Nailfold Videocapillaroscopic Alterations as Markers of Microangiopathy in COVID-19 Patients

Abstract

Nailfold videocapillaroscopic alterations have been described in COVID-19, but their correlations with biomarkers of inflammation, coagulation and endothelial perturbation are still unclear, and no information is available on nailfold histopathology. Nailfold videocapillaroscopy was performed on fifteen patients with COVID-19 in Milan, Italy and the signs of microangiopathy were correlated with plasma biomarkers of inflammation (C reactive protein [CRP], ferritin), coagulation (D-dimer, fibrinogen), endothelial perturbation (Von Willebrand factor [VWF]) and angiogenesis (vascular endothelial growth factor [VEGF]) along with genetic drivers of COVID-19 susceptibility. Histopathological analysis of autoptic nailfold excisions was performed on fifteen patients who died for COVID-19 in New Orleans, United States. All COVID-19 patients studied with videocapillaroscopy showed alterations rarely seen in healthy individuals consistent with microangiopathy, such as hemosiderin deposits (sign of microthrombosis and microhemorrhages) and enlarged loops (sign of endotheliopathy). The number of hemosiderin deposits correlated both with ferritin and CRP levels (r = 0.67, p = 0.008 for both) and the number of enlarged loops significantly correlated with the levels of VWF (r = 0.67, p = 0.006). Ferritin levels were higher in non-O groups, determined by the rs657152 C > A cluster, (median 619, min-max 551-3266 mg/dL) than in the O group (373, 44-581 mg/dL, p = 0.006). Nailfold histology revealed microvascular damage, i.e., mild perivascular lymphocyte and macrophage infiltration and microvascular ectasia in the dermal vessels of all cases, and microthrombi within vessels in five cases. Alterations in nailfold videocapillaroscopy and elevated biomarkers of endothelial perturbation that match histopathologic findings open new perspectives in the possibility of non-invasively demonstrating microangiopathy in COVID-19.

Keywords: COVID-19; Von Willebrand factor; endothelial perturbation; hemosiderin; nailfold videocapillaroscopy.

Figure 1

Capillaroscopic findings in patients with mild COVID-19. (A), enlarged loops (black arrow); (B), pearl necklace appearance of microhemorrhages (red arrow); (C), microthrombosis (green arrow); (D), one-loop cross (yellow arrow); (E), normal.

Figure 2

Histopathological images of nailfold skin from patients with death due to COVID-19. (A), dilated capillary loops in the papillary dermis with a mild chronic inflammatory infiltrate and hemosiderin deposition (teal arrows); (B), iron stain confirming hemosiderin deposition in the papillary and superficial dermis with occasional hemosiderin-laden macrophages (blue); (C), dilated blood vessels in the papillary and superficial dermis with blood clot present (teal arrows); (D), a CD68 immunostaining confirming the presence of hemosiderin-laden macrophages in the same distribution (blue arrows).