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.

A clinicopathological description of COVID-19-induced chilblains (COVID-toes) correlated with a published literature review.

BACKGROUND: The abundance of publications of COVID-19-induced chilblains has resulted in a confusing situation. METHODS: This is a prospective single-institution study from 15 March to 13 May 2020. Thirty-two patients received PCR nasopharyngeal swabs. Of these, 28 patients had a thoracic CT-scan, 31 patients had blood and urine examinations, 24 patients had skin biopsies including immunohistochemical and direct immunofluorescence studies, and four patients had electron microscopy. RESULTS: COVID-19-induced chilblains are clinically and histopathologically identical to chilblains from other causes. Although intravascular thrombi are sometimes observed, no patient had a systemic coagulopathy or severe clinical course. The exhaustive clinical, radiological, and laboratory work-up in this study ruled-out other primary and secondary causes. Electron microscopy revealed rare, probable viral particles whose core and spikes measured from 120 to 133 nm within endothelium and eccrine glands in two cases. CONCLUSION: This study provides further clinicopathologic evidence of COVID-19-related chilblains. Negative PCR and antibody tests do not rule-out infection. Chilblains represent a good prognosis, occurring later in the disease course. No systemic coagulopathy was identified in any patient. Patients presenting with acral lesions should be isolated, and chilblains should be distinguished from thrombotic lesions (livedo racemosa, retiform purpura, or ischemic acral necrosis).

Patient characteristics in tardive COVID-19 pseudoperniosis: a case series of 16 patients.

BACKGROUND: Acute pseudoperniosis (PP) has a recognized association with COVID-19 and tends to occur without cold precipitation in young, healthy patients, often without a clear history of COVID-19. These lesions usually resolve within 2 weeks and without long-term sequelae. In the early months of 2021, patients with delayed and protracted PP began to emerge. We have called this presentation 'tardive COVID-19 PP (TCPP)'. AIM: To consolidate and expand knowledge on TCPP, we describe the clinical characteristics, treatments and outcomes of 16 patients with TCPP who were reviewed by our outpatient dermatology service. RESULTS: The initial clinical manifestations were erythema, swelling and PP of the fingers in 56.2%, and of the toes in 31.2%, desquamation in 56.2% and acrocyanosis in 12.5%. Ten patients had eventual involvement of all acral sites. The median duration of symptoms was 191 days. Six patients reported close contact with a confirmed or suspected case of COVID-19, but only two had positive COVID-19 tests. Four patients experienced complete or almost complete resolution of symptoms, while the rest remain under active treatment. CONCLUSION: Unlike acute PP, TCPP has a protracted and delayed presentation that is typically associated with profound acrocyanosis. Patients with TCPP represent a new phenomenon that is part of the post-COVID-19 syndrome, with risk factors and pathophysiology that are not yet fully understood. Our data indicate that likely predisposing factors for developing TCPP include young age, a preceding history of cold intolerance and an arachnodactyloid phenotype. Anorexia, connective tissue disorders or sickle cell trait may also predispose to TCPP. In addition, low titre antinuclear antibody positivity, the presence of cryoglobulins, or low complement levels may represent further risk factors. Finally, prolonged low temperatures are also likely to be contributing to the symptoms.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

The clinical spectrum of COVID-19-associated cutaneous manifestations: An Italian multicenter study of 200 adult patients.

BACKGROUND: COVID-19 is associated with a wide range of skin manifestations. OBJECTIVE: To describe the clinical characteristics of COVID-19-associated skin manifestations and explore the relationships among the 6 main cutaneous phenotypes and systemic findings. METHODS: Twenty-one Italian Dermatology Units were asked to collect the demographic, clinical, and histopathologic data of 200 patients with COVID-19-associated skin manifestations. The severity of COVID-19 was classified as asymptomatic, mild, moderate, or severe. RESULTS: A chilblain-like acral pattern was significantly associated with a younger age (P < .0001) and, after adjusting for age, significantly associated with less severe COVID-19 (P = .0009). However, the median duration of chilblain-like lesions was significantly longer than that of the other cutaneous manifestations taken together (P < .0001). Patients with moderate/severe COVID-19 were more represented than those with asymptomatic/mild COVID-19 among the patients with cutaneous manifestations other than chilblain-like lesions, but only the confluent erythematous/maculo-papular/morbilliform phenotype was significantly associated with more severe COVID-19 (P = .015), and this significance disappeared after adjustment for age. LIMITATIONS: Laboratory confirmation of COVID-19 was not possible in all cases. CONCLUSIONS: After adjustment for age, there was no clear-cut spectrum of COVID-19 severity in patients with COVID-19-related skin manifestations, although chilblain-like acral lesions were more frequent in younger patients with asymptomatic/pauci-symptomatic COVID-19.

Eruptions and related clinical course among 296 hospitalized adults with confirmed COVID-19.

BACKGROUND: Limited information exists on mucocutaneous disease and its relation to course of COVID-19. OBJECTIVE: To estimate prevalence of mucocutaneous findings, characterize morphologic patterns, and describe relationship to course in hospitalized adults with COVID-19. METHODS: Prospective cohort study at 2 tertiary hospitals (Northwell Health) between May 11, 2020 and June 15, 2020. RESULTS: Among 296 hospitalized adults with COVID-19, 35 (11.8%) had at least 1 disease-related eruption. Patterns included ulcer (13/35, 37.1%), purpura (9/35, 25.7%), necrosis (5/35, 14.3%), nonspecific erythema (4/35, 11.4%), morbilliform eruption (4/35, 11.4%), pernio-like lesions (4/35, 11.4%), and vesicles (1/35, 2.9%). Patterns also showed anatomic site specificity. A greater proportion of patients with mucocutaneous findings used mechanical ventilation (61% vs 30%), used vasopressors (77% vs 33%), initiated dialysis (31% vs 9%), had thrombosis (17% vs 11%), and had in-hospital mortality (34% vs 12%) compared with those without mucocutaneous findings. Patients with mucocutaneous disease were more likely to use mechanical ventilation (adjusted prevalence ratio, 1.98; 95% confidence interval, 1.37-2.86); P < .001). Differences for other outcomes were attenuated after covariate adjustment and did not reach statistical significance. LIMITATIONS: Skin biopsies were not performed. CONCLUSIONS: Distinct mucocutaneous patterns were identified in hospitalized adults with COVID-19. Mucocutaneous disease may be linked to more severe clinical course.

Discordant anti-SARS-CoV-2 spike protein and RNA staining in cutaneous perniotic lesions suggests endothelial deposition of cleaved spike protein.

BACKGROUND: Prior studies have shown the presence of immunohistochemical staining for the SARS-CoV-2 spike protein (SP) in endothelial cells and eccrine epithelium of acral perniosis classified as "COVID toes." Yet, other studies have been unable to detect SARS-CoV-2 RNA in skin biopsies of "COVID toes" by reverse-transcriptase polymerase chain reaction testing. OBJECTIVE: In order to address these apparently conflicting findings, we compared detection of SARS-CoV-2 SP, through RNA in situ hybridization (ISH) vs immunohistochemistry (IHC), in skin biopsies of acral perniotic lesions presenting during the COVID-19 pandemic. RESULTS: Three of six cases showed positive immunohistochemical labeling of endothelial cells, with one of three cases with sufficient depth also having labeling of eccrine glands, using an anti-SP SARS-CoV-2 antibody. These three cases positive with IHC were negative for SP by RNA ISH. CONCLUSION: While the gold standard for detection of SARS-CoV-2 in tissue sections has yet to be determined, the detection of SARS-CoV-2 SP alone without spike RNA suggests that cleaved SP may be present in cutaneous endothelial cells and eccrine epithelium, providing a potential pathogenetic mechanism of COVID-19 endotheliitis.

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.

COVID Purpura (Toes) Case Series: A Chilblains-Like Vasculopathy.

ABSTRACT: Biopsies were taken from 4 patients who presented to their dermatologist with violaceous papules and plaques of the dorsal toes (COVID Toes) associated with varying degrees of severe acute respiratory syndrome coronavirus 2 exposure and COVID-19 testing. Major histopathologic findings were lymphocytic eccrine inflammation and a spectrum of vasculopathic findings to include superficial and deep angiocentric-perivascular lymphocytic inflammation, lymphocytes in vessel walls (lymphocytic vasculitis), endothelial swelling, red blood cell extravasation, and focal deposits of fibrin in both vessel lumina, and vessel walls. Interface changes were observed to include vacuolopathy and apoptotic keratinocytes at the basement membrane. Immunostains showed a dominant T-cell lineage (positive for T-cell receptor beta, CD2, CD3, CD5, and CD7). B-cells were rare and clusters of CD123-positive dermal plasmacytoid dendritic cells were observed surrounding eccrine clusters and some perivascular zones. The consistent perieccrine and vasculopathic features represent important pathologic findings in the diagnosis of COVID toes and are suggestive of pathogenetic mechanisms. Clinicopathologic correlation, the epidemiological backdrop, and the current worldwide COVID-19 pandemic favor a viral causation and should alert the physician to initiate a workup and the appropriate use of COVID-19 testing.

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.

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.

A Review of COVID-19 Chilblains-like Lesions and Their Differential Diagnoses.

GENERAL PURPOSE: To familiarize wound care practitioners with the differential diagnoses of chilblains-like lesions that could be associated with the complications of COVID-19. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Identify the population most often affected by COVID toes.2. Select the assessments that help differentiate the various conditions that cause chilblains-like lesions.3. Choose appropriate treatment options for the various conditions that cause chilblains-like lesions.

This review article focuses on the pathogenesis, clinical features, and diagnostic testing of the common pathologies that can manifest as chilblains-like lesions. These differentials include "COVID toes," Raynaud phenomenon, acrocyanosis, critical limb ischemia, thromboangiitis obliterans, chilblains associated with lupus erythematosus, and idiopathic chilblains. The authors present a helpful mnemonic, ARCTIC, to assist clinicians in recognition and diagnosis.

SARS-CoV-2 endothelial infection causes COVID-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases.

BACKGROUND: Chilblains ('COVID toes') are being seen with increasing frequency in children and young adults during the COVID-19 pandemic. Detailed histopathological descriptions of COVID-19 chilblains have not been reported, and causality of SARS-CoV-2 has not yet been established. OBJECTIVES: To describe the histopathological features of COVID-19 chilblains and to explore the presence of SARS-CoV-2 in the tissue. METHODS: We examined skin biopsies from seven paediatric patients presenting with chilblains during the COVID-19 pandemic. Immunohistochemistry for SARS-CoV-2 was performed in all cases and electron microscopy in one. RESULTS: Histopathology showed variable degrees of lymphocytic vasculitis ranging from endothelial swelling and endotheliitis to fibrinoid necrosis and thrombosis. Purpura, superficial and deep perivascular lymphocytic inflammation with perieccrine accentuation, oedema, and mild vacuolar interface damage were also seen. SARS-CoV-2 immunohistochemistry was positive in endothelial cells and epithelial cells of eccrine glands. Coronavirus particles were found in the cytoplasm of endothelial cells on electron microscopy. CONCLUSIONS: Although the clinical and histopathological features were similar to other forms of chilblains, the presence of viral particles in the endothelium and the histological evidence of vascular damage support a causal relation of the lesions with SARS-CoV-2. Endothelial damage induced by the virus could be the key mechanism in the pathogenesis of COVID-19 chilblains and perhaps also in a group of patients severely affected by COVID-19 presenting with features of microangiopathic damage. What is already known about this topic? Despite the high number of cases of chilblains seen during the COVID-19 pandemic, a definite causative role for SARS-CoV-2 has not yet been proven. Different pathogenetic hypotheses have been proposed, including coagulation anomalies, interferon release and external factors. What does this study add? The demonstration of SARS-CoV-2 in endothelial cells of skin biopsies by immunohistochemistry and electron microscopy confirms that these lesions are part of the spectrum of COVID-19. Virus-induced vascular damage and secondary ischaemia could explain the pathophysiology of COVID-19 chilblains. Our findings support the hypothesis that widespread endothelial infection by SARS-CoV-2 could have a pathogenetic role in the severe forms of COVID-19. Linked Comment: Wetter. Br J Dermatol 2020; 183:611.

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.

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.

Cutaneous manifestations and considerations in COVID-19 pandemic: A systematic review.

COVID-19 had a great impact on medical approaches among dermatologist. This systematic review focuses on all skin problems related to COVID-19, including primary and secondary COVID-related cutaneous presentations and the experts recommendations about dermatological managements especially immunomodulators usage issues. Search was performed on PubMed, Scopus, Embase and ScienceDirect. Other additional resources were searched included Cochrane, WHO, Medscape and coronavirus dermatology resource of Nottingham university. The search completed on May 3, 2020. Three hundred seventy-seven articles assigned to the inclusion and exclusion groups. Eighty-nine articles entered the review. Primary mucocutaneous and appendageal presentations could be the initial or evolving signs of COVID-19. It could be manifest most commonly as a maculopapular exanthamatous or morbiliform eruption, generalized urticaria or pseudo chilblains recognized as "COVID toes" (pernio-like acral lesions or vasculopathic rashes). During pandemic, Non-infected non-at risk patients with immune-medicated dermatologic disorders under treatment with immunosuppressive immunomodulators do not need to alter their regimen or discontinue their therapies. At-risk o suspected patients may need dose reduction, interval increase or temporary drug discontinuation (at least 2 weeks). Patients with an active COVID-19 infection should hold the biologic or non-biologic immunosuppressives until the complete recovery occur (at least 4 weeks).

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.

A clinical, histopathological and laboratory study of 19 consecutive Italian paediatric patients with chilblain-like lesions: lights and shadows on the relationship with COVID-19 infection.

BACKGROUND: Acral chilblain-like lesions are being increasingly reported during COVID-19 pandemic. However, only few patients proved positivity for SARS-CoV-2 infection. The relationship between this skin manifestation and COVID-19 infection has not been clarified yet. OBJECTIVE: To thoroughly characterize a prospective group of patients with chilblain-like lesions and to investigate the possible relationship with SARS-CoV-2 infection. METHODS: Following informed consent, patients underwent (i) clinical evaluation, (ii) RT-PCR and serology testing for SARS-CoV-2, (iii) digital videocapillaroscopy of finger and toe nailfolds, (iv) blood testing to screen for autoimmune diseases and coagulation anomalies, and (v) skin biopsy for histopathology, direct immunofluorescence and, in selected cases, electron microscopy. RESULTS: Nineteen patients, all adolescents (mean age: 14 years), were recruited. 11/19 (58%) of them and/or their cohabitants reported flu-like symptoms one to two months prior to skin manifestation onset. Lesions were localized to toes and also heels and soles. Videocapillaroscopy showed pericapillary oedema, dilated and abnormal capillaries, and microhaemorrhages both in finger and toe in the majority of patients. Major pathological findings included epidermal basal layer vacuolation, papillary dermis oedema and erythrocyte extravasation, perivascular and perieccrine dermal lymphocytic infiltrate, and mucin deposition in the dermis and hypodermis; dermal vessel thrombi were observed in two cases. Blood examinations were normal. Nasopharyngeal swab for SARS-CoV-2 and IgG serology for SARS-CoV-2 nucleocapsid protein were negative. Importantly, IgA serology for S1 domain of SARS-CoV-2 spike protein was positive in 6 patients and borderline in 3. CONCLUSIONS: Chilblain-like lesions during COVID-19 pandemic have specific epidemiologic, clinical, capillaroscopic and histopathological characteristics, which distinguish them from idiopathic perniosis. Though we could not formally prove SARS-CoV-2 infection in our patients, history data and the detection of anti-SARS-COV-2 IgA strongly suggest a relationship between skin lesions and COVID-19. Further investigations on the mechanisms of SARS-CoV-2 infection in children and pathogenesis of chilblain-like lesions are warranted.

Chilblain-like lesions in children following suspected COVID-19 infection.

During the COVID-19 pandemic, chilblain-like lesions have been reported in mildly symptomatic children and adolescents. We present four children investigated for suspected COVID-19 infection who presented with acral skin findings and mild systemic symptoms. Histology from one case showed signs of vasculitis with evident fibrin thrombus.

Clustered cases of acral perniosis: Clinical features, histopathology, and relationship to COVID-19.

BACKGROUND/OBJECTIVES: A recent marked increase in pediatric and adult patients presenting with purpuric acral lesions concerning for ischemia, thrombosis and necrosis has been observed in COVID-19 prevalent regions worldwide. The clinical and histopathological features and relationship to COVID-19 have not been well described. The objective of this case series is to describe the clinical features and determine the histopathologic findings and clinical implications of the clusters of acral perniosis cases identified in pediatric patients. METHODS: We describe six otherwise healthy adolescents-three siblings per family from two unrelated families-presented within a 48-hour period in April, 2020, with acral perniosis-like lesions in the context of over 30 similar patients who were evaluated within the same week. RESULTS: Affected patients had mild symptoms of viral upper respiratory infection (URI) or contact with symptomatic persons 1-2 weeks preceding the rash. They all presented with red to violaceous macules and dusky, purpuric plaques scattered on the mid and distal aspects of the toes. Skin biopsies performed on each of the six patients demonstrated near identical histopathologic findings to those of idiopathic perniosis, with a lymphocytic inflammatory infiltrate without evidence of thromboembolism or immune complex vasculitis. While SARS-CoV-2 polymerase chain reaction was negative, testing was performed 1-2 weeks after URI symptoms or sick contact exposure. CONCLUSION: We offer a clinical approach to evaluation of patients with this presentation and discuss the possibility that these skin findings represent a convalescent-phase cutaneous reaction to SARS-CoV-2 infection.