Lack of association between pandemic chilblains and SARS-CoV-2 infection.

An increased incidence of chilblains has been observed during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and attributed to viral infection. Direct evidence of this relationship has been limited, however, as most cases do not have molecular evidence of prior SARS-CoV-2 infection with PCR or antibodies. We enrolled a cohort of 23 patients who were diagnosed and managed as having SARS-CoV-2-associated skin eruptions (including 21 pandemic chilblains [PC]) during the first wave of the pandemic in Connecticut. Antibody responses were determined through endpoint titration enzyme-linked immunosorbent assay and serum epitope repertoire analysis. T cell responses to SARS-CoV-2 were assessed by T cell receptor sequencing and in vitro SARS-CoV-2 antigen-specific peptide stimulation assays. Immunohistochemical and PCR studies of PC biopsies and tissue microarrays for evidence of SARS-CoV-2 were performed. Among patients diagnosed and managed as "covid toes" during the pandemic, we find a percentage of prior SARS-CoV-2 infection (9.5%) that approximates background seroprevalence (8.5%) at the time. Immunohistochemistry studies suggest that SARS-CoV-2 staining in PC biopsies may not be from SARS-CoV-2. Our results do not support SARS-CoV-2 as the causative agent of pandemic chilblains; however, our study does not exclude the possibility of SARS-CoV-2 seronegative abortive infections.

Prevalence of phalangeal bone marrow edema on MRI before and during the COVID-19 pandemic and correlation with chilblain skin lesions.

OBJECTIVE: The purpose of this study is to establish the prevalence bone marrow edema of the phalanges of the feet and hands before and during the COVID-19 pandemic on MRI studies and correlate with clinically chilblain skin lesions and epidemiological data. METHODS: This observational retrospective study. In patients with confirmed bone marrow edema of the phalanges, epidemiological data and clinical findings were collected, including the history of current or remote COVID-19 infection and vaccination status. The two-proportion test was used to compare the frequency of bone marrow edema in the phalanges before and during the pandemic, and the comparison between the categories variables was performed using the one-proportion test. RESULTS: Of the total of 7215 patients, only 20 presented isolated bone marrow edema of the digits in MRI studies; 2 (0.05%) were found two years before the pandemic's beginning, and 18 (0.64%) after the pandemic's onset, demonstrating an increase of 13-fold in this period. 16 were women with a mean age of 40.3 years and 4 were men with a mean age of 53.5 years. The most frequently reported clinical symptoms by the patients were pain (85.0%), and erythema of the skin (45.0%). Of the 18 patients found after the pandemic's onset, only 27.8% had COVID-19 infections confirmed by RT-PCR before the imaging study, and all cases were mild. CONCLUSION: This study demonstrated a significant increase in the prevalence of bone marrow edema of the phalanges after the onset of the COVID-19 pandemic, particularly in middle-aged and younger women.

Chilblain-Like Lesions (CLL) Coinciding With the SARS-CoV-2 Pandemic in Children: A Systematic Review.

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.

Pandemic chilblains: Are they SARS-CoV-2-related or not?

The exact etiopathology of chilblains observed during the Coronavirus Disease 2019 (COVID-19) pandemic is still unclear. Initially, SARS-CoV-2 appeared as the obvious causing agent, but two years of various investigations have failed to convincingly support its direct implication. Most affected individuals have no detectable virus, no anti-SARS-CoV-2 antibodies and no symptoms of COVID-19. Analyses of skin biopsies similarly failed to unambiguously demonstrate presence of the virus or its genome. In a recent hypothesis, SARS-CoV-2 would cause the lesions before being promptly eliminated by unusually strong type I interferon responses. With others, we feel that environmental factors have not been sufficiently considered, in particular cold exposure related to unprecedented containment measures. The cause of pandemic chilblains remains a stimulating puzzle which warrants further investigation.

Pernio and early SARS-CoV-2 variants: natural history of a prospective cohort and the role of interferon.

Cases of new-onset pernio and recurrences in our cohort align tightly with trends in mean 7-day COVID-19 positivity in Wisconsin and mean temperature in Madison, Wisconsin by month.

Oral cinnarizine for the treatment of COVID-19-associated chilblain-like lesions: An old drug for a new disease?

During SARS-CoV-2 pandemic, an outbreak of chilblain-like lesions has been developed, even if the relationship with the virus infection is still debated. We report the good results obtained in 12 patients with chilblain lesions and the use of oral cinnarizine, a piperazine derivative with many pharmacological properties among whom antihistaminic and calcium channel blocking activities.

Chilblain or perniosis-like skin lesions in children during the COVID-19 pandemic: A systematic review of articles.

COVID toes or chilblain-like skin lesions represent a widespread and specific skin presentation mostly in the feet that may be attributed to COVID-19 infection. They may last for several months. We conducted this study to investigate chilblain-like lesions in children during the COVID-19 pandemic, any predisposition, location, clinical course, and prognosis. We searched Google Scholar, Scopus, and Medline (PubMed) databases using the following keywords: "Coronavirus" OR "COVID-19" AND "Chilblains" OR "Pernio" OR "Perniosis" OR "Children" OR "Cutaneous" OR "skin." The inclusion criteria were: (a) Studies that described the specific vascular skin lesion. (b) Studies that included patients aged >1 month till 18 years. (c) Case reports, case series, retrospective or prospective cohort studies, case-control studies. A total of 28 articles were included. The total number of children with chiblain-like lesions (CLL) was 433. The mean age of children presenting CLL during the COVID-19 pandemic was estimated as 12.58 ± 2.15. Of note, 53.6% of them were male. The nasopharyngeal SARS-CoV-2 RT-PCR test and anti-SARS-CoV-2 antibodies were mostly negative for the virus. In conclusion, it is crucial to be familiar with various presentations of COVID-19 infection and their clinical significance to approach the earliest diagnosis, immediate treatment, estimate the prognosis, and finally isolate the patients to prevent spreading. Chilblain-like lesions as a possible cutaneous presentation of COVID-19 in children may last several months with the indolent course.

Evolution of incidence of chilblain-like lesions in children during the first year of COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has brought innumerable reports of chilblains. The relation between pernio-like acral eruptions and COVID-19 has not been fully elucidated because most reported cases have occurred in patients with negative microbiological tests for SARS-CoV-2. METHODS: A retrospective study of 49 cases of chilblains seen during the first year of the pandemic in a children's hospital in Madrid, Spain. The incidence of these skin lesions was correlated with the number of COVID-19 admissions and environmental temperatures. Patients were separated into two groups depending on the day of onset (strict lockdown period vs. outside the lockdown period). RESULTS: Most chilblains cases presented during the first and third waves of the pandemic, paralleling the number of COVID-19 admissions. The first wave coincided with a strict lockdown, and the third wave coincided with the lowest ambient seasonal temperatures of the year. Systemic symptoms preceding chilblains were more frequent in the first wave (45.8% vs. 8.0%, p = .002), as was the co-occurrence with erythema multiforme-like lesions (16.7% vs. 0%, p = .033). Laboratory test and skin biopsies were performed more frequently in the first wave (75.0% vs. 12.0%, p < .001; and 25.0% vs. 0%, p = .007; respectively). Five patients developed recurrent cutaneous symptoms. CONCLUSIONS: An increased incidence of chilblains coincided not only with the two major waves of the pandemic, but also with the strict lockdown period in the first wave and low seasonal temperatures during the third wave. Both increased sedentary behaviors and cold environmental temperatures may have played an additive role in the development of COVID-19-related chilblains.

Idiopathic perniosis presenting as acral purpuric lesions: Clustering of cases before COVID-19 pandemic and their comparison with chilblain like lesions reported in the literature.

Perniosis/chilblains are the acral inflammatory skin lesions developing in susceptible individuals as an abnormal reaction to cold. In the absence of a discernible cause, it is labeled as idiopathic perniosis (IP). With the ongoing COVID-19 pandemic, there was an upsurge of reports of chilblain like lesions (CLL) especially in young patients possibly implicated to the SARS-CoV-2 virus. Twelve clinically suspected and histopathologically confirmed cases of IP seen from November 2019 through February 2020 were retrospectively recruited. Clinical, dermoscopic, and histopathological characteristics of these were reviewed and compared with CLL reported in the literature. Mean age of patients was 26.58 ± 15.18 years with an equal male to female ratio. Characteristic histopathology findings were spongiosis (100%), dermal edema (100%), perivascular lymphocytic infiltrate (100%) with peri-eccrine accentuation (66.7%), keratinocyte necrosis (50%), focal basal vacuolar damage (58.3%), and lymphocytic vasculitis (58.3%). Significant dermoscopy findings were variable background color ranging from dull red and violaceous to copper red and brown orange, coiled vessels (44.4%) and orange-red structureless areas (63.9%). Lesions over palms and soles preferentially had white dots/clods and lines (38.9%). There appears no exclusive histopathological as well as dermoscopy features of CLL and IP, yet certain clues can be appreciated. Keratinocyte necrosis and severe dermal edema favors IP, whereas fibrin thrombi with involvement of both superficial and deep dermal vessels favor CLL. Dermoscopically presence of irregular, linear or branching vessels, red/purple dots and clods and gray brown reticule supports CLL while white dots/clods and lines supports IP.

Long-term Outcome of Chilblains Associated with SARS-CoV-2.

Numerous cases of chilblains have been observed in the course if the COVID-19 pandemic. The aims of this study were to provide comprehensive follow-up data for patients reporting chilblains, and to determine the risk factors for incomplete recovery. Patients referred to 5 hospitals in France between March and May 2020 for chilblains were surveyed on December 2020. A teleconsultation was offered. Among 82 patients reporting chilblains, 27 (33%) reported complete recovery, 33 (40%) had recurrences of chilblains after their hands and feet had returned to normal, and 22 (27%) developed persistent acral manifestations, mostly acrocyanosis, with or without further recurrences of chilblains. Most recurrences of chilblains occurred during the following autumn and winter. A past history of chilblains was not associated with recurrences or persistent acral manifestations. Women had a significantly higher risk of developing recurrences or persistent acral manifestations (odds ratio 1.30; 95% confidence interval 1.06-1.59). In conclusion, two-thirds of patients reporting chilblains at the start of the COVID-19 pandemic experienced persistent or recurrent acral manifestations after a 10-month follow-up.

Chilblain-Like Lesions (CLL) Associated With COVID-19 ("COVID Toes"): A Systematic Review.

Reports of chilblain-like lesions (CLL) coinciding with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described in the literature, but this phenomenon has not been critically summarized. The aim of this paper is to summarize reports of CLL coinciding with SARS-CoV-2 infection to clarify the prevalence, clinical relevance, and prognostic value of these lesions. A literature search was conducted using the Embase, Pubmed, and Scopus databases from December 2019 to June 16, 2020 using the search terms ("COVID-19" OR "coronavirus" OR "2019-nCoV" OR "SARS-CoV-2") AND ("chilblain-like" OR "COVID toes" OR "acral"). Papers that described skin changes in patients with suspected or confirmed COVID-19 were included. A total of 31 papers were summarized, representing 813 cases of CLL. Available data suggests an equal gender distribution, mean age of 21 years, and median age of 14 years. Mild extracutaneous symptoms were reported in 53% of cases and 47% were asymptomatic. CLL occurred an average of 16 days after extracutaneous symptoms. Patients with CLL were positive for SARS-CoV-2 in 15% of cases. Lesions were mainly described as asymptomatic and/or pruritic erythematous to violaceous acral macules and plaques. Partial or complete resolution occurred in 85% of cases in a mean of 13 days. The most common histologic findings were perivascular and perieccrine superficial and deep lymphocytic infiltrates. Although a causal relationship between CLL and SARS-CoV-2 has not been confirmed, the temporal association and 15% positive SARS-CoV-2 rate in affected individuals should not be ignored.

[COVID-toes, a cutaneous sign of innate resistance to SARS-CoV-2]. / «â€ Orteils Covid†¼, expression cutanée d'une résistance innée au SARS-CoV-2.

Since the beginning of the COVID-19 pandemic, dermatologists around the world have reported patients with chilblain-like skin lesions on their toes, called COVID-toes. Surprisingly, the majority of these patients do not develop COVID-19 symptoms, and their nasal swabs and serological tests are unable to confirm SARS-CoV-2 infection, despite a clear exposure to the virus. Recent evidence suggests that these patients mount a robust type I interferon response to SARS-CoV-2, making them resistant to the infection. Because chilblains are hallmarks of excessive type I interferons, COVID-toes may represent the skin expression of interferon-mediated resistance to SARS-CoV-2. Uncovering the molecular patho-mechanisms of COVID-toes may provide new avenues to promote SARS-CoV-2 resistance and control the COVID-19 pandemic.

Depuis le début de la pandémie de Covid-19, les dermatologues du monde entier ont signalé des cas inexpliqués de pseudo-engelures, surnommées «â€…orteils Covid ¼ (COVID-toes). Cette recrudescence inhabituelle de pseudo-engelures est d'autant plus intrigante que la majorité des cas ne présentent pas de symptômes de Covid-19 ni de PCR ou de sérologie positive, malgré une exposition probable au SARS-CoV-2. Les données actuelles suggèrent que ces personnes sont prédisposées à induire une immunité innée robuste contre le SARS-CoV-2, ce qui les rend résistantes à l'infection. Une forte réponse interféron de type I, dont les pseudo-engelures sont l'expression clinique, pourrait favoriser une clairance rapide du virus, évitant à la fois la maladie et la séroconversion. Les mécanismes génétiques et moléculaires qui sous-tendent cette résistance naturelle au SARS-CoV-2 restent cependant à élucider.

Pernio-like skin lesions associated with COVID-19: A case series of 318 patients from 8 countries.

BACKGROUND: Increasing evidence suggests pernio-like lesions are cutaneous manifestations of coronavirus infectious disease 2019 (COVID-19). OBJECTIVE: To describe clinical and pathologic findings of pernio-like lesions in patients with confirmed or suspected COVID-19. METHODS: An international dermatology registry was circulated to health care providers worldwide through the American Academy of Dermatology, International League of Dermatologic Societies, and other organizations. RESULTS: We documented 505 patients with dermatologic manifestations associated with COVID-19, including 318 (63%) with pernio-like lesions. Patients with pernio-like lesions were generally young and healthy, with relatively mild COVID-19. Of 318 patients with confirmed or suspected COVID-19 by providers, 23 (7%) were laboratory-confirmed COVID-19 positive, and 20 others (6%) were close contacts of patients with confirmed COVID-19. Given current testing criteria, many patients lacked COVID-19 testing access. For 55% of patients, pernio-like lesions were their only symptom. In patients with other COVID-19 symptoms, pernio-like lesions typically appeared after other symptoms. Pernio-like lesions lasted a median of 14 days (interquartile range, 10-21 days). LIMITATIONS: A case series cannot estimate population-level incidence or prevalence. In addition, there may be confirmation bias in reporting. We cannot exclude an epiphenomenon. CONCLUSIONS: Pernio-like skin changes of the feet and hands, without another explanation, may suggest COVID-19 infection and should prompt confirmatory testing.

Perniosis during the COVID-19 pandemic: Negative anti-SARS-CoV-2 immunohistochemistry in six patients and comparison to perniosis before the emergence of SARS-CoV-2.

BACKGROUND: Acral inflammatory lesions that have some resemblance to idiopathic or autoimmune-associated perniosis (chilblains) have been described in multiple countries during the COVID-19 pandemic. METHODS: We examined histopathologic findings in six consecutive such cases from five patients received in mid-May to mid-June of 2020, evaluating immunohistochemical staining for the SARS-CoV-2 nucleocapsid protein. We compared these six cases to eight cases diagnosed as perniosis between January and June of 2019. RESULTS: Five of six lesions with perniosis-like histopathology during the COVID-19 pandemic had distinctive tight cuffing of lymphocytes; intravascular material was present in one case. SARS-CoV-2 immunohistochemical staining using an antibody directed at the nucleocapsid protein was negative in all six cases. Only one of eight specimens with microscopic findings of perniosis received prior to the COVID-19 pandemic had tightly cuffed perivascular lymphocytes, and none had obvious intravascular occlusion. CONCLUSIONS: A tightly cuffed pattern of perivascular lymphocytes is a feature of perniosis during the COVID-19 pandemic. The absence of SARS-CoV-2 nucleocapsid protein in these cases suggests against the virus being directly present in these lesions.

Chilblain-like lesions in pediatrics dermatological outpatients during the COVID-19 outbreak.

In Spain, with full confinement measures and coinciding with the pandemic, pediatricians and dermatologists have received, through teledermatology/teleconsultation and social networks, a barrage of diverse images, which have subsequently allowed us to approach some of them by direct physical examination of early and late skin manifestations associated with SARS-Cov-2 infection. We designed a retrospective, cross-sectional study to evaluate the dermatological care of all those patients under the age of 16 who consulted, in person or telematically, for acral lesions (chilblain-like or erythema multiforme-like) in the context of the Coronavirus disease (COVID-19) pandemic, since 15 March 2020 to 24 April 2020, both included in the health area of the Hospital Universitario San Cecilio de Granada. Of all the patients collected, 18 (66%) were male and the overall mean age was 14.44 years. All lacked a personal history of interest and denied previous episodes of chilblains or Raynaud's phenomenon/disease. The clinic was limited to purpuric lesions located on acral regions distributed on hands and feet. Dermatologists and pediatricians should be aware of the lesions associated with COVID-19 infection and their possible complications. It remains to be identified if there are different dermatological patterns in the pediatric and adult population.

Do we have serological evidences that chilblain-like lesions are related to SARS-CoV-2? A review of the literature.

The outbreak of chilblain-like lesions (CLL) coincidentally to the COVID-19 pandemic is a topic of great concern. SARS-CoV-2 was initially hypothesized as the etiologic agent of CLL, but, since nasopharyngeal swabs seldom resulted positive, dermatologists' attention focused on the search for specific SARS-CoV-2 antibodies. Many papers were published contemporarily on this topic, reporting limited case series. We reviewed the English literature up to the first July 2020 and, excluding single case reports, we considered 13 studies that serologically investigated 220 patients. The presence of specific antibodies was detected in 18 subjects (8.2%): isolated IgA were found in 6 patients, IgA and IgG in 1, isolated IgG in 5, and IgM in 2. In 4 patients, isotypes were not specified. Our review demonstrated a high prevalence of negative serological results in CLL: antibodies were observed only in a few patients, that are even less excluding those with positive IgA, not clearly involved in the pathogenesis of the disease. In conclusion, although it is still uncertain whether CLL are related to SARS-CoV-2 infection, patients affected by CLL seem not to be prone to shedding the virus, hence, if they are asymptomatic, we can reassure them, thus avoiding hospital referral.

Major cluster of paediatric 'true' primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown.

BACKGROUND: Over the last months, during the COVID-19 pandemic, a growing number of chilblain-like lesions were reported mainly in children and rarely in young adults. The relationship with SARS-CoV-2 infection was postulated, often without any laboratory, instrumental or clinical confirmation. The disclosure of information about chilblain-like lesions as a COVID-19 manifestation in social media has created concern in children's families and paediatricians. OBJECTIVES: To verify whether the chilblain-like lesions were caused by SARS-CoV-2 infection. METHODS: Prospective study on a case series including children who presented with acral lesions at the Pediatric Dermatology Outpatient and Pediatric Emergency Unit of the University of Bologna, from 1 April to 30 April 2020. We reported demographical, laboratory and clinical features, history of close contact with COVID-19 patients, presence of similar skin lesions in other family members, precipitating and risk factors for chilblain onset. RESULTS: We evaluated eight patients (five females, three males) aged between 11 and 15 years. We excluded acute or previous SARS-CoV-2 infection with RT-PCR nasopharyngeal swab, serum antibody levels using chemiluminescent immunoassays. Other acute infections causing purpuric lesions at the extremities were negative in all patients. Skin lesion biopsy for histological and immunohistochemical evaluation was made in two cases and was consistent with chilblain. PCR assay on skin lesion biopsy for parvovirus B19, Mycoplasma pneumoniae and SARS-CoV-2 was performed in a patient and resulted negative. We identified common precipitating and risk factors: physical (cold and wet extremities, low BMI), cold and wet indoor and outdoor environment, behaviours, habits and lifestyle. We therefore reached a diagnosis of primary chilblains. CONCLUSIONS: During the COVID-19 pandemic, a 'cluster' of primary chilblains developed in predisposed subjects, mainly teenagers, due to cold exposure in the lockdown period. Laboratory findings support our hypothesis, although it is also possible that an unknown infectious trigger may have contributed to the pathogenesis.