Thread by @NAChristakis

There is an intriguing theory about “COVID toes.” You can get it as a result of SARS-CoV-2 infecting you.

But you can also – perhaps – get it *without* being infected, as a result of hanging out at home for long periods without shoes. It's an epidemiological puzzle. 1/

COVID toes are thought to be a known, albeit formerly rare, condition called chilblains (also known as pernio). This used to be the bane of people living in cold damp climates (think British boarding schools, or New England). #COVIDtoes 2/

Chilblains is characterized by inflammatory skin lesions in patients exposed to non-freezing weather during late winter or early spring. These lesions typically present as painful erythrocyanotic (red-blue) discoloration, often with dead skin, on the toes, fingers, or both. 3/

Chilblains is frequently misdiagnosed as vasculitis or an embolic event (both of which are much more serious), leading to elaborate and expensive workups.

And there has been an epidemic of COVID toes worldwide, in the spring of 2020 and now 2021. 4/

Chilblains or COVID toes can arise from the *direct* effect of being infected with the SARS-CoV-2 virus and the physiological changes the infection induces. Here is a very recent review via @MayoProceedings: mayoclinicproceedings.org/article/S0025-… 5/

Clinical and histopathologic features of chilblains are well described, though the pathogenesis is not entirely understood. Vasospasm and a type I interferon (IFN-I) immune response are likely involved. 6/

And age and sex discrepancies in COVID toes are likely explained by age-related immune and vascular differences influenced by sex hormones and genetics which affect susceptibility to viral infection, renin-angiotensin-aldosterone system balance, and IFN-I response. 7/

So, it seems that being younger and female tends to make COVID-19 less severe in patients, but COVID toes more likely. Perhaps.

And to be clear, older people and men can still get COVID toes. 8/

But here it something else, which is cool: another very intriguing possibility is that at least some cases of COVID toes are NOT induced by the virus itself, but rather as an *indirect* result, because of the stay-at-home measures. 9/

COVID toes are frequently seen in patients with no cold exposure, no prior history of chilblains, and with COVID tests that are negative! 10/

In a case series assembled in Brussels (April 10-17, 2020), 31 patients (mostly – but not exclusively! – young and female) with new chilblains were seen. NONE of them had positive SARS-CoV-2 tests by RT-PCR or serum antibodies. jamanetwork.com/journals/jamad… via @JAMADerm 11/

In another case series in Spain (April 9-15, 2020), 32 patients with COVID toes were seen. Again, none had positive antibodies to SARS-CoV-2 either. jamanetwork.com/journals/jamad… via @JAMADerm 12/

The concomitant increase in reports of chilblains during the spring or 2020 (even in test-negative patients), in conjunction with the first wave of the COVID-19 pandemic worldwide, suggests that there may be an indirect link between these events. 13/

One hypothesis points to an indirect consequence of the COVID-19 pandemic related to the imposition of community containment and lockdown measures which led to lifestyle changes that may be risk factors for developing chilblains. 14/

Many patients with COVID toes and negative tests for the virus report that they: were working or schooling from home; had decreased physical activity; spent more time in sedentary positions; and remained barefoot or in socks most of the day. 15/

Hence, lifestyle changes associated with COVID-19 containment and lockdowns are a possible explanation for COVID toes, in addition to (the majority?) of cases due to infection with the virus itself. And the lifestyle changes could be a risk even in test-positive patients 16/

It's also possible that people have slow-burning COVID19, with negative (conventional) antibody tests, and get COVID toes. Or the link in many patients may truly be lifestyle related, as hypothesized above. More research is needed (as we say). 17/