Should we look beyond the interferon signature in chilblain-like lesions associated with COVID-19?

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, but not in severe disease. The link between IFN signalling and CLL is supported by the occurrence of chilblains in inherited type I interferonopathies. 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 Toll‐like receptors, retinoic acid‐inducible gene receptors and NOD‐like receptors that initiate a signalling pathway resulting in expression of IFN regulatory factors ‐7 and ‐3, inducing IFN‐β and IFN‐α, respectively. The IFN‐α response is greater in infancy and childhood, but decreases with age, 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. 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 markers – in addition to histological comparisons – revealed 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. 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.

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. 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, 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. AT2R activation results in increased nitric oxide (NO), vasodilation and anti‐inflammatory effects; in contrast, AT1R activation results in decreased NO, vasoconstriction and inflammation, 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. 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.

Author Contribution

Suzanne Margaret Pilkington: Conceptualization (equal); Writing‐original draft (equal); Writing‐review & editing (equal). Rachel Watson: Conceptualization (equal); Writing‐original draft (equal); Writing‐review & editing (equal).