It’s been a while since I published any updates from the literature on this evolving topic. In the latter part of this year, there have been several papers published which are helping to piece together the COVID toe puzzle. In this blog I will be summarising a few of them. These papers are listed in the references at the end and are free to download from the journal websites. In the first paper, the authors have attempted to assemble and distil all the data from the many reports studying the COVID toe phenomenon.
This article has also been published via the Royal College of Podiatry Newsletter/Website in January 2022
"COVID toes” - a systematic review [1].
The emergence of COVID toes (also called chilblain like lesions [CLL]) has been a rapid event alongside the COVID 19 pandemic, consequently evidence, particularly in the beginning, was limited clarifying what it was and indeed, if it was truly associated with the infection at all. Classic chilblains are defined as cold induced, erythematous or violaceous lesions accompanied by itching, oedema, pain or burning, blistering or ulceration. However, COVID-19 led to a wave of perniosis associated without any cold exposure.
Consequently, hundreds of papers have been published since the pandemic began as case histories and case series, reporting the main clinical observations and latterly some of the histopathological findings from early biopsies. A paper published in late 2021 the journal Paediatric Dermatology systematically reviewed all of the observational, histopathological and laboratory findings in an attempt to distill this knowledge into meaningful data.
Using the recognised guidelines for reporting systematic reviews and meta-analyses (known as PRISMA) the authors searched three major databases and after removing duplicates screened 412 published papers. At the conclusion of the search a total of 43 case reports and case series and 18 observational series were included. Papers were predominantly from European countries (Spain, Italy, Germany, United Kingdom and Austria). The main findings of this work confirmed what had been suspected:
COVID toes were predominantly a paediatric problem (although a few cases were reported in adults of all ages).
There was no gender difference.
The reasons for the development of CLL’s were multifactorial.
The histopathological findings from tissue biopsies were non-specific to COVID-19.
The authors also commented on the low rate of positive COVID 19 tests. It’s important to stress that the data reviewed in this work related to the period of January to November 2020, so in one sense this could already be out of date by a year but since that time a similar pattern has continued with subsequent waves of the pandemic.
From your nose to your toes [2]
In the Journal of Investigative Dermatology, Arkin and colleagues [2] published a paper which further examines the mechanism by which CLL’s are thought to develop. The work favours the Interferon-1 pathway driving the development as a response to infection by the innate immune system. The authors highlight how patients tending to develop these lesions are young and had close contact with others infected with the COVID-19 virus. The fact that the emergence and reporting of these CLL’s occurred in a manner mirroring the spread of COVID-19 across multiple countries and continents supports the idea that CLL’s were in fact a COVID-19 infection phenomenon and not just a coincidence.
COVID-19 infection stimulates cells in the blood to release Interferon 1 (IFN-1). Its appearance consequently switches on genes which can obstruct viral replication and propagation. The authors highlight how some patients with serious illness due to COVID-19 have a reduced ability to produce IFN-1. In patients with conditions such as familial chilblain lupus, cold exposure can lead to over-expression of IFN-1 and patients subsequently develop chilblains in a similar manner.
So why are the hands and feet affected most? The Angiotensin-converting enzyme receptor, which the COVID-19 can latch onto with its spike protein, is present in dermal blood vessels, the basal layer of the epidermis and on eccrine sweat glands. Consequently, as the skin on the hands and feet have the highest density of sweat glands on the body, the effects could be localised to these areas. This has been supported by the discovery of spike protein discovered in biopsies of chilblains in patients with suspected COVID toes.
The final discussion point from the authors is around the foot itself. The foot is an extremity and consequently has a lower temperature than the core body temperature of 37 degrees centigrade. IFN-1 effectiveness relies on body temperature for an optimal effect as the COVID-19 virus replicates significantly more in colder temperatures. Consequently, the authors suggest that when exposed to the virus through a respiratory route, the IFN-1 pathway is effective at clearing the infection in these warmer areas like the lungs but is less effective in colder areas such as the feet and toes where the virus may thrive. However, as the toes reheat, the IFN-1 pathway is triggered locally leading to the development of the chilblains.
Understanding the pathology of SARS-COV-2 [3]
The most recently published paper in December 2021, probably offers the best explanation so far as to how COVID-19 can cause these CLL’s. According to the authors, the virus has two points of entry into epithelial tissue. Firstly, through the Angiotensin converting enzyme 2 (ACE2) receptors and transmembrane protein serine 2 (TMPSS2). It enters by endocytosis where the virus shell is disassembled but the RNA inside is then replicated to make new viruses. As the author points out, ACE2 receptors are not only found on endothelial cells but also on monocytes, macrophages and T cells.
The presence of the virus in the bloodstream stimulates the release of Interferon-1 (IFN-1). This may arise from the endothelial cells of the vessel or through the direct effect of the virus attaching to Natural killer and T cells in the bloodstream. Consequently, genes are activated that stimulate a cascade (or “cytokine storm”) as other cells join in via several pathways, including the release of interleukin 6, which recruits monocytes and neutrophils within the bloodstream. Consequently, endotheliitis occurs within the vessel and local clotting cascades are triggered causing thrombi to appear. This occurs through both the intrinsic pathway (neutrophils traps) and extrinsic pathway (via monocytes inducing IL-6 and stimulating coagulation factor III). These may manifest in superficial capillaries of the skin as the reported COVID-19 skin lesions, along with COVID toes appearing as a late feature of this cytokine storm. As the author points out this gives the best explanation of how COVID toes may arise as the by-product of the cytokine storm.
Who gets long “COVID toes”? Strangely, people with longer toes…? [4]
A paper was published in the journal of Clinical and Experimental Dermatology [3] looking at a more recent aspect of the COVID toe story. Reports from 2020 suggested that chilblains in COVID-19 exposed patients lasted for around 2 weeks [5]. However, sometime after the first wave of the pandemic, reports began to emerge of persistent CLL’s with some patients having lesions for many months without resolution. The term “Long COVID toes” was coined but latterly replaced by “Tardive COVID-19 Pseudoperniosis” (TCPP). A UK paper examined 16 patients (Feb to June 2021) with suspected TCPP to expand knowledge on the phenomenon.
Amongst the group, there were twice as many females as males with an average age of 29 years. Interestingly, the group could be divided into three types of patients:
Compromised patients with known connective tissue disorders such as chilblain lupus, juvenile psoriatic arthritis or Raynaud phenomenon (RP).
Patients with a history of primary Raynauds, acrocyanosis, cool peripheries or a history of previous chilblains in cold weather.
Only 2 patients amongst the 16 had no history of auto-immune disorders or previous cold intolerance.
The chilblains presented on the hands and/or feet of patients but eventually 10 patients reported them developing on all acral sites. Nailfold dermoscopy was abnormal in the seven out of twelve patients assessed. In addition, 5 of these patients had a low titre of antinuclear antibodies. Interestingly, 12 of the 16 patients had arachnodactyloid phenotype (long spindly fingers and toes). The duration of symptoms for the patients ranged from 79-495 days, averaging around 191 days for the group.
The paper summarises that predisposing factors for TCPP include young age, a previous history of cold intolerance and long spindly digits. In addition, anorexia, connective tissue disease, sickle cell trait, a low titre antinuclear antibodies or low complement may predispose to its development.
References
1. Rocha KO, Zanuncio VV, Freitas BACd, Lima LM: “COVID toes”: A meta-analysis of case and observational studies on clinical, histopathological, and laboratory findings. Pediatr Dermatol 2021, 38(5):1143-1149.
2. Arkin LM, Moon JJ, Tran JM, Asgari S, O’Farrelly C, Casanova J-L, Cowen EW, Mays JW, Singh AM, Drolet BA et al: From Your Nose to Your Toes: A Review of Severe Acute Respiratory Syndrome Coronavirus 2 Pandemic‒Associated Pernio. J Invest Dermatol 2021, 141(12):2791-2796.
3. Ionescu M-A: COVID-19 skin lesions are rarely positive at RT-PCR test: the macrophage activation with vascular impact and SARS-CoV-2-induced cytokine storm. Int J Dermatol 2022, 61(1):3-6.
4. Ganatra B, Amarnani R, Alfallouji Y, Dear K, Twigg E, Westwood JP, Goulden B, Morris V, Hillman T, Goolamali S et al: Patient characteristics in tardive COVID-19 pseudoperniosis: a case series of 16 patients. Clin Exp Dermatol 2021,
5. Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Takeshita J, French LE, Thiers BH, Hruza GJ, Fox LP: Pernio-like skin lesions associated with COVID-19: a case series of 318 patients from 8 countries. J Am Acad Dermatol 2020, 83(2):486-492.