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.

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.

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.

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.

Designation of Autoinflammatory Skin Manifestations With Specific Genetic Backgrounds.

"Autoinflammatory disease (AiD)" has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, "autoinflammation" has been designated for dysregulated innate immunity in contrast to "autoimmunity" with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as "autoinflammatory keratinization diseases (AiKD)" and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.

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.

[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.

CD30 positive atypical lymphocytes in perniosis: a potential histopathologic pitfall in a benign condition.

In classical clinical perniosis (chilblains), the presence of atypical lymphocytes with immunohistochemical staining positive for CD30 is unusual and rarely reported. Here we report 2 cases of clinical perniosis, one in a 16-year-old girl and another in a 67-year-old woman. The biopsies revealed lymphocytic infiltrates, papillary dermal edema, and atypical cells highlighted with a CD30 immunohistochemical stain. Our cases demonstrate the importance of clinicopathologic correlation in the assessment of CD30 positive lymphocytes in benign nonneoplastic conditions. Dermatopathologists must be aware of this potential histologic pattern in perniosis to prevent misdiagnosis and overtreatment of this condition.

Innate immune processes in lupus erythematosus.

The innate immune system is involved in the pathogenesis of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) or dermatomyositis. The important role of complement factors of the classical pathway and of Toll like receptors (TLRs) is well established, based on genetic and clinical evidence. Immune complexes activate tumor necrosis factor (TNF) in myeloid cells and interferon-α (IFNα) in plasmacytoid dendritic cells. The latter initiates a positive feedback loop that drives autoimmunity. More recently, mutations in genes encoding intracellular enzymes involved in RNA and DNA handling, which likewise lead to increased IFNα, have been found to cause familial chilblain lupus and to be associated with SLE. Within the immunological disease continuum, these disorders can be placed between autoinflammation and autoimmunity, and we would propose the term autoadjuvant for this group, since the activation of the innate immune system in these diseases appears to lower the threshold for (auto)immune reactions.

Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy.

Nakajo-Nishimura syndrome (ORPHA2615; also registered as Nakajo syndrome in OMIM#256040) is a distinct inherited inflammatory and wasting disease, originally reported from Japan. This disease usually begins in early infancy with a pernio-like rash, especially in winter. The patients develop periodic high fever and nodular erythema-like eruptions, and gradually progress lipomuscular atrophy in the upper body, mainly the face and the upper extremities, to show the characteristic thin facial appearance and long clubbed fingers with joint contractures. So far about 30 cases have been reported from Kansai, especially Wakayama and Osaka, Tohoku and Kanto areas. At present, about 10 cases are confirmed to be alive only in the Kansai area, including one infant case in Wakayama. However, more cases are expected to be added in the near future. Although cause of the disease has long been undefined, a homozygous mutation of the PSMB8 gene, which encodes the ß5i subunit of immunoproteasome, has been identified to be responsible in 2011. By analyses of the patients-derived cells and tissues, it has been suggested that accumulation of ubiquitinated and oxidated proteins due to immunoproteasome dysfunction causes hyperactivation of p38 mitogen-activated protein kinase and interleukin-6 overproduction. Since similar diseases with PSMB8 mutations have recently been reported from Europe and the United States, it is becoming clear that Nakajo-Nishimura syndrome and related disorders form proteasome disability syndromes, a new category of autoinflammatory diseases distributed globally.

Perniosis: clinical and histopathological analysis.

Perniosis are inflammatory cutaneous lesions, located on acral skin, which present in association with cold exposure. They can appear as an idiopathic dermatosis or with an underlying autoimmune disease. The use of cutaneous biopsy to distinguish between both types is controversial. We analyze the histological findings in 9 cases of idiopathic perniosis (IP) and compare them with those obtained from 11 cases of perniosis associated with an autoimmune disease (autoimmune perniosis). The most frequent histopathological features observed in cases of IP were a lymphocytic infiltrate with perivascular (8 cases, 89%) and perieccrine distribution (6 cases, 66%), dermal edema (5 cases, 55%), and necrotic keratinocytes (5 cases, 55%), whereas those found in perniosis associated with an autoimmune disease were lymphocytic infiltrate with perivascular distribution (11 cases, 100%) but without perieccrine distribution (3 cases, 27%), vacuolation of the basal layer (7 cases, 63%), and necrotic keratinocytes (5 cases, 45%). The only significant difference between both groups was the perieccrine distribution of the lymphocytic infiltrate in cases of IP, which, as mentioned in previous studies, could be considered a histopathological clue to differentiate both types of perniosis.

[Chilblain lupus in an adolescent]. / Chilblain lupus la adolescent.

Chilblain lupus or lupus pernio is a particular clinical type of cutaneous chronic lupus erythematosus, more frequently met in adults and difficult do diagnose without specific lesions at the level of the face and/or the scalp. The patient B.A., female, aged 16 is hospitalized in the Dermatological Clinic Iasi for some red-to-violaceous plaques, infiltrated, slightly scaling located around the nails and on the hands and legs finger sides. The lesions come up at the age of 13 become even more serious and painful in cold weather, getting better in the warm season when they become slightly pruriginous and are accompanied by a discrete facial erythema in "vespertilio", completely neglected by the patient. The general status was very good during this time, without general manifestations or visceral touches. The clinical diagnosis that was initially suggested, pernio, was afterwards denied by a detailed anamnesis, by laboratory testes (positive antinuclear antibodies, positive anti-double-stranded DNA antibodies) and by the histopathological examination of the biopsy from cutaneous lesions. The introduction of the antimalarial drugs (Plaquenil 200 mg/ day) associated with photoprotective creams, led to cure of cutaneous lesions.

A histologic and immunohistochemical study of chilblains.

BACKGROUND: The histopathologic diagnosis of chilblains is controversial and the histologic changes are often considered nonspecific, mainly because they are poorly documented. Although a dermal inflammation in chilblains has been noticed, the infiltrate has not yet been characterized. OBJECTIVE: Our purpose was to analyze microscopic and immunohistochemical findings in a large series of chilblains and to compare the results with those of lupus erythematosus (LE). METHODS: We included 36 cases of clinically typical chilblains of the hands, of which 17 were thoroughly investigated to rule out cryopathy or LE. Ten biopsy specimens of hand lesions from patients with proven LE were included as controls. All slides were analyzed by conventional microscopy and by immunohistochemistry with anti-CD3, anti-CD20, and anti-CD68 antibodies. RESULTS: The most characteristic finding in chilblains (47% of cases) was the association of edema and reticular dermis infiltrate that showed a perieccrine reinforcement. Such a combination of changes was not observed in LE. Epidermal changes in chilblains consisted mainly in necrotic keratinocytes in 52% of cases. The comparison of 17 idiopathic chilblains with LE showed significant differences in spongiosis (58% vs 0% respectively), vacuolation of basal layer (6% vs 60%), edema of the dermis (70% vs 20%), and deep perieccrine inflammation (76% vs 0%). Immunohistochemistry showed that the infiltrate was composed of a majority of T cells associated with macrophages and a few B lymphocytes. The same pattern was observed in both chilblains and LE. CONCLUSION: Our results show that a predominantly T-cell papillary and deep infiltrate with a perieccrine reinforcement, associated with dermal edema and necrotic keratinocytes, are the hallmarks of chilblains of the hands. These changes can help differentiate idiopathic perniosis from LE; immunohistochemistry is of no use in differentiation.

Chilblain lupus erythematosus of Hutchinson responding to surgical treatment: a report of two patients with anti-Ro/SS-A antibodies.

We report two patients with chilblain lupus erythematosus of Hutchinson (CL) who responded to surgical treatment. One of them was a 72-year-old woman (case 1), and the other a 62-year-old man (case 2). We attempted to treat these patients by excising the lesions and subsequently performing full-thickness free skin grafting, using skin from the abdominal region. No recurrence was seen in the operated area 7 years (case 1) and 3 years (case 2) after surgery. However, lesions persisted in the areas not operated upon, and in the areas where lesions had not been adequately excised. These results suggest that surgical removal of local factors reduces the rash in these cases. In addition, both patients were serologically positive for the anti-Ro/SS-A antibody suggesting that local expression of the Ro/SS-A antigen may be involved in the pathogenesis of the skin lesions. To our knowledge, full thickness free skin grafting has not been used previously to treat CL-associated skin lesions, and is promising as a treatment for patients who do not respond to conventional means.