Update to the COVID toes story
January 2022

In the latter part of 2021, there have been several papers published which are helping to piece together the COVID toe puzzle. In this article, a few selected papers are reviewed and listed in the references at the end (free to download from their respective journal websites).

Ivan Bristow PhD
Royal College of Podiatry

"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 this year in the journal Paediatric Dermatology systematically reviewed all of the observational, histopathological and laboratory findings in an attempt to distil 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:

  1. COVID toes were predominantly a paediatric problem (although a few cases were reported in adults of all ages)
  2. There was no gender difference
  3. The reasons for the development of CLL’s was multifactorial
  4. 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the data reviewed in this work related to the period of January to November 2020, so in one sense this could already be out of date by a year but since that time a similar pattern has continued with subsequent waves of the pandemic.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 370 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 Dermatology3 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 two 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:

  1. Compromised patients with known connective tissue disorders such as chilblain lupus, juvenile psoriatic arthritis or Raynaud phenomenon (RP)
  2. Patients with a history of primary Raynauds, acrocyanosis, cool peripheries or a history of previous chilblains in cold weather
  3. Only two 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, five 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, n/a(n/a).

  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.

COVID toes

Ivan Bristow PhD
On behalf of the COVID-19 Committee, College of Podiatry, London
Updated April 2021

Despite the falling infection rates in the United Kingdom of COVID-19, in other countries further increases in infections are currently being observed. In previous reports, the author has highlighted the issue of chilblain-like lesions (CLL) (or COVID toes) amongst predominantly younger patients, who frequently demonstrate limited or no symptoms of the disease, which have been observed throughout the pandemic. A common feature of these patients is the high proportion of patients who test negative for the disease. In the bulletin of 23 March 2021, it was reported that a proportion of patients are reporting persistent chilblains which is now considered to be a symptom of the long COVID syndrome.

This month, further work has been published in the literature, demonstrating a resurgence of the phenomenon as infection rates rise in many countries. Moreover, a recent paper1 has highlighted confirmed cases of relapse of CLL in 10 patients (average age 15 years), both during the first and second waves of the infection. In all cases the serology and nasal pharyngeal swabs were negative. The explanation for this relapse is purely speculative but does fit with the favoured hypothesis that COVID-19 in younger patients leads to the release of interferon,2 known as the type one interferon pathway. The release leads to the rapid clearing of the infection before any immunity is developed and consequently, chilblains develop, particularly in the toes, often with no other symptoms of COVID exposure. Consequently, upon second exposure to the virus, as there is no immunity generated from the first exposure, the cycle is repeated and interferon released resulting in further chilblain-like lesions.

This hypothesis was strengthened by a study of 40 consecutive patients with CLL.3 All demonstrated negative findings when tested for the virus using polymerase chain reaction testing and only 12 (30%) had positive serology results for antibodies to COVID. However, all showed significant rises in interferon-α levels when tested against control patients with PCR positive and mild to severe symptoms of COVID suggesting that interferon release is a key aspect of chilblain development. This work has been reinforced by a second piece of research which demonstrated induction of the type one interferon pathway in three biopsies taken from patients with chilblains.4

References

  1. Recalcati, S., et al., Relapse of chilblain-like lesions during the second wave of coronavirus disease 19. Journal of the European Academy of Dermatology and Venereology, 2021. 35(5): p. e315-e316.
  2. Lipsker, D., A chilblain epidemic during the COVID-19 pandemic. A sign of natural resistance to SARS-CoV-2? Med Hypotheses, 2020. 144: p. 109959.
  3. Hubiche, T., et al., Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic. JAMA Dermatology, 2021. 157(2): p. 202-206.
  4. Aschoff, R., et al., Type I Interferon Signature in Chilblain-Like Lesions Associated with the COVID-19 Pandemic. Dermatopathology (Basel), 2020. 7(3): p. 57-63


Long COVID toes

Ivan Bristow PhD
On behalf of the COVID-19 Committee, College of Podiatry, London
Updated 23 March 2021

The story of COVID toes continues to unfold as covered in my previous blogs (see below). I recently attended the PCDS Spring Meeting (online, of course) and was interested to see the presentation by Dr George Kravvas, a dermatologist from Bristol, discussing the dermatological manifestations of COVID-19.1 He opened the talk discussing the phenomenon we now know as COVID toes – chilblain like lesions (pseudo-chilblains) which have frequently been observed over the pandemic. Of course, a question which has hung over the diagnosis has been are they really chilblains or a sign of COVID-19 exposure? Dr Kravvas suggested that chilblains occurring over the warmer periods were certainly suspicious, particularly in those without a previous history of chilblains. He suggested a COVID test would be appropriate, even though frequently these tests are negative. Treatment is not needed in most cases, but topical steroids and analgesia may help for troublesome lesions. Typically, they heal within 14 days.

He went onto discuss a similar presentation which had been alluded to in the recent literature by Mehta and colleagues.2 They report a subset of patients (both adult and children), who appear to have more persistent digital lesions. This was first reported last year in a small group of six patients whose chilblains lasted over 60 days - see COVID Toes - November 2020 Update. The lesions resemble the vasculopathy sometimes observed in rheumatological diseases. Where lesions persist for more than a month, they recommend further investigations to rule out other causes, which may possibly have been triggered initially by the COVID-19 infection. Routine blood screening can be helpful here including anti-nuclear antibodies (ANA), extracted nuclear antigen (ENA) and antineutrophil cytoplasmic antibodies (ANCA). Typically, patients present with chilblain like lesions on a dusky blue background similar to acrocyanosis. Limbs typically may be described by patients as burning hot forcing them to immerse them in cold water. This can be counterproductive as it may exacerbate the condition further.

Dermoscopy can also be helpful in these cases. By studying the nailfold capillaries (also known as capillaroscopy) can demonstrate any changes. A study by Natallelo and colleagues3 of the nailfolds of COVID patients (acute and recovered) demonstrated that during acute disease showed microhaemorrhages and capillary oedema compared to the recovered patient who mainly demonstrated swollen capillaries in reduced numbers. Treatment for long COVID chilblains to date has been suggested as topical steroids, oral aspirin and vaso-dilators such as nifedipine.2

References

  1. Kravvas, G. Skin manifestations of COVID 19. in Primary Care Dermatology Society Spring Meeting. 2021. Online: PCDS.
  2. Mehta, P., et al., Chilblain-like acral lesions in long COVID-19: management and implications for understanding microangiopathy. The Lancet Infectious Diseases, 2021.
  3. Natalello, G., et al., Nailfold capillaroscopy findings in patients with coronavirus disease 2019: Broadening the spectrum of COVID-19 microvascular involvement. Microvascular Research, 2021. 133: p. 104071.

COVID toes

Ivan Bristow PhD
On behalf of the COVID-19 Committee, College of Podiatry, London
Updated 11 December 2020

Further to previous updates for College of Podiatry members circulated in November, new published cases and research have appeared in the medical literature regarding the phenomenon colloquially known as “COVID toes” – chilblain like lesions arising in children and young adults with suspected or confirmed COVID-19 infection. Last month, three CPD articles were published in the British dermatology journal Clinical and Experimental Dermatology.1-3 The first of these papers examined(2) COVID toes summarising what has been reported to date in terms of the presentation and prognosis. The authors also include various hypotheses as to why they may arise in children, including the idea that children at the beginning of infection are able to release large amounts of interferon to attenuate viral replication. A side effect of this release is the development of chilblains, but further work is required to fully explain and understand the phenomenon. All three papers are currently free to access (links given below) and offer a good means to update podiatrists on the current knowledge around COVID toes along with other skin manifestations in children.

In another recently published paper  on the subject,4 the authors have highlighted how the majority of published photos of COVID toes have been in patients with Fitzpatrick skin types 1 or 2. In addition they suggest that lesions in darker skin types may be more difficult to recognise resulting in delays in diagnosis and treatment.  Consequently, they have presented seven cases of COVID toes in patients with Fitzpatrick skin types 3 – 5 to assist clinicians. The full paper, including the images can be downloaded from the link given below.

References

    1. Andina D, Belloni-Fortina A, Bodemer C, Bonifazi E, Chiriac A, Colmenero I, et al. Skin manifestations of COVID-19 in children: Part 3. Clin Exp Dermatol. 2020. https://doi.org/10.1111/ced.14481
    2. Andina D, Belloni-Fortina A, Bodemer C, Bonifazi E, Chiriac A, Colmenero I, et al. Skin manifestations of COVID-19 in children: Part 1. Clin Exp Dermatol. 2020. https://doi.org/10.1111/ced.14482
    3. Andina D, Belloni-Fortina A, Bodemer C, Bonifazi E, Chiriac A, Colmenero I, et al. Skin manifestations of COVID-19 in children: Part 2. Clin Exp Dermatol. 2020. https://doi.org/10.1111/ced.14483
    4. Daneshjou R, Rana J, Dickman M, Yost JM, Chiou A, Ko J. Pernio-like eruption associated with COVID-19 in skin of color. JAAD case reports. 2020;6(9):892-7. https://doi.org/10.1016/j.jdcr.2020.07.009

COVID toes

Ivan Bristow PhD
On behalf of the COVID-19 Committee, College of Podiatry, London
Updated 2 November 2020

The connection between COVID-19 infection and chilblains in younger adults and children was raised early on in the coronavirus pandemic with many published papers reporting their appearance and postulating that the that two were associated.

With the global pandemic continuing into November, data from John Hopkins University suggests nearly 30 million people globally have been infected with over 1 million deaths (Data as of 31/10/2020: https://coronavirus.jhu.edu/map.html). Research into the disease continues to be published at a significant rate. A range of skin presentations have been observed and reported.1-4 Common lesions patterns include:

          • Morbilliform (measles-like) rash
          • Urticaria
          • Macular erythema
          • Vesicular (blistering, chickenpox-like) eruption
          • Papulosquamous presentation
          • Retiform (net-like) purpura
          • Chilblain-like lesions

Published data from the International Registry of COVID-19 Associated Dermatologic Manifestations has been collated from 31 countries to date. Analysis shows that lesions have been reported across all continents, in a full range of skin types (including white, Asian, Black African / African American and Latin / Hispanic patients).5

Literature pertaining to the phenomenon of chilblain-like lesions (often labelled COVID toes) has been reviewed and circulated by the College of Podiatry to members in its regular e-bulletins.  This week, media interest in COVID toes was reignited by a presentation made at the European Academy of Dermatology in Switzerland. Dr Esther Freeman who leads the International COVID Dermatology Register presented data to dermatologists which included collected data on the phenomenon. They reported that the chilblain lesions, in line with previous research, lasted around 12 days on average however, they cited 6 patients who continued with the purple lesions on their toes lasting over 60 days in patients who tested positive for the disease with two of these showing skin lesions at 130 days after diagnostic confirmation. They conclude that such a prolonged presence of the lesions may represent a symptom of the condition termed “Long COVID” where symptoms of the disease may manifest for many weeks after the initial infection but further research is required to fully explain this.

Data published so far on COVID-19 and the skin has been analysed in a paper by Danaheshgaran et al.In their work, thirty-four papers describing nearly 1000 patients with various skin symptoms were included and demonstrated that chilblains were the most reported dermatological condition, representing 40% of all dermatological conditions in COVID patients. The average age of these patients was 23.2 years old. Lesions generally developed after the onset of the signature symptoms (persistent cough, temperature etc.,) which concurs with earlier observations that such lesions are generally a later manifestation of the disease. Although viral particles have been recovered from chilblain-like lesion biopsies,7,8 the exact mechanism by which they develop is still requires further investigation.

References

    1. Manalo IF, Smith MK, Cheeley J, Jacobs R: A Dermatologic Manifestation of COVID-19: Transient Livedo Reticularis. J Am Acad Dermatol 2020
    2. Marzano AV, Genovese G, Fabbrocini G, Pigatto P, Monfrecola G, Piraccini BM, Veraldi S, Rubegni P, Cusini M, Caputo V et al: Varicella-like exanthem as a specific COVID-19-associated skin manifestation: multicenter case series of 22 patients. J Am Acad Dermatol 2020:early view
    3. Recalcati S: Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol 2020
    4. Gianotti R, Veraldi S, Recalcati S, Cusini M, Ghislanzoni M, Boggio F, Fox LP: Cutaneous Clinico-Pathological Findings in three COVID-19-Positive Patients Observed in the Metropolitan Area of Milan, Italy. Acta Derm Venereol 2020
    5. Freeman EE, McMahon DE, Lipoff JB, Rosenbach M, Kovarik C, Desai SR, Harp J, Takeshita J, French LE, Lim HW et al: The spectrum of COVID-19-associated dermatologic manifestations: an international registry of 716 patients from 31 countries. J Am Acad Dermatol 2020
    6. Daneshgaran G, Dubin DP, Gould DJ: Cutaneous Manifestations of COVID-19: An Evidence-Based Review. Am J Clin Dermatol 2020, 21(5):627-639
    7. Colmenero I, Santonja C, Alonso-Riaño M, Noguera-Morel L, Hernández-Martín A, Andina D, Wiesner T, Rodríguez-Peralto JL, Requena L, Torrelo A: SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases. Br J Dermatol 2020, n/a(n/a)
    8. Santonja C, Heras F, Núñez L, Requena L: COVID-19 chilblain-like lesion: immunohistochemical demonstration of SARS-CoV-2 spike protein in blood vessel endothelium and sweat gland epithelium in a polymerase chain reaction-negative patient. Br J Dermatol 2020, n/a(n/a)
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