key: cord-0904127-tckn43qe
authors: Pilkington, S.M.; Watson, R.E.B.
title: Should we look beyond the interferon signature in chilblain‐like lesions associated with COVID‐19?
date: 2021-11-08
journal: Br J Dermatol
DOI: 10.1111/bjd.20784
sha: 1a2ccfe2bab589ef7c5150610d6b2261f3757f9a
doc_id: 904127
cord_uid: tckn43qe

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The appearance of chilblain-like lesions (CLL) ('COVID toes') during the COVID-19 pandemic has been associated with a type I interferon (IFN) response that is present in asymptomatic and mild cases, 1 but not in severe disease. 2 The link between IFN signalling and CLL is supported by the occurrence of chilblains in inherited type I interferonopathies. 3 Type I IFNs typically participate in the innate immune response to viral pathogens and are powerful inflammatory molecules expressed by both immune and nonimmune cells. The accumulation of double-stranded nucleic acids in the nucleus results in cytotoxic sensing by Tolllike receptors, retinoic acid-inducible gene receptors and NODlike receptors that initiate a signalling pathway resulting in expression of IFN regulatory factors -7 and -3, inducing IFN-b and IFN-a, respectively. The IFN-a response is greater in infancy and childhood, but decreases with age, 4 which may explain why CLL are more prevalent in younger individuals.

While there are many reports of CLL in association with the COVID-19 outbreak, Frumholtz et al. 5 are the first to study the pathophysiology of these cutaneous lesions using transcriptomics, and to include comparisons with a number of control groups (healthy individuals, those with a history of seasonal chilblains, and those without chilblains who tested positive for COVID-19). Analysis of blood markersin addition to histological comparisonsrevealed a systemic and local immune response characterized by a type I IFN signature and IgA antineutrophil cytoplasmic antibodies, in addition to endothelial dysfunction. Viral particles of SARS-CoV-2 have previously been detected in the cytoplasm of skin endothelial cells, supporting an association between the virus and CLL. 6 In cases of severe COVID-19 disease, SARS-CoV-2 particles were also detected in endothelium of other organs in association with endothelialitis resulting in the hypothesis that stabilization of endothelium maybe beneficial for vulnerable patients. 7 However, while transcriptomic analysis supports the role of IFN signalling in endothelial dysfunction in both CLL and seasonal chilblains, other contributing factors should be considered. Interestingly, it has been proposed that mast cell hyperactivation could contribute to COVID-19 progression and to cutaneous manifestations. Ricke et al. 8 suggest that viral-driven vascular ischaemia and mast cell-derived histamine are primary initiating factors in COVID-19-related cutaneous lesions. As SARS-CoV-2 is predicted to bind and activate the cyclooxygenase-2 promoter, 9 a subsequent increase in prostaglandin E2 expression could facilitate hyperactivation of mast cells. However, this theory remains to be explored.

Another interesting consideration is the role of sex hormone differences. The angiotensin-converting enzymes 1 and 2 provide entry of the SARS-CoV-2 virus into endothelial cells and in male patients, there is a preference for downstream activation of the angiotensin (AT)1R, compared with AT2R, which is more predominant in female patients. 10 AT2R activation results in increased nitric oxide (NO), vasodilation and antiinflammatory effects; in contrast, AT1R activation results in decreased NO, vasoconstriction and inflammation, 11 potentially contributing to the prevalence of CLL in men.

Still, there is no proven direct causality between COVID-19 and CLL and a recent epidemiological analysis suggests that changes in behaviour during the pandemic may have resulted in increased diagnosis of chilblains. 12 Thus, while this article contributes important insights into the pathophysiology of CLL, further exploration of the wider tissue inflammatory response, and the influence of age and sex could be explored to better understand the impact of COVID-19 and guide treatments for associated cutaneous effects. 

Clinical, laboratory, and interferon-alpha response characteristics of patients with chilblain-like lesions during the COVID-19 pandemic

Vascular skin manifestations in patients with severe COVID-19 in intensive care units: a monocentric prospective study

Genetic interferonopathies: an overview

Type I interferons in infectious disease

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak

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

Endothelial cell infection and endotheliitis in COVID-19

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Nucleocapsid protein of SARS-CoV activates the expression of cyclooxygenase-2 by binding directly to regulatory elements for nuclear factor-kappa B and CCAAT/enhancer binding protein

The "his and hers" of the renin-angiotensin system

Angiotensin II signal transduction: an update on mechanisms of physiology and pathophysiology

Epidemiologic analysis of chilblains cohorts before and during the COVID-19 pandemic