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Clinical presentation of chilblain-like lesions on the feet and toes of three young men. Purple to red, tender chilblain-like lesions, superficial blisters and ulcerations on acral locations of the feet occurring 5 weeks after a travel through Germany in February 2020 in Patient 1 (A), 1 month after severe respiratory infection in Patient 2 (B), and 1 month after holidays in Tirol, Austria, that became a hotspot for COVID-19, in Patient 3 (C).
Source publication
Contemporarily to the new SARS-CoV-2 mediated COVID-19 pandemic, a rise in patients with acral chilblain lesions has been described. They manifest late after mild disease or asymptomatic exposure to SARS-CoV-2. Their pathogenic evolution is currently unknown. In biopsies from three patients with acral partially ulcerating chilblain lesions that occ...
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Citations
... Therefore, early and sufficient type I IFN immunity has been associated with a mild course of COVID-19. Pernio-like lesions ("COVID toes") have been regarded as proof of a robust antiviral response [30], and human recombinant IFN-β has been proposed as an early treatment for patients with COVID-19 [31]. In contrast, patients with STAT1-GOF show an excessive response to type I IFNs [12,13], which seems like a contradiction when discussing the mechanisms that underlie COVID-19 aggravation. ...
While SARS-CoV-2 infection causes a mild disease in most children, SARS-CoV-2 infection may be lethal in a few of them. In the defense against SARS-CoV-2, type I interferons are key players, and several studies have identified a defective or neutralized interferon response as the cause of overwhelming viral infection. However, inappropriate, untimely, or excessive interferon production may also be detrimental to the host. Here, we describe two patients with STAT1 gain-of-function (GOF), a known type I interferonopathy, who died of COVID-19. Whole-exome sequencing and interferon-gamma-activated sequence (GAS) and interferon-sensitive responsive element (ISRE) reporter assay were performed to identify and characterize STAT1 variants. Patient 1 developed hemophagocytic lymphohistiocytosis (HLH) in the context of COVID-19 infection and died in less than a week at the age of 4 years. Patient 2 developed a high fever, cough, and hypoxemia and succumbed to COVID-19 pneumonia at the age of 5 years. Two heterozygous missense variants, p.E563Q and p.K344E, in STAT1 were identified. Functional validation by reporter assay and immunoblot confirmed that both variants are gain-of-function (GOF). GOF variants transiently expressing cells exhibited enhanced upregulation of downstream genes, including ISG15, MX1, and OAS1, in response to IFN-α stimulation. A catastrophic course with HLH or acute respiratory failure is thought to be associated with inappropriate immunoregulatory mechanisms to handle SARS-CoV-2 in STAT1 GOF. While most patients with inborn errors of immunity who developed COVID-19 seem to handle it well, these cases suggest that patients with STAT1-GOF might be at risk of developing fatal complications due to SARS-CoV-2.
... Despite case reports and exploratory research, the exact cause of this reaction is not fully understood. However, several theories have been proposed to explain its development [4][5][6][7][8]. ...
We present a case of self-limiting pernio-like Covid-Toe reaction in a 40-year-old female with a history of kidney/pancreas transplant who received the Oxford-AstraZeneca Covid-19 mRNA vaccine. The patient experienced bilateral digital skin inflammation
... The authors believe that their observation supports the hypothesis that vaccines induce an infection-like immune reaction driven by type I interferon. 5 lesions after an inactivated virus vaccine also suggests these manifestations are related to the immune reaction to the virus, and not directly to the virus. ...
... 12,13 This discrepancy could be explained by increased care-seeking by asymptomatic individuals due to increased media attention to "COVID toes" and milder COVID-19 symptoms in the pediatric population generally. It has been proposed that CLL represent a virally-induced interferonopathy, [18][19][20] and individuals with CLL have a robust immune reaction characterized by a T-cell and interferonrich microenvironment, leading to a mild course of illness. 20 In 85% of cases, ECM preceded CLL, consistent with previous observations that CLL tend to arise late in the course or in the post-acute phase of COVID-19. ...
... Low rates of positive PCR tests may be due to rapid clearance of virus by the innate immune system 7 and tests occurring outside the time window of viral replication and shedding in the nasopharynx. 18,26,27 Generalizability of IgA results is limited due to the small sample size (68). The high positivity rate with IgA testing may be explained by pediatric patients with SARS-CoV-2 producing more IgA than IgG. ...
Chilblain-like lesions (CLL) coinciding with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have been described in the literature. Available reviews of the literature suggest that CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous manifestations (ECM) associated with COVID-19 infection. This systematic review aims to provide a summary of reports of CLL associated with the early SARS-CoV-2 pandemic in children to clarify the prevalence, clinical characteristics, and resolution outcomes of these skin findings. Sixty-nine studies, published between May 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 1,119 cases of CLL. Available data showed a slight male predominance (591/1002, 59%). Mean age was 13 years, ranging from 0 to 18 years. Most cases had no ECM (682/978, 70%). Overall, 70/507 (14%) of patients tested positive for COVID-19 using PCR and/or serology. In the majority the clinical course was benign with 355/415 (86%) of cases resolving, and 97/269 (36%) resolving without any treatment. This comprehensive summary of pediatric CLL suggests these lesions are rarely associated with COVID-19 symptoms or test positivity.
... BMI, body mass index; CRP, C-reactive protein; IF, immunofluorescence; IFN, interferon; INR, international normalized ratio; PCR, polymerase chain reaction; PT, prothrombin time there is a defective regulation that causes excess production of interferons. [14][15][16][17] The mechanisms are comparable of the interferon-mediated, pre-COVID-19 era pernio-like rashes; specifically, there is an activation of the angiotensin II pathway-mediated proinflammatory and prothrombotic activity as well as increased vasospasm associated with increased release of IFN-I. [17][18][19] Thrombotic microangiopathy is a common histopathological marker of interferonopathies that is known to cause chilblain-like lesions. ...
SARS‐CoV‐2 infection can manifest many rashes. However, thrombotic retiform purpura rarely occurs during COVID‐19 illness. Aggressive anti‐COVID‐19 therapy with a high‐dose steroid regimen led to rapid recovery. This immunothrombotic phenomenon likely represents a poor type 1 interferon response and complement activation on the endothelial surface in response to acute infection. COVID‐associated rashes in adults usually associate with more severe COVID‐19 illness. For older, comorbid patients with mild to moderate COVID‐19 illness who develop a rash, administer early immunomodulating therapy to mitigate disease progression.
... 23 Low rates of positive PCR tests may be due to rapid clearance of virus by the innate immune system 24 and tests occurring outside the time window of viral replication and shedding in the nasopharynx. [25][26][27] Generalizability of IgA results is limited due to small sample size (n=204). ...
Chilblain-like lesions (CLL) coinciding with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described. Previous systematic reviews suggest CLL are associated with younger age, an equal sex ratio, negative testing for SARS-CoV-2, and mild to no extracutaneous symptoms. A systematic review was conducted according to PRISMA guidelines on CLL coinciding with SARS-CoV-2 to clarify the demographic characteristics, clinical features, and resolution outcomes of these skin findings. One hundred and twenty-eight studies, published between March 2020 and January 2022, met inclusion criteria and were summarized in this review, representing 4,982 cases of CLL. Available data showed a slight female predominance (55%, n=2471/4472). Mean age was 25 years, ranging from 0 to 95 years. Most cases were not associated with extracutaneous symptoms (63%, n=1649/2636). Overall, 19% (n=347/1838) of patients tested positive for SARS-CoV-2 using polymerase chain reaction (PCR), serology, or tissue biopsy. Clinical course was generally benign with 80% (n=979/1224) of cases resolving, and 47% (n=204/432) resolving without receiving treatment. In summary, this review provides a comprehensive summary of CLL associated with SARS-CoV-2. CLL occurred at a mean age of 25 years with slight female predominance. The majority had negative COVID-19 testing, no extracutaneous symptoms, and resolved without recurrence.
... Yet, previous histopathological findings revealed that CAC comprise a highly lymphocytic inflammatory process with an IFN-I microenvironment, as evidenced by extensive epidermal and dermal expression of MxA (myxovirus resistance protein) and pJAK1 (phosphorylated Janus kinase 1) in the endothelial cells and surrounding tissue, and rich presence of plasmacytoid dendritic cells. 7,8 Thus, if a pivotal role of IFN-I should be envisaged in the pathogenesis of CAC, it may be rather through local tissue-specific susceptibility to a physiological antiviral IFN-I response than to systemic overexpression of ISGs after COVID-19. (iv) chilblains of the toes associated with BASCULE syndrome, characterized by Bier anaemic macules, cyanosis, and multiple irregular red-orange macules (white arrows); (v) dilated capillaries and subungual splinter haemorrhages on the distal part of the nail plate. ...
Dear Editor,
Since the onset of the SARS‐CoV‐2 pandemic, the direct causative role of the virus in COVID‐19‐associated chilblains (CAC) has remained under question due to the low rate of positivity to SARS‐CoV‐2 nasopharyngeal polymerase chain reaction (PCR) and blood serology.¹ Likewise, the suspected pivotal pathogenic role of upregulation of interferon type I (IFN‐I) is mainly indirectly supported by assessment of in situ immune response.²
From April 2020 to January 2022, we prospectively assessed children and adults with new‐onset CAC seen in the dermatology, infectious diseases, and adult and paediatric emergency departments, as well as the intensive care unit of the University Hospital of Montpellier. The study was approved by the local institutional review board (ID: 202000442).
Overall, 50 consecutive outpatients were seen, mostly white European and with a female predominance (sex ratio 1·5), a median age of 21 years (range 6–74) and a median body mass index of 19·8 kg m⁻² (range 14·8–26·6). CAC involved the feet and the hands, respectively, in 86% and 66% of patients. Raynaud phenomenon, BASCULE syndrome (Bier anaemic spots, cyanosis, urticaria‐like eruption) and subungual splinter haemorrhages (Figure 1a) were present in 18%, 13% and 8%, respectively. Complete recovery, persistence and recurrence of CAC were noted, respectively, in 93% (median duration 12 weeks, range 1–30), 7% (12 months of follow‐up) and 42·9%.
... Other important studies were conducted on chilblain-like lesions typically affecting children and young adults and usually yielding negative serology. The role of type I interferon was investigated, and its increase may indeed explain the mild disease in this particular population subgroup and the negativity of serology [7]. Moreover, some authors proposed that a vigorous innate immune response against the virus in this subset can control the infection without effectively generating antibodies through the adaptive response [8]. ...
Since December 2019, a novel coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been rapidly spreading across the world, leading to the declared pandemic of COVID-19 [...]
... RT-qPCR on nasopharyngeal swabs and anti-SARS-CoV-2 antibodies are negative in most patient series reported [3,4]. Attempts have been made to identify the virus in the lesions, and the role of virus-induced type I interferon (IFN-I) response has been suggested [5][6][7][8][9][10][11]. However, the results remain insufficiently validated and many questions remain unanswered [12]. ...
Background:
Type 1 interferon (IFN-I) response induced by SARS-CoV-2 has been hypothesized to explain the association between chilblain lesions (CL) and SARS-CoV-2 infection.
Objective:
To explore direct cytopathogenicity of SARS-CoV-2 in CL and to focus on IFN-I expression in patients with chilblains.
Materials & methods:
A monocentric cohort of 43 patients presenting with CL from April 2020 to May 2021 were included. During this period, all CL were, a priori, considered to be SARS-CoV-2-related. RT-qPCR on nasopharyngeal swabs and measurements of anti-SARS-CoV-2 antibodies were performed. Anti-SARS-CoV-2 immunostainings as well as SARS-CoV-2 RT-qPCR were performed on biopsy specimens of CL and controls. Expression of MX1 and IRF7 was analysed on patients’ biopsy specimens and/or PBMC and compared with controls and/or chilblains observed before the pandemic. Serum IFN-α was also measured.
Results:
RT-qPCR was negative in all patients and serological tests were positive in 11 patients. Immunostaining targeting viral proteins confirmed the lack of specificity. SARS-CoV-2 RNA remained undetected in all CL specimens. MX1 immunostaining was positive in CL and in pre-pandemic chilblains compared to controls. MX1 and IRF7 expression was significantly increased in CL specimens but not in PBMC. Serum IFN-α was undetected in CL patients.
Conclusion:
CL observed during the pandemic do not appear to be directly related to SARS-CoV-2 infection, either based on viral cytopathogenicity or high IFN-I response induced by the virus.
... In addition, lesional vessels showed complement and Ig deposition. 17 The authors' proposed pathogenesis was a local response to endothelial infection by SARS-CoV-2, driven by type I IFN F I G U R E 1 (a−f) Moderately painful chilblain-like lesions localized on the toes and fingers in male and female adolescents aged 12−17 years old immunity. 17 Furthermore, CLLs are mostly observed in patients without severe COVID-19 organ manifestations, who express low rate of specific antibody positivity against SARS-CoV-2. ...
... 17 The authors' proposed pathogenesis was a local response to endothelial infection by SARS-CoV-2, driven by type I IFN F I G U R E 1 (a−f) Moderately painful chilblain-like lesions localized on the toes and fingers in male and female adolescents aged 12−17 years old immunity. 17 Furthermore, CLLs are mostly observed in patients without severe COVID-19 organ manifestations, who express low rate of specific antibody positivity against SARS-CoV-2. The high levels of IFN-I could be associated with a precocious effective response against the virus leading to a milder course of the disease with suppressed antibody production. ...
... 18 The role of IFN-I pathway in the induction of CLLs is further supported by the observation that patients with chronic type I IFN activation in the setting of rare type I interferonopathies frequently develop chilblain-like lesions too. 17 Further studies are still required to definitely confirm the link between CLLs and COVID-19. ...
Introduction
It has been almost 2 years since the first reports on cutaneous manifestations of COVID‐19. Those reported in children are different and include macular, papular, lichenoid, vesicular, urticarial, and vascular morphologies, among others. The prognosis of isolated cutaneous involvement in COVID‐19 in children is usually self‐limiting but the extreme variety of clinical presentations complicates the clinical approach.
Methods
Numerous reviews have been systematically drafted and edited giving the clinicians a future direction for skin presentations during pandemics.
Results and Discussion
Hereby we report the rare and common manifestations of COVID‐19 in children and question the recurrence phenomena and age‐related distribution of the eruptions.
