The Differing Pathophysiologies That Underlie COVID-19-Associated Perniosis and Thrombotic Retiform Purpura

A Case Series

C.M. Magro; J.J. Mulvey; J. Laurence; S. Sanders; A.N. Crowson; M. Grossman; J. Harp; G. Nuovo

Disclosures

The British Journal of Dermatology. 2021;184(1):141-150. 

In This Article

Abstract and Introduction

Abstract

Background: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19.

Objectives: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19.

Methods: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19.

Results: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+, CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen.

Conclusions: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.

Introduction

The severe acute respiratory distress syndrome-associated coronavirus-2 (SARS-CoV-2), the aetiological agent of coronavirus disease 2019 (COVID-19), was identified in Wuhan, Hubei, China in December 2019 and declared a pandemic by the World Health Organization in early March 2020. Its higher infectivity and lower mortality rates differentiate it from SARS-CoV.[1–3] Most patients with COVID-19 have a self-limited illness. However, there are predisposed populations, including the elderly and patients with certain pre-existing conditions such as diabetes, hypertension and obesity, in whom higher mortality rates have been observed.[4]

We recently reported that a complement-driven pauci-inflammatory thrombotic form of septal capillary injury causes severe progressive acute respiratory distress syndrome (ARDS) in the setting of COVID-19.[5] We showed that patients critically ill with COVID-19 have widespread systemic complement activation destroying microvasculature and exacerbating concurrent thrombophilia, resulting in organ dysfunction attributable to vascular thrombosis. This type of complement-driven thrombotic syndrome is rarely encountered as a complication of COVID-19 in the paediatric setting, where the clinical course is typically banal.[6] However, uncommonly, children have developed perniosis or a multisystemic inflammatory syndrome resembling Kawasaki disease during the COVID-19 pandemic and presumably in response to SARS-CoV-2 infection.[7–12]

The skin is an easily accessible window to understand the pathophysiological basis of COVID-19 and its heterogeneous clinical phenotype. One pole of the cutaneous spectrum is the perniosis-like acral dermatitis occurring predominantly in children and less commonly in adults, who present with no or mild additional symptoms of viral infection such as cough or low-grade fever. For the purposes of this paper we will designate this eruption as 'COVID-19-associated perniosis', defining it as a form of virally triggered perniosis to distinguish it from cold-induced ('idiopathic') perniosis.[13] The opposite pole, COVID-19-associated thrombotic retiform purpura, is a cutaneous extension of the severe microangiopathic ARDS seen in the critically ill.[5] The hallmarks are a pauci-inflammatory thrombogenic vasculopathy associated with activation of the mannan-binding lectin and alternative complement pathways.

We describe three cases of COVID-19-associated perniosis and compare them with six cases of idiopathic perniosis and six cases of thrombotic retiform purpura seen in critically ill patients with COVID-19 from a clinical, light microscopic, immunophenotypic, viral and molecular perspective. We propose that COVID-19-associated perniosis represents a virally induced archetypical interferonopathy, reflective of the robust immune response typical of children and mechanistically distinct from the interferon-poor complement-driven retiform purpura encountered in very sick patients with COVID-19.[13]

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