- acral lesions
- chilblain-like lesions (CBLL)
- COVID toes
- cutaneous vasculitis
- Epstein-Barr virus (EBV)
- factor V Leiden
- humoral immunity
- interferon (IFN)
- lipoprotein A
- postacute sequelae of COVID-19 (PASC)
- skin of color
Abbreviations used:CBLL (chilblain-like lesion), EBV (Epstein-Barr virus), IFN (interferon), Ig (immunoglobulin), RT-PCR (reverse transcriptase polymerase chain reaction)
- •“COVID toes” is the colloquial name of chilblain-like lesions, which are thought to be a sequela of COVID-19 infection. Over two years and approximately 300 publications later, this association remains controversial.
- •Here, we summarize key clinical, serological, biologicalal, histological, and immunological evidence that supports and rejects this relationship.
Emergence and temporal association of chilblain-like lesions (CBLLs) with the arrival of COVID-19
Geographic and racial distribution
- Rabin R.C.
- Lipper G.M.
- Feldman S.R.
- Freeman E.E.
Biological, immunologic, and serologic evidence of COVID-19 infection
Polymerase chain reaction as well as immunoglobulin (Ig)G and IgM immunostaining
Histologic evidence of the sars-cov-2 virus in biopsy specimens
In situ hybridization
Theories of pathogenesis
Type I interferon response
- Salamon M.
- Belluck P.
|Variable||Evidence of association with COVID-19||No evidence of association with COVID-19|
|Temporal association of an outbreak of CBLLs with the arrival of COVID-19||Reports from Europe documented increased cases of CBLLs concurrent with a surge of COVID-19.|
|Studies from other heavily impacted areas, such as New York City and Sao Paolo, found no increased incidence or paucity of cases of CBLLs concurrent with similar surges of COVID-19.|
Geographic and racial distribution of cases of CBLLs
|CBLLs were the most common cutaneous manifestation associated with COVID-19 in Europe and the United States, with cases overwhelmingly reported in Caucasian patients.|
Dermatology has a problem with skin color. New York Times.
|Conspicuously few cases of CBLLs have been documented in Asia, and there is a paucity of cases identified in patients with skin of color.|
Clinical presentation suggestive of COVID-19 infection in patients with CBLLs
|Reports of patients with CBLLs having concurrent and/or prior upper respiratory infection symptoms or illness suggestive of COVID-19.|
Skin and acral rashes were predictive of COVID-19 infection in a large survey study.
|Patients with CBLLs often report no prior systemic symptoms and are commonly asymptomatic at the time of infection, clinically, not suggestive of a concurrent or prior infectious process.|
|Laboratory evidence of COVID-19 infection coincident with the presentation of CBLLs||CBLLs have been identified after PCR-diagnosed infection due to SARS-CoV2.|
|RT-PCR for active COVID-19 infection (nasopharyngeal swab) is commonly negative in patients with CBLLs at the time of presentation, and many patients with CBLLs never tested positive for the virus.|
|Evidence of prior COVID-19 infection||Development of anti-SARS-CoV-2 IgA in up to 20% of cases of CBLLs.|
|Commercially available antibodies indicative of prior COVID-19 infection (IgG and IgM) are often undetectable in cases of CBLL.|
|Immunostaining||A monoclonal antibody against the spike protein of SARS-CoV-2 detected the virus in biopsied samples of CBLLs.|
|Biopsies of CBLLs stained with antibodies against the nucleocapsid protein of SARS-CoV-2 failed to detect the virus.|
|Genomic evidence of COVID-19 in the skin||SARS-CoV-2 was detectable at low copy numbers using PCR on a biopsied rash from the flank of an adult woman with symptoms suspicious for COVID-19.|
|SARS-CoV-2 RNA has been undetectable using RT-PCR and in situ hybridization in biopsied samples of CBLLs.|
|Theories of pathogenesis|
|Type I IFN immune response/viral reactivation||IFN-α levels were significantly elevated in some patients with CBLLs, all of whom had mild disease.|
|An increased IFN response has also been observed in patients with chilblains lupus, and the induction of type I IFN is an important part of the host’s innate immune response to common viral infections such as EBV, which is also linked to the development of chilblains.|
Conflicts of interest
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Funding sources: None.
IRB approval status: Not applicable.
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