Researchers found that the SARS-CoV-2 virus was present in skin biopsies in children with symptoms of COVID toes

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There’s considerable controversy over whether “COVID toes”–red sores or lesions on the feet and hands in children and young adults–are truly caused by COVID-19.

A new study published in the British Journal of Dermatology provides evidence in support of the link.

In most cases, affected individuals test negative with traditional COVID-19 tests involving throat swabs and measurements of circulating antibodies, but this study’s investigators found that the SARS-CoV-2 virus that causes COVID-19 was present in skin biopsies in children with symptoms of COVID toes, despite negative results from traditional tests.

Analyses detected the virus in skin’s blood vessel endothelial cells, as well as in the sweat glands. Electron microscopy in one biopsy also found evidence of viral particles within endothelial cells.

“Our findings support a causal relation of SARS-CoV-2 with COVID toes. Endothelial damage induced by the virus could be the key mechanism causing these lesions,” said lead author Isabel Colmenero, MD, of Hospital Infantil Universitario Niño Jesús, in Spain.

“Furthermore, vascular damage could also explain some clinical features seen in patients with severe COVID-19.”


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the respiratory illness COVID-19, has led to a global pandemic. COVID-19 is the focus of a nascent and rapidly evolving medical literature.

Amidst a panoply of unusual findings for a viral respiratory illness including induced coagulopathies,1 renal dysfunction2 and cardiac arrests,3,4 a suspected cutaneous manifestation of COVID-19, chilblain-like skin lesions – “COVID toes” – has garnered particular attention both in the medical literature and in the national media.5-14

While COVID-19 was initially reported to have few or no cutaneous findings,15 a multitude of skin manifestations have now been described. Purported cutaneous manifestations of COVID-19 range from those commonly observed with viral illnesses, e.g., maculopapular and urticarial eruptions,7,16 to the more unusual, e.g., varicella-like eruptions7 or livedoid and necrotic skin lesions.5,7

These findings merit further study to parse true viral associations from those of potential confounders including acute or latent co-infections, medical complications of disease and adverse reactions to medication.

Similarly, the chilblain-like presentation is an unexpected association with COVID-19. Historically chilblains, or pernio, has been defined as an exaggerated skin response to cold in predisposed individuals.17 It is characterized clinically by pink to violaceous papules arising on acral surfaces, most commonly the hands and feet ( Figures 1 and ​22 ).

Histologically, chilblains is an inflammatory disorder showing dermal edema along with a superficial and deep perivascular lymphocytic infiltrate. Chilblains may be idiopathic or associated with systemic disease, such as autoimmune conditions, certain genetic mutations, hematologic malignancy and less commonly infections, such as Epstein-Barr virus (EBV).17

Cold agglutinins appear to play a role in chilblains associated with EBV.17 Chilblains is a relatively rare condition; a Minnesota case series recorded an average of 9-10 diagnoses per year across an entire tertiary academic department.17

Figure 2
Figure 3
Early chronology of chilblain-like lesions in the setting of the COVID-19 pandemic.
Figure 1
Figure 1
New-onset chilblain-like lesions diagnosed in May 2020 in Boston, Massachusetts. Red-purple edematous plaque on the 5th (A) and 1st (B) digits of a 15-year-old with no preceding respiratory symptoms. Patient’s mother had similar findings. PCR testing for SARS-CoV-2 was negative. Red-brown edematous papules on the distal fingers (C), (D) of an otherwise asymptomatic 16-year-old. PCR testing was not obtained. Red-purple superficially desquamating patches on the dorsal (E) and plantar (F) digits with significant digital edema of an otherwise healthy and asymptomatic 19 year old. Photos courtesy of Marilyn Liang, MD and Kristen Corey, MD.
Figure 2
Figure 2
Idiopathic chilblains. Targetoid red-purple patches on distal toes with superficial desquamation seen in a 12-year-old healthy male following cold exposure in Boston, Massachusetts in 2019, prior to onset of COVID-19 pandemic.

In early March 2020, nearly 3 weeks after community spread of COVID-19 was documented in Italy, a 13-year-old boy developed pruritic red-violet lesions on the toes in the setting of fever, myalgia and headache.11

Family members were reported to have had fever, cough and dyspnea six days prior. While testing for COVID-19 was not possible in this case an association was suspected. Shortly after this index report, images of similar acral lesions in the feet of children with suspected COVID-19 were circulated on “Amici DermPed,” an Italian pediatric dermatology forum.11 In mid-March, the French Union of Dermatologists and Venereologists (SNDV) created a text messaging group on WhatsApp® to share information.6

One week later, a case of chilblain-like lesions was reported via WhatsApp® and with the help of ‘re-posts’ through Facebook® between the two platforms, 146 individual chilblain-like cases were subsequently circulated.6

Intensified medical and lay interest in this phenomenon was reflected in unprecedented Google searches for “coronavirus toes”.18 In the second week in April, just one month after the initial report of chilblain-like lesions in Italy, the American Academy of Dermatology, the Pediatric Dermatology Research Alliance and the Spanish General Council of Podiatrists announced registries that would facilitate the study of chilblain-like lesions and COVID-19.10,19,20

This month-long evolution from first informal reports to national specialty-level registry formation is striking. A detailed timeline is presented in Figure 2 .

Dermatologists in the United States and around the world now report a dramatically increased frequency of chilblain-like diagnoses, not infrequently in members of the same family, amidst the COVID-19 pandemic.

The increased incidence,6 coupled with the temporal association with viral symptoms, has led to the colloquialization “COVID toes.” Chilblain-like lesions appear to have a predilection for younger patients who are often minimally or asymptomatic and do not require hospitalization.10,21

Lesions appear late in the evolution of COVID-19 symptoms, often during convalescence. Finally, although a history of upper respiratory tract infection in patients and family members is sometimes elicited,7,22 evidence of infection is not consistently or regularly found when evaluated by polymerase chain reaction (PCR) for SARS-CoV-2.

In one of the first studies on the topic, Piccolo et al reported 63 cases of chilblain-like lesions during the Italian COVID-19 outbreak; PCR data was available for 11 patients, and only 2 (18%) were positive.10 Recalcati et al reported no positive cases in a separate Italian series of 14 patients.21

In a Spanish series of 12 cases with available PCR data, again no patients were found to be positive.23 The strongest correlation between COVID-19 and chilblain-like lesions is provided by a Spanish study in which 71 cases were reported, 41% with confirmed COVID-19.7

At the time of this writing in early May 2020, 17 reports have detailed a pooled 566 patients with new-onset chilblain-like lesions suspected to be related to COVID-19 (Table 1 );5-11,21-29 formal investigation for active infection, usually by PCR, was undertaken in 172 instances. Among these patients, COVID-19 infection was confirmed in 41, yielding an overall rate of 23.8%.

Table 1

Early reports of chilblain-like lesions amidst the COVID-19 pandemic.

e-Pub DateFirst AuthorCountryPatients in series (n)Patients formally assessed for active infection (n)COVID-19 Confirmed (n)
N/AMazzota11Italy1
4/18/20Alramthan25Kuwait222
4/18/20Kolivras26Belgium111
4/21/20Hedou24France3
4/22/20Romaní23Spain12120
4/24/20Piccolo10Italy63112
4/24/20Recalcati21Italy1450
4/24/20Fernandez-Nieto27Spain132112
4/25/20Landa9Spain632
4/25/20Duong5,6France146
4/28/20Bouaziz5France4282
4/29/20Galvan Casas7Spain717129
5/6/20Lopez-Robles8Spain41190
5/7/20Colonna22Italy440
5/9/20Andina28Italy22191
5/12/20Cordoro29USA660
Totals56641
The initial report by Mazzota is not formally published as of this writing. Most assessments for active COVID-19 infection were by PCR.

This is a strikingly low rate of testing positivity for a viral-associated phenomenon, especially as SARS-CoV-2 can shed for up to 37 days in some patients;30 at the same time, 23.8% is also well above any expected background rate of active COVID-19 infection.

Possible explanations for the discrepancy include insufficiently sensitive diagnostic testing, delayed onset of symptoms after clearance of infection, enhanced viral clearance in patients with chilblain-like skin lesions or admixed diagnoses of non-COVID-19 related chilblains due to confounding factors; regarding the latter, it has been an unseasonably cold Spring in the United States and heightened self-detection may be occurring in patients with idiopathic chilblains following COVID-19-associated media attention.31

A mechanistic explanation for the low rate of testing positivity among these patients was put forth by Kolivras and colleagues, who hypothesized that a robust antiviral type I interferon response in young patients may simultaneously truncate the clinical course and induce microangiopathic changes leading to chilblain-like skin lesions.26

According to this hypothesis, patients present with chilblain-like lesions only after mounting a successful viral response; thus, lesions are detected when symptoms are likely to be subsiding. While more studies are needed to validate this hypothesis, it is consistent with the findings presented by Galván-casas et al which showed chilblain-like lesions are unique amongst the cutaneous manifestations of COVID-19 in occurring primarily late in the disease course.7

Regarding its possible association with a robust immune response, emerging data on the occurrence of a pediatric Kawasaki-like syndrome, termed multisystem inflammatory syndrome in children by the U.S. Centers for Disease Control and Prevention, amongst children with suspected or confirmed COVID-19 infection suggest that immune complications may eventually be recognized in a larger fraction of those infected.13,32

Rigorous studies with improved diagnostic testing, including validated antibody-based assays, measurement of COVID-19 viremia and tissue biopsies with lesional PCR or immunohistochemistry are needed to fully elucidate the relationship between chilblain-like lesions and COVID-19.

These data may have significant implications for clinicians, patients and public health officials, including the potential for transmissibility and the need for self-isolation. The impact of the latter may be somewhat limited if these lesions occur in the period of convalescence.

The study of chilblain-like lesions, as in many domains of the global COVID-19 pandemic, is intense and ongoing. The usually deliberate scientific process has moved apace, from the first documented case of chilblain-like lesions in March 2020 to the formation of national registries a mere month later.

These undertakings may eventually explain current knowledge gaps, including strikingly low rates of testing positivity and a pauci-symptomatic presentation in many patients. While elusive yet, the pathogenesis of chilblain-like lesions may provide important clues both to the virulence of SARS-CoV-2 as well as the host response.

References

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22. Colonna C, Monzani NA, Rocchi A, Gianotti R, Boggio F, Gelmetti C. Chilblains-like lesions in children following suspected Covid-19 infection. Pediatr Dermatol. 2020.

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29. Cordoro KM, Reynolds SD, Wattier R, McCalmont TH. Clustered cases of acral perniosis: clinical features, histopathology and relationship to COVID-19. Pediatr Dermatol. 2020.

30. Wolfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020.

31. Rosenbach M. COVID-19, “COVID toes,” and clinical manifestations. The profound dermatological manifestations of COVID-19: Part IV Cutaneous features Web site. https://www.aad.org/dw/dw-insights-and-inquiries/2020-archive/april/dermatological-manifestations-covid-19-part-4. Published 2020. Accessed May 5th, 2020.

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Source:
Wiley

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