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.

The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series.

BACKGROUND: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19. OBJECTIVES: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19. METHODS: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19. RESULTS: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen. CONCLUSIONS: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.

Skin manifestations of COVID-19 in children: Part 1.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discuss one of the first and most widespread cutaneous manifestation of COVID-19, chilblain-like lesions. In Part 2, we review other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome, while in Part 3, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children, for both COVID-19 and any other pre-existing conditions.

Coronavirus (COVID-19) Infection-Induced Chilblains: A Brisk Perieccrine Inflammatory Response.

ABSTRACT: The varying cutaneous and pathological manifestations of coronavirus 2 (SARS-CoV-2 or COVID-19) may have prognostic implications. Acral ischemic findings present with a hypercoagulable state in critically ill COVID-19 patients. Pathologically confirmed varicella-like exanthem and perniosis COVID-19 cases have correlated with paucisymptomatic and asymptomatic patients in previous reports. We present the second case of biopsy-proven COVID-19 infection-induced chilblains (pernio) in a paucisymptomatic patient with a brisk perieccrine lymphocytic response. Based on an antecedent pathological study, we know coronavirus particles have been seen in the eccrine gland associated with a brisk peri-inflammatory response. The prominent perieccrine inflammation is helpful in the diagnosis of COVID-19 infections. Currently, nonischemic pathological findings correlate with a good prognosis based on the paucisymptomatic or asymptomatic nature of their disease courses. Patients presenting with suspected COVID-19 infection-induced chilblains who are paucisymptomatic or asymptomatic should be isolated and immediately tested with polymerase chain reaction (PCR) testing (as there is a delay in diagnosis based on the poor sensitivity of the current rapid test). We continue to stress the importance of early diagnosis and quarantining to prevent spread to the older and immunocompromised patients.

Most chilblains observed during the COVID-19 outbreak occur in patients who are negative for COVID-19 on polymerase chain reaction and serology testing.

BACKGROUND: Acral lesions, mainly chilblains, are the most frequently reported cutaneous lesions associated with COVID-19. In more than 80% of patients tested, nasopharyngeal swabs were negative on reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 when performed, and serology was generally not performed. METHODS: A national survey was launched on 30 March 2020 by the French Society of Dermatology asking physicians to report cases of skin manifestations in patients with suspected or confirmed COVID-19 by using a standardized questionnaire. We report the results for acral manifestations. RESULTS: We collected 311 cases of acral manifestations [58.5% women, median age 25.7 years (range 18-39)]. The most frequent clinical presentation (65%) was typical chilblains. In total, 93 cases (30%) showed clinical suspicion of COVID-19, 67 (22%) had only less specific infectious symptoms and 151 (49%) had no clinical signs preceding or during the course of acral lesions. Histology of skin biopsies was consistent with chilblains. Overall, 12 patients showed significant immunological abnormalities. Of the 150 (48%) patients who were tested, 10 patients were positive. Seven of 121 (6%) RT-PCR-tested patients were positive for SARS-CoV-2, and five of 75 (7%) serology-tested patients had IgG anti-SARS-CoV-2. Tested/untested patients or those with/without confirmed COVID-19 did not differ in age, sex, history or acral lesion clinical characteristics. CONCLUSIONS: The results of this survey do not rule out that SARS-CoV-2 could be directly responsible for some cases of chilblains, but we found no evidence of SARS-CoV-2 infection in the large majority of patients with acral lesions during the COVID-19 lockdown period in France. What is already known about this topic? About 1000 cases of acral lesions, mainly chilblains, were reported during the COVID-19 outbreak. Chilblains were reported to occur in young people within 2 weeks of infectious signs, which were mild when present. Most cases did not have COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR), and few serology results were available. What does this study add? Among 311 patients with acral lesions, mainly chilblains, during the COVID-19 lockdown period in France, the majority of patients tested had no evidence of SARS-CoV-2 infection. Overall, 70 of 75 patients were seronegative for SARS-Cov-2 serology and 114 of 121 patients were negative for SARS-CoV-2 RT-PCR.

Chilblain-like acral lesions during the COVID-19 pandemic ("COVID toes"): Histologic, immunofluorescence, and immunohistochemical study of 17 cases.

BACKGROUND: During the coronavirus disease 2019 pandemic, several acral chilblain-like lesions were observed in young patients with suspected, but mostly unconfirmed, infection with severe acute respiratory syndrome coronavirus 2. The histopathologic aspect of these lesions is as yet poorly known. OBJECTIVE: To investigate the pathologic features of chilblain-like lesions. METHODS: Biopsies were obtained from 17 cases of chilblain-like lesions during the coronavirus disease 2019 pandemic in France and were studied by routine histologic examination, immunohistochemistry, and direct immunofluorescence. The patients had suspected but unconfirmed infection with severe acute respiratory syndrome coronavirus 2 (negative nasopharyngeal polymerase chain reaction and serologic test results). RESULTS: Chilblain-like lesions showed many features in common with those reported in idiopathic and autoimmune-related chilblains, including epidermal necrotic keratinocytes, dermal edema, perivascular and perieccrine sweat gland lymphocytic (predominantly CD3/CD4+) inflammation, and frequent vascular changes (endothelialitis, microthromboses, fibrin deposition, and immunoreactant deposits on vessels). CONCLUSIONS: Chilblain-like lesions show histopathologic features similar to those of idiopathic and autoimmune-related chilblains, with a high rate of vascular changes and direct immunofluorescence positivity. The role of severe acute respiratory syndrome coronavirus 2 in the development of these puzzling lesions remains to be elucidated.

No SARS-CoV-2 antibody response in 25 patients with pseudo-chilblains.

Chilblain-like acral lesions have been identified in some coronavirus disease 2019 (COVID-19) patients. It has been suggested that these pseudo-chilblains could be a specific marker of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Most patients with these lesions have had negative polymerase chain reactions (PCRs), but some authors believe serology tests are likely to give positive results. We designed a prospective study including all patients with pseudo-chilblains treated in outpatient department in April and May 2020 and then performed SARS-CoV-2 PCR and serology tests on all available patients. We evaluated 59 patients, of whom 17 had undergone PCR before the study period, all with negative results. For the present study, we performed 20 additional PCRs, serology tests in 25 patients, and a parvovirus B19 antibody test in 15 patients. All results were negative. Our findings counter the hypothesis that serology is likely to reveal SARS-CoV-2 infection in patients with pseudo-chilblains. One hypothesis for our negative results is that the time period between symptom onset and antibody production is longer in these patients; another is that the lesions are caused by behavioral changes during lockdown rather than SARS-CoV-2 infection. We nevertheless maintain that COVID-19 should be ruled out in people presenting with chilblain-like lesions.

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.

Comparative Analysis of Chilblain Lupus Erythematosus and Idiopathic Perniosis: Histopathologic Features and Immunohistochemistry for CD123 and CD30.

Distinction of chilblain lupus erythematosus (CLE) from idiopathic perniosis (IP) could predict an underlying connective tissue disease; however, histopathologic discrimination of the two is difficult. Increased CD123 plasmacytoid dendritic cells and CD30 lymphocytes have been demonstrated in various forms of cutaneous lupus erythematosus and IP, respectively. To our knowledge, CD123 and CD30 have not been examined in CLE. Our objective was to identify helpful histopathologic and immunohistochemical features in distinguishing CLE and IP. Skin biopsies classified as CLE (n = 20) and IP (n = 39) based on clinicopathologic correlation were collected from 2000 to 2015. Various histopathologic features were examined on hematoxylin and eosin and alcian blue stains. CD123 and CD30 immunostains were performed and characterized. We identified dermal interstitial fibrin exudate (P = 0.0352) and increased dermal mucin (P = 0.0002) as features significantly associated with CLE. Other histopathologic features and CD123 failed to distinguish between groups. CD30 lymphocytes were sparse in all cases. Despite being the largest series of CLE and IP to date, the number of CLE cases in this study remained relatively limited, and some patients in the IP group may have yet to develop diagnostic features of systemic lupus erythematosus. In conclusion, histopathologic distinction between CLE and IP remains challenging. Interstitial fibrin and abundant dermal mucin help favor CLE. The number and distribution of CD123 plasmacytoid dendritic cells and CD30 lymphocytes have no discriminatory role.

Familial chilblain lupus due to a gain-of-function mutation in STING.

OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-ß reporter and Western blotting. IFN signatures in patient blood in response to tofacitinib treatment were measured by RT-PCR of IFN-stimulated genes. RESULTS: In a multigenerational family with five members affected with chilblain lupus, we identified a heterozygous mutation of STING, a signalling molecule in the cytosolic DNA sensing pathway. Structural and functional analyses indicate that mutant STING enhances homodimerisation in the absence of its ligand cGAMP resulting in constitutive type I IFN activation. Treatment of two affected family members with the Janus kinase (JAK) inhibitor tofacitinib led to a marked suppression of the IFN signature. CONCLUSIONS: A heterozygous gain-of-function mutation in STING can cause familial chilblain lupus. These findings expand the genetic spectrum of type I IFN-dependent disorders and suggest that JAK inhibition may be of therapeutic value.

Familial Chilblain Lupus - What Can We Learn from Type I Interferonopathies?

PURPOSE OF REVIEW: Familial chilblain lupus belongs to the group of type I interferonopathies and is characterized by typical skin manifestations and acral ischaemia. This review aims to give an overview of clinical signs and the pathophysiological mechanisms. RECENT FINDINGS: There are several mutations that can lead to this autosomal dominant disease. Most frequent is a mutation of the gene for TREX-1. However, as well cases of families with mutations in the SAMHD1 gene and, recently, with one for the gene that codes for the protein stimulator of interferon genes have been described. These genes are involved in the process of the detection of intracellular DNA, and their mutation results in an increased production of type I interferons and their gene products, resulting in auto-inflammation and auto-immunity. JAK inhibitors have been successfully used to treat this disorder. Familial chilblain is a rare disorder with very distinct clinical signs. Its pathophysiological mechanism gives insight into the process of interferon-induced inflammation in auto-immune diseases.

[Type I interferonopathies]. / Interféronopathies de type I.

Type I interferonopathies are a group of Mendelian disorders characterized by a common physiopathology: the up-regulation of type I interferons. To date, interferonopathies include Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, PRoteasome-associated auto-inflammatory syndrome (PRAAS) and Singleton-Merten syndrome. These diseases present phenotypic overlap including cutaneous features like chilblain lupus, that can be inaugural or present within the first months of life. This novel set of inborn errors of immunity is evolving rapidly, with recognition of new diseases and genes. Recent and improved understanding of the physiopathology of overexpression of type I interferons has allowed the development of targeted therapies, currently being evaluated, like Janus-kinases or reverse transcriptase inhibitors.