positivity for SARS‐CoV‐2 spike protein in endothelial cells (immunohistochemistry, original magnification × 400). (d) Case 2. Ultrastructural image of an endothelial cell showing coronavirus‐like particles consistent with SARS‐CoV‐2 (arrow), next to a mitochondrion for size comparison (electron microscopy, × 60 000).